instruction
stringlengths 22
321
| context
stringlengths 75
3.6k
| context_neg
stringlengths 75
3.6k
|
|---|---|---|
Does slow N-acetyltransferase 2 genotype affect the incidence of isoniazid and rifampicin-induced hepatotoxicity? | Japanese in-patients with pulmonary tuberculosis and normal liver function receiving treatment with isoniazid and rifampicin (INH + RMP). To elucidate the relationship between N-acetyltransferase 2 (NAT2) genotype and the incidence of isoniazid + rifampicin-induced hepatotoxicity. Prospective study. After NAT2* genotyping, 77 patients were classified into three groups according to their NAT2* genotypes: rapid-type (a homozygote of NAT2*4), intermediate-type (a heterozygote of NAT2*4 and mutant alleles) and slow-type (a combination of mutant alleles). Their biochemical profiles of liver function test were investigated for 3 months to assess the development of serum aminotransferase elevation. Of the 77 patients, 18.2% developed adverse hepatic reaction within the first month of INH + RMP treatment. A significant association was observed between hepatotoxicity and NAT2* genotype: compared with rapid-type, the relative risk was 4.0 (95% CI 1.94-6.06) for intermediate-type and 28.0 (95%CI 26.0-30.0) for slow-type. Especially in slow-type, the incidence of hepatotoxicity and serum aminotransferase elevation was significantly higher than in the other two types. | Women who seek treatment for pelvic organ prolapse strive for an improvement in quality of life. Body image has been shown to be an important component of differences in quality of life. To date, there are no data on body image in patients with advanced pelvic organ prolapse. Our objective was to compare body image and quality of life in women with advanced pelvic organ prolapse with normal controls. We used a case-control study design. Cases were defined as subjects who presented to a tertiary urogynecology clinic with advanced pelvic organ prolapse (stage 3 or 4). Controls were defined as subjects who presented to a tertiary care gynecology or women's health clinic for an annual visit with normal pelvic floor support (stage 0 or 1) and without urinary incontinence. All patients completed a valid and reliable body image scale and a generalized (Short Form Health Survey) and condition-specific (Pelvic Floor Distress Inventory-20) quality-of-life scale. Linear and logistic regression analyses were performed to adjust for possible confounding variables. Forty-seven case and 51 control subjects were enrolled. After controlling for age, race, parity, previous hysterectomy, and medical comorbidities, subjects with advanced pelvic organ prolapse were more likely to feel self-conscious (adjusted odds ratio 4.7; 95% confidence interval 1.4 to 18, P = .02), less likely to feel physically attractive (adjusted odds ratio 11; 95% confidence interval 2.9 to 51, P < .001), less likely to feel feminine (adjusted odds ratio 4.0; 95% confidence interval 1.2 to 15, P = .03), and less likely to feel sexually attractive (adjusted odds ratio 4.6; 95% confidence interval 1.4 to 17, P = .02) than normal controls. The groups were similar in their feeling of dissatisfaction with appearance when dressed, difficulty looking at themselves naked, avoiding people because of appearance, and overall dissatisfaction with their body. Subjects with advanced pelvic organ prolapse suffered significantly lower quality of life on the physical scale of the SF-12 (mean 42; 95% confidence interval 39 to 45 versus mean 50; 95% confidence interval 47 to 53, P < .009). However, no differences between groups were noted on the mental scale of the SF-12 (mean 51; 95% confidence interval 50 to 54 versus mean 50; 95% confidence interval 47 to 52, P = .56). Additionally, subjects with advanced pelvic organ prolapse scored significantly worse on the prolapse, urinary, and colorectal scales and overall summary score of Pelvic Floor Distress Inventory-20 than normal controls (mean summary score 104; 95% confidence interval 90 to 118 versus mean 29; 95% confidence interval 16 to 43, P < .0001), indicating a decrease in condition-specific quality of life. Worsening body image correlated with lower quality of life on both the physical and mental scales of the SF-12 as well as the prolapse, urinary, and colorectal scales and overall summary score of Pelvic Floor Distress Inventory-20 in subjects with advanced pelvic organ prolapse. |
Does gastrin receptor antagonist CI-988 inhibit growth of human colon cancer in vivo and in vitro? | Whilst gastrin has been found to be trophic for some colorectal cancer cell lines, and gastrin receptor antagonists are able to block this phenomenon, their potency has been modest. The effect of a new, potent and selective CCK B receptor antagonist, CI-988 on the growth of LoVo, a human colon cancer cell line both in vitro and in vivo was instigated. Basal growth of LoVo in vitro was inhibited by up to 58.93 +/- 7.30% with concentrations of CI-988 as low as 1 X 10(-11) mol/L whereas the addition of gastrin (G17) at 0.5 nmol/L had no effect. LoVo was also grown in vivo for 10 days in nude mice subsequently treated with CI-988 at 10 mg/kg per day orally for 20 days. CI-988 inhibited the growth of xenografts by 53%. | Diabetes is a risk factor for atherosclerosis and low-degree inflammation may play a central role in both diseases. Glycosylated haemoglobin A(1c) (HbA(1c)) is an established measure of long-term glycaemic control but data on its correlation with markers of inflammation are limited, especially in patients with atherosclerotic manifestations. The aim of the present study was thus to investigate the associations between HbA(1c) and a panel of inflammation-sensitive parameters in patients with and without diabetes. This single centre cross-sectional study comprised 314 consecutive subjects who underwent coronary angioplasty for stable coronary artery disease. Sixty-six patients had diabetes mellitus. Haemoglobin A(1c) and markers of inflammation, i.e., plasma levels of CRP, fibrinogen, and albumin, erythrocyte sedimentation rate and white blood cell count were measured. All inflammation markers were altered in a more inflammatory direction in diabetic patients. Furthermore, when non-diabetic patients with HbA(1c) levels within the normal range were studied separately, all inflammation-sensitive parameters except albumin correlated significantly with HbA(1c). |
Does prevalence and correlate of personality disorder in Great Britain? | Epidemiological data on personality disorders, comorbidity and associated use of services are essential for health service policy. To measure the prevalence and correlates of personality disorder in a representative community sample. The Structured Clinical Interview for DSM-IVAxis II disorders was used to measure personality disorder in 626 persons aged 16-74 years in households in England, Scotland and Wales, in a two-phase survey. The weighted prevalence of personality disorder was 4.4% (95% CI 2.9-6.7). Rates were highest among men, separated and unemployed participants in urban locations. High use of healthcare services was confounded by comorbid mental disorder and substance misuse. Cluster B disorders were associated with early institutional care and criminality. | Transplanted cell survival might greatly improve the therapeutic efficacy of cell therapy. Diazoxide (DZ), a highly selective mitochondrial ATP-sensitive potassium channel opener, is known to suppress cell apoptosis and protect cells in oxidative stressed ischemic environment. We explored the mechanisms involved in DZ pre-treatment-induced anti-apoptotic effect on L6 skeletal myoblast (SKM). L6 SKMs were divided into control group, H2O2 group, DZ + H2O2 group and DZ + LY + H2O2 group. Treatments of 400 μmol/L H2O2 for 24 h alone, or after 200 μmol/L DZ pre-treatment for 30 min, or after DZ and 50 μmol/L LY294002 co-administration for 30 min were performed. The cell apoptosis rates were assessed by flow cytometric analysis. The changes of mitochondrial membrane potential were determined by JC-1 mitochondrial staining. The activation of phosphatidylinositol-3 kinase (PI3K)/Akt, caspase-9 and caspase-3 was detected by western blot. Compared with the H2O2 group, DZ pre-treatment protected cells from H2O2-induced damage, increased Akt phosphorylation, prevented mitochondrial membrane depolarization as well as the activation of caspase-9 and caspase-3 and decreased the cell apoptosis rate. However, the DZ-induced cytoprotective and anti-apoptosis effects were partly inhibited by co-administration of a PI3K inhibitor, LY294002. |
Does effects of rapid smoking on post-cessation urge to smoke? | Rapid smoking (RS) is a smoking cessation technique with sufficient indications of promise to warrant further investigation. The main presumed effect of RS is on reducing desire to smoke. To evaluate the effect of a single session of RS immediately prior to quitting smoking on urges to smoke over the first week of abstinence. Randomized controlled trial. Specialist smoking cessation clinic (SSCC). A total of 100 smokers attending the quit day session. Participants in the rapid smoking group underwent a single session of RS immediately prior to quitting smoking. Participants in the control group watched a health promotion video on giving up smoking. Ratings of urges to smoke in the first 24 hours and 1 week of abstinence. The RS procedure was well tolerated. It led to significantly lower urges to smoke compared to the control procedure during the first 24 hours (mean rating of 2.6 versus 3.2, P < 0.001) and the first week of abstinence (1.8 versus 2.5, P < 0.01). In patients abstinent for 4 weeks, urges to smoke were low and the difference was no longer significant (1.4 versus 1.8). | We previously reported that human OA subchondral bone osteoblasts could be discriminated into two subpopulations identified by their levels of endogenous production (low [L] or high [H]) of PGE(2). Here, we investigated the OPG and RANKL expression levels, the histologic analysis of the subchondral bone as well as the osteoclast differentiation effect of osteoblasts on normal and both OA subpopulations (L and H), and further examined on the L OA osteoblasts the modulation of bone remodelling factors on the OPG and RANKL levels, as well as on the resorption activity. Gene expression was determined using real-time PCR, PGE2 and OPG levels by specific ELISA, and membranous RANKL by flow cytometry. Histological observation of the subchondral bone was performed on human knee specimens. Osteoclast differentiation and formation was assayed by using the pre-osteoclastic cell line RAW 264.7. OPG and RANKL modulation on L OA osteoblasts was monitored following treatment with osteotropic factors, and the resorption activity was studied by the co-culture of differentiated PBMC/osteoblasts. Human OA subchondral bone osteoblasts expressed less OPG than normal. Compared to normal, RANKL gene expression levels were increased in L OA and decreased in H OA cells. The OPG/RANKL mRNA ratio was significantly diminished in L OA compared to normal or H OA (p<0.02, p<0.03), and markedly increased in H OA compared to normal. Inhibition of endogenous PGE(2) levels by indomethacin markedly decreased the ratio of OPG/RANKL on the H OA. In contrast to H OA osteoblasts, L OA cells induced a significantly higher level of osteoclast differentiation and formation (p<0.05). Histological analysis showed a reduced subchondral bone on the L OA and an increased bone mass on the H OA compared to normal. Treatment of L OA osteoblasts with osteotropic factors revealed that the OPG/RANKL mRNA expression ratio was significantly reduced by vitamin D(3) and significantly increased by TNF-alpha, PTH and PGE(2), while IL-1Beta demonstrated no effect. OPG protein levels showed similar profiles. No true effect was noted on membranous RANKL upon treatment with IL-1Beta, PGE(2) and PTH, but a significant increase was observed with vitamin D3 and TNF-alpha. The resorption activity of the L OA cells was significantly inhibited by all treatments except IL-1Beta, with maximum effect observed with vitamin D(3) and PGE(2). |
Is pRNP 1368 polymorphism associated with sporadic Creutzfeldt-Jakob disease in the Korean population? | Human prion protein gene (PRNP) is considered a critical and fundamental gene in determining the incidence of human prion diseases. Codons 129 and 219 play an important role in the susceptibility to sporadic Creutzfeldt-Jakob disease (CJD). An association between sporadic CJD and the polymorphism (PRNP 1368) in an upstream of PRNP exon 1 has been reported in the British and German populations, but study in the Dutch population has failed to confirm an association. To investigate whether the PRNP 1368 polymorphism is associated with sporadic CJD in the Korean population. We compared the genotype and allele frequencies of PRNP 1368 polymorphism in 171 sporadic CJD patients with those in 212 healthy Koreans. | The interval between neoadjuvant chemoradiation treatment and surgery has been described as an important predictor of pathologic response to therapy in nonesophageal cancer sites. We retrospectively reviewed our experience with patients who underwent neoadjuvant chemoradiation and esophagectomy to better understand the impact of the timing of surgery on pathologic complete response rates in esophageal cancer. Two hundred thirty-one sequentially treated patients from 2000 to 2011 were identified for this study; 88 of these patients completed neoadjuvant chemoradiation followed by esophagectomy at our institution. The interval between completion of chemoradiation and surgery was calculated for each patient. The patients were categorized into quartiles and also into 3-week interval groups. Treatment factors and surgical morbidity data, including the estimated blood loss and length of operative stay, were also assessed. Quartiles for the neoadjuvant chemoradiation to surgery interval were less than 45 days, 46 to 50 days, 51 to 63 days, and 64+ days. Corresponding pathologic complete response rates were 12.5%, 20.0%, 22.7%, and 40.9% (p = 0.03). Results for 3-week intervals were similar (p = 0.02). There was no association between increasing time interval between the ending of neoadjuvant chemoradiation to surgery and length of stay longer than 2 weeks. |
Is plasmacytoid dendritic cell interferon-α production to R-848 stimulation decreased in male infants? | Sex differences in response to microbial infections, especially viral ones, may be associated with Toll-like receptor (TLR)-mediated responses by plasmacytoid dendritic cells (pDCs). In this study, we identified sex differences in human infant pDC interferon-α production following challenge with the TLR7/8 agonist R-848. Male pDC responses were significantly lower than those of females during early infancy. This difference may be attributed to the androgen surge experienced by males during the early infancy period. Pretreatment of human pDCs with dihydrotestosterone produced a significant reduction in interferon-α production following R-848 challenge. | This study examined the correlation between P53 and vascular endothelial growth factor (VEGF) expression together with tumour vascularity and investigated their clinical significance in the prognosis of gastric carcinoma. Ninety-five patients with gastric carcinoma who underwent curative surgical resection were studied using immunohistochemical staining. Correlation between the expression of p53, VEGF microvessel count (MVC) and various clinicopathologic factors were studied. No significant correlation was found between p53 expression and clinicopathologic factors. The rate of VEGF positivity was significantly higher in patients with haematogenous metastasis than in those without haematogenous metastasis. Both p53 and VEGF expression were associated with MVC. The MVC in p53 positive tumours was significantly higher than that in p53 negative tumours. Similarly, the same trend was seen between VEGF expression and MVC. The p53 and VEGF were co-expressed in 61 of 95 tumours (64.2%), and a significant (p < 0.01) association between p53 and VEGF expressions was demonstrated. The rate of VEGF positivity was significantly (p < 0.01) higher in the patients with disease recurrence than in those without recurrence, whereas no significant correlation was found between disease recurrence and the expression of p53. |
Does cilostazol inhibit oxidative stress-induced premature senescence via upregulation of Sirt1 in human endothelial cells? | Cilostazol, a selective inhibitor of PDE3, has a protective effect on endothelium after ischemic vascular damage, through production of nitric oxide (NO). The purpose of the present study was to clarify the molecular mechanisms underlying the preventive effect of treatment with cilostazol on oxidative stress-induced premature senescence in human endothelial cells. Prematurely senescent human umbilical vein endothelial cells (HUVECs) were induced by treatment with hydrogen peroxide (H(2)O(2)) as judged by senescence-associated beta-galactosidase assay (SA-betagal), cell morphological appearance, and plasminogen activator inhibitor-1 (PAI-1) expression. Treatment with H(2)O(2) caused 93% of the cells to be SA-betagal positive, whereas 46% of cilostazol (100 micromol/L)-treated cells were positive. HUVECs treated with other cAMP-elevating agents and DETA-NO showed a reduction of SA-betagal-positive cells as well. Cilostazol increased phosphorylation of Akt at Ser(473) and of endothelial nitric oxide synthase (eNOS) at Ser(1177), with a dose-dependent increase in Sirt1 expression. Moreover, the effect of cilostazol on premature senescence was abrogated through inhibition of Sirt1. | Nonspecific symptoms are common in all areas of medicine. Patients and caregivers can be frustrated when an illness cannot be reduced to a discrete pathophysiological process that corresponds with the symptoms. We therefore asked the following questions: 1) Which demographic factors and psychological comorbidities are associated with change from an initial diagnosis of nonspecific arm pain to eventual identification of discrete pathophysiology that corresponds with symptoms? 2) What is the percentage of patients eventually diagnosed with discrete pathophysiology, what are those pathologies, and do they account for the symptoms? We evaluated 634 patients with an isolated diagnosis of nonspecific upper extremity pain to see if discrete pathophysiology was diagnosed on subsequent visits to the same hand surgeon, a different hand surgeon, or any physician within our health system for the same pain. There were too few patients with discrete pathophysiology at follow-up to address the primary study question. Definite discrete pathophysiology that corresponded with the symptoms was identified in subsequent evaluations by the index surgeon in one patient (0.16% of all patients) and cured with surgery (nodular fasciitis). Subsequent doctors identified possible discrete pathophysiology in one patient and speculative pathophysiology in four patients and the index surgeon identified possible discrete pathophysiology in four patients, but the five discrete diagnoses accounted for only a fraction of the symptoms. |
Does increased blood hemoglobin attenuate splanchnic vasodilation in portal-hypertensive rats by nitric oxide inactivation? | Nitric oxide, which is quenched by hemoglobin, has been implicated in the pathogenesis of portal hypertension. The aim of this study was to investigate the effects of increasing blood hemoglobin concentration by erythropoietin treatment on the gastrointestinal vasodilation associated with portal hypertension. Portal-hypertensive and sham-operated rats treated with erythropoietin were studied 2 weeks after surgery. Hemodynamic and rheological parameters were measured in baseline conditions and after N(G)-nitro-L-arginine methyl ester (L-NAME) or sodium nitroprusside treatment. In portal-hypertensive rats, erythropoietin attenuated the increase in gastric mucosal and superior mesenteric artery blood flows and the decrease in arterial blood pressure and splanchnic vascular resistances. Those parameters were not affected by erythropoietin in sham-operated rats. A direct vascular effect of erythropoietin was ruled out by the lack of changes in blood pressure or mesenteric blood flow after intravenous erythropoietin administration and by a similar in vitro relaxation to acetylcholine in mesenteric artery rings. In portal-hypertensive rats, erythropoietin blunted the blood pressure response to sodium nitroprusside and attenuated the gastric and mesenteric blood flow response to L-NAME. | Prognostication of breast cancer using clinicopathologic variables, although useful, remains imperfect. Many reports suggest that gene expression profiling can refine the current approach. Alternatively, it has been shown that panels of proteins assessed by immunohistochemistry might also be useful in this regard. We evaluate the prognostic potential of a panel of markers by immunohistochemistry in a large case series to establish if either a single marker or a panel could improve the prognostic power of the Nottingham Prognostic Index (NPI). We validated the results in an independent series. The expression of 13 biomarkers was evaluated in 930 breast cancers on a tissue microarray. Eight markers [estrogen receptor (ER), progesterone receptor (PR), Bcl-2, cyclin E, p53, MIB-1, cytokeratin 5/6, and HER2] showed a significant association with survival at 10 years on univariate analysis. On multivariate analysis that included these eight markers and the NPI, only the NPI [hazard ratio (HR), 1.35; 95% confidence interval (95% CI), 1.16-1.56; P = 0.0005], ER (HR, 0.59; 95% CI, 0.39-0.88; P = 0.011), and Bcl-2 (HR, 0.68; 95% CI, 0.46-0.99; P = 0.055) were significant. In a subsequent multivariate analysis that included the NPI, ER, and Bcl-2, only Bcl-2 (HR, 0.62; 95% CI, 0.44-0.87; P = 0.006) remained independent of NPI (HR, 1.50; 95% CI, 1.16-1.56; P = 0.004). In addition, Bcl-2, used as a single marker, was more powerful than the use of a panel of markers. Based on these results, an independent series was used to validate the prognostic significance of Bcl-2. ER and PR were also evaluated in this validation series. Bcl-2 (HR, 0.83; 95% CI, 0.71-0.96; P = 0.018) retained prognostic significance independent of the NPI (HR, 2.04; 95% CI, 1.67-2.51; P < 0.001) with an effect that was maximal in the first 5 years. |
Do heat shock protein 70-2+1267 AA homozygotes have an increased risk of septic shock in adults with community-acquired pneumonia? | Heat shock protein (HSP)70-2 is an important immunomodulatory protein induced in response to inflammatory stimuli. We assessed whether HSP70-2+1267 genotype influenced the risk of septic shock in a prospective cohort study of community-acquired pneumonia and whether HSP70-2+1267 genotype is a better predictor of septic shock than the genotype at lymphotoxin-alpha +250. Prospective cohort study. A large, nonprofit, private hospital system in Memphis, TN. Adults admitted with community-acquired pneumonia between 1998 and 2001. Septic shock was defined according to consensus criteria (American College of Chest Physicians/Society of Critical Care Medicine, 1992). Blood sampling. A total of 343 subjects were enrolled; 30 had septic shock. HSP70-2+1267 and lymphotoxin-alpha +250 genotype was determined using polymerase chain reaction and restriction enzyme digestion. HSP70-2+1267 AA genotype was the strongest predictor of septic shock (p =.0005; relative risk, 3.5). Lymphotoxin-alpha +250 AA genotype was also associated with an increased risk of septic shock (p =.002; relative risk, 2.7). Logistic regression analysis found only age (p =.04) and HSP70-2+1267 genotype (p =.006) were predictors of septic shock. The greatest risk of septic shock was associated with carriage of the HSP70-2+1267 A/lymphotoxin-alpha +250 A haplotype (p <.0001). | The Eph receptor tyrosine kinases and their ephrin ligands are key players in tumorigenesis and many reports have correlated changes in their expression with a poor clinical prognosis in many solid tumours. Agents targeting the Eph-ephrin system might emerge as new tools useful for the inhibition of different components of cancer progression. Even if different classes of small molecules targeting Eph-ephrin interactions have been reported, their use is hampered by poor chemical stability and low potency. Stable and potent ligands are crucial to achieve robust pharmacological performance. UniPR129 (the L-homo-Trp conjugate of lithocholic acid) was designed by means of computational methods, synthetized and tested for its ability to inhibit the interaction between the EphA2 receptor and the ephrin-A1 ligand in an elisa binding study. The ability of UniPR129 to disrupt EphA2-ephrin-A1 interaction was functionally evaluated in a prostate adenocarcinoma cell line and its anti-angiogenic effect was tested in vitro using cultures of HUVECs. UniPR129 disrupted EphA2-ephrin-A1 interaction with Ki = 370 nM in an elisa binding assay and with low micromolar potency in cellular functional assays, including inhibition of EphA2 activation, inhibition of PC3 cell rounding and disruption of in vitro angiogenesis, without cytotoxic effects. |
Do essential amino acid ratios and mTOR affect lipogenic gene networks and miRNA expression in bovine mammary epithelial cells? | The objective of this study was to study how changing the ratio of Lys to Thr, Lys to His, and Lys to Val affects the expression of lipogenic genes and microRNA (miRNA) in bovine mammary epithelial cells. Triplicate cultures with the respective "optimal" amino acid (AA) ratio (OPAA = Lys:Met 2.9:1; Thr:Phe 1.05:1; Lys:Thr 1.8:1; Lys:His 2.38:1; Lys:Val 1.23:1) plus rapamycin (OPAARMC; positive control), OPAA, Lys:Thr 2.1:1 (LT2.1), Lys:Thr 1.3:1 (LT1.3), Lys:His 3.05:1 (LH3.0), or Lys:Val 1.62:1 (LV1.6) were incubated in lactogenic medium for 12 h. The expression of 15 lipogenic genes and 7 miRNA were evaluated. Responses to LT2.1, LT1.3, LH3.0, and LV1.6 relative to the control (OPAARMC) included up-regulated expression of ACSS2, FABP3, ACACA, FASN, SCD, LPIN1, INSIG1, SREBF1, PPARD, and NR1H3 (commonly known as LXR-α). Furthermore, LV1.6 up-regulated expression of ACSL1, DGAT1, and RXRA and down-regulated PPARG expression. Although no effect of OPAA on expression of PPARG was observed, compared with the control, OPAA up-regulated expression of the PPAR targets ACSS2, FABP3, ACACA, FASN, SCD, LPIN1, INSIG1, and SREBF1. Compared with the control, the expression of the anti-lipogenic MIR27AB was down-regulated by OPAA, LT2.1, LT1.3 and LH3.0. In contrast, compared with the control, the expression of the pro-lipogenic MIR21 was up-regulated by LT2.1, LT1.3, LH3.0, and LV1.6. | Raves may be considered recreational settings in which drug use and health risks related to polydrug use are higher than in others. Harm reduction behaviors implemented by ravers are of particular relevance in reducing such risks. This study analyzes harm reduction behaviors and their relationship to raver polysubstance use patterns. Cross-sectional study of 248 ravers recruited at underground raves in Andalusia (Spain). A questionnaire was developed to collect information about their sociodemographics, drug use, and harm reduction behaviors. The results show that ravers employ harm reduction behaviors for minimizing drug-related harm. Nevertheless, only a small minority of the participants frequently employed harm reduction behavior for polysubstance use as well. Ravers identified as high polysubstance users protected themselves significantly less than those identified as low polysubstance users. |
Do patient-oncologist alliance and psychosocial well-being in Chinese society strongly affect cancer management adherence with cancer of unknown primary? | Patient-oncologist alliance and psychosocial well-being have strong associations with adherence to cancer management. For patients with cancer of unknown primary (CUP), adherence is crucial to treatment or occult primary screening plans. There has been no study investigating the relationship between alliance, psychosocial factors, and adherence in such patients or in Chinese sociocultural settings. The measures of alliance, psychosocial well-being, and adherence willingness were administered to patients with CUP, with a mean age of 58.33 ± 11.24 years. Multiple linear regression models were applied to investigate the independent relationship between alliance and adherence by controlling for socioeconomic and psychosocial confounders. Alliance was found to be independently and positively associated with greater adherence willingness and adherence to treatment and follow-up screening after controlling for significant confounders, including medical conditions, psychosocial well-being variables, and socioeconomic factors. | Little is known about whether peripheral nerve injury during the early postnatal period modulates synaptic efficacy in the immature superficial dorsal horn (SDH) of the spinal cord, or whether the neonatal SDH network is sensitive to the proinflammatory cytokine TNFalpha under neuropathic conditions. Thus we examined the effects of TNFalpha on synaptic transmission and intrinsic membrane excitability in developing rat SDH neurons in the absence or presence of sciatic nerve damage. The spared nerve injury (SNI) model of peripheral neuropathy at postnatal day (P)6 failed to significantly alter miniature excitatory (mEPSCs) or inhibitory (mIPSCs) postsynaptic currents in SDH neurons at P9-11. However, SNI did alter the sensitivity of excitatory synapses in the immature SDH to TNFalpha. While TNFalpha failed to influence mEPSCs or mIPSCs in slices from sham-operated controls, it significantly increased mEPSC frequency and amplitude following SNI without modulating synaptic inhibition onto the same neurons. This was accompanied by a significant decrease in the paired-pulse ratio of evoked EPSCs, suggesting TNFalpha increases the probability of glutamate release in the SDH under neuropathic conditions. Similarly, while SNI alone did not alter action potential (AP) threshold or rheobase in SDH neurons at this age, TNFalpha significantly decreased AP threshold and rheobase in the SNI group but not in sham-operated littermates. However, unlike the adult, the expression of TNFalpha in the immature dorsal horn was not significantly elevated during the first week following the SNI. |
Does toll-like receptor 2 mediate Staphylococcus aureus-induced myocardial dysfunction and cytokine production in the heart? | Staphylococcus aureus sepsis is associated with significant myocardial dysfunction. Toll-like receptor 2 (TLR2) mediates the inflammatory response to S aureus and may trigger an innate immune response in the heart. We hypothesized that a TLR2 deficiency would attenuate S aureus-induced cardiac proinflammatory mediator production and the development of cardiac dysfunction. Wild-type and TLR2-deficient (TLR2D) mice were studied. S aureus challenge significantly increased tumor necrosis factor, interleukin-1beta, and nitric oxide expression in hearts of wild-type mice. This response was significantly blunted in TLR2D mice. Hearts from TLR2D mice had impaired S aureus-induced activation of interleukin-1 receptor-associated kinase, c-Jun NH2 terminal kinase, nuclear factor-kappaB, and activator protein-1. Moreover, hearts from TLR2D mice were protected against S aureus-induced contractile dysfunction. | The histopathological work-up of colorectal cancer is of critical importance for prognosis and therapy. Therefore we retrospectively analyzed all colorectal carcinomas diagnosed at our institution from January 2002 through March 2003. 735 of a total of 777 carcinomas could be followed up. These tumors comprised 74 polypectomy specimens, 32 transanal microscopic surgery specimens, 322 surgical resection specimens analyzed at our own institution (subgroup A) and 263 surgical resection specimens that had been worked up at other pathological institutions (subgroup B) after the diagnosis of carcinoma had been established in our own institution in biopsies. 44 tumors were not treated locally until the end of the study. Quantitative quality parameters were analyzed statistically using Fisher's exact test. Between subgroups A and B significant differences were found within 1. the proportion of specimens with less than 12 lymph nodes examined (11 vs. 25 %), 2. for the detection of an R1 situation despite macroscopic R0 resection (9 vs. 1 %), 3. the proportion of early colonic cancers (9 vs. 4 %), 4. of mucinous adenocarcinomas (19 vs. 4 %), 5. of lymphatic (48 vs. 23 %) and venous invasion (25 vs. 8 %), 6. the frequency of a macroscopic description of mesorectum quality (85 vs. 14 %). In 7 of 32 surgically treated patients with a high-risk carcinoma originally found within a polypectomy specimen, residual tumor was detected in the surgical resection specimen (at the polypectomy site and/or in regional lymph nodes). |
Do endodontic treatment of permanent teeth in children with a new calcium-carbamide-formaldehyde paste? | AIM, MATERIAL AND METHODS: Endodontic treatment of a total of 303 teeth with pulpitis and periodontitis was performed with a new calcium-carbamide-formaldehyde paste. In three children with fractured teeth with complications, the applied treatment was combined (2 teeth with apical osteotomy and 1 with cystectomy). Control examinations were carried out at months 6, 12 and 24 and clinically healthy teeth and teeth with complications were registered. In the pulpitis group the clinically healthy teeth were 97.55% +/- 1.08 at the 6th month; 96.85% +/- 1.26 at the 12th month and 92.92% +/- 2.41 at the 24th month. In teeth with periodontitis 91.56% +/- 3.05 were clinically healthy at the 6th month; 93.83% +/- 2.67 at the 12th month and 98.03% +/- 1.98 at the 24th month. No statistical significance of the differences between pulpites and periodontites was found (P > 0.05). Recovery of the bone structure was observed in the teeth with combined endodontic and surgical treatment at the 12th month. | The relationship between post-exercise heart-rate recovery (HRR) and resting cardiac autonomic modulation is an incompletely explored issue. To correlate HRR with resting supine and orthostatic autonomic status. HRR at the 1st, 3th, and 5th min following maximal treadmill exercise were correlated with 5-min time-domain (CV, pNN50 and rMSSD) and frequency-domain (TP, LF, HF, LFn, HFn, and LF/HF ratio) indices of heart-rate variability (HRV) in both supine and standing positions in 31 healthy physically active non-athletes men. Statistical analysis employed non-parametric tests with two-tailed p value set at 5 %. Absolute HRR and Δ %HRR at each post-exercise time did not correlated with HRV in supine position, as well as at 1st min in standing position. At the 3rd min and 5th min, these measures negatively correlated with pNN50, rMSSD, TP, and HF indices, and only in the 5th min, they showed negative correlation with HFn and positive correlation with LF, LFn, and LF/HF ratio in the standing position. Coefficient of HRR (CHRR) at the 1st min negatively correlated with pNN50 and rMSSD and at 3rd and 5th min showed positive correlation with LFn and LF/HF ratio in supine position. With HRV indices in standing position CHRR from the 1st to 5th min showed the same respective negative and positive correlations as the other measures. |
Does passive leg raising predict fluid responsiveness in the critically ill? | Passive leg raising (PLR) represents a "self-volume challenge" that could predict fluid response and might be useful when the respiratory variation of stroke volume cannot be used for that purpose. We hypothesized that the hemodynamic response to PLR predicts fluid responsiveness in mechanically ventilated patients. Prospective study. Medical intensive care unit of a university hospital. We investigated 71 mechanically ventilated patients considered for volume expansion. Thirty-one patients had spontaneous breathing activity and/or arrhythmias. We assessed hemodynamic status at baseline, after PLR, and after volume expansion (500 mL NaCl 0.9% infusion over 10 mins). We recorded aortic blood flow using esophageal Doppler and arterial pulse pressure. We calculated the respiratory variation of pulse pressure in patients without arrhythmias. In 37 patients (responders), aortic blood flow increased by > or =15% after fluid infusion. A PLR increase of aortic blood flow > or =10% predicted fluid responsiveness with a sensitivity of 97% and a specificity of 94%. A PLR increase of pulse pressure > or =12% predicted volume responsiveness with significantly lower sensitivity (60%) and specificity (85%). In 30 patients without arrhythmias or spontaneous breathing, a respiratory variation in pulse pressure > or =12% was of similar predictive value as was PLR increases in aortic blood flow (sensitivity of 88% and specificity of 93%). In patients with spontaneous breathing activity, the specificity of respiratory variations in pulse pressure was poor (46%). | ID4 gene is a member of the inhibitor of DNA binding (ID) family proteins that inhibit DNA binding of basic helix-loop-helix transcription factors. The epigenetic inactivation of ID4 gene on colorectal cancer (CRC) development and its clinical significance was assessed. In CRC cell lines, ID4 methylation status of the promoter region was assessed by methylation-specific PCR and bisulfite sequencing. The mRNA expression level was assessed by quantitative real-time reverse transcription-PCR. The methylation status of 9 normal epithelia, 13 adenomas, 92 primary CRCs, and 26 liver metastases was assessed by methylation-specific PCR. ID4 protein expression was assessed by immunohistochemistry analysis of tissue specimen. CRC cell lines were shown to be hypermethylated, and mRNA expression was suppressed and could be restored by 5-aza-cytidine treatment. In clinical specimens from normal epithelia, adenomas, primary CRCs, and liver metastases, the frequency of ID4 hypermethylation was 0 of 9 (0%), 0 of 13 (0%), 49 of 92 (53%), and 19 of 26 (73%), respectively, with a significant elevation according to CRC pathological progression. Methylation status of primary CRCs significantly correlated with histopathological tumor grade (P = 0.028). Immunohistochemistry analysis showed ID4 expression of normal colon epithelia, adenomas, and unmethylated primary CRCs but not hypermethylated CRC specimens. Among 76 American Joint Committee on Cancer stage I to IV patients who had undergone curative surgical resection, overall survival was significantly poorer in patients with hypermethylated ID4 bearing tumors (P = 0.0066). |
Does the Decline of Amylase Level of Pancreatic Juice After Pancreaticoduodenectomy predict Postoperative Pancreatic Fistula? | Postoperative pancreatic fistula (POPF) is a life-threatening complication after pancreaticoduodenectomy (PD). The aim of this study is to evaluate the significance of pancreatic amylase level of pancreatic juice for PF after PD. The subjects were 46 patients who underwent PD between January 2012 and August 2015 at Jikei University Hospital. We retrospectively investigated the relation between patient characteristics including pancreatic amylase level of pancreatic juice through the pancreatic drainage tube and the incidence of POPF (grade B or grade C according to the International Study Group on the Pancreatic Fistula) using univariate and multivariate analyses. The decline of pancreatic amylase level of pancreatic juice was evaluated by 1 - postoperative day 3/postoperative day 1 ratio. In univariate analysis, nonductal adenocarcinoma (P = 0.0252), soft pancreatic remnant (P = 0.0155), and decline of pancreatic amylase level of pancreatic juice ≥ 80% (P = 0.0010) were significant predictors of POPF. In multivariate analysis, decline of pancreatic amylase level of pancreatic juice of 80% or greater (P = 0.0192) was the only significant independent parameter. | The lycophyte Selaginella moellendorffii is a vascular plant that diverged from the fern/seed plant lineage at least 400 million years ago. Although genomic information for S. moellendorffii is starting to be produced, little is known about basic aspects of its molecular biology. In order to provide the first glimpse to the epigenetic landscape of this early divergent vascular plant, we used the methylation filtration technique. Methylation filtration genomic libraries select unmethylated DNA clones due to the presence of the methylation-dependent restriction endonuclease McrBC in the bacterial host. We conducted a characterization of the DNA methylation patterns of the S. moellendorffii genome by sequencing a set of S. moellendorffii shotgun genomic clones, along with a set of methylation filtered clones. Chloroplast DNA, which is typically unmethylated, was enriched in the filtered library relative to the shotgun library, showing that there is DNA methylation in the extremely small S. moellendorffii genome. The filtered library also showed enrichment in expressed and gene-like sequences, while the highest-copy repeats were largely under-represented in this library. These results show that genes and repeats are differentially methylated in the S. moellendorffii genome, as occurs in other plants studied. |
Is obstructive sleep apnea associated with visit-to-visit variability in low-density lipoprotein-cholesterol in patients with coronary artery disease? | Visit-to-visit variability in low-density lipoprotein-cholesterol (LDL-C) was found to be a novel predictor of adverse cardiac events. Obstructive sleep apnea (OSA), an emerging cardiovascular risk factor, is characterized by sympathetic activation and increased oxidative stress which are regulators of LDL-C metabolism. We hypothesized that OSA was associated with LDL-C variability. We prospectively recruited 190 patients with coronary artery disease for an overnight sleep study. Statin was prescribed upon discharge for 186 patients. Serum LDL-C levels were measured at clinic every 3 to 6 months. Severity of OSA (on the basis of apnea-hypopnea index (AHI)) was correlated with visit-to-visit LDL-C variability (on the basis of variation independent of mean (VIM)) in outpatient clinic. The mean AHI was 21.9 ± 18.9. Using an AHI cut-off of 5-14.9, 15-29.9, and ≥30, the prevalence of mild, moderate, and severe OSA was 26.3, 18.9, and 27.4 %, respectively. After 53.2 ± 25.3 months, LDL-C was recorded over 8.1 ± 4.2 measurements. VIM positively correlated with AHI (Pearson's r = 0.183, p = 0.016), but not body mass index, baseline and mean follow-up LDL-C levels, and number of LDL-C measurements. In multiple linear regression analysis, AHI remained an independent predictor of VIM after adjusting for diabetes mellitus and hyperlipidemia. A 10-unit rise in AHI led to a 3.8 % increase in VIM (95 % CI 0.1 to 7.4 %; p = 0.044). | To determine the antibiotic resistance patterns of pathogenic Escherichia coli on goat meat carcass at Huruma and Kiserian abattoirs in Kenya. Laboratory based study. Huruma and Kiserian abattoirs in Kenya, 400 slaughtered goats inspected by veterinary health officers and approved for human consumption. A Total of 400 slaughtered goats which were inspected by veterinary health officers and approved for human consumption were sampled from Huruma and Kiserian abattoir. Goat carcass swabs were collected by passing each swab tissue on four parts of the carcass mainly neck, right and left forelimbs, right and left hind limbs, and brisket. A total of 54 E. coli isolates were isolated and confirmed to be pathogenic. The percentage of isolates resistant to various microbial agents was recorded as follows: ampicillin (26 %), amoxycillin-clavulanic acid (17%), tetracycline (15%), chroramphenicol (4%), and ceftrixone (2% each). All Escherichia coli isolates were susceptible to gentamicin sulphamethaxazole-trimethomprin, kanamycin, cetriazididine (CAZ, 30pg), ciproxacin, nalidixic acid and chloramphenicol. Isolates were resistant to one or more of the antibiotics tested. Among the drugs tested, resistance was more frequently observed against ampicillin, amoxycillin-clavulanic acid, tetracycline, ceftrixone and chroramphenicol antibiotics. Among the isolates 26(48%) were positive for the stx1 gene, 19(35%) had the eae gene, 10(19%) possessed est gene,while 8(15%) harboured elt gene. Overall five isolates (10%) possessed aspu gene and two (4%) had aggR gene. No isolate possessed ipah gene. |
Does a negative nontreponemal and/or specific antitreponemal IgM test exclude active infectious syphilis : evidence from a rabbit infectivity test : A case report? | The diagnostic criteria for active infectious syphilis in the clinic are important matter of controversy and debate. So far, clinicians habitually do use the negative results of the nontreponemal and/or the specific antitreponemal IgM as the evidences of disease-free or active infection-free status. We present a case study involving a patient who was admitted to Zhongshan Hospital because of cerebral infarct. Clinical examination indicated he had a history of latent syphilis with negative nontreponemal and specific antitreponemal IgM tests. The cerebrospinal fluid sample from the patient was inoculated into seronegative New Zealand rabbit. Motile Treponema pallidum was detected by a rabbit infectivity test in the patient's cerebrospinal fluid. This syphilis strain was confirmed by DNA subtyping form of "centers for disease control subtype/tp0548 sequence type", and the strain type was 14d/f. Treatment with benzathine penicillin provided no apparent benefit, but treatment with aqueous crystalline penicillin G, especially recommended for neurosyphilis, led to disease regression. No evidence of cerebral infarct was observed during a 2-year follow-up period. | Understanding the fundamental mechanisms of tumorigenesis remains one of the most pressing problems in modern biology. To this end, stem-like cells with tumor-initiating potential have become a central focus in cancer research. While the cancer stem cell hypothesis presents a compelling model of self-renewal and partial differentiation, the relationship between tumor cells and normal stem cells remains unclear. We identify, in an unbiased fashion, mRNA transcription patterns associated with pluripotent stem cells. Using this profile, we derive a quantitative measure of stem cell-like gene expression activity. We show how this 189 gene signature stratifies a variety of stem cell, malignant and normal tissue samples by their relative plasticity and state of differentiation within Concordia, a diverse gene expression database consisting of 3,209 Affymetrix HGU133+ 2.0 microarray assays. Further, the orthologous murine signature correctly orders a time course of differentiating embryonic mouse stem cells. Finally, we demonstrate how this stem-like signature serves as a proxy for tumor grade in a variety of solid tumors, including brain, breast, lung and colon. |
Does fungal metabolite myriocin promote human herpes simplex virus-2 infection? | Myriocin is a fungal metabolite with antiviral activity, including influenza, hepatitis B, and hepatitis C viruses. We investigated whether myriocin has activity against human HSV-2, one of the most prevalent pathogens of sexually transmitted disease. Cell culture systems were used to evaluate myriocin effect on HSV-2 infection. Plaque forming assay and immunoblotting studies were used to determine virus production and viral protein expression, respectively. Myriocin showed no cytotoxic effect at up to 5 μM. Myriocin treatment did not inhibit HSV-2 infection. Instead, the treatment resulted in accelerated replication of HSV-2 and increased titers of infectious virion. The effect was detected at concentrations as low as 3 nM and plateaued at approximately 30 nM. Myriocin at 30 nM increased HSV-2 production by approximately 1.7 logs. Myriocin also promoted HSV-1 infection but required higher concentrations. A time course study revealed that myriocin promoted HSV-2 infection by acceleration of virus replication. Unlike trichostatin A that promotes HSV-2 infection and histone modifications, myriocin treatment did not alter histone modifications. Myriocin is a well characterized inhibitor of sphingolipid biosynthesis pathway. Structurally different inhibitors of the pathway showed no effect on HSV-2 infection. Exogenous sphingolipids did not reverse the effect of myriocin on HSV-2 infection either. | Previous research has shown some maladaptive psychological reactions and even increased incidence of various mental disorders in patients with spinal cord injury during their rehabilitation. Self-concept and suicidal risk in particular have not been studied often in these samples. Our principal goal was to explore suicidal ideation and behavior, self-concept, posttraumatic stress disorder (PTSD) symptoms, and correlations among these traits, in subjects after a motor vehicle accident (MVA) resulting in permanent physical disability. Our sample consisted of 50 individuals with paraplegia, tetraplegia, or significant amputation, of whom eight had a family history of suicidal behavior. The following assessment instruments were used: an anamnestic data questionnaire; the Tennessee Self-Concept Scale; the Impact of Event Scale-Revised; and the Suicidal Ideations and Behaviour Questionnaire. Rehabilitating patients with spinal cord injury were characterized by low total self-concept, presence of PTSD symptoms, and suicidal ideation and behavior. PTSD symptoms were correlated with low self-concept and suicidal tendencies. |
Are multiple pathways responsible for anti-inflammatory and cardiovascular activities of Hordeum vulgare L? | Hordeum vulgare L. (HV or barley) is used by traditional healers to treat various inflammatory and cardiovascular diseases, without the knowledge of pharmacologic rationale behind its actions. This study was designed to explore the potential scientific mechanism(s) that could explain the use of Hordeum vulgare in traditional medicine as a treatment for various inflammatory and cardiovascular diseases. A crude extract and its three fractions were prepared from HV and screened for the inhibition of platelet aggregation and various metabolites of cyclooxygenase (COX), lipoxygenase (LOX) pathways of arachidonic acid (AA) metabolism as well as for its effects on certain antioxidant enzymes. Platelet aggregation was monitored using turbidometric principle, AA metabolism through radioimmunoassay and antioxidant enzymes by commercial kits using spectrophotometer. Results show that HV exhibited activities against all human platelet agonists used except adenine diphosphate, and inhibited both COX and LOX pathways of AA metabolism. It also elevated the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). However, these activities were distributed in various fractions of HV. Aqueous fraction was most potent in elevating SOD activity; chloroform fraction had concentrated compounds responsible for COX inhibition while n-hexane seems to possess compounds responsible for LOX inhibition as well as the only fraction enhancing the activity of GPx. | The purpose of this study was to determine the rates and predictors of HIV testing and receipt of results among homeless adults with serious mental illness in the initial 3-month period after contact with a community-based case management program. Baseline and follow-up interview data came from clients (N=5,890) in the Access to Community Care and Effective Services and Supports program, an 18-site, 5-year federally sponsored demonstration designed to evaluate the effect of service system integration on outcomes for homeless persons with serious mental illness. Overall, 38.0% of clients were tested for HIV in the 3 months after program entry; of these, 88.8% returned to receive their test results. Likelihood of being tested was independently associated with having been tested before, more severe psychiatric symptoms and drug problems, level of worry about getting AIDS, younger age, less education, minority status, longer-term homelessness, being sexually assaulted, being arrested, and health services utilization. Among those tested, likelihood of receiving the test results was higher among those with a history of prior testing and return for results, a higher frequency of testing, and more years of education and lower among those with drug abuse problems, outpatient medical service utilization, disability, and sexually transmitted disease. Interaction analyses showed that, for men, greater social support increased the likelihood of both HIV testing and receipt of results, while sexual victimization during follow-up decreased the likelihood that men would return for their HIV results. |
Do academic mothers have a pronounced seasonal variation in their offspring sex ratio? | Environmental and socio-demographic factors can influence the variation of the human sex ratio at birth (SRB = the ratio of males to males plus females). In particular, findings of seasonal, parental education, birth order, and maternal age effects on the SRB are not always in agreement, and a number of works report minimal variation. Here, we investigated the seasonality of SRB in academic and non-academic mothers employed at the University of Vienna, and who gave birth between 1963 and 2000 (n = 1932 births). All data were available from an anonymous employee database. Both groups, academic and non-academic mothers do not differ between their overall SRB. In academic mothers the SRB is significantly (P = 0.004) increased during the springtime and decreased during the summertime. Although in non-academic mothers the trend is comparable, it is far less pronounced and not significant (P = 0.345). When a multiple logistic model was applied to the data of academic mothers the only significant influencing factor on the SRB is the season, while birth order of children and mothers' age at childbirth has no effect. None of the three independent variables influence the SRB in non-academic mothers. These findings suggest a more flexible SRB rate in academic mothers than in non-academics within the seasons. | Vascular smooth muscle cell (VSMC) proliferation is central to the pathophysiology of neo-intima formation. Interferon regulatory factor 3 (IRF3) inhibits the growth of cancer cells and fibroblasts. However, the role of IRF3 in vascular neo-intima formation is unknown. We evaluated the protective role of IRF3 against neo-intima formation in mice and the underlying mechanisms. IRF3 expression was down-regulated in VSMCs after carotid wire injury in vivo, and in SMCs after platelet-derived growth factor (PDGF)-BB challenge in vitro. Global knockout of IRF3 (IRF3-KO) led to accelerated neo-intima formation and proliferation of VSMCs, whereas the opposite was seen in SMC-specific IRF3 transgenic mice. Mechanistically, we identified IRF3 as a novel regulator of peroxisome proliferator-activated receptor γ (PPARγ), a negative regulator of SMC proliferation after vascular injury. Binding of IRF3 to the AB domain of PPARγ in the nucleus of SMCs facilitated PPARγ transactivation, resulting in decreased proliferation cell nuclear antigen expression and suppressed proliferation. Overexpression of wild-type, but not truncated, IRF3 with a mutated IRF association domain (IAD) retained the ability to exert anti-proliferative effect. |
Does aggregation substance promote colonic mucosal invasion of Enterococcus faecalis in an ex vivo model? | Bacterial translocation through the gastrointestinal tract is the crucial step in the pathogenesis of intraabdominal infections. We assessed whether aggregation substance (AS), a bacterial adhesin and virulence factor of Enterococcus faecalis, promotes bacterial translocation and colonic mucosal invasion in an ex vivo experiment. Colonic mucosa of male Wistar rats was placed in a modified Ussing system. The mucosal side of the chamber was filled with a suspension of E. faecalis OG1X:pAM721 (AS-positive) or E. faecalis OG1X (AS-negative). The serosal side was filled with sterile Dulbecco's modified Eagle's medium. For assessment of colonic mucosal invasion the mucosal side was incubated for 2.5 h with a suspension of AS-positive or AS-negative enterococci. After being washed, a solution of gentamicin and penicillin G in tissue culture medium was added on both sides in order to kill extracellular bacteria. Subsequently, the mucosa was removed from the system, washed, lysed with Triton X-100, and homogenized. Viable intramural bacteria were quantified by plating serial dilutions of the homogenate on Todd-Hewitt broth agar plates. To quantify bacterial translocation samples which were taken at various time points from the serosal side were plated on Todd-Hewitt broth agar plates and colony forming units (CFU) were determined. Invasion of the AS-positive E. faecalis strain OG1X:pAM721 into the colonic mucosa was significantly higher than invasion rates of the AS-negative strain OG1X (2.88 log(10) CFU/ml vs 1.73 log(10) CFU/ml; P = 0.02). However, none of the tested strains was found to translocate from the mucosal to the serosal side within the incubation time of 4 h. | Altered autonomic nervous system (ANS) functioning may help to explain the relationship between depression and cardiac mortality. Heart rate (HR) recovery after the cessation of a treadmill stress test assesses ANS functioning and predicts mortality. This study examined the relationship between depression symptoms and HR recovery among patients entering phase II cardiac rehabilitation. Two hundred sixty patients were assessed at the time of their enrollment in cardiac rehabilitation. Patients completed a ramped-protocol treadmill stress test, providing an assessment of exercise capacity and HR recovery at 2 minutes post exercise. Depression symptoms were measured using the Beck Depression Inventory. Other medical information was obtained by chart review. Patients with higher Beck Depression Inventory scores exhibited slower HR recovery after exercise. This remained true after controlling for age, sex, and beta-blocker usage. Controlling for exercise capacity rendered the relationship between depression score and HR recovery non significant, suggesting that exercise capacity may partly account for this relationship. |
Is iodopropynylbutyl carbamate 0.2 % suggested for patch testing of patients with eczema possibly related to preservatives? | Iodopropynyl butylcarbamate (IPBC) is a new preservative in medical and cosmetic leave-on products. Although cases of allergic contact dermatitis to IPBC have been reported, it is not known whether the usual test concentration of 0.1% is appropriate for screening tests with IPBC. To determine the concentration of IPBC that should be used in screening patch tests. An analysis was made of data filed by 26 centres of dermatology on patch tests performed with one or two concentrations of IPBC (0.1%, 0.2%, 0.3% or 0.5%) in 8106 unselected patients. Criteria used to determine the best test concentration of IPBC were the reaction index, the positivity ratio, the rate of crescendo reactions, and the relations between IPBC reactions and the MOAHLFA index irritant reactions to sodium lauryl sulphate (SLS), and allergic reactions to other contact allergens including preservatives. IPBC 0.1%, 0.2%, 0.3% and 0.5% yielded 0.5%, 0.8%, 1.3% and 1.7% positive reactions, but this increase was accompanied by an even greater increase in doubtful and irritant reactions. These figures and the other criteria examined suggested the range of suitable test concentrations of IPBC to lie between 0.2% and 0.3%. A detailed analysis of MOAHLFA indices and of associations between reactions to IPBC and reactions to other allergens and to SLS showed that most of the positive reactions to IPBC 0.2% can be assumed to be allergic ones and that with IPBC 0.2% fewer false-positive reactions can be expected than with IPBC 0.3%. | Cellular miRNAs play an important role in the regulation of gene expression in eukaryotes. Recently, miRNAs have also been shown to be able to target and inhibit viral gene expression. Computational predictions revealed earlier that the HIV-1 genome includes regions that may be potentially targeted by human miRNAs. Here we report the functionality of predicted miR-29a target site in the HIV-1 nef gene. We find that the human miRNAs hsa-miR-29a and 29b are expressed in human peripheral blood mononuclear cells. Expression of a luciferase reporter bearing the nef miR-29a target site was decreased compared to the luciferase construct without the target site. Locked nucleic acid modified anti-miRNAs targeted against hsa-miR-29a and 29b specifically reversed the inhibitory effect mediated by cellular miRNAs on the target site. Ectopic expression of the miRNA results in repression of the target Nef protein and reduction of virus levels. |
Is interleukin-4 production from human basophils critically dependent on the storage conditions employed prior to stimulation? | Marked variations in the interleukin-4 (IL-4)-producing capacity of basophils can be observed when aliquots from the same cell preparation are kept under different conditions before stimulation. The aim of this study was to identify factors affecting the functional activity of basophils and to determine optimal storage conditions. Healthy blood donors. Aliquots of purified basophils were kept for different time intervals on ice or at 37 degrees C, in buffer or culture medium, respectively. Following subsequent stimulation with anti-IgE, IL-4 release was determined. Upon storage times up to 4 h, basophils produced more IL-4 when kept at 37 degrees C as compared to 4 degrees C. Surprisingly, buffer was superior compared to culture medium for storage. When the storage time was 20 h, IL-4 release was reduced significantly under all conditions studied. | SLIT-ROBO families of proteins mediate axon pathfinding and their expression is not solely confined to nervous system. Aberrant expression of SLIT-ROBO genes was repeatedly shown in a wide variety of cancers, yet data about their collective behavior in hepatocellular carcinoma (HCC) is missing. Hence, we quantified SLIT-ROBO transcripts in HCC cell lines, and in normal and tumor tissues from liver. Expression of SLIT-ROBO family members was quantified by real-time qRT-PCR in 14 HCC cell lines, 8 normal and 35 tumor tissues from the liver. ANOVA and Pearson's correlation analyses were performed in R environment, and different clinicopathological subgroups were pairwise compared in Minitab. Gene expression matrices of cell lines and tissues were analyzed by Mantel's association test. Genewise hierarchical clustering revealed two subgroups with coordinate expression pattern in both the HCC cell lines and tissues: ROBO1, ROBO2, SLIT1 in one cluster, and ROBO4, SLIT2, SLIT3 in the other, respectively. Moreover, SLIT-ROBO expression predicted AFP-dependent subgrouping of HCC cell lines, but not that of liver tissues. ROBO1 and ROBO2 were significantly up-regulated, whereas SLIT3 was significantly down-regulated in cell lines with high-AFP background. When compared to normal liver tissue, ROBO1 was found to be significantly overexpressed, while ROBO4 was down-regulated in HCC. We also observed that ROBO1 and SLIT2 differentiated histopathological subgroups of liver tissues depending on both tumor staging and differentiation status. However, ROBO4 could discriminate poorly differentiated HCC from other subgroups. |
Does holoturia arenicola extract modulate bile duct ligation-induced oxidative stress in rat kidney? | Acute Renal Failure (ARF) in patients with cirrhosis is one of the most frequently encountered complications of obstructive jaundice. Marine organisms from the Mediterranean Coast of Egypt are considered potential sources of bioactive molecules. The present study was undertaken to explore the curative effects of Holothuria arenicola extract (HaE) against renal injury induced by bile duct ligation in male albino rats. Fifty four male Wistar albino rats were assigned into two main groups, the Sham-operated control (received distilled water only for 28 days) and bile duct ligated (BDL) group, which divided into 2 subgroups, animals of these subgroups treated for 28 consecutive days as follow: Subgroup I (BDL), rats of this subgroup administered distilled water orally. Subgroup II, animals of this subgroup treated orally with HaE (200 mg/kg body weight). BDL induced marked alteration on renal functions as manifested by a significant increase in the kidney function markers, serum creatinine, urea and uric acid. In addition, BDL caused significant increase in MDA level and significant decrease in GSH level as well as antioxidant enzymes activities (GST, SOD and CAT). However, administration of HaE for consecutive 28 days significantly reversed these changes, suggesting that the renal curative effect of HaE against oxidative stress- induced injury might be involved in decreasing lipid peroxide generation and stimulating antioxidant status. | We characterized cardiac surgery-induced dynamic changes of the corrected QT (QTc) interval and tested the hypothesis that genetic factors are associated with perioperative QTc prolongation independent of clinical and procedural factors. All study subjects were ascertained from a prospective study of patients who underwent elective cardiac surgery during August 1999 to April 2002. We defined a prolonged QTc interval as > 440 msec, measured from 24-hr pre- and postoperative 12-lead electrocardiograms. The association of 37 single nucleotide polymorphisms (SNPs) in 21 candidate genes -involved in modulating arrhythmia susceptibility pathways with postoperative QTc changes- was investigated in a two-stage design with a stage I cohort (n = 497) nested within a stage II cohort (n = 957). Empirical P values (Pemp) were obtained by permutation tests with 10,000 repeats. After adjusting for clinical and procedural risk factors, we selected four SNPs (P value range, 0.03-0.1) in stage I, which we then tested in the stage II cohort. Two functional SNPs in the pro-inflammatory cytokine interleukin-1β (IL1β), rs1143633 (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.53 to 0.95; Pemp = 0.02) and rs16944 (OR, 1.31; 95% CI, 1.01 to 1.70; Pemp = 0.04), remained independent predictors of postoperative QTc prolongation. The ability of a clinico-genetic model incorporating the two IL1B polymorphisms to classify patients at risk for developing prolonged postoperative QTc was superior to a clinical model alone, with a net reclassification improvement of 0.308 (P = 0.0003) and an integrated discrimination improvement of 0.02 (P = 0.000024). |
Does inhibition during early adolescence predict alcohol and marijuana use by late adolescence? | Adolescent substance use has been associated with poorer neuropsychological functioning, but it is unclear if deficits predate or follow the onset of use. The goal of this prospective study was to understand how neuropsychological functioning during early adolescence could predict substance use by late adolescence. At baseline, participants were 175 substance-use-naïve healthy 12- to 14-year-olds (41% female) recruited from local schools. Participants completed extensive interviews and neuropsychological tests. Each year, participants' substance use was assessed. By late adolescence (ages 17 to 18), 105 participants transitioned into substance use and 75 remained substance-naïve. Hierarchical linear regressions examined how baseline cognitive performance predicted subsequent substance use, controlling for common substance use risk factors (i.e., family history, externalizing behaviors, gender, pubertal development, and age). Poorer baseline performance on tests of cognitive inhibition-interference predicted higher follow-up peak drinks on an occasion (β = -.15; p < .001), more days of drinking (β = -.15; p < .001), and more marijuana use days (β = -.17; p < .001) by ages 17 to 18, above and beyond covariates. Performances on short-term memory, sustained attention, verbal learning and memory, visuospatial functioning, and spatial planning did not predict subsequent substance involvement (ps > .05). | Tissue-engineered xenografts represent a promising treatment option in heart valve disease. However, inflammatory response leading to graft failure and incomplete in vitro repopulation with recipient cells remain challenging. Shock waves (SWs) were shown to modulate inflammation and to enhance re-epithelialization. We therefore aimed to investigate whether SWs could serve as a feasible adjunct to tissue engineering. Porcine aortic pieces were decellularized using sodium deoxycholate and sodium dodecylsulphate and implanted subcutaneously into C57BL/6 mice (n = 6 per group). The treatment (shock wave therapy, SWT) group received SWs (0.1 mJ/mm(2), 500 impulses, 5 Hz) for modulation of inflammatory response directly after implantation; control animals remained untreated (CTR). Grafts were harvested 72 h and 3 weeks after implantation and analysed for inflammatory cytokines, macrophage infiltration and polarization, osteoclastic activity and calcification. Transmission electron microscopy (TEM) was performed. Endothelial cells (ECs) were treated with SWs and analysed for macrophage regulatory cytokines. In an ex vivo experimental set-up, decellularized porcine aortic valve conduits were reseeded with ECs with and without SWT (0.1 mJ/mm(2), 300 impulses, 3 Hz), fibroblasts as well as peripheral blood mononuclear cells (all human) and tested in a pulsatile flow perfusion system for cell coverage. Treated ECs showed an increase of macrophage migration inhibitory factor and macrophage inflammatory protein 1β, whereas CD40 ligand and complement component C5/C5a were decreased. Subcutaneously implanted grafts showed increased mRNA levels of tumour necrosis factor α and interleukin 6 in the treatment group. Enhanced repopulation with recipient cells could be observed after SWT. Augmented macrophage infiltration and increased polarization towards M2 macrophages was observed in treated animals. Enhanced recruitment of osteoclastic cells in proximity to calcified tissue was found after SWT. Consequently, SWT resulted in decreased areas of calcification in treated animals. The reseeding experiment revealed that fibroblasts showed the best coverage compared with other cell types. Moreover, SW-treated ECs exhibited enhanced repopulation compared with untreated controls. |
Do higher glycosylated hemoglobin levels increase the risk of overactive bladder syndrome in patients with type 2 diabetes mellitus? | To assess overactive bladder and its component symptoms among patients with type 2 diabetes mellitus and to explore whether higher glycosylated hemoglobin and other factors increase the risk of overactive bladder symptoms. A total of 279 diabetes mellitus patients from our outpatient clinic, and 578 age- and sex-matched subjects without diabetes mellitus from public health centers were enrolled from May to September of 2010. The collected data included overactive bladder and its component symptoms measured by using the Overactive Bladder Symptom Score, and collecting demographic and clinical data. Overactive bladder was defined as total Overactive Bladder Symptom Score ≥3 and urgency score ≥2 (once a week or more). Diabetes mellitus patients had a significantly higher proportion of overactive bladder symptoms/urgency compared with the controls (28.0% vs 16.3%, odds ratio 2.03, 95% confidence interval 1.44-2.86), as well as nocturia (48.0% vs 39.1%, odds ratio 1.44, 95% confidence interval 1.08-1.93). There were no significant effects of diabetes mellitus on urge urinary incontinence (14.0% vs 10.9%, odds ratio 1.32, 95% confidence interval 0.86-2.04) and daytime frequency (26.9% vs 32.4%, odds ratio 0.77, 95% confidence interval 0.56-1.05). After adjusting for all variables, high glycosylated hemoglobin levels were significantly associated with overactive bladder/urgency (odds ratio 1.24, 95% confidence interval 1.06-1.45), urge urinary incontinence (odds ratio 1.20, 95% confidence interval 1.00-1.45) and nocturia (odds ratio 1.17, 95% confidence interval 1.01-1.35). | To study the role of E2F1/4 pathway in vitamin C reversing benzo (a) pyrene [B (a) P]-induced changes of cell cycle in human embryo lung fibroblasts (HELF) and the relationship between E2F1 and cyclin D1/CDK4. The stable transfectants, HELF transfected with antisense cyclin D1 and antisense CDK4, were established to detect the relationship of signaling pathway. Cells were cultured and pretreated with vitamin C before stimulation with B (a) P for 24 hours. The expression levels of cyclin D1, CDK4, E2F1 and E2F4 were determined by Western blot and the band intensity was analysed as the relative value to control by using the Gel-Pro 3.0 software. Flow Cytometric Analysis was employed to detect the distributions of cell cycle. B (a) P significantly elevated the expression levels of cyclin D1, CDK4, E2F1 and E2F4 in HELF cells. Vitamin C decreased the expression levels of above proteins in B (a) P-stimulated HELF cells. The expression levels of these proteins in B (a) P-treated above transfectants were lower than those in B (a) P-treated HELF cells. The expression levels of above proteins with vitamin C combined with antisense cyclin D1 were decreased as compared to those with antisense cyclin D1 alone. B (a) P increased the percentage of S phase as compared to the controls [(41.1 +/- 0.2)% vs (33.5 +/- 3.2)%, P < 0.05]. Both vitamin C [(33.2 +/- 0.6)% vs (41.1 +/- 0.2)%, P < 0.05] and antisense cyclin D1 [(31.2 +/- 1.3)% vs (41.1 +/- 0.2)%, P < 0.05] suppressed the changes of cell cycle induced by B (a) P. Vitamin C combined with antisense CDK4 markedly suppressed B (a) P-induced changes of cell cycle as compared to those with antisense CDK4 alone. |
Do prevalence of mood and substance use disorders among patients seeking primary care office-based buprenorphine/naloxone treatment? | Psychiatric comorbidity can adversely affect opioid dependence treatment outcomes. While the prevalence of psychiatric comorbidity among patients seeking methadone maintenance treatment has been documented, the extent to which these findings extend to patients seeking primary care office-based buprenorphine/naloxone treatment is unclear. To determine the prevalence of mood and substance use disorders among patients seeking primary care office-based buprenorphine/naloxone treatment, via cross sectional survey. 237 consecutive patients seeking primary care office-based buprenorphine/naloxone treatment were evaluated using modules from the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Current (past 30 days) and past diagnoses were cataloged separately. Patients ranged in age from 18 to 62 years old (M=33.9, SD=9.9); 173 (73%) were men; 197 (83%) were white. Major depression was the most prevalent mood disorder (19% current, 24% past). A minority of patients met criteria for current dysthymia (6%), past mania (1%), or past hypomania (2%). While 37 patients (16%) met criteria for current abuse of or dependence on at least one non-opioid substance (7% cocaine, 4% alcohol, 4% cannabis, 2% sedatives, 0.4% stimulants, 0.4% polydrug), 168 patients (70%) percent met criteria for past abuse of or dependence on at least one non-opioid substance (43% alcohol, 38% cannabis, 30% cocaine, 9% sedatives, 8% hallucinogens, 4% stimulants, 1% polydrug, and 0.4% other substances). | Vessel formation is a crucial event in tissue repair after injury. Thus, one assumption of innovative therapeutic approaches is the understanding of its molecular mechanisms. Notwithstanding our knowledge of the role of Protein Kinase C epsilon (PKCε) in cardio-protection and vascular restenosis, its role in vessel progenitor differentiation remains elusive. Given the availability of PKCε pharmacological modulators already tested in clinical trials, the specific aim of this study is to unravel the role of PKCε in vessel progenitor differentiation, with implications in vascular pathology and vasculogenesis. Mouse Peri-Vascular Adipose Tissue (PVAT) was used as source of mesenchymal vessel progenitors. VEGF-induced differentiation of PVAT cells down-regulates both PKCε and p-PAK1 protein expression levels. PKCε overexpression and activation: i) reduced the expression levels of SMA and PECAM in endothelial differentiation of PVAT cells; ii) completely abrogated tubules formation in collagen gel assays; iii) increased the expression of p-PAK1. |
Does brain-derived neurotrophic factor enhance the contraction of intestinal muscle strips induced by SP and CGRP in mice? | Brain-derived neurotrophic factor (BDNF) has been found in the intestinal tract of a variety of species. Its effects on visceral hyperalgesia have been examined to some degree, but limited studies have focused on gut motility. The aim of the present study was to investigate the effects of BDNF on gut motility of mice. Longitudinal muscle (LM) strips were prepared from mice ileum and distal colon. The motility of gut was evaluated by the contraction of LM strips, which was recorded by a polyphisograph in vitro. Firstly, the roles of substance P (SP), calcitonin gene-related peptide (CGRP), and acetylcholine (ACh) on the contraction of LM strips were clarified. Then the exogenous BDNF was administered, and the alterations of SP/CGRP/ACh-induced contractions of the muscle strips were explored. Finally, heterozygous BDNF(+/-) mice and antibody of TrkB were introduced to investigate the role of endogenous BDNF on the SP/CGRP/ACh-induced gut motility. SP (10(-8)-10(-6) mol L(-1)), CGRP (10(-8)-10(-7) mol L(-1)) and ACh (10(-8)-10(-6) mol L(-1)) dose-dependently caused the contraction of LM strips from ileum and distal colon, while the excitatory effect of CGRP was preceded by a transient inhibition. But 10(-6) mol L(-1) CGRP inhibited the contraction of LM strips. Pretreatment with exogenous BDNF (10(-8) mol L(-1)) remarkably enhanced the contraction of LM strips induced by SP (10(-9)-10(-7) mol L(-1)) and CGRP (10(-8)-10(-9) mol L(-1)). However, exogenous BDNF couldn't affect the contraction induced by ACh (10(-9)-10(-7) mol L(-1)). The excitatory effects of SP (10(-8)-10(-6) mol L(-1)) and CGRP (10(-8)-10(-7) mol L(-1)) on the contractions of LM strips from ileum and distal colon were significantly attenuated in BDNF(+/-) mice compared with those in BDNF(+/+) mice, while no difference of the effects of ACh (10(-8)-10(-6) mol L(-1)) on LM strips was observed between BDNF(+/-) mice and BDNF(+/+) mice. The monoclonal antibody of TrkB (TrkB-Ab) dramatically attenuated the excitatory effects of SP and CGRP on the contractions of LM strips, without affecting the excitatory effects of ACh. | There is controversy over whether or not chronic HIV infection contributes to atherosclerosis. We investigated the relationship between HIV infection, antiretroviral medication and ultrasound evidence of early atherosclerosis in the context of vascular risk factors. A case-control design with 292 HIV-positive subjects and 1168 age- and sex-matched controls. We assessed vascular risk factors, blood pressure, serum lipids and carotid intima media thickness (IMT) in cases and controls. With multivariate regression models, we investigated the effects of HIV status and antiretroviral medication on IMT. The common carotid artery (CCA) IMT value was 5.70% (95% confidence interval [3.08-8.38%], p<0.0001) or 0.044 mm [0.021-0.066 mm] (p=0.0001) higher in HIV-positives, adjusted for multiple risk factors. In the carotid bifurcation (BIF), the IMT values were 24.4% [19.5-29.4%] or 0.250 mm [0.198-0.303 mm] higher in HIV patients (p<0.0001). An investigation of antiretroviral substances revealed higher CCA- and BIF-IMT values in patients receiving combination antiretroviral therapy (HAART). |
Does folic acid supplementation reduce the development of some blood cell abnormalities in children receiving carbamazepine? | Carbamazepine is a commonly used anticonvulsant agent; however, it has been linked with various blood cell abnormalities. This study evaluated the effect of low-dose folic acid supplementation on the prevention of carbamazepine-induced hematological derangements in children. This randomized clinical trial was conducted in children with epilepsy who received carbamazepine monotherapy. Group 1 received carbamazepine alone, and group 2 received carbamazepine plus folic acid. The two groups were age- and sex-matched. Each group comprised 41 children with epilepsy. Complete blood counts were obtained before starting medication (baseline) and then serially. The patients were followed for at least 1 year. In group 1, 31.4% of the patients developed leukopenia and 17.1% neutropenia, but in group 2, these figures were 14.6 and 9.8% (P = 0.067 and P = 0.331, respectively). At the end of the first year of follow up, white blood cell and polymorphonuclear cell counts were significantly higher in group 2 (P = 0.007 and P = 0.001, respectively). Hemoglobin concentration dropped in group 1, but rose slightly in group 2; these changes were significant. Platelet, lymphocyte, and monocyte counts and changes in serial blood tests did not differ significantly between the two groups. | Adipose tissue (AT) content of the thigh is generally not considered to be associated with insulin resistance (IR), but it is unclear whether the distribution of AT in the thigh is a determinant of IR. We investigated whether subcompartments of AT within the thigh are determinants of IR. Midthigh AT, muscle composition, and insulin sensitivity were compared in 11 obese patients with type 2 diabetes mellitus (DM); 40 obese, glucose-tolerant (GT) and 15 lean, GT volunteers; and 38 obese subjects who completed a weight-loss program. Midthigh AT area measured with computed tomography was partitioned into 3 components: subcutaneous AT (SCAT), AT beneath the fascia (SFAT), and AT infiltrating muscle groups (IMAT). Muscle attenuation characteristics were determined. Obese DM and obese GT subjects had lower insulin sensitivity than lean GT subjects. SCAT was greater in obesity, yet did not correlate with insulin sensitivity. SFAT was approximately 8% of total thigh AT and correlated with insulin sensitivity. IMAT was highest in obese DM, and although it accounted for only approximately 3% of thigh AT, it was a strong correlate of insulin sensitivity. Mean attenuation was highest in lean subjects and was associated with higher insulin sensitivity. Weight loss reduced the amount of thigh AT, the proportion of thigh IMAT, and the amount of low-density thigh muscle. |
Are decreased blood riboflavin levels correlated with defective expression of RFT2 gene in gastric cancer? | To investigate the relationship between blood riboflavin levels and riboflavin transporter 2 (RFT2) gene expression in gastric carcinoma (GC) development. High-performance liquid chromatography was used to detect blood riboflavin levels in patients with GC. Real-time fluorogenic quantitative polymerase chain reaction and immunohistochemistry were used to analyze the expression of RFT2 mRNA and protein in samples from 60 GC patients consisting of both tumor and normal tissue. A significant decrease in the RFT2 mRNA levels was detected in GC samples compared with those in the normal mucous membrane (0.398 ± 0.149 vs 1.479 ± 0.587; P = 0.040). Tumors exhibited low RFT2 protein expression (75%, 16.7%, 8.3% and 0% for no RFT2 staining, weak staining, medium staining and strong staining, respectively), which was significantly lower than that in the normal mucous membrane (10%, 16.7%, 26.7% and 46.7% for no RFT2 staining, weak staining, medium staining and strong staining, respectively; P < 0.05). Tumors with low RFT2 expression were significantly associated with tumor stage and histological grade. Moreover, a significantly decrease in Uyghur patients was observed compared with Han patients. However, other parameters-gender, tumor location and lymph node metastasis-showed no significant relationship with RFT2 expression. Blood riboflavin levels were reverse correlated with development of GC (1.2000 ± 0.97569 ng/mL in high tumor stage patients vs 2.5980 ± 1.31129 ng/mL in low tumor stage patients; P < 0.05). A positive correlation of plasma riboflavin levels with defective expression of RFT2 protein was found in GC patients (χ² = 2.619; P = 0.019). | To compare endocrine profiles and IVF outcomes after using GnRH agonists (GnRHa) to trigger final oocyte maturation in women with polycystic ovary syndrome (PCOS) with other hyper-responders. Retrospective cohort study. Academic center. Forty women with PCOS and 74 hyper-responders without PCOS. GnRHa trigger. Number of oocytes. Serum E2, LH, and P levels on the day of GnRHa trigger and the day after trigger did not differ significantly between groups. There were no significant differences in total number of oocytes or percent mature oocytes obtained between groups after controlling for age, antral follicle count, and total days of stimulation. The overall rate of no retrieval of oocytes after trigger was low (2.6%). Fertilization, implantation, clinical pregnancy, and live-birth rates were similar in the two groups. No patients developed ovarian hyperstimulation syndrome (OHSS). |
Does timothy grass pollen major allergen Phl p 1 activate respiratory epithelial cells by a non-protease mechanism? | Group 1 allergens from grass pollen (e.g. Phl p 1, the major allergen of timothy grass Phleum pratense) cause IgE reactivity in about 95% of allergic subjects and exist in all grass species. The respiratory epithelium represents a first line of contact of the immune system with airborne allergens, functions as physical barrier and is an important immunological regulation system. The aim of this study was to investigate the interaction of Phl p 1 with human respiratory epithelium to elucidate the contribution of epithelial cells to the development of allergic reactions. Purified Phl p 1 was used to stimulate A549 cells and transient transfected HEK293 cells. mRNA level of different mediators were investigated by real-time PCR, release of the mediators was determined by ELISA. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and an ex vivo model of the murine trachea were used to investigate a potential proteolytic activity of Phl p 1. Phl p 1 activates respiratory epithelial cells as measured by induction of IL-6, IL-8 and TGF-beta mRNA and release. Phl p 1, in contrast to Der p 1 from the house dust mite, does not exert proteolytic activity, as investigated by microscopic observation and MTT test. In an ex vivo model of the murine trachea we were able to show that Der p 1, in contrast to Phl p 1, enhances the transportation velocity of particles by the trachea, presumably by ATP released from the injured epithelium. | To evaluate the relationship between chronic cerebrospinal venous insufficiency (CCSVI) and the presence of a Chronic Venous Disorder (CVD). We included 55 subjects with CCSVI aged >18 years, and 186 controls without CCSVI. Each subject was evaluated with color Doppler sonography in accordance with Zamboni's five criteria, examined by two neurologists and interviewed with an ad-hoc designed form. The neurologists and the sonographers were mutually blinded. CVD were classified according to CEAP. Mean age was 42 years (SD = 9) in cases and 43 years (10) in controls (p = ns). The odds ratios in subjects CCSVI were 0.6 (0.2-2.2) for CEAP 1, 0.9 (0.2-4.5) for CEAP 2, and 1.0 (0.6-1.9) for family history of varicose veins. The prevalence of CVD and, family history of varicose veins, was similar between cases and controls for each Zamboni criterion. |
Is dexamethasone-associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia augmented by concurrent use of daunomycin? | The goals of the current study were to examine the incidence and severity of toxicity resulting from dexamethasone and prednisone during induction therapy for children with precursor B-cell acute lymphoblastic leukemia (ALL) and to determine whether the addition of daunomycin affected toxicity. Medical records of patients with precursor B-cell ALL from January 1996 through June 2000 were reviewed retrospectively for toxicity during the 4-week induction phase and the 2 weeks after the induction phase. One hundred seventy-six patients age < 14 years were diagnosed with precursor B-cell ALL from January 1996 through June 2000. Of the 156 evaluable patients, 106 were treated with prednisone and 50 with dexamethasone. Fifty-two patients received steroids, L-asparaginase, and vincristine, whereas 104 high-risk patients received daunomycin in addition to these 3 agents. The incidence of gastritis was significantly higher among patients receiving dexamethasone (P = 0.01); incidence rates of hyperglycemia, hypertension, and myopathy were similar for all treatment groups. Dexamethasone led to more weight gain than did prednisone (+11.9% vs. +5.4%; P = 0.002). Serious infections were observed in 27 (25.5%) and 18 (36%) patients receiving prednisone and dexamethasone, respectively (P < or = 0.2). Five patients, four of whom received prednisone and one of whom received dexamethasone, died of infection. The addition of daunomycin to treatment regimens increased overall toxicity (P < 0.01). When daunomycin was included in treatment regimens, toxicity was greater among patients receiving dexamethasone; in contrast, when daunomycin was not included, toxicity was equal for both treatment groups. Regardless of daunomycin use, there was no difference in the incidence of serious infection between the two groups. ALL treatment was not compromised by steroid-related toxicity in either group. | Arterial stiffening and thickening and endothelial dysfunction may be associated with cognitive decline or white matter hyperintensities (WMH) independently of blood pressure level. We aimed to investigate, using an integrative approach, the relative contributions of structural and functional vascular factors to the degree of cognitive impairment (primary outcome) and the severity of WMH (secondary outcome) in elderly hypertensive patients with subjective memory complaints, a group prone to dementia. A prospective, dedicated, cross-sectional population of 198 elderly hypertensive patients (mean age 69.3+/-6.2 years) with subjective memory complaints underwent a full set of cognitive function assessments, brain MRI with semiquantification of WMH, carotid ultrasonography, carotid-femoral pulse wave velocity, brachial endothelial function, and plasma von Willebrand Factor measurements. After adjustment for the usual cardiovascular risk factors, increased arterial stiffness (as assessed by pulse wave velocity) was significantly and independently associated with memory impairment in men. The severity of WMH was independently associated with increased carotid intima media thickness and stiffness (as assessed by augmentation index) as well as with increased age and plasma levels of von Willebrand Factor, a biomarker of endothelial dysfunction. |
Does toll-like receptor 2/4 heterodimer mediate inflammatory injury in intracerebral hemorrhage? | Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced secondary brain injury. However, the upstream events that initiate inflammatory responses following ICH remain elusive. Our previous studies suggested that Toll-like receptor 4 (TLR4) may be the upstream signal that triggers inflammatory injury in ICH. In addition, recent clinical findings indicated that both TLR2 and TLR4 may participate in ICH-induced brain injury. However, it is unclear how TLR2 functions in ICH-induced inflammatory injury and how TLR2 interacts with TLR4. The role of TLR2 and TLR2/TLR4 heterodimerization in ICH-induced inflammatory injury was investigated in both in vivo and in vitro models of ICH. TLR2 mediated ICH-induced inflammatory injury, which forms a heterodimer with TLR4 in both in vivo and in vitro models of ICH. Hemoglobin (Hb), but not other blood components, triggered inflammatory injury in ICH via assembly of TLR2/TLR4 heterodimers. MyD88 (myeloid differentiation primary response gene 88), but not TRIF (Toll/IR-1 domain-containing adaptor protein inducing interferon-beta), was required for ICH-induced TLR2/TLR4 heterodimerization. Mutation of MyD88 Arg196 abolished the TLR2/TLR4 heterodimerization. | There have been conflicting results from studies to determine whether factors unrelated to endoscopist skill, such as fatigue, affect the quality of screening colonoscopy. We studied the effects of human and system factors on screening colonoscopy withdrawal time and likelihood of detecting an adenoma in a large cohort of patients. We performed a retrospective analysis of operation and quality improvement data in colonoscopies performed at single academic medical center from November 2012 through February 2014. We collected data from the Northwestern Medicine Enterprise Data Warehouse on endoscopy procedure reports, patient demographics, and pathology reports of all patients undergoing endoscopy. We identified all screening colonoscopies during the study period and determined whether an adenoma was identified in each screening colonoscopy procedure. Our study included data from 7004 screening colonoscopies of patients 50-75 years old performed by endoscopists who performed at least 100 screening colonoscopies during the study period (n = 18). Approximately 27% of procedures began on time; the median colonoscope insertion time was 5.9 minutes (interquartile range, 4.0-8.6). In multivariable logistic regression analysis adjusting for covariates and endoscopist-level clustering, adenoma detection was not associated with procedure delay (P = .48), hour of day (P = .40), or performing the second of 2 colonoscopy blocks in 1 day (P = .88). Adenoma detection was associated with insertion time overall (P = .006), but there was no consistent directional relationship across insertion quintiles. |
Are higher maternal serum concentrations of nicotinamide and related metabolites in late pregnancy associated with a lower risk of offspring atopic eczema at age 12 months? | Evidence that atopic eczema partly originates in utero is increasing, with some studies linking the risk of developing the condition with aspects of maternal diet during pregnancy. Nicotinamide, a naturally occurring nutrient that is maintained through the dietary intakes of vitamin B3 and tryptophan, has been used in the treatment of some skin conditions including atopic eczema. To examine the relation of maternal serum concentrations of nicotinamide and related tryptophan metabolites to the risk of atopic eczema in the offspring. Within the UK Southampton Women Survey, infantile atopic eczema at ages 6 and 12 months was ascertained (modified UK Working Party Criteria for the Definition of Atopic Dermatitis). Maternal serum levels of kynurenine, kynurenic acid, anthranilic acid, tryptophan, nicotinamide and N1-methylnicotinamide were measured in late pregnancy by mass spectrometry (n = 497) and related to the odds ratio of infantile atopic eczema. Maternal nicotinamide and related metabolite concentrations were not associated with offspring atopic eczema at age 6 months. Higher concentrations of nicotinamide and anthranilic acid were, however, associated with a lower risk of eczema at age 12 months (odds ratios 0.69, 95% CI 0.53-0.91/SD change, P = 0.007 and 0.63, 0.48-0.83, P = 0.001, respectively). The associations were robust to adjustment for potentially confounding variables. | Advanced ischemic heart failure can be treated with surgical ventricular restoration (SVR). While numerous risk factors for mortality and recurrent heart failure have been identified, no plain predictor for identifying SVR patients with left ventricular damage beyond recovery is yet available. We tested echocardiographic wall motion score index (WMSI) as a predictor for mortality or poor functional result. One hundred and one patients electively operated between April 2002 and April 2007 were included for analysis. All patients had advanced ischemic heart failure (NYHA-class>or=III and LVEF<or=35%). Mean logistic EuroSCORE was 10+/-8. All patients were evaluated at 1-year follow-up. Risk factors for poor outcome, defined as mortality or poor functional result (NYHA class>or=III) at 1-year follow-up were identified by univariable logistic regression analysis. Preoperatively, a 16-segment echocardiographic WMSI was calculated and receiver operating characteristic curve analysis was used to identify cut-off values for WMSI in predicting poor outcome. Early mortality was 9.9%, late mortality 6.6%. NYHA class improved from 3.2+/-0.4 to 1.5+/-0.7. At 1-year follow-up, 10 patients (12%) were in NYHA class III and the remaining patients were in NYHA class I or II (75 patients, 88%). WMSI was found to be the only statistically significant predictor for poor outcome (odds ratio 139, 95% confidence interval (CI) 17-1116, p<0.0001). The optimal cut-off value for WMSI in predicting mortality or poor functional result was 2.19 with a sensitivity and specificity of 82% (95% CI 81.5-82.5% and 81.4-82.6%). The area under the curve was 0.94 (95% CI 0.90-0.99). Positive and negative predictive values were 67% and 92% respectively (95% CI 66.4-67.6% and 91.4-92.6%). |
Do pro-inflammatory cytokine genes influence the clinical features of frontotemporal lobar degeneration? | Recent studies suggested a role for pro-inflammatory mediators in frontotemporal lobar degeneration (FTLD). The objective of this study was to evaluate the association of functionally active polymorphisms in pro-inflammatory cytokine genes with the occurrence and the clinical features of the disease. Using a case-control study, we compared allelic and genotypic frequencies of several polymorphisms in the interleukin (IL)-1alpha, interleukin (IL)-1beta, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha genes between 110 FTLD patients and 119 healthy controls. No significant association between the examined polymorphisms and the disease was found. However, in comparison with remaining genotypes, patients carrying the T/T genotype of the IL-1beta gene showed a significantly lower age at onset of the disease. In addition, scores of the Frontal Assessment Battery were significantly modified by the IL-6 -174G>C polymorphism. | Patient experience is an essential component of quality care. Few studies have comprehensively evaluated patient experiences of abortion care. The objectives of this study were to describe women's experiences of abortion care in their own words, and to determine themes across patient experiences. Data for this thematic analysis, a qualitative method that allows for the identification, analysis, and report of patterns or themes within data, come from a larger study of safety and quality of aspiration abortion care across 22 clinical sites. Participants completed an abortion experience survey including fixed choice questions and an open-ended question: "Is there anything you would like to tell us about your experience?" The data were then categorized by responses to another survey question: "Overall, was your experience about, better, or worse than you expected?" A total of 5,214 responses were analyzed. Women reported positive abortion care experiences with the majority of women rating their experience as better than expected (n = 3,600). Two major themes that emerged from the data include clinic- and patient-level factors that impact how patients rate their experiences. Analysis of the responses categorized in the worse than expected group (n = 136) found that women primarily faulted clinic-level factors for their negative experiences, such as pain control and management, and wait time for appointments and in clinic. |
Does cyclovirobuxinum D suppress lipopolysaccharide-induced inflammatory responses in murine macrophages in vitro by blocking JAK-STAT signaling pathway? | Cyclovirobuxinum D (CVB-D), an alkaloid isolated from the Chinese medicinal plant Buxus microphylla, has been found to be effective to treat cardiac insufficiency, arrhythmias and coronary heart disease. In the present study, we investigated the effects of CVB-D on the inflammatory responses in lipopolysaccharide (LPS)-stimulated murine macrophages in vitro and the underlying mechanisms. Murine macrophage cell line RAW264.7 cells were incubated in the presence of LPS (0.1 μg/mL) for 24 h. The cell viability was measured using MTT assay. The release of NO and cytokines were detected using the Griess test and ELISA, respectively. The mRNA and protein levels were determined using RT-PCR and Western blot, respectively. Reporter gene assays were used to analyze the transcriptional activity of NF-κB. Treatment of RAW264.7 cells with CVB-D (25-300 μmol/L) did not affect the cell viability. Pretreatment with CVB-D (50, 100 and 200 μmol/L) concentration-dependently decreased NO release and iNOS expression in LPS-treated RAW264.7 cells (its IC50 value in inhibition of NO production was 144 μmol/L). CVB-D also concentration-dependently inhibited the secretion and mRNA expression of IL-1β and IL-6 in LPS-treated RAW264.7 cells. Furthermore, CVB-D remarkably inhibited the phosphorylation of STAT1 and STAT3, as well as JAK2 in LPS-treated RAW264.7 cells, but did not affect the activation of NF-κB and MAPKs pathways. Pretreatment with the JAK2 specific inhibitor AG490 (30 μmol/L) produced similar effects on NO release and iNOS expression in LPS-treated RAW264.7 cells. | The normal anterior translation of the articular surface of the distal humerus with respect to the humeral diaphysis facilitates elbow flexion. We hypothesize that there is a correlation between anterior translation of the distal humeral articular surface and flexion after open reduction and internal fixation (ORIF) of a fracture of the distal humerus. Two independent observers evaluated 141 lateral radiographs of patients more than 6 months after fracture of the distal humerus and 155 lateral radiographs of patients without injury of the distal humerus. The distance between the most anterior point of the distal humerus articular surface, perpendicular to the humeral shaft, from the anterior border of the distal part of the humeral diaphysis, was measured on lateral radiographs as a percentage of the width of the humeral shaft. The technique of measuring anterior translation of the distal humeral articular surface had good intra- and interobserver reliability. The most anterior point of the distal humeral articular surface lies an average of 11.7 mm (range, 6.8 to 17.0 mm) in front of the most anterior border of the humeral shaft in normal distal humeri, which represents 62% of the humeral shaft diameter (range, 33% to 91%). There was a limited but significant correlation between flexion and anterior translation as a percentage of the humeral shaft diameter in distal humeri after fracture that was maintained in multivariable statistical models. |
Does casein glycomacropeptide-derived peptide IPPKKNQDKTE ameliorate high glucose-induced insulin resistance in HepG2 cells via activation of AMPK signaling? | Recently, casein glycomacropeptide (GMP)-derived peptide was found to possess potent antioxidant and anti-inflammatory activities. In this study, the improvement effects and underlying molecular mechanisms of GMP-derived peptide on hepatic insulin resistance were investigated. The peptide IPPKKNQDKTE was identified from GMP papain hydrolysates by LC-ESI-MS/MS. Effects of IPPKKNQDKTE on glucose metabolism and expression levels of the hepatic insulin signaling proteins in high glucose-induced insulin-resistant HepG2 cells were evaluated. Results showed that IPPKKNQDKTE dose-dependently increased glucose uptake and intracellular glycogen in insulin-resistant HepG2 cells without affecting cell viability. IPPKKNQDKTE increased the phosphorylation of Akt and GSK3β and decreased the expression levels of p-GS, G6Pase and PEPCK. These IPPKKNQDKTE-mediated protection effects were reversed by PI3K/Akt inhibitor LY294002, showing the mediatory role of PI3K/Akt. Moreover, treatment with IPPKKNQDKTE reduced IRS-1 Ser307 phosphorylation and increased phosphorylation of AMPK. Knockdown AMPK using siRNA in HepG2 cells increased Ser307 phosphorylation of IRS-1 and reduced Akt phosphorylation in IPPKKNQDKTE-treated insulin-resistant cells. | The introduction of the National Health Service (NHS) Breast Screening Programme has led to a considerable increase in the detection of impalpable breast cancer. Patients with impalpable breast cancer typically undergo oncological resection facilitated either by the insertion of guide wires placed stereo-tactically or through ultra-sound guided skin markings to delineate the extent of a lesion. The need for radiological interventions on the day of surgery adds complexity and introduces the risk that a patient may accidentally transferred to the operating room directly without the image guidance procedure. A case is described of a patient who required a pre-operative ultrasound scan in order to localise an impalpable breast cancer but who was accidentally taken directly to the operating theatre (OR) and anaesthetised without pre-operative intervention. The radiologist was called to the OR and an on-table ultrasound was performed without further consequence. |
Does telomerase prolong the lifespan of normal human ovarian surface epithelial cells without inducing neoplastic phenotype? | The aim of this study was to determine the effects of exogenous expression of the catalytic subunit of telomerase (hTERT) on the lifespan, growth characteristics, and tumorigenicity of normal human ovarian surface epithelial (OSE) cells. Low-passage primary cultures of normal human OSE cells were transfected with hTERT and the resulting cell lines were characterized. The ectopic expression of hTERT stabilized the telomeres of the OSE cultures above 8 kb. The hTERT-transfected OSE cell lines grew beyond the normal lifespan seen in OSE cells and propagated in culture for more than 40 passages before senescing. Moreover, the hTERT-transfected cells demonstrated extensive proliferative capacity as evidenced by their ability to continuously grow even when seeded at low dilutions. The morphologic features and normal differentiation patterns seen in normal OSE cells were likewise retained by the hTERT-transfected cells. In addition, the cultures remained responsive to physiologic concentrations of epidermal growth factor and transforming growth factor-beta. Changes associated with neoplastic transformation like anchorage-independent growth, tumorigencity and karyotypic instability were not observed. | Our goal was to analyze the association of the level of antiphospholipid antibodies (aPLs) with stroke severity and outcome in patients with antiphospholipid syndrome (APS). Observational study included consecutive patients with ischemic stroke younger than 55 years (2007-2012). We analyzed serum levels of aPLs, including anticardiolipin (aCL) antibodies, anti-β2-glycoprotein I antibodies (anti-β2GPI) and antiprothrombin antibodies (aPS/PT) within the first 48 h after admission, and again, in the case of a positive result, at least 12 weeks after the first measurement. Stroke severity was measured by the National Institutes of Health Stroke Scale (NIHSS), and the three-month stroke outcome by the modified Rankin Scale (mRS). Multiple linear regression models were used to analyze the correlation between the aPLs and stroke severity and outcome. Overall 255 stroke patients were included, 22 (8.6%) with APS. Among them, a positive correlation was found between immunoglobulin M (IgM) aCL levels within 48 h and NIHSS (rho = 0.471; p = 0.027), as well as a tendency toward a positive correlation between immunoglobulin G (IgG) anti-β2GPI levels within 48 h and three-month mRS (rho = 0.364; p = 0.096). Multiple linear regression analyses showed a positive correlation between levels of IgM aCL < 48 h and the NIHSS (β-coefficient [standard error; SE] = 0.127 [0.044]), as well as the levels of IgG anti-β2GPIwithin 48 h and the three-month mRS (β-coefficient [SE] = 0.034 [0.011]). |
Are coupling interval dispersion and body mass index independent predictors of idiopathic premature ventricular complex-induced cardiomyopathy? | Patients with frequent premature ventricular complexes (PVCs) might be at risk for the developing or exacerbation of left ventricular (LV) dysfunction. However, some patients with a high-PVC burden do not develop cardiomyopathy, while other patients with low-PVC burden can develop cardiomyopathy. The purpose of this study was to evaluate the positive predictors of idiopathic PVCs-induced cardiomyopathy. We investigated 214 patients undergoing successful ablation of PVCs who had no other causes of cardiomyopathy. We divided the study cohort into 2 groups: ejection fraction (EF) ≥ 50% (normal LV) and EF < 50% (LV dysfunction). We analyzed the clinical characteristics, including the electrocardiogram and findings at electrophysiology study. Among these patients, 51 (24%) had reduced LVEF and 163 (76%) had normal LV function. Patients with LV dysfunction had significantly longer coupling interval (CI) dispersion (maximum-CI-minimum-CI) and had significantly higher PVC burden compared to those with normal LV function (CI-dispersion: 115 ± 25 milliseconds vs. 94 ± 19 milliseconds; P < 0.001; PVC burden: 19% vs. 15%; P = 0.04). Furthermore, patients with LV dysfunction had significantly higher body mass index (BMI) compared to those with normal LV function (BMI > 30 kg/m(2) ; 37% vs. 13%; P = 0.001). Logistic regression analysis showed that CI-dispersion, PVC burden, and BMI (>30 kg/m(2) ) are independent predictors of PVC-induced cardiomyopathy. | The chemokine CCL27 attracts skin-homing T cells. CCL27 production by keratinocytes is enhanced in skin lesions from patients with atopic dermatitis or psoriasis vulgaris. It is suggested that prostaglandin E(2) (PGE(2)) regulates skin inflammation. We examined the in vitro effects of PGE(2) on CCL27 production in human keratinocytes. Keratinocytes were incubated with TNF-alpha in the presence or absence of PGE(2) . CCL27 secretion and mRNA level were analyzed by means of ELISA and RT-PCR, respectively. Nuclear factor kappaB (NF-kappaB)-dependent transcriptional activity was analyzed by using luciferase assays. TNF-alpha increased CCL27 secretion and mRNA levels in parallel to NF-kappaB activity in keratinocytes. NF-kappaB p50 or p65 antisense oligonucleotides suppressed TNF-alpha-induced CCL27 production, indicating the requirement of NF-kappaB for CCL27 production. PGE(2) , EP2, or EP3 agonists reduced TNF-alpha-induced CCL27 secretion and mRNA levels in parallel to NF-kappaB activity and CCL2, CCL5, CXCL8, and CXCL10 mRNA levels. Either EP3-specific or dual EP1-EP2 antagonist partially blocked the inhibitory effects of PGE(2) on CCL27 production and NF-kappaB activity, and the addition of both completely abrogated the inhibition, whereas EP1 or EP4 antagonists were ineffective. Intracellular Ca(2+) chelator BAPTA/AM or cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor H-89 partially blocked the inhibitory effects of PGE(2) on CCL27 production and NF-kappaB activity, and the addition of both completely abrogated the inhibition. PGE(2) or EP3 agonist increased intracellular Ca(2+) concentrations. PGE(2) or EP2 agonist increased intracellular cAMP concentrations. |
Does pLZF regulate Pbx1 transcription and Pbx1-HoxC8 complex leads to androgen-independent prostate cancer proliferation? | Promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor and negative regulator of the cell cycle, has been characterized as a prostatic androgen-responsive gene. DU145 cells show androgen-independent growth and lack PLZF gene expression. We analyzed PLZF-regulating genes by DNA microarray using DU145 cells infected with LacZ- or PLZF-carrying adenoviruses. DNA microarray revealed that Pbx1 is a prominent suppressed gene in PLZF-overexpressing DU145 cells. Androgen receptor (AR)-expressing DU145 cells recovered androgen-dependent PLZF expression and subsequent repression of Pbx1 expression. Immunoprecipitation of Pbx1 in DU145 cells revealed a Pbx1-HoxC8 heterocomplex. siRNAs for Pbx1 and HoxC8 knocked downexpression of each, and this suppressed androgen-independent cell growth. Double knockdown of both Pbx1 and HoxC8 suppressed cell growth much more significantly. | This study was designed to investigate the hepatoprotective effect of an extract from Shinzami, a variety of purple sweet potato, in rats injured by hepatic ischaemia-reperfusion (I/R). Pretreatment with Shinzami extract decreased the aspirate aminotransferase and alanine aminotransferase serum levels in our hepatic I/R rat model. The glutathione level and superoxide dismutase activity level were significantly higher in the rats pretreated with the Shinzami extract compared with the hepatic I/R rats, and the glutathione peroxidase activity level was higher in pretreated rats. The total anthocyanins extracted from Shinzami, however, only increased the superoxide dismutase activity level in the hepatic I/R rats. Rats pretreated with the Shinzami extract or anthocyanins demonstrated attenuated hepatic pathological changes, such as hepatic distortion, haemorrhage, necrosis and inflammatory cell infiltration compared with the hepatic I/R control rats. |
Are we also interested in how fathers feel : a qualitative exploration of child health center nurses ' recognition of postnatal depression in fathers? | To become a parent is an emotionally life-changing experience. Paternal depression during the postnatal period has been associated with emotional and behavioral problems in children. The condition has predominantly been related to mothers, and the recognition of paternal postnatal depression (PND) has been paid less attention to. PND in fathers may be difficult to detect. However, nurses in pediatric services meet a lot of fathers and are in a position to detect a father who is suffering from PND. Therefore, the aim of this study was (a) to explore Child Health Center nurses' experiences of observing depression in fathers during the postnatal period; and (b) to explore hindrances of observing these fathers. A qualitative descriptive study was conducted. Ten nurses were interviewed in 2014. A thematic data analysis was performed and data were analyzed for meaning. Paternal PND was experienced as being vague and difficult to detect. Experiences of fathers with such problems were limited, and it was hard to grasp the health status of the fathers, something which was further complicated when routines were lacking or when gender attitudes influenced the daily work of the nurses. | OLC1 was recently identified to be a potential oncogene. However, the role of OLC1 in human esophageal cell carcinoma (ESCC) is unknown. The aim of this study was therefore to evaluate the expression of OLC1 in human ESCC from normal, premalignant, and malignant lesions, and to clarify the mechanisms by which OLC1 contributes to the progression of ESCC. Two hundred and fourteen paired ESCC specimens, and an independent set from 28 ESCC patients, were used to analyze the correlation between OLC1 expression and the pathological characteristics of tumors using immunohistochemistry. Stable OLC1-overexpressing and OLC1-interfering esophageal cancer cells were established and a series of experimental methods were used to investigate the biological functions and mechanisms of action of OLC1. We showed that OLC1 was overexpressed in 145 of 214 (67.8%) of human ESCC specimens, compared with in only 59 of 214 (27.57%) paired adjacent normal tissues (P<0.001). OLC1 overexpression occurred at a rate of 35% (10/28) at the stage of mild/moderate dysplasia, but was significantly upregulated to 66% (22/33) at the stages of severe dysplasia and in situ carcinoma, while 71% positive staining (22/28) was observed in invasive carcinoma tissues compared with normal tissues (P<0.05). We also provided evidence that OLC1 abnormalities significantly altered the cell proliferation and apoptosis induced by cytotoxic agents. OLC1 overexpression suppressed apoptosis, and was associated with attenuated caspase-3 activation and increased Bcl-2 stability. |
Is knee extensor torque of men with early degrees of osteoarthritis associated with pain , stiffness and function? | Osteoarthritis (OA) is a chronic-degenerative disease. The knee is the most commonly affected joint and the symptoms are generally attributed to quadriceps muscle weakness. However, few studies have evaluated this relationship in a population with early stages of knee OA. To investigate whether a correlation among the knee extensor torque and the three subscales of the WOMAC questionnaire in men with early stages of knee OA exists. Twenty-one men with knee OA grades I or II (according to Kellgren and Lawrence criteria) participated in this study. The concentric and eccentric knee extensor torque were assessed using a Biodex System 3 Pro® isokinetic dynamometer, at a speed of 90º/s. Self-reported symptoms and disability were assessed using the WOMAC questionnaire. Spearman's correlation coefficient was used to test the relationship between the dependent variables (three subscales of WOMAC questionnaire) and the independent variables (average knee extensor peak torque). We found a strong negative correlation between the concentric extensor torque and pain (r=-0.7, p<0.001) and a moderate and negative correlation among the concentric extensor torque and stiffness (r=-0.62, p=0.002) and physical function (r=-0.54, p=0.011). Eccentric extensor torque presented a moderate and negative correlation with the three subscales of the WOMAC (r=-0.40 to 0.69, p<0.05). | The p16 gene is one of the tumor suppressor genes, and its inactivation results in abnormal regulation of the cell cycle in human neoplasms. Promoter hypermethylation, a mechanism of p16 gene inactivation, has been reported to play an important role in tumorigenesis and to be related to patient prognosis in several carcinomas. To determine the role of the p16 gene in extrahepatic bile duct (EBD) carcinomas. We examined promoter hypermethylation of the p16 gene using a methylation-specific polymerase chain reaction and the expression of the p16 protein using an immunohistochemical staining method in 90 cases of EBD carcinomas. We then compared the data with various clinicopathologic parameters, including survival rate. Promoter hypermethylation was observed in 69 (77%) of the 90 cases. Of 69 hypermethylated cases, 32 (46%) demonstrated loss of p16 expression. Promoter hypermethylation of the p16 gene was more commonly observed in tumors with vascular invasion (22 [92%] of 24 cases) than without vascular invasion (71%, P = .03). Furthermore, p16 promoter hypermethylation with loss of p16 expression was more frequently observed in cases with lymph node metastasis (P = .006) and higher tumor stage group (P = .04). However, there was no significant difference in survival rate according to the status of p16 promoter methylation and/or p16 expression. |
Is amifampridine phosphate ( Firdapse ( ® ) ) effective and safe in a phase 3 clinical trial in LEMS? | We evaluated the efficacy and safety of amifampridine phosphate (Firdapse(®)) for symptomatic treatment in Lambert-Eaton myasthenic syndrome (LEMS). Phase 3, randomized, double-blind, study. Patients were treated initially with amifampridine phosphate for 7-91 days, followed by randomization to continue amifampridine phosphate for 14 days or placebo (7-day taper, 7-day placebo). The primary efficacy endpoints were changes from baseline at day 14 in Quantitative Myasthenia Gravis and Subject Global Impression scores. The coprimary efficacy end points and 1 of the secondary efficacy end points were met, showing a significant benefit of aminfampridine phosphate over placebo at Day 14. All 5 primary, secondary, and tertiary endpoints achieved statistical significance at Day 8. Amifampridine phosphate was well tolerated; the most common adverse events were oral and digital paresthesias, nausea, and headache. | Metastasis is a primary cause of colorectal cancer (CRC)-related death, and cancer stem cells (CSCs) are thought to be majorly responsible for initiating metastatic behaviors. Doublecortin-like kinase 1 (DCLK1) was recently discovered to be a marker for gastrointestinal CSCs. Here, we aimed to explore whether DCLK1 is associated with CRC metastasis through clinical and in vitro investigations. The expression levels of DCLK1 mRNA and protein in human CRC tissues were analyzed through quantitative RT-PCR and immunohistochemistry staining, respectively. Human CRC cell line SW480 was selected to explore the effect of DCLK1 overexpression on cell migration and invasion. Besides, the associations between DCLK1 and epithelial-mesenchymal transition (EMT) were determined. Compared to normal colorectal tissues, DCLK1 expression was significantly up-regulated in human CRC tissues and correlated well with high lymphatic metastasis and poor prognosis in patients. DCLK1 expression was inversely associated with overall survival in CRC patients. Overexpression of DCLK1 in SW480 cells markedly promoted cell migration and invasion. Furthermore, we validated that DCLK1 could facilitate EMT in cancer cells by up-regulation of the mesenchymal markers Vimentin and ZEB1 and down-regulation of the epithelial marker E-cadherin in SW480 cells. |
Are red-blood-cell to plasma ratios transfused during massive transfusion associated with mortality in severe multiple injury : a retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie? | To test whether an acute transfusion practice of packed red blood cells (pRBC) : fresh-frozen plasma (FFP) 1 : 1 would be associated with reduced mortality in acute bleeding multiply injury. Retrospective analysis using the TR-DGU database (Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie 2002-2006) on primary admissions with substantial injury (Injury Severity Score > 16) and massive transfusion (> 10 pRBCs). Seven hundred thirteen patients were divided into three groups according to the pRBC : FFP ratio transfused, that is, (i) pRBC : FFP > 1.1; (ii) pRBC : FFP 0.9-1.1 (1 : 1); and (iii) pRBC : FFP < 0.9, and mortality rates were compared. Four hundred ninety-seven (69.7%) of patients were male, the mean age was 40.1 (+/- 18.3) years. Injury characteristics and pathophysiological state upon emergency room arrival were comparable between groups. Out of 713, 484 patients had undergone massive transfusion with pRBC : FFP > 1.1, 114 with pRBC : FFP 0.9-1.1 (1 : 1), and 115 with pRBC : FFP < 0.9 ratios. Acute mortality (< 6 h) rates for pRBC : FFP > 1.1, pRBC : FFP 0.9-1.1 (1 : 1), and pRBC : FFP < 0.9 ratios were 24.6, 9.6 and 3.5% (P < 0.0001), 24-h mortality rates were 32.6, 16.7 and 11.3% (P < 0.0001), and 30-day mortality rates were 45.5, 35.1 and 24.3% (P < 0.001). The frequency for septic complications and organ failure was higher in the pRBC : FFP 0.9-1.1 (1 : 1) group, ventilator days and length of stays for intensive care unit and overall in-hospital were highest in the pRBC : FFP < 0.9 ratio group (P < 0.0005). | Anxiety is a common non-motor symptom among patients with Parkinson's disease (PD). Although the etiology of anxiety in PD is likely to be multifactorial, a dysfunction in the dopaminergic system might be implicated in its pathogenesis. The aim of our study was to investigate a possible dopaminergic mechanism involved in anxiety in newly diagnosed never-medicated PD patients using SPECT and ¹²³I-FP-CIT as the dopamine transporter ligand. Thirty-four newly diagnosed, untreated PD patients with asymmetric motor symptoms were included in the study: 17 patients with right- and 17 with left-motor onset, matched for age, disease duration and motor disability constituted the group. They were all evaluated for anxiety and depression and underwent an SPECT with ¹²³I-FP-CIT. Dopamine transporter (DAT) availability values for right and left caudate and putamen were calculated and compared between patients with and without anxiety. Regression analyses were also performed in order to correlate DAT availability with the severity of the anxiety symptoms. Comparison between PD patients with and those without anxiety revealed significant differences of DAT availability in all the examined regions except the right putamen. In the group of patients considered as a whole, a significant correlation was found between increased anxiety severity and decreased DAT availability in right caudate. |
Does double-Stranded RNA interact With Toll-Like Receptor 3 in Driving the Acute Inflammatory Response Following Lung Contusion? | Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. We set to determine the role of toll-like receptor 3 and the binding of double-stranded RNA in the pathogenesis of sterile injury following lung contusion. Toll-like receptor 3 expression was analyzed in postmortem lung samples from patients with lung contusion. Unilateral lung contusion was induced in toll-like receptor 3 (-/-), TIR-domain-containing adapter-inducing interferon-β (-/-), and wild-type mice. Subsequently, lung injury and inflammation were evaluated. Apoptotic indices, phagocytic activity, and phenotypic characterization of the macrophages were determined. Double-stranded RNA in bronchoalveolar lavage and serum samples following lung contusion was measured. A toll-like receptor 3/double-stranded RNA ligand inhibitor was injected into wild-type mice prior to lung contusion. Toll-like receptor 3 expression was higher in patients and wild-type mice with lung contusion. The degree of lung injury, inflammation, and macrophage apoptosis was reduced in toll-like receptor 3 (-/-), TIR-domain-containing adapter-inducing interferon-β (-/-), and wild-type mice with toll-like receptor 3 antibody neutralization. Alveolar macrophages from toll-like receptor 3 (-/-) mice had a lower early apoptotic index, a predominant M2 phenotype and increased surface translocation of toll-like receptor 3 from the endosome to the surface. When compared with viral activation pathways, lung injury in lung contusion demonstrated increased p38 mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 phosphorylation with inflammasome activation without a corresponding increase in nuclear factor-κB or type-1 interferon production. Additionally, pretreatment with toll-like receptor 3/double-stranded RNA ligand inhibitor led to a reduction in injury, inflammation, and macrophage apoptosis. | Within pediatric diabetes management, two electronic measures of adherence exist: frequency of daily blood glucose monitoring (BGM) and the BOLUS score, a measure of frequency of mealtime insulin bolusing. Past research has demonstrated that the BOLUS score is superior to daily BGM in predicting youths' glycated hemoglobin (HbA1c) in a cross-sectional study. We present data comparing the two adherence measures in predicting HbA1c using a prospective, longitudinal design. Blood glucose meter data and insulin pump records were collected from a clinical database of 175 youths with type 1 diabetes (mean age, 11.7 ± 3.6 years at baseline). Youths' HbA1c levels occurring at the download time and at 3, 6, 9, and 12 months post-downloads were also collected. We calculated youths' mean BGM and BOLUS score using a standardized protocol. Intraclass correlations (ICCs) revealed significant absolute equivalence between youths' predicted HbA1c values using BOLUS and BGM scores and future actual HbA1c values up to 12 months post-download. However, the ICCs of BOLUS scores with future HbA1c values were consistently higher than those of the BGM scores. Also, the predictions of the BOLUS scores were significantly more accurate (P ≤ 0.002) than those of the BGM scores based on the root mean squared error of predictions. |
Does precessation treatment with nicotine patch significantly increase abstinence rates relative to conventional treatment? | Previous studies have reported that smoking abstinence rates are increased when nicotine skin patch treatment is initiated prior to the target quit smoking date, as compared with conventional treatment beginning on the quit date. We hypothesized that smoking in the presence of continuous levels of nicotine would attenuate the reinforcing effects of cigarette smoking and lead to a decline in dependence on inhaled nicotine, thus facilitating cessation. This study involved four groups of smokers (n = 100 per group) who received either nicotine patch (21 mg/24 hr) or placebo patch treatment for 2 weeks before the quit smoking date, and during this period, smoked their usual brands of cigarettes or switched to low-tar and nicotine cigarettes: a 2 (nicotine patch) x 2 (cigarette type) factorial design. From the quit date on, all groups received standard nicotine patch treatment, consisting of 6 weeks of 21 mg/24 hr, 2 weeks of 14 mg/24 hr, and 2 weeks of 7 mg/24 hr. Abstinence was defined as self-report of no smoking from the quit date on, confirmed by expired-air carbon monoxide. Continuous abstinence rates were approximately doubled by precessation nicotine patch treatment. The treatment mainly benefited smokers with lower levels of dependence, based on Fagerström Test for Nicotine Dependence score. All treatments were well tolerated. | Congenital cytomegalovirus (cCMV) infection can result in poor outcomes including cerebral palsy (CP). The aim of this study was to describe the incidence and comorbidities of CP reported to the Australian Cerebral Palsy Register (ACPR) as attributed to cCMV infection. This was a retrospective population-based study. Cases were drawn from Australian state CP registers with population level ascertainment, 1993 to 2003 (n=2265; 56.4% males, Gross Motor Function Classification System [GMFCS] ratings available for Victorian cases only: 70% GMFCS levels I to III and 30% GMFCS levels IV to V). Clinical data were extracted and cases with cCMV reported as a known cause were compared with cases where cCMV was not reported. Children with cCMV (n=34; 12 males, 22 females; mean [SD] gestational age, 36.4 wk [4.4], range 24-41 wk) accounted for 1.5% of CP cases; 2.9 per 100,000 live births, (95% confidence intervals 1.9-3.9). When compared with CP cases where cCMV was not reported, proportionally, more CP cases with cCMV were born to younger mothers (p<0.001), were female (64% vs 43%, p=0.014), had spastic quadriplegia (73% vs 21%, p<0.001), required wheeled mobility i.e. GMFCS IV or V (78% vs 28%, p<0.001), had epilepsy (70% vs 30%, p<0.001), deafness (40% vs 2%, p<0.001), functional blindness (20% vs 5%, p<0.001), and severe communication impairment (71% vs 25%, p<0.001). |
Is phytanic acid accumulation associated with conduction delay and sudden cardiac death in sterol carrier protein-2/sterol carrier protein-x deficient mice? | The sterol carrier protein-2 gene encodes two functionally distinct proteins: sterol carrier protein-2 (SCP2, a peroxisomal lipid carrier) and sterol carrier protein-x (SCPx, a peroxisomal thiolase known as peroxisomal thiolase-2), which is involved in peroxisomal metabolism of bile acids and branched-chain fatty acids. We show in this study that mice deficient in SCP2 and SCPx (SCP2null) develop a cardiac phenotype leading to a high sudden cardiac death rate if mice are maintained on diets enriched for phytol (a metabolic precursor of branched-chain fatty acids). In 210 surface and 305 telemetric ECGs recorded in wild-type (C57BL/6; wt; n = 40) and SCP2 null mice (n = 40), no difference was observed at baseline. However, on diet, cycle lengths were prolonged in SCP2 null mice (262.9 +/- 190 vs 146.3 +/- 43 msec), AV conduction was prolonged (58.3 +/- 17 vs 42.6 +/- 4 ms), and QRS complexes were wider (19.1 +/- 5 vs 14.0 +/- 4 ms). In 11 gene-targeted Langendorff-perfused hearts isolated from SCP2 null mice after dietary challenge, complete AV blocks (n = 5/11) or impaired AV conduction (Wenckebach point 132 +/- 27 vs 92 +/- 10 msec; P < 0.05) could be confirmed. Monophasic action potentials were not different between the two genotypes. Left ventricular function studied by echocardiography was similar in both strains. Phytanic acid but not pristanic acid accumulated in the phospholipid fraction of myocardial membranes isolated from SCP2 null mice. | Our purpose was to investigate whether conization for cervical intraepithelial neoplasia eliminates human papillomavirus deoxyribonucleic acid and effects the levels of serum and cervical mucus antibodies against human papillomavirus antigens. Analysis of paired cervical brush and serum samples taken from 23 women with cervical intraepithelial neoplasia before and 16 to 27 months after conization was performed for presence of human papillomavirus deoxyribonucleic acid by polymerase chain reaction and for human papillomavirus antibodies by enzyme-linked immunosorbent assay. Four women had recurrent cervical intraepithelial neoplasia, whereas 19 women were disease free. Eighteen of 23 women were positive for human papillomavirus deoxyribonucleic acid before treatment. At follow-up only the 4 women with recurrent cervical intraepithelial neoplasia were positive. Serum immunoglobulin G levels and A levels and immunoglobulin A levels in cervical mucus against most of the tested human papillomavirus antigens had declined at follow-up. |
Does ethanol washing attenuate the hypocholesterolemic potential of soy protein? | A feeding study in rats investigated the principal active component for the hypocholesterolemic effect of soy protein isolate (SPI) by comparing the effect before and after ethanol washing. Five-week-old male Sprague-Dawley rats were fed cholesterol-enriched AIN-93G diets containing 20% casein (CAS), 20% SPI, 20% ethanol-washed SPI (EWS), 18.4% EWS plus 1.6% ethanol extract (EE), or 20% CAS plus 1.6% EE for 2 wk. Plasma cholesterol concentrations in rats fed EWS and SPI were comparable and were significantly lower than those in rats fed CAS. The addition of EE to EWS and CAS did not influence plasma cholesterol level. Fecal steroid excretion of the three SPI groups was higher than that of the two CAS groups. The addition of EE to EWS and CAS showed a tendency to increase acidic steroid and decrease neutral steroid. | Elevated arterial PCO2 (hypercapnia) is a known risk in diving with closed circuit breathing apparatus. In a retrospective study, we determined CO2 retention and the ability to detect CO2 in novice divers who were either CO2-recognition-trained subjects (TS) or untrained subjects (UTS). Ventilatory and perceptual responses to variations in inspired CO2 (range 0-5.6 kPa, 0-42 mm Hg) during moderate exercise were assessed in novice Israeli Navy divers on active duty. Tests were carried out on 231 TS and 213 UTS. The minimal mean inspired PCO2 that could be detected was 4.8 +/- 1.6 kPa (36 +/- 12 mm Hg) in UTS and 2.9 +/- 0.7 kPa (22 +/- 5 mm Hg) in TS (p < 0.0001). No significant changes were found in PETCO2 between the two groups during exposure to a PICO2 of 5.6 kPa (42 mm Hg). There were 46 TS who were found to be CO2 retainers (more than +1 SD above the mean) and 19 were classified as poor detectors (more than +1 SD above the mean). Seven subjects exhibited both traits. During actual oxygen diving performed later by this group, the only four cases of CNS-oxygen toxicity were among those seven subjects (p < 0.01). |
Do biomechanics of halo-vest and dens screw fixation for type II odontoid fracture? | An in vitro biomechanical study of halo-vest and odontoid screw fixation of Type II dens fracture. The objective were to determine upper cervical spine instability due to simulated dens fracture and investigate stability provided by the halo-vest and odontoid screw, applied individually and combined. Previous studies have evaluated posterior fixation techniques for stabilizing dens fracture. No previous biomechanical study has investigated the halo-vest and odontoid screw for stabilizing dens fracture. A biofidelic skull-neck-thorax model was used with 5 osteoligamentous whole cervical spine specimens. Three-dimensional flexibility tests were performed on the specimens while intact, following simulated dens fracture, and following application of the halo-vest alone, odontoid screw alone, and halo-vest and screw combined. Average total neutral zone and total ranges of motion at C0/1 and C1/2 were computed for each experimental condition and statistically compared with physiologic motion limits, obtained from the intact flexibility test. Significance was set at P < 0.05 with a trend toward significance at P < 0.1. Type II dens fracture caused trends toward increased sagittal neutral zone and lateral bending range of motion at C1/2. Spinal motions with the dens screw alone could not be differentiated from physiologic limits. Significant reductions in motion were observed at C0/1 and C1/2 in flexion-extension and axial rotation due to the halo-vest, applied individually or combined with the dens screw. At C1/2, the halo-vest combined with the dens screw generally allowed the smallest average percentages of intact motion: 3% in axial rotation, 17% in flexion-extension, and 18% in lateral bending. | Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with poor survival rates. Fast detection of PDAC appears to be the most relevant strategy to improve the long-term survival of patients. Our objective was to identify new markers in peripheral blood that differentiates between PDAC patients and healthy controls. Peripheral blood samples from PDAC patients (n = 18) and controls (n = 18) were analyzed by whole genome cDNA microarray hybridization. The most relevant genes were validated by quantitative real-time PCR (RT-qPCR) in the same set of samples. Finally, our gene prediction set was tested in a blinded set of new peripheral blood samples (n = 30). Microarray studies identified 87 genes differentially expressed in peripheral blood samples from PDAC patients. Four of these genes were selected for analysis by RT-qPCR, which confirmed the previously observed changes. In our blinded validation study, the combination of CLEC4D and IRAK3 predicted the diagnosis of PDAC with 93 % accuracy, with a sensitivity of 86 % and specificity of 100 %. |
Is the protein expression profile of meningioma cells associated with distinct cytogenetic tumour subgroups? | Limited information exists about the impact of cytogenetic alterations on the protein expression profiles of individual meningioma cells and their association with the clinicohistopathological characteristics of the disease. The aim of this study is to investigate the potential association between the immunophenotypic profile of single meningioma cells and the most relevant features of the tumour. Multiparameter flow cytometry (MFC) was used to evaluate the immunophenotypic profile of tumour cells (n = 51 patients) and the Affymetrix U133A chip was applied for the analysis of the gene expression profile (n = 40) of meningioma samples, cytogenetically characterized by interphase fluorescence in situ hybridization. Overall, a close association between the pattern of protein expression and the cytogenetic profile of tumour cells was found. Thus, diploid tumours displayed higher levels of expression of the CD55 complement regulatory protein, tumours carrying isolated monosomy 22/del(22q) showed greater levels of bcl2 and PDGFRβ and meningiomas carrying complex karyotypes displayed a greater proliferation index and decreased expression of the CD13 ectoenzyme, the CD9 and CD81 tetraspanins, and the Her2/neu growth factor receptor. From the clinical point of view, higher expression of CD53 and CD44 was associated with a poorer outcome. | This study investigated whether hyperbaric oxygen therapy (HBOT) improves recovery after exercise-induced muscle injury. Healthy male subjects (N = 24) were randomly assigned to either a placebo group or a HBOT group. Subjects were tested for maximal isometric strength (preexercise) of their right elbow flexors. Each subject then completed a high-force eccentric workout of the elbow flexor muscle group to induce delayed onset muscle soreness (DOMS). On the seven successive days after this workout, the subjects were exposed to a hyperbaric environment of 2.5 ATA for 60 min, inspiring either a normoxic mixture (P(I)O2 = 0.2 ATA; placebo group) or a hyperoxic gas mixture (P(I)O2 = 2.5 ATA; HBOT group). Before the eccentric workout and daily for the next 10 d, measurements were obtained regarding: maximal isometric muscle strength of the elbow flexor muscles, right upper arm circumferences, and rating of the perceived muscle soreness. Isometric strength decreased significantly from preexercise levels of 25.1 +/- 3.8 kp to postexercise levels of 12.0 +/- 4.6 kp, for the HBOT group, and from 24.6 +/- 3.4 kp to 12.5 +/- 3.7 kp, respectively, for the placebo group. Over the 10-d recovery period, there was no difference in the rate of recovery of muscle strength between the two groups. Perceived soreness peaked at about 48 h after exercise with no difference between groups. Also, the exercise-induced increases in arm circumference were similar in the two groups. |
Does provision of a soy-based intravenous lipid emulsion at 1 g/kg/d prevent cholestasis in neonates? | One of the most common and severe complications of long-term parenteral nutrition (PN) is PN-associated cholestasis. The soybean oil-based lipid emulsion administered with PN has been associated with cholestasis, leading to an interest in lipid reduction strategies. The purpose of this study was to determine whether the provision of a soybean oil-based lipid emulsion at 1 g/kg/d compared with 2-3 g/kg/d is associated with a reduced incidence of cholestasis. Retrospective review of neonates admitted between 2007 and 2011 with a gastrointestinal condition necessitating ≥ 21 days of PN support. Neonates were divided into 2 groups based on the intravenous lipid emulsion dose: 1-g group (1 g/kg/d) and 2- to 3-g group (2-3 g/kg/d). The primary outcome measure was the incidence of cholestasis. Sixty-one patients met inclusion criteria (n = 29, 1-g group; n = 32, 2- to 3-g group). The 2 groups did not differ in any baseline characteristics other than associated comorbidities that were more common in the 2- to 3-g group. The duration of PN, the number of operative procedures and bloodstream infections, and enteral nutrition (EN) were similar between groups. The incidence of cholestasis was not different between groups (51.7%, 1-g group; 43.8%, 2- to 3-g group; P = .61), and there was no difference between groups in the time to cholestasis (32.6 ± 24.1 days, 1-g group; 27.7 ± 10.6 days, 2- to 3-g group; P = .48). Overall, 44.8% of patients with cholestasis were transitioned to full EN, and 55.2% were transitioned to a fish oil-based lipid emulsion after which the direct bilirubin normalized in all patients. | To evaluate the expression of CXCR4, its ligand SDF-1, β-catenin and E-cadherin throughout the local tumor microenvironment of prostate cancer. A total of 64 prostate cancer specimens, 24 frozen and 40 paraffin-embedded sections, were obtained from patients treated with radical prostatectomy for clinically localized cancer. Real-time RT-PCR was used for mRNA quantification of CXCR4 and SDF-1 in the tumor center (T), tumor front (F) and distant peritumoral tissue (D). Immunohistochemical analysis was used to investigate the expression patterns of CXCR4, E-cadherin and β-catenin. Clinical records of these patients were studied for follow-up data, and the prognostic value of these molecules' expression was statistically assessed. CXCR4 mRNA and protein were significantly increased at the tumor front as compared to distant tissue or tumor center. In comparison, SDF-1 mRNA level gradually increased from the tumor center to the distant peritumoral tissue. High CXCR4 at the tumor front was associated with high Gleason score. Low SDF-1 at the tumor front was associated with locally advanced cancer and disease recurrence. Moreover, high CXCR4 staining at the tumor front and increased cytosolic E-cadherin expression in the same location was associated with locally advanced disease. |
Does terminalia arjuna reverse impaired endothelial function in chronic smokers? | Smoking, largely through increased oxidative stress, causes endothelial dysfunction which is an early key event in atherosclerosis. Smoking cessation and antioxidant vitamin therapy are shown to have beneficial role by restoring altered endothelial physiology. The present study was aimed to determine whether Terminalia arjuna, an Indian medicinal plant with potent antioxidant constituents, would improve endothelial dysfunction in smokers. Eighteen healthy male smokers (age 28.16+/-9.45 years) and equal number of age-matched non-smoker controls participated in the study. The baseline brachial artery reactivity studies were performed using high frequency ultrasound according to standard protocol under identical conditions to determine endothelium-dependent, flow-mediated dilation and endothelium-independent nitroglycerine-mediated dilation. The two groups were matched regarding age, body mass index, blood pressure, serum cholesterol, mean resting vessel diameters and post-occlusion flow velocities (all p=NS). While flow-mediated dilation was significantly impaired amongst smokers compared to controls (4.71+/-2.22 v. 11.75+/-5.94%, p <0.005), the nitroglycerine-mediated dilation was similar in the two groups (20.35+/-3.89 v. 19.68+/-3.74%, p=NS). Subsequently the smokers were given Terminalia arjuna (500 mg q8h) or matching placebo randomly in a double blind cross-over design for two weeks each, followed by repetition of brachial artery reactivity studies to determine various parameters including flow-mediated dilation after each period. There was no significant difference as regards vessel diameter and flow velocities between the two therapies. However, the flow-mediated dilation showed significant improvement from baseline values after Terrminalia arjuna therapy but not with placebo (9.31+/-3.74 v. 5.17+/-2.42%, p <0.005). | To construct phage display library of anti-chymopapain scFv. V(H) and V(L) gene repertoires were amplified from splenocyte mRNA by RT-PCR and joined by a (Gly(4)ser)3 linker to obtain scFv genes. The scFv genes were then cloned into phagemid pFAB5C to construct phage display library. Affinity selection and ELISA were used to identify specific phage antibody to chymopapain. After 4 rounds of panning, high affinity scFv was obtained. |
Does porphyromonas gingivalis-induced autophagy suppress cell proliferation through G1 arrest in oral cancer cells? | We investigated the response of oral cancer cells to intracellular invasion of Porphyromonas gingivalis to define changes in the biological characteristics of oral cancer cells evoked by the presence of oral pathogenic bacteria within a tumour microenvironment. The proliferative activity, cell cycle, and autophagic response were evaluated in oral cancer cells infected with P. gingivalis 381. ROS generation was detected in these cells by DCFDA assay, and its role in the responses of oral cancer cells to P. gingivalis infection was further investigated. P. gingivalis inhibited proliferation of oral cancer cells by inducing G1 cell cycle arrest, but had no effect on apoptosis. Following infection with P. gingivalis, the expression of cyclin D1 and cdk4 was decreased in oral cancer cells, whereas p21, a Cdk inhibitor, was upregulated, in comparison with non-infected controls. Autophagy was prominently enhanced in these infected cells, presumably contributing to the suppressed proliferation. Further experiments revealed that such autophagic response was activated by the formation of reactive oxygen species, as evidenced by the lack of autophagic response and cell proliferation upon removal of reactive oxygen species. | Glucocorticoid receptor (GR) polymorphisms modulate glucocorticoid (GC) sensitivity and are associated with altered metabolic profiles. To evaluate the presence of GR polymorphisms (BclI (rs41423247), N363S (rs56149945), ER22/23EK (rs6189/rs6190), and 9β (rs6198) and investigate their associations with metabolic alterations in patients in long-term remission of Cushing's syndrome (CS). Cross-sectional case-control study. Sixty patients in long-term remission of CS were genotyped. Associations between GR polymorphisms and multiple vascular, body composition and metabolic parameters were investigated. Allelic frequencies of the polymorphisms and their associations with several cardiometabolic risk factors. This study shows that carriers of the 9β polymorphism have a higher systolic blood pressure and lower resistin levels. The GC sensitizing BclI polymorphism is associated with an adverse cardiometabolic risk factor profile: higher fat percentages of extremities and legs, higher serum leptin and E-selectin levels, and higher intima media thickness in carriers versus non-carriers. |
Does [ Suppression of WWOX gene by RNA interference reverse platinum resistance acquired in SKOV3/SB cells ]? | To assess the suppression effect on WWOX gene in SKOV3/SB cell line by small interference RNA (siRNA). Transfection of siRNA using lipofectamine 2000 was conducted to silence WWOX gene expression, the expression levels of WWOX mRNA and protein were evaluated, and the effects on the cell cycles at 48 hours of transfection were assessed by RT-PCR, western blot and flow cytometry (FCM) respectively. The cisplatin resistance index was assayed after transfection of SKOV3/SB with siRNA by methyl thiazolyl tetrazolium (MTT) and the cisplatin concentration of SKOV3/SB cells transfected with siRNA of WWOX was measured by high performance liquid chromatography. (1) In SKOV3/SB cells transfected with WWOX interference fragment, whether at the mRNA or protein level, the expression of both of WWOX decreased. There was a significant difference (P < 0.05) compared with SKOV3 cells and non-transfected cells. (2) After transfection of the WWOX interference fragment, the index of platinum resistance of SKOV3/SB decreased from 5.04 to 3.89. (3) The number of cell transfected with the WWOX interference fragment in G(1) phase was increased, while that in S-phase was decreased. (4) The cisplatin concentration of SKOV3/SB cells transfected with the WWOX interference fragment was increased from 9.43 ng/L to 23.45 ng/L compared with SKOV3/SB cells non-transfected with a significant difference (P < 0.05). | In several reports, C3 and C4 have been linked to diabetes and cardiovascular disease (CVD). Here, we investigate this link and the degree of C3 activation in elderly individuals. In this study, C3 and C4 and the activation fragment C3a-desArg were analysed in 1016 subjects aged 70, in which blood pressure, lipid variables and fasting blood glucose were assessed. C3 levels were related to all the investigated classical cardiovascular risk factors and the metabolic syndrome (BMI, waist circumference, fat distribution, blood pressure, blood glucose levels, TG) except total cholesterol and LDL cholesterol in a highly significant fashion (Spearman up to 0,5; P < 0·0001). C4 and C3a-desArg were associated in the same fashion but less significantly, while the ratios C4/C3 or C3a-desArg/C3 were not, indicating that the association was not directly related to complement activation. The levels C3 and to a lesser degree C4 and C3a-desArg were associated particularly with CRP, but also with E-selectin and ICAM-1. In addition, C3 and C4 levels were shown to decline significantly in 15 female subjects enrolled in a weight-reduction programme over 4 months. |
Is variation in mortality among populations higher for pymetrozine than for imidacloprid and spiromesifen in Trialeurodes vaporariorum in greenhouses in Finland? | Insecticide resistance in Trialeurodes vaporariorum W. is unknown in the species' northern distribution range where it inhabits mainly commercial greenhouses. Resistance development in whiteflies feeding on year-round crops in greenhouses is possible owing to the use of chemical treatments to back up biocontrol. The authors tested the response levels to spiromesifen, pymetrozine and imidacloprid in whiteflies collected from seven greenhouses within a 35 km radius in western Finland. All except one (PR) population had LC50 values below the recommended concentrations for the tested compounds. However, some populations showed reduced susceptibility to pymetrozine in comparison with the reference susceptible population. Resistance ratios to pymetrozine were highly variable (resistance ratio 0.5-39.7), even among closely located greenhouses, and higher than those for imidacloprid (resistance ratio 1.05-10.5) and spiromesifen (resistance ratio 0.8-11.5). LC50 values and application frequencies of pymetrozine correlated positively among the sampled populations. | Bone perforation may induce bone marrow cell migration into a collagen sponge onlay implant. This study investigated the efficacy of bone perforation and collagen sponge onlay placement with regard to new bone formation. One hundred sixty femurs of 80 Wistar male rats were used in four groups: bone perforation and sponge (PS) group: after perforating the femur, fibrillar and heat-denatured collagen (FC-HAC) sponges were placed on the femur; sponge (S) group: a FC-HAC sponge was placed directly on the femur without bone perforation; perforation (P) group: femur perforation without collagen sponge placement; and control (C) group: neither bone perforation nor sponge placement was used. Histologic and histomorphometric analyses were performed after the surgery. Numerous osteoblastic and fibroblastic cells were seen during the early repopulation in and at the periphery of the sponge in the PS group. These cells were seen only at the periphery of the sponge in the S group. In the PS group, angiogenesis was noted frequently, and it exhibited significantly greater new bone area compared to the other groups at days 14 and 28. |
Does probenecid interact with the pharmacokinetics of morphine-6-glucuronide in humans? | Evidence obtained from porcine cell cultures and experiments in laboratory animals indicates that transmembrane transporters may play a role in the distribution of the active morphine metabolite morphine-6-glucuronide (M6G). This was evaluated in a study in healthy volunteers. Ten subjects received an intravenous M6G infusion for 30 min at a dosage of 0.5 mg/kg body weight, leading to M6G plasma concentrations approximately two to three times higher than those observed with analgesic morphine doses in subjects with normal kidney function. In a randomized, double-blind, three-way crossover fashion, subjects received 800 mg quinidine for inhibition of P-glycoprotein; 500 mg probenecid for inhibition of other transporters, including organic anion transporter peptide, multidrug resistance-related protein, and organic anion transporter families; or placebo 1 h before the start of M6G administration. Plasma concentrations of M6G and pupil size were measured for 7 h. Probenecid pretreatment resulted in a decrease in the clearance of M6G from 8.3 +/- 1 l/h to 6.7 +/- 1.3 l/h (factor of 0.8; P < 0.05 vs. placebo cotreatment). This was paralleled by an increase by a factor of 1.2 of the area under the miotic effect-versus-time curves (P < 0.05 vs. placebo). In contrast, quinidine pretreatment had no influence on the pharmacokinetics of M6G. | Although the echolucent plaque in carotid stenosis is associated with future ischemic stroke, the predictive value of echogenicity in small and medium size carotid plaques on vascular events has not been thoroughly examined. Thus, we prospectively tested the hypothesis that plaque echogenicity of carotid atheroma can predict the future total cardiovascular events in patients with vascular risk factors. Ultrasound assessment of carotid intima-media complex thickness (IMT) and plaque echogenicity using integrated backscatter (IBS) analysis was performed in 596 patients aged 40 or more, with any history of vascular events or with at least 1 risk factor, who were enrolled between 2001 and 2006 in the Osaka Follow-up Study for Carotid Atherosclerosis, part 2 (OSACA2). We followed the incidence of total cardiovascular events including cerebrovascular events, coronary heart disease (CHD), and peripheral artery disease (PAD) for 6.4 years. We divided the patients into two groups according to the IBS index above (echorich plaques) and under (echolucent plaque) the median value, and calculated the hazard ratios (HR) of the echolucent group compared with the echogenic group in the risk of cardiovascular events. Among 596 patients, carotid stenosis was found only in 87 patients. During the follow-up period, we observed 121 cardiovascular events including 63 cerebrovascular events, 45 CHD cases, and 13 PAD cases. The patients with incident cardiovascular events had larger plaque thickness and lower IBS index than those without incident vascular events. The relative risk of vascular events for echolucent versus echorich plaques was 1.45 (95% confidence interval [CI] 0.99-2.13, p = 0.058) after adjustment for risk factors and plaque thickness. In patients with plaque size above the median value (>2.1 mm), the relative risk of vascular events for echolucent plaques was 1.72 (95% CI 1.06-2.85, p = 0.029), but this association was not observed in patients with plaque size <2.0 mm. |
Do high hepatic glutathione stores alleviate Fas-induced apoptosis in mice? | The agonistic Jo2 anti-Fas antibody reproduces human fulminant hepatitis in mice. We tested the hypothesis that enhancing hepatic glutathione (GSH) stores may prevent Jo2-induced apoptosis. We fed mice with a normal diet or a sulfur amino acid-enriched (SAA(+)) diet increasing hepatic GSH by 63%, and challenged these mice with Jo2. The SAA(+) diet markedly attenuated the Jo2-mediated decrease in hepatic GSH and the increase in the oxidized glutathione (GSSG)/GSH ratio in cytosol and mitochondria. The SAA(+) diet prevented protein kinase Czeta (PKCzeta) and p47(phox) phosphorylations, Yes activation, Fas-tyrosine phosphorylation, Bid truncation, Bax, and cytochrome c translocations, the mitochondrial membrane potential collapse, caspase activation, DNA fragmentation, hepatocyte apoptosis, and mouse lethality after Jo2 administration. The protective effect of the SAA(+) diet was abolished by a small dose of phorone decreasing hepatic GSH back to the levels observed in mice fed the normal diet. Conversely, administration of GSH monoethyl ester after Jo2 administration prevented hepatic GSH depletion and attenuated toxicity in mice fed with the normal diet. | Brain white-matter lesions and cognitive impairment are increasing because of the increasing number of patients aged ≥80 y. Wall shear stress (WSS) plays a pivotal role as a fluid mechanical mediator in vascular reactivity and atherosclerosis. In this study, we investigated the associations among common carotid artery (CCA) WSS, white-matter lesions, and cognitive impairment in patients aged ≥80 y We enrolled 384 patients aged ≥80 y. All subjects had CCA-WSS, brain white-matter hyperintensities (WMH), and Mini-Mental State Examination (MMSE) assessments and were divided into three groups using tertiles of mean and peak CCA-WSS. For groups classified by the tertile of mean CCA-WSS, WMH, and WMH fraction were decreased; the MMSE score increased from low to high in the respective groups. Differences in WMH, WMH fraction, and the MMSE score were significant between any two groups (all adjusted p < 0.001). Groups classified by the tertile of peak CCA-WSS had the same pattern. Mean and peak CCA-WSS were significantly and inversely correlated with WMH (r = -0.575 and -0.570, respectively; p < 0.001) and WMH fraction (r = -0.574 and -0.569, respectively; p < 0.001) but positively correlated with the MMSE score (r = 0.390 and 0.278, respectively; p < 0.001). Multiple linear backward stepwise regression indicated the mean and peak CCA-WSS were significantly and independently associated with WMH, WMH fraction, and the MMSE score (all adjusted p < 0.001). |
Does glutamine depletion by crisantaspase hinder the growth of human hepatocellular carcinoma xenografts? | A subset of human hepatocellular carcinomas (HCC) exhibit mutations of β-catenin gene CTNNB1 and overexpress Glutamine synthetase (GS). The CTNNB1-mutated HCC cell line HepG2 is sensitive to glutamine starvation induced in vitro with the antileukemic drug Crisantaspase and the GS inhibitor methionine-L-sulfoximine (MSO). Immunodeficient mice with subcutaneous xenografts of the CTNNB1-mutated HCC cell lines HepG2 and HC-AFW1 were treated with Crisantaspase and/or MSO, and tumour growth was monitored. At the end of treatment, tumour weight and histology were assessed. Serum and tissue amino acids were determined by HPLC. Gene and protein expression were estimated with RT-PCR and western blot and GS activity with a colorimetric method. mTOR activity was evaluated from the phosphorylation of p70S6K1. Crisantaspase and MSO depleted serum glutamine, lowered glutamine in liver and tumour tissue, and inhibited liver GS activity. HepG2 tumour growth was significantly reduced by either Crisantaspase or MSO, and completely suppressed by the combined treatment. The combined treatment was also effective against xenografts of the HC-AFW1 cell line, which is Crisantaspase resistant in vitro. | Total disc replacement is a novel approach for dynamically stabilizing a painful intervertebral segment. While this approach is gaining popularity, and several types of implants are used, the effect of disc arthroplasty on lumbar biomechanics has not been widely reported. Consequently, beneficial or adverse effects of this procedure may not be fully realized, and data for kinematic optimization are unavailable. To characterize kinematic and load transfer modifications at L5/S1 secondary to joint replacement. A human cadaveric biomechanical study in which the facet forces and instant axes of rotation (IAR) were measured for different spinal positions under simulated weightbearing conditions before and after total disc replacement at L5/S1 using semiconstrained (3 degrees of freedom [DOF]; Prodisc) and unconstrained (5 DOF; Charité) articulated implants. Twelve radiographically normal human cadaveric L5/S1 joints (age range 45-64 years) were tested before and after disc replacement using Prodisc II implants (Spine Solutions, Paoli, PA) in six specimens and SB Charité III (Johnson & Johnson, New Brunswick, NJ) in six other specimens. Semiconstrained fixtures in combination with a servo-hydraulic materials testing system subjected the test specimens to a physiologic combination of compression and anterior shear. Multiple intervertebral positions were studied and included up to 6 degrees of flexion, extension, and lateral bending. The IAR was calculated for every 3-degree intervals, and the force through the facet joints was simultaneously measured using flexible intra-articular sensors. Data were analyzed using repeated-measures analysis of variance. During flexion/extension, the average IAR positions and directions were not significantly modified by implantation with the exception that the IAR was higher relative to S1 end plate with the Charité (p=.028). The IAR had a vertically oriented centrode throughout flexion/extension with the Prodisc (p<.001) and the Charité (p<.016). The centrode tended to be greater with the Prodisc. There was a trend that the facet force was decreased throughout flexion/extension for the Prodisc; however, this was statistically significant only at 6 degrees extension (27%, p=.013). In lateral bending, the IAR was significantly modified by Prodisc replacement, with a decreased inclination relative to S1 end plate, (ie, increased coupled axial rotation). While the IAR moved in the horizontal plane toward the side of bending, this effect was more pronounced with the Prodisc. The ipsilateral facet force was significantly increased in 6 degrees lateral bending with the Charité (85%; p=.001). |
Does intensity of murmurs correlate with severity of valvular regurgitation? | To evaluate the relationship between the intensity of murmurs and severity of mitral and aortic regurgitation. Consecutive patients with chronic isolated aortic (n = 40) or mitral (n = 170) regurgitation undergoing echocardiographic quantitation of regurgitation between 1990 and 1991 were studied. Regurgitant volume and fraction were measured using two simultaneous methods (quantitative Doppler echocardiography and quantitative two-dimensional echocardiography); the intensity of the regurgitant murmur (grade 0 to 6) was noted by physicians unaware of the study. Correlations between murmur intensity and regurgitant volume and fraction were good in aortic regurgitation (r = .60 and r = .67, respectively; P < 0.001) and mitral regurgitation (r = .64 and r = .67, respectively; P < 0.001) but weaker (r = .47 and r = .45, respectively) in the subset of mitral regurgitation of ischemic or functional cause. Murmur intensity grades > or = 3 for aortic regurgitation and > or = 4 for mitral regurgitation predicted severe regurgitation (regurgitant fraction > or = 40%) in 71% and 91% of patients, respectively. Murmur grades < or = 1 for aortic regurgitation and < or = 2 for mitral regurgitation predicted "not severe" regurgitation in 100% and 88% of patients, respectively. Murmur grades 2 for aortic regurgitation and 3 for mitral regurgitation were not correlated to degree of regurgitation. The severity of regurgitation was the most powerful determinant of intensity of murmur. | Human LSECtin (liver and lymph node sinusoidal endothelial cell C-type lectin, CLEC4G) is a C-type lectin encoded within the L-SIGN/DC-SIGN/CD23 gene cluster. LSECtin acts as a pathogen attachment factor for Ebolavirus and the SARS coronavirus, and its expression can be induced by interleukin-4 on monocytes and macrophages. Although reported as a liver and lymph node sinusoidal endothelial cell-specific molecule, LSECtin could be detected in the MUTZ-3 dendritic-like cell line at the messenger RNA (mRNA) and protein level, and immunohistochemistry analysis on human liver revealed its presence in Kupffer cells coexpressing the myeloid marker CD68. The expression of LSECtin in myeloid cells was further corroborated through the analysis of the proximal regulatory region of the human LSECtin gene, whose activity was maximal in LSECtin+ myeloid cells, and which contains a highly conserved PU.1-binding site. PU.1 transactivated the LSECtin regulatory region in collaboration with hematopoietic-restricted transcription factors (Myb, RUNX3), and was found to bind constitutively to the LSECtin proximal promoter. Moreover, knockdown of PU.1 through the use of small interfering RNA led to a decrease in LSECtin mRNA levels in THP-1 and monocyte-derived dendritic cells, thus confirming the involvement of PU.1 in the myeloid expression of the lectin. |
Do cAMP-Epac Pathway Stimulation Modulate Connexin-43 and MicroRNA-21 Expression in Glioma Cells? | Malignant astrocytic gliomas are the most common and lethal brain malignancies due to their refractory to the current therapies. Nowadays, molecular targeted therapy has attracted great attention in treatment of glioma. Connexin 43 (Cx43) and micro ribonucleic acid-21(miR-21) are among molecules that are involved in glioma development and progression. These molecules showed potential to be as target molecules with regard to glioma. Some studies have reported that cyclic adenosine monophosphate (cAMP) signaling could be effective on Cx43 and miR-21 in tissues other than in brain. We investigate possible relationship between β-adrenergic receptor and its newly described downstream, exchange protein directly activated by cAMP (Epac) signaling pathway and expression of Cx43 and miR-21 in low (1321N1) and high grade (U87MG) glioma cell lines. We treated cells with β-adrenergic agonist and Epac activator with and without adenyl cyclase inhibitor. Cx43 and miR-21 expression were measured with real-time PCR. Our data showed that in 1321N1 cells, β-adrenergic-Epac pathway stimulation up and down-regulated Cx43 and miR-21 expression respectively. Whereas, in U87MG cells these interventions had no effect on Cx43 and miR-21 expression. | Detection of smear-positive pulmonary tuberculosis (PTB) cases is vital for tuberculosis (TB) control. Methods to augment sputum collection are available, but their additional benefit is uncertain in resource-limited settings. To compare the diagnostic yields using five methods to obtain sputum from adults diagnosed with smear-negative PTB in Malawi. Self-expectorated sputum was collected under supervision for microscopy and mycobacterial culture in the study laboratory. Confirmed smear-negative patients provided physiotherapy-assisted sputum and induced sputum, followed the next morning by gastric washing and bronchoalveolar lavage (BAL) samples. A total of 150 patients diagnosed with smear-negative PTB by the hospital service were screened; 39 (26%) were smear-positive from supervised self-expectorated sputum examined in the study laboratory. The remaining 111 confirmed smear-negative patients were enrolled in the study; 89% were human immunodeficiency virus positive. Seven additional smear-positive cases were diagnosed using the augmented sputum collection techniques. No differences were observed in the numbers of cases detected using the different methods. Of the 46 smear-positive cases, 44 (95.6%) could be detected from self-expectorated and physiotherapy-assisted samples. |
Does cigarette suppress the expression of P4Halpha and vascular collagen production? | Collagen plays a major role in arterial wall remodeling, aneurysm formation, and atherosclerotic cap stability. Smokers often have weakened arterial walls associating with aneurysm and thinned atherosclerotic plaque caps leading to rupture and acute coronary syndromes. We hypothesize that these detrimental effects on arterial wall by tobacco are partially mediated by disturbed collagen metabolism. We first investigated the effect of cigarette smoke extracts (CSE) on prolyl-4-hydroxylase (P4H) expression and collagen production in human aortic endothelial cells (HAECs) and human coronary artery smooth muscle cells (HCSMCs). After exposure to 0.01-U CSE for 24 h, expression of P4Halpha-a rate limiting subunit of P4H enzyme responsible for the formation of 4-hydroxyproline in mature functional collagen, was significantly down-regulated according to Western blotting and quantitative RT-PCR (HAEC p < 0.01 and HCSMC p < 0.001) when treated by CSE. The decreased P4Halpha expression was corresponded with reduced cellular collagen levels (HAEC p < 0.001 and HCSMC p < 0.001). We also found that one of the cigarette components benzo(a)pyrene exerted similar effect as CSE, but not nicotine or acrolein. We further examined P4H expression in a few human atherosclerotic abdominal aortas. These in vivo data demonstrated that smokers had thinner atherosclerotic cap thickness and lower levels of P4Halpha and collagen. | To identify the risk factors for suboptimal response to GnRH agonist (GnRH-a) trigger and evaluate the effect of hCG on the outcome of patients with suboptimal response to GnRH-a. A retrospective data analysis. A tertiary-care academic medical center. A total of 8,092 women undergoing 8,970 IVF/intracytoplasmic sperm injection (ICSI) treatment cycles. All women underwent hMG + medroxyprogesterone acetate (MPA)/P treatment cycles during IVF/ICSI, which were triggered using a GnRH-a alone or in combination with hCG (1,000, 2,000, or 5,000 IU). Viable embryos were cryopreserved for later transfer. The rates of oocyte retrieval, mature oocytes, fertilization, and the number of oocytes retrieved, mature oocytes, and embryos frozen. In total, 2.71% (243/8,970) of patients exhibited a suboptimal response to GnRH-a. The suboptimal responders (LH ≤15 mIU/mL) had a significantly lower oocyte retrieval rate (48.16% vs. 68.26%), fewer mature oocytes (4.10 vs. 8.29), and fewer frozen embryos (2.32 vs. 3.54) than the appropriate responders. Basal LH levels served as the single most valuable marker for differentiating suboptimal responders with the areas under the receiver operating curve of 0.805. Administering dual trigger (GnRH-a and hCG 1,000, 2,000, 5,000 IU) significantly increased oocyte retrieval rates (60.04% vs. 48.16%; 68.13% vs. 48.16%; and 65.76% vs. 48.16%, respectively) in patients with a suboptimal response. |
Does a cumulative genetic risk score predict progression in Parkinson 's disease? | The contribution of genetic variability to clinical heterogeneity in Parkinson's disease is insufficiently understood. We aimed to investigate the effect of cumulative genetic risk on clinical outcomes. In a single-center study of 336 patients we genotyped 19 independent susceptibility variants identified in genome-wide association studies of Parkinson's disease. We tested for association between a cumulative genetic risk score and 3 outcome measures: survival, time until progression to Hoehn and Yahr stage 3, and Unified Parkinson's Disease Rating Scale motor score severity. Genetic risk score was significantly associated with time from diagnosis to Hoehn and Yahr stage 3 in a Cox regression model (P = 0.010). We observed no clear association for the other outcomes. | To detect the presence of somatostatin (SOM) in normal aqueous humor and to characterize its immunosuppressive activity. Fresh rabbit aqueous humor was assayed for SOM by competitive ELISA. Primed T cells stimulated through their T-cell receptor (TCR) were treated with SOM at concentrations that ranged the level of SOM found in normal aqueous humor. The T cells were assayed for proliferation, lymphokine production, and immunosuppressive activity. Normal rabbit aqueous humor contained 196 +/- 45 pg/mL (10(-10) M) of SOM. At concentrations between 10 and 300 pg/mL, SOM suppressed IFN-gamma production by TCR-stimulated primed T cells in culture. Frozen and thawed aqueous humor depleted of SOM no longer suppressed IFN-gamma production by the TCR-stimulated primed T cells. SOM induced TGF-beta but not IL-4 production, nor did it suppress proliferation by TCR-stimulated primed T cells. The SOM-treated T cells functioned as regulatory T cells, and this regulatory activity was neutralized by anti-alpha-MSH antibodies. Furthermore, SOM induced alpha-MSH production by the TCR-stimulated primed T cells. |
Are older patients still under-represented in clinical trials of Alzheimer 's disease? | The age gap between participants in trials and patients who could benefit from the drugs studied has been widely documented across different clinical areas. Patients with dementia included in clinical research are systematically younger than those in the general population. We examined the age gap between participants in recent clinical trials testing interventions for Alzheimer's disease and epidemiological data. We systematically searched literature databases (MedLine, EMBASE, the Cochrane Library) and ClinicalTrials.gov from 2000 to July 2015 to retrieve clinical trials testing pharmacologic treatments for Alzheimer's disease, other than cholinesterase inhibitors and memantine. We included ongoing and completed phase II/III randomized clinical trials, irrespective of their publication status. From each study reporting the participants' ages, we extracted size of sample, mean age, and standard deviation, and estimated the proportions of participants in different age classes. The number of patients with Alzheimer's disease by age class in the USA population was used for comparison. We included 165 clinical trials testing almost 100 different compounds, which enrolled or planned to enroll about 74,300 participants. Seventy-nine of these trials, accounting for about 26,800 participants, reported the age of the participants. The weighted mean age was 73.6 years (standard deviation, 8.2). People younger than 80 years were highly represented in clinical trials (78 %), despite the fact that those aged 80 and older form the majority (72 %) of patients with Alzheimer's disease. Only 8 % of clinical trial participants were 85 years or older. | Acute scrotum (AS) is a clinical syndrome, in which authors indicate a surgical exploration of the scrotum. We retrospectively analyzed the group of 354 patients in 10 years (1997-2006) to compare the preoperative findings with the diagnosis of surgical exploration. The aim was to actualize diagnostics and therapeutic management. We focused on the age of patients, incidence of nosological units of AS and preoperative and surgical diagnosis. 334 boys were operated on from the whole group - 354 patients. Most frequent incidence of AS was in the age group 8-12 (55%). Torsion of testicular appendix or epididymis is the most frequent cause of AS in our group - 204, 59%. In this group of patients ultrasound confirmed the diagnosis only in 120 patients, 65%. Testicular torsion was managed in 74 boys (30 neonates), in 40 of them we decided, mostly at the second look operation after 48-72 hours, for testicle ablation caused by the organ avitality. In all patients with testicular torsion ultrasound confirmed the diagnosis, 100%. In 10 boys we found testicular tumor. In the group of 334 patients operated on, there were no serious complications. |
Does periodic direct current promote wound closure in an in vitro dynamic model of cell migration? | A prevailing paradigm is that electrical fields can promote cell migration and tissue healing. To further validate this paradigm, we tested the hypothesis that periodic direct current (DC) can enhance wound closure using an in vitro dynamic model of cell migration. Layers of primary fibroblasts were wounded and treated with DC under various voltages. Repair area, cell velocity, and directionality as well as lamellipodium area were evaluated at different times. Direct current had no beneficial effect on cell migration. Moreover, prolonged stimulation under the highest voltage led to significant reduction in wound closure and cell velocity. The reduction of membrane protusions in stimulated cells may be associated with the deleterious effect of DC. | Coronary heart disease is the second cause of death in Chilean women, with higher mortality among women, especially at younger ages. The objective was to analyze in-hospital case-fatality by sex and age in patients with acute myocardial infarction in Chile and to evaluate associated factors. From the nationwide hospital admissions database and the GEMI registry (a multicenter registry), we selected all cases of acute myocardial infarction (code: I.21) that occurred between 2001 and 2007 in Chile. We estimated odds ratios for in-hospital case-fatality in women by age (crude and adjusted for clinical characteristics and treatment). In total, 49,287 cases of acute myocardial infarction were hospitalized, 31.3% of them women; 9278 patients were incorporated in the GEMI registry (27.1% women). In-hospital case-fatality was higher (P<.001) in women than men (national database, 20.4% vs 11.3%; GEMI, 14.2% vs 7.3%, irrespective of age. In-hospital case-fatality risk was higher in women aged<45 years: national odds ratio=2.3 (95% confidence interval, 1.5-3.3) and GEMI, odds ratio=2.7 (1.1-6.8). The estimated risk was lower in women aged 75 or more years in both databases, 1.3 (1.2-2.4) and 1.5 (1.2-1.9), respectively. Younger women less often received statins, odds ratio=0.7 (0.6-0.8); acetylsalicylic acid, odds ratio=0.4 (0.2-0.6); betablockers, odds ratio=0.8 (0.6-0.9), and thrombolytics, odds ratio=0.6 (0.5-0.8). An interaction was found between Killip class and sex. After adjusting for covariates, women aged<55 years with ST-segment elevation myocardial infarction and Killip class I-II, had the highest risk, odds ratio=4.3 (2.1-8.9). |
Does recovery from neuromuscular block in dogs : restoration of spontaneous ventilation exclude residual blockade? | To evaluate if return of spontaneous ventilation to pre-relaxation values indicates complete recovery from neuromuscular blockade. Prospective, with each individual acting as its own control. Ten healthy adult female Beagle dogs weighing 6.2-9.4 kg. Dogs were anesthetized with propofol, dexemedetomidine and isoflurane. Spontaneous ventilation was assessed by measuring end-tidal CO2 , expired tidal volume, peak inspiratory flow, respiratory rate and minute ventilation. Vecuronium 25 μg kg(-1) IV was administered and neuromuscular block was evaluated by measuring the train-of-four (TOF) ratio with acceleromyography in the hind limb. During spontaneous recovery from neuromuscular block, the TOF ratio when each ventilatory variable returned to baseline was recorded. This dose of vecuronium produced moderate neuromuscular block in all dogs, with TOF ratio values of 0-18% at maximal block. Expired tidal volume, peak inspiratory flow and minute ventilation returned to pre-relaxation values when the median TOF ratio was ≤ 20%. The median TOF ratio was 42% when the end-tidal CO2 returned to pre-relaxation values. | Nagashima-type palmoplantar keratosis (NPPK) is a distinct autosomal recessive genodermatosis characterized by diffuse transgressive palmoplantar keratoderma (PPK). Very recently, putative loss-of-function mutations in SERPINB7, which encodes a member of the serine protease inhibitor superfamily and is abundantly expressed in the epidermis, have been identified as a cause of NPPK. To confirm further the role of SERPINB7 mutations in the pathogenesis of NPPK. We analysed 10 Japanese families with NPPK using Sanger and/or whole-exome sequencing. We identified one novel and three recurrent null mutations in SERPINB7. In all the families, the NPPK trait was inherited in an autosomal recessive manner; in one of the families, there was pseudodominant inheritance, which had not been described in NPPK. |
Does ultrasonic cardiac output monitor provide accurate measurement of cardiac output in recipients after liver transplantation? | The ultrasonic cardiac output monitor (USCOM; USCOM Pty. Ltd., Sydney, NSW, Australia) has been accepted as a noninvasive device for measuring cardiac function in various clinical conditions. The present study aimed at comparing the accuracy of this device with that of the thermodilution technique in recipients in the early postoperative period after liver transplantation. Fifteen mechanically ventilated patients were studied on the first postoperative day after liver transplantation. We compared the left-sided and right-sided cardiac output (CO) determined by USCOM with that obtained from the thermodilution technique with a pulmonary artery catheter every 8 hours in the intensive care unit. Each patient received a total of four paired measurements. Bland-Altman analysis was used for bias and precision testing. The CO measured by USCOM and the thermodilution method were considered interchangeable if the limits of agreement lay within +/- 1 L per minute or 20% of the mean CO. Forty-eight paired left-sided CO measurements were obtained from 12 patients. Three patients were excluded due to unacceptable signals. Comparison of these two techniques revealed a bias of 0.13 L per minute and limits of agreement at -0.65 L and 0.92 L per minute. Fifty-six paired right-sided CO measurements were obtained from 14 patients with one patient excluded due to an unobtainable optimal signal. A bias of 0.11 L per minute with limits of agreement at -0.51 L and 0.72 L per minute were found for these two techniques. | Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of growth factors that have been implicated in skin patho-physiology. Although endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) appear to be involved in mitogenesis and chemotaxis in epidermal keratinocytes, the activation of eNOS and VEGF production induced by HB-EGF and its signaling mechanism remains undefined. We examined possible signal transduction pathways by which HB-EGF leads to eNOS activation and VEGF production in human epidermal keratinocyte cell line (HaCaT cells). The phosphorylation of epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK; p42/p44 MAPK), Akt and eNOS were examined by Western blotting analysis. VEGF production was determined by enzyme-linked immunosorbent assay. Various inhibitors were utilized to investigate the signaling mechanisms of eNOS activation and VEGF production. HB-EGF-induced phosphorylation of EGFR with maximum phosphorylation at 1h. HB-EGF-induced phosphorylation of p42/p44 MAPK in a few minutes. It activated Akt with maximum phosphorylation at 1h and eNOS with maximum phosphorylation at 3h. The HB-EGF-induced eNOS activation was significantly blocked by the p42/p44 MAPK inhibitor U0126 and the phosphatidylinositol 3-kinase (P13K) inhibitor LY294002. HB-EGF increased VEGF production. The HB-EGF-induced VEGF production was blocked by U0126 and LY294002. Finally, the HB-EGF-induced activation of Akt and eNOS was suppressed by VEGF competitive antagonist, CBO-P11. |
Does artesunate as an Anti-Cancer Agent Targets Stat-3 and Favorably suppress Hepatocellular Carcinoma? | Aberrant signal transducer and activator of transcription 3 (STAT-3) molecular signaling elicit hepatocellular carcinoma (HCC) in humans. Therefore, targeting STAT-3 is considered as an attractive option towards suppression of HCC in humans. Our objective is to identify a potential small molecule inhibitor that can specifically target STAT-3 and suppress HCC. In this study, we analyze a group of sesquiterpene lactone (STL) candidates that has been recently reported in preclinical trials against cancer by a unified computational and experimental approach. Our virtual analysis of the STL candidates revealed Artesunate (ATS) as the best potential inhibitor of STAT-3 with comparable potency to specific inhibitor S3I-201. We also observed that ATS inhibited IL-6 driven STAT-3-DNA binding activity with comparable potency to S3I-201 in a cell free system. Furthermore ATS was observed to interfere with STAT-3 dimerization and suppression of both constitutive and IL-6 inducible STAT-3 in vitro. Nevertheless, we also observed that ATS modulated STAT-3 dependent targets (procaspase-3, Bcl-xl and survivin) favoring occurrence of apoptosis in vitro. Overall, the putative inhibition of STAT-3 by ATS suggested its capacity to interfere with STAT-3 dimerization by binding to the SH2 domain of STAT-3 monomer. It resulted in suppression of STAT-3 and also favored promotion of in vitro cells towards apoptosis. Consequently, ATS also exhibited selective cytotoxicity of cancer cells over normal cells in vitro. | To investigate the alteration of the retinal nerve fiber thickness (NFLT) before and after vitreous surgery for a macular hole in cases with or without visual field defects. The NFLT of 23 eyes with idiopathic macular hole was measured with scanning laser polarimeter upto 12 months after surgery. The NFLT was divided into superior, inferior, nasal, and temporal quadrants. The mean NFLT of each quadrant was analyzed statistically and compared to the results of visual field tests. In all cases, the NFLT decreased significantly upto 3 months after surgery, but increased gradually upto 12 months. In cases with visual field loss, the thickness of the nerve fiber layer that corresponds to the visual field defect diminished strongly, in contrast with other quadrants. Even in cases without visual field loss, the NFLT decreased significantly a month after surgery, especially in the nasal and inferior quadrants. |
Do insulin resistance/compensatory hyperinsulinemia predict carotid intimal medial thickness in patients with essential hypertension? | Approximately 50% of subjects with essential hypertension (EH) are insulin resistant, and this defect in insulin action could contribute to increased cardiovascular disease (CVD) risk in these patients. To test this hypothesis, we attempted to see if there was a link between insulin resistance (IR) and carotid intimal medial thickness (IMT), an early index of CVD, in patients with essential hypertension. Ultrasound quantification of carotid IMT was performed in 79 hypertensive patients, and 63 patients (31 m and 32 f), defined as being free of plaque (IMT < 1.3 mm), were further subdivided into normal (<1.0 mm) and thickened (1-1.3 mm) IMT groups. Subjects in the thickened IMT group were older and had significantly (p < 0.05) higher plasma concentrations of fasting insulin, nitric oxide (NO(x)) and intercellular adhesion molecule 1 (ICAM-1). However, the two groups were not significantly different in terms of blood pressure, overall or regional obesity, fasting lipid levels, uric acid, concentrations of other cellular adhesion molecules or levels of C-reactive protein. There were significant (p < 0.05) correlations in the whole population between IMT and age, fasting insulin and NO(x), and multiple regression analysis identified fasting insulin as an independent predictor of IMT. | Oesophageal cancer is generally associated with late presentation and poor prognosis. Therefore palliative surgery has been largely superseded by less invasive non-surgical techniques. Once palliation is indicated, the aims of the management should be: the maintenance of oral intake, minimizing hospital stay, relief of pain, elimination of reflux and regurgitation and the prevention of aspiration. This study was a review of all published English language data on the palliation of malignant dysphagia between 1994-1999. The Medline and Bids databases were searched and other references were derived from the material perused. |
Do prophylaxis against heterotopic ossification after elbow and acetabular fractures - Do we really need it? | To compare the efficacy and safety of prophylactic modalities for heterotopic ossification prevention after elbow and acetabular surgeries. The retrospective chart review was conducted at the Aga Khan University Hospital and comprised record of patients who underwent open reduction and internal fixation for elbow and acetabular fractures between 2010 and 2013. Data was classified into three groups: Group A patients had received single dose of radiotherapy; Group B patients had received indomethacin, and Group C patients had not received any prophylaxis. Outcome variables included time-to-fracture healing, heterotopic ossification, non-union and wound infection. Of the 104patients 70(67.3%) had elbow fractures and 34(32.7%) had acetabular fractures. Out of the 70patients with elbow fractures, 28(27%) were in Group A, 24(23%) in Group B, and 18(17%) in Group C. In Group A, 4(22%) patients had wound infection compared to 1(5.5%) patient in Group C (p=0.131). One (4%) patient in Group B and 1(5.5%) in Group C developed heterotopic ossification (p=0.486). Non-union occurred in 1(4%) patient in Group B and 1(5.5%) in Group C. Out of the 34 patients with acetabular fractures, 11(32.3%) were in Group A, 10(29.4%) in Group B, and 13(38.2%) in Group C. In Group A, 2(18.2%) patients developed wound infection. Only 1(7.6%) patient in Group C developed heterotopic ossification. | The serotonin receptor type 3 (Htr3) blocker is associated with QT prolongation and torsades de pointes. However, little is known about effects of Htr3 on the heart arrhythmia. An electrophysiological study Involving knock-out (KO) female mice lacking functional Htr3a (Htr3a(-/-)) and their wild-type littermates during non-pregancy (NP) and late pregnancy (LP) was performed. Htr3a mRNA was present in the wild-type, but not in the Htr3a(-/-)mouse hearts. Serotonin and tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme of serotonin synthesis in hearts, is increased during pregnancy. The heart weight and size were increased in the pregnant mice regardless of a mutation. The QTc intervals were prolonged after pregnancy in both the wild (NP: 171.2±16.8 vs. LP: 247.7±14.3 ms; P<0.001) and Htr3a(-/-)mice (NP: 187.9±18.7 vs. LP: 275.6±11.0 ms, P<0.001). Compared with wild-type LP mice, Htr3a(-/-)LP mice had increased spontaneous ventricle tarchycardia (VT; 56% vs. 0%, P=0.002), VT inducibility (66% vs. 25%, P=0.002) and mortality (56% vs. 0%, P=0.002). Pharmacologic administration of serotonin and Htr3 agonists (m-CPBG) decreased the QT interval in wild mice, but not in Htr3a(-/-)mice. |
Is atrophy of type I and II muscle fibers reversible in the case of grade > 2 fatty degeneration of the supraspinatus muscle : an experimental study in rabbits? | Although clinical investigations indicate that the limit of reversibility of rotator cuff muscles fibers type I and II atrophy is grade 2 of fatty degeneration (FD) according to the Goutallier computed tomography classification, little is known about the morphometric verification of these findings. The supraspinatus tendon was detached from the greater tubercle and the infraspinatus and subscapularis in 12 rabbits, and a 12-week observation period followed. This proved to be sufficient for development of grade >2 FD of the supraspinatus tendon. The tendon was then reinserted. The animals were euthanized 24 weeks after tendon reconstruction. The sections of middle part of supraspinatus were stained for adenosine triphosphatase reaction, and morphometric measurements were taken of type I and II muscle fiber diameters. The contralateral shoulders served as controls. The macroscopic inspection of the supraspinatus tendons revealed complete healing in all cases. No statistically significant differences were found between controls and operated-on shoulders for type I (P = .13) and type II (P = .55) muscle fibers. | While low socioeconomic status (SES) has been associated with inferior cancer outcome among adults, its impact in pediatric oncology is unclear. Our objective was therefore to conduct a systematic review to determine the impact of SES upon outcome in children with cancer. We searched Ovid Medline, EMBASE and CINAHL from inception to December 2012. Studies for which survival-related outcomes were reported by socioeconomic subgroups were eligible for inclusion. Two reviewers independently assessed articles and extracted data. Given anticipated heterogeneity, no quantitative meta-analyses were planned a priori. Of 7,737 publications, 527 in ten languages met criteria for full review; 36 studies met final inclusion criteria. In low- and middle-income countries (LMIC), lower SES was uniformly associated with inferior survival, regardless of the measure chosen. The majority of associations were statistically significant. Of 52 associations between socioeconomic variables and outcome among high-income country (HIC) children, 38 (73.1%) found low SES to be associated with worse survival, 15 of which were statistically significant. Of the remaining 14 (no association or high SES associated with worse survival), only one was statistically significant. Both HIC studies examining the effect of insurance found uninsured status to be statistically associated with inferior survival. |
Is self-criticism a key predictor of eating disorder dimensions among inpatient adolescent females? | Although the unipolar depression-eating disorder comorbidity is adequately documented, examination of the role of depressive personality styles in eating disorders is relatively scarce. Associations between depressive symptoms, depressive risk and resilience (i.e., dependency, self-criticism, and sense of efficacy), and eating disorder symptoms (as measured by the Eating Disorder Inventory-2) were examinedin inpatient adolescent females (N = 81). Self-criticism emerged as independent, robust, and strong predictor of eating disorder symptoms. | To investigate whether the umbilical cord mesenchymal stem cells (UC-MSCs) transplantation in the MRL/lpr mice has effect or not on their pneumonitis and the possible mechanisms underlying this treatment. Twenty four 18-week-old MRL/lpr female mice were divided into three groups as following: the group 2 (UC-MSCT group) have been transplanted with 1×10(6) UC-MSCs through caudal vein, the group 3 (multi-UC-MSCT Group) have been transplanted with 1×10(6) UC-MSCs three times and the group 1 (control group) have been treated with 0.5 mL phosphate buffer saline (PBS) as control. The histopathology of the lung was observed. The pulmonary expression of high mobility group box protein-1 (HMGB-1) was measured by western blot and detected by quantitation real time polymerase chain reaction (PCR). Immunohistochemistry method was used to detect HMGB-1 expressions in pulmo. In comparision to control ground mice, UC-MSCs significantly reduced interstitial pneumonitis in the MRL/lpr mice. The lung peribronchiolar lesion index of UC-MSCT group (1.40±0.24) and multi-UC-MSCT group (1.02±0.29) were significantly decreased as compared to control group (1.95±0.35) (P<0.01). The perivascular lesion index of UC-MSCT group (1.20±0.18) and multi-UC-MSCT group (1.08±0.16) were also significantly reduced as compared to control group (1.56±0.32) (P=0.018, 0.002) and the lung alveolar areas lesion index of control group (1.72±0.34) was significantly increased as compared to UC-MSCT group (1.30±0.21) and multi-UC-MSCT group (1.05±0.15) (P=0.011, 0.000). The lung HMGB-1 protein in UC-MSCT group (0.32±0.04) and in multi-UC-MSCT group (0.28±0.06) were both significantly decreased as compared to that in control group (0.80±0.21) (P<0.05). The level of HMGB-1 mRNA in UC-MSCT group (4.68±0.37) and in multi-UC-MSCT group (4.35±0.10) lung were both significantly decreased as compared to those in control group (16.29±3.84) (P<0.05). In immunohistochemical staining lung sections, high expression of HMGB-1 was found mainly located in the cytoplasm and extracellular matrix of MRL/lpr mice pulmonary epithelial cells, the expression of HMGB-1 in UC-MSCT group and multi-UC-MSCT group was significantly decreased as compared to that in the control group. |
Does intestinal ischemia/reperfusion injury trigger activation of innate toll-like receptor 4 and adaptive chemokine programs? | Ischemia/reperfusion injury (IRI) is a major problem in intestinal transplantation. Toll-like receptor 4 (TLR4) has been implicated as a possible link between the innate and adaptive immune systems, however little data exists regarding TLR4 in intestinal IRI. The goal of this study is to evaluate the involvement of TLR4 in intestinal IRI and to assess the effect on T cell related chemokine programs. C57BL6 mice underwent 100 minutes of warm intestinal ischemia by SMA clamping. Control WT mice underwent laparotomy without vascular occlusion. Separate survival and analysis groups were performed, and intestinal tissue was harvested at 1 hour, 2 hours, 4 hours, and 24 hours post-reperfusion. Analysis included histology, CD3 immunostaining, myeloperoxidase activity, Western blot, and PCR. Survival was significantly worse in the IRI group vs control (50% vs. 100%). IRI caused severe histopathological injury including mucosal erosions and villous congestion and hemorrhage. Myeloperoxidase activity increased in a time-dependent manner after IRI (2.71 0.25 at 1 hour, 2.92 0.25 at 2 hours, 4 0.16 at 4 hours, 5.1 0.25 at 24 hours vs 0.47 0.11 controls, P < .05). Protein expression of TLR4 followed by NF-kappaB was increased after IRI. Additionally, mRNA production of IP-10, MIP-2, MCP-1, and RANTES was increased at all time-points, as was mRNA for ICAM-1 and E-selectin. | To investigate the effects of the Chinese herbal medicine of Longbixiao (LBX) Capsule on the expressions of TGF-beta1 and Smoothelin in human prostatic stromal cells cultured in vitro. Blood serum medicated with LBX was incubated with the stromal cells isolated from men with benign prostatic hyperplasia (BPH) and cultured in vitro. The mRNA expression levels of TGF-beta1 and Smoothelin were detected by real-time RT-PCR and other relevant techniques. In the high and low concentration groups, the gene relative expressions of TGF-beta1 were (0.158 +/- 0.020) and (0.169 +/- 0.020) , while those of Smoothelin were (0.035 +/- 0.007) and (0.036 +/- 0.007) respectively, both significantly decreased in comparison with the control group(P < 0.01). |
Does androgen deprivation therapy impact cause-specific or overall survival in high-risk prostate cancer managed with brachytherapy and supplemental external beam? | To determine cause-specific survival (CSS), biochemical progression-free survival (bPFS), and overall survival (OS) in high-risk prostate cancer patients undergoing brachytherapy with or without supplemental therapies. Between April 1995 and July 2002, 204 patients with high-risk prostate cancer (Gleason score > or = 8 or prostate-specific antigen [PSA] >20 ng/mL or clinical stage > or = T2c) underwent brachytherapy. Median follow-up was 7.0 years. The bPFS was defined by a PSA < or = 0.40 ng/mL after nadir. Multiple clinical, treatment, and dosimetric parameters were evaluated for the impact on survival. The 10-year CSS, bPFS, and OS were 88.9%, 86.6%, and 68.6%, respectively. A statistically significant difference in bPFS was discerned between hormone naive, ADT < or = 6 months, and ADT >6 month cohorts (79.7% vs. 95.% vs. 89.9%, p = 0.032). Androgen deprivation therapy (ADT) did not impact CSS or OS. For bPFS patients, the median posttreatment PSA was <0.04 ng/mL. A Cox linear regression analysis demonstrated that Gleason score was the best predictor of CSS, whereas percent positive biopsies and duration of ADT best predicted for bPFS. The OS was best predicted by Gleason score and diabetes. Thirty-eight patients have died, with 26 of the deaths from cardiovascular/pulmonary disease or second malignancy. Eleven patients have died of metastatic prostate cancer. | Intravenous immunoglobulin (IVIg) has been used to treat a variety of autoimmune disorders including multiple sclerosis (MS); however its mechanism of action remains elusive. Recent work has shown that interleukin-11 (IL-11) mRNAs are upregulated by IVIg in MS patient T cells. Both IVIg and IL-11 have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The objective of this study was to determine whether the protective effects of IVIg in EAE occur through an IL-11 and IL-11 receptor (IL-11R)-dependent mechanism. We measured IL-11 in the circulation of mice and IL-11 mRNA expression in various organs after IVIg treatment. We then followed with EAE studies to test the efficacy of IVIg in wild-type (WT) mice and in mice deficient for the IL-11 receptor (IL-11Rα-/-). Furthermore, we evaluated myelin-specific Th1 and Th17 responses and assessed spinal cord inflammation and demyelination in WT and IL-11Rα-/- mice, with and without IVIg treatment. We also examined the direct effects of mouse recombinant IL-11 on the production of IL-17 by lymph node mononuclear cells. IVIg treatment induced a dramatic surge (>1000-fold increase) in the levels of IL-11 in the circulation and a prominent increase of IL-11 mRNA expression in the liver. Furthermore, we found that IL-11Rα-/- mice, unlike WT mice, although initially protected, were resistant to full protection by IVIg during EAE and developed disease with a similar incidence and severity as control-treated IL-11Rα-/- mice, despite initially showing protection. We observed that Th17 cytokine production by myelin-reactive T cells in the draining lymph nodes was unaffected by IVIg in IL-11Rα-/- mice, yet was downregulated in WT mice. Finally, IL-11 was shown to directly inhibit IL-17 production of lymph node cells in culture. |
Does uric acid correlate with the severity of histopathological parameters in IgA nephropathy? | Immunoglobulin-A nephropathy (IgAN) is the most common chronic glomerulonephritis worldwide. Many clinical and histopathological risk factors for progression have been found previously. Recently, metabolic risk factors, such as hyperuricaemia and hypertriglyceridaemia, also have been associated with the progression of IgAN. In the present study we correlated clinical and metabolic risk factors with histopathological parameters in 202 patients with IgAN. Morphological changes in glomerular, tubulointerstitial and vascular tissue were semiquantitatively graded into three classes. Mesangial proliferation activity and the amount of inflammatory cells were also evaluated by immunohistochemical staining of Ki-67 (MIB-1), CD45 (LCA) and CD68 stainings. Serum uric acid, triglycerides and cholesterol, urine protein excretion (UPE), blood pressure and body mass index (BMI) were measured. Smoking habits and occurrence of diabetes mellitus also were evaluated. The independent role of serum uric acid in the development of renal morphological changes was evaluated in multivariate analysis. Serum uric acid and UPE level correlated with several histological parameters. Uric acid level showed the strongest correlation with tubulointerstitial changes and UPE with glomerulosclerosis. The level of serum triglycerides correlated with interstitial fibrosis and hyaline arteriolosclerosis. Blood pressure correlated with hyaline arteriolosclerosis, glomerulosclerosis and tubulointerstitial changes. BMI and diabetes mellitus correlated with both tubulointerstitial and vascular changes. We found no significant correlations between histopathological parameters and smoking habits or serum cholesterol level. Serum uric acid had independent associations with the presence of tubular atrophy and interstitial fibrosis and inflammation. | Electrical acustimulation can reduce postoperative nausea and vomiting (PONV). The primary purpose of this study was to investigate the effectiveness of acustimulation in relation to known risk factors for PONV. We also tested the secondary hypothesis that pre- or post-induction application of acustimulation results in differences in PONV reduction. Two hundred women undergoing vaginal hysterectomy were enrolled in this prospective, observer-blind, randomized controlled trial. Patients received randomly for 24 h acustimulation (n=101), subdivided into groups of pre-induction (n=48) and post-induction (n=53), or sham stimulation (n=99), subdivided into groups of pre-induction (n=49) or post-induction (n=50). Nausea and vomiting/retching was recorded for 24 h after operation in the whole group and stratified by risk factors (female gender, non-smoker, history of PONV/motion sickness, and postoperative morphine usage). The incidence of PONV and need for rescue therapy was significantly lower in the acustimulation than in the sham group (PONV, 33% vs 63%, P<0.001; rescue therapy, 39% vs 61%, P=0.001). The risk ratio for acustimulation and PONV was 0.29 [95% confidence interval (CI) 0.16-0.52] and for rescue therapy, it was 0.38 (95% CI 0.21-0.66). Subgroup analyses according to the simplified risk score by Apfel and colleagues revealed a reduction in high-risk patients, that is, when three or four risk factors were present. Binary logistic regression analysis revealed that no history of PONV and usage of acustimulation were independent predictors for risk reduction of all PONV qualities. No significant difference in PONV reducing effects could be detected between pre- and post-induction. |
Are women , patients with severe asthma , and patients attended by primary care physicians , at higher risk of suffering from poorly controlled asthma? | The aim of this exploratory study was to identify those factors associated with asthma control assessed according to GINA Guidelines. 809 (56% female) subjects with asthma were recruited consecutively from both specialist and primary care centres. Asthma control was assessed over a 4-week follow-up period using a composite measure. A multivariate analysis was performed, in which asthma control was included as the dependent variable and several explanatory variables were included as independent variables. Analysis performed on the whole population rendered gender (p=0.003), the type of physician (p<0.001), and age group (p<0.001), as significant factors associated with asthma control. In adults, gender (p=0.001), asthma severity (p<0.001), and type of physician (p<0.001) were significant, and only asthma severity was significant (p=0.043) in children. | In vivo tissue regeneration depends on migration of stem cells into injured areas, their differentiation into specific cell types, and their interaction with other cells that are necessary to generate new tissue. Human mesenchymal stem cells, a subset of bone marrow stromal cells (BMSCs), can migrate and differentiate into osteoblasts in bone tissue. This can be facilitated by recombinant growth factors and cytokines. In many animal species, the availability of genomic sequences, recombinant proteins, and/or antibodies is limited so that new approaches are needed to generate resources that facilitate migration of stem cells into tissue defect areas. Here we used bone marrow stromal cells of human, ovine, equine, and canine origin to generate hypoxia-conditioned media (HCM) in order to attract BMSCs of the respective species in migration assays. We show that HCM contain attractors even more potent than vascular endothelial growth factor and can therefore be used in many animal species without the need for purified proteins. |
Does dietary beet pulp decrease taurine status in dogs fed low protein diet? | It is known that large dogs who are fed lamb and rice diets are at increased risk to develop taurine-deficiency-induced dilated cardiomyopathy. Since dogs obligatorily conjugate bile acids (BA) with taurine, we determined whether rice bran (RB) or other fibers (cellulose; CL, beet pulp; BP) would affect BA excretion and/or the taurine status of dogs. Eighteen medium/large mixed-breed dogs were given purified diets containing CL, BP, or RB for 12 weeks. Taurine concentrations in plasma and whole blood were significantly decreased at week 12. The BP group, compared to the CL or RB groups, showed significantly lower taurine concentrations in plasma (6.5 ± 0.5 vs 20.4 ± 3.9 and 13.1 ± 2.0 μmol/L, respectively, P < 0.01, mean ± SEM) and in whole blood (79 ± 10 vs 143 ± 14 and 127 ± 14 μmol/L, respectively, P < 0.01), lower apparent protein digestibility (81.9 ± 0.6 vs 88.8 ± 0.6 and 88.1 ± 1.2 %, respectively, P < 0.01), and higher BA excretions (5.6 ± 0.1 vs 3.4 ± 0.5 and 3.4 ± 0.4 μmol/g feces, respectively, P < 0.05) at week 12. | Sleep is defined as a reversible state of reduction in sensory responsiveness and immobility. A long-standing hypothesis suggests that a high arousal threshold during non-rapid eye movement (NREM) sleep is mediated by sleep spindle oscillations, impairing thalamocortical transmission of incoming sensory stimuli. Here we set out to test this idea directly by examining sensory-evoked neuronal spiking activity during natural sleep. We compared neuronal (n = 269) and multiunit activity (MUA), as well as local field potentials (LFP) in rat core auditory cortex (A1) during NREM sleep, comparing responses to sounds depending on the presence or absence of sleep spindles. We found that sleep spindles robustly modulated the timing of neuronal discharges in A1. However, responses to sounds were nearly identical for all measured signals including isolated neurons, MUA, and LFPs (all differences < 10%). Furthermore, in 10% of trials, auditory stimulation led to an early termination of the sleep spindle oscillation around 150-250 msec following stimulus onset. Finally, active ON states and inactive OFF periods during slow waves in NREM sleep affected the auditory response in opposite ways, depending on stimulus intensity. |
Does infrapatellar fat pad preservation reduce wound complications after minimally invasive total knee arthroplasty? | The aim of this study was to determine whether pain intensity and wound complication rates differ between patients with and without preservation of the infrapatellar fat pad (IPFP) after minimally invasive total knee arthroplasty (TKA). The authors also sought to determine whether IPFP preservation affects operation time. This retrospective study included 448 knees with primary TKA. The IPFP was totally resected in 201 knees (IPFP-R group), and was preserved in 247 knees (IPFP-P group). Pain score was determined using the visual analog scale during the first 72 h after surgery. Wound complication rates and operation times were also evaluated. A wound complication was defined as persistent wound drainage for three or more days after surgery. There was no difference in pain levels between the two groups. However, there were fewer wound complications in the IPFP-P group (3 %) than in the IPFP-R group (13 %). The operation time was longer in the IPFP-P group than in the IPFP-R group (70 vs. 64 min, respectively). | To evaluate the association between dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) levels in primary gastric tumors and clinical response to S-1 or S-1 plus irinotecan in patients with unresectable advanced gastric cancer, and to investigate the molecular mechanism of augmented antitumor activity of the combination using human gastric cancer xenografts with high TS activity. TS mRNA expression and DPD mRNA expression were measured by reverse transcription polymerase chain reaction in initial primary cancer biopsy specimens in 29 patients with advanced gastric cancer who had received S-1 alone (n=18) or in combination with irinotecan (n=11). In an experimental study, antitumor effects of S-1, irinotecan, and the combination were assessed in mice bearing human gastric tumors with high TS expression (4-1-ST and AZ-521 tumors) and low TS expression (SC-2 tumors), and activities of 5-fluorouracil-metabolizing enzymes were measured. In the clinical study, a strong statistical association between high TS expression and clinical resistance to S-1 alone was found (P = .009). In the experimental studies, S-1 plus irinotecan showed augmented antitumor activity against tumors with high TS activity (P < .01) compared with either agent alone. A potential mechanism for this effect was suggested by the significant reduction in TS activity observed following irinotecan administration in tumors with high TS activity. |
Does iCAM-1 deficiency suppress host allosensitization and rejection of MHC-disparate corneal transplants? | We used a murine model of orthotopic corneal transplantation to determine whether host deficiency in ICAM-1 promotes survival of corneal grafts with different degrees of allodisparity. ICAM-1-/- and wild-type C57BL/6 (ICAM-1+/+) received corneal grafts from the following strains of mice: BALB/c (fully mismatched), BALB.b (mismatched at multiple minor H only), or B10.D2 [including major histocompatibility complex (MHC) mismatch]. Graft rejection, induction of allospecific delayed-type hypersensitivity (DTH) responses, and leukocytic infiltration of grafts were measured. There were no differences in long-term survival of allografts that were either fully mismatched or had only minor H disparity in ICAM-1+/+ vs. ICAM-1-/-hosts. However, whereas B10.D2 grafts were accepted in only 58% of the ICAM-1+/+ hosts, graft survival in ICAM-1-/- recipients was 100% (P=0.006). Moreover, none of the ICAM-1-/- mice receiving B10.D2 grafts developed allospecific DTH. | To examine if greater nutrition knowledge vs gains in knowledge promote more successful weight loss in low-income, overweight and obese mothers with young children. A convenience sample of mothers and their children were measured for height and weight; mothers completed demographic and nutrition knowledge questionnaires pre- and post-intervention. Participants (N=141) were recruited from government and public health clinics and elementary schools. Inclusion criteria for mothers were: family income <200% federal poverty level; overweight/obese; and Hispanic, African-American, or white race/ethnicity. Eight weekly weight-loss classes emphasizing diet, physical activity, and behavior modification based on Social Cognitive Theory were administered to mothers. Improvements in maternal nutrition knowledge and weight loss. Paired-samples t tests, repeated measures analysis of variance, analysis of covariance, Pearson correlations, and chi(2) statistics. Nutrition knowledge of mothers increased in all areas. Participants with weight loss > or =2.27 kg (responders) had greater knowledge than those who did not; however, the actual net gain was similar for those who lost and did not lose weight. Weight gainers only improved in two areas on the test, whereas weight-loss responders increased knowledge in all six. Responders appeared more cognizant of diet, weight loss, and health information. |
Does the genome of Rhizobium leguminosarum have recognizable core and accessory components? | Rhizobium leguminosarum is an alpha-proteobacterial N2-fixing symbiont of legumes that has been the subject of more than a thousand publications. Genes for the symbiotic interaction with plants are well studied, but the adaptations that allow survival and growth in the soil environment are poorly understood. We have sequenced the genome of R. leguminosarum biovar viciae strain 3841. The 7.75 Mb genome comprises a circular chromosome and six circular plasmids, with 61% G+C overall. All three rRNA operons and 52 tRNA genes are on the chromosome; essential protein-encoding genes are largely chromosomal, but most functional classes occur on plasmids as well. Of the 7,263 protein-encoding genes, 2,056 had orthologs in each of three related genomes (Agrobacterium tumefaciens, Sinorhizobium meliloti, and Mesorhizobium loti), and these genes were over-represented in the chromosome and had above average G+C. Most supported the rRNA-based phylogeny, confirming A. tumefaciens to be the closest among these relatives, but 347 genes were incompatible with this phylogeny; these were scattered throughout the genome but were over-represented on the plasmids. An unexpectedly large number of genes were shared by all three rhizobia but were missing from A. tumefaciens. | Statins have been proposed as a potential treatment for systemic lupus erythematosus (SLE) due to their immunomodulatory properties, their role restoring endothelial function and preventing atherosclerosis. We evaluate the effect of a short period treatment with a low dose of atorvastatin and its withdrawal on early stage subclinical atherosclerosis. Thirty-seven SLE females received 20 mg/day atorvastatin during eight weeks. At baseline, at the end of treatment and six months after atorvastatin withdrawal, disease activity, subclinical atherosclerosis -assessed by measuring carotid-femoral pulse wave velocity (PWV) - and quantification of circulating endothelial progenitor cells (EPC) - as a surrogate biological marker of subclinical atherosclerosis - were carried out. The group of SLE patients with baseline pathological arterial stiffness showed a significant decrease of PWV after atorvastatin therapy (8.43 ± 1.45 m/s vs 7.42 ± 1.06 m/s; p = 0.002) that is maintained six months after treatment finished. Only patients of the middle-aged group showed a nearly significant decrease in the PWV measured along the study (7.16 ± 1.23 m/s vs 6.76 ± 0.82 m/s; p = 0.05). Atorvastatin induced a significant decrease in the circulating EPC percentage (0.65 ± 0.67 vs 0.40 ± 0.31; p = 0.023) as well as a downward trend of disease activity that it is observed by a decrease in SLE disease activity index simultaneously with an increase in C3 complement and significant decrease in serum concentration of vascular endothelial grow factor (VEGF) and sVCAM-1. |
Do simple anatomical measurements correlate significantly to individual peripheral nerve stimulation thresholds as measured in MRI gradient coils? | To examine peripheral nerve stimulation (PNS) thresholds for normal human subjects in magnetic resonance imaging (MRI) gradient coils, and determine if observed thresholds could be predicted based on gross physiologic measurements. PNS thresholds for 21 healthy normal subjects were measured using a whole-body gradient coil. Subjects were exposed to a trapezoidal echo-planar imaging (EPI) gradient waveform and the total change in gradient strength (DeltaG) required to cause PNS as a function of the duration of the gradient switching time (tau) were measured. Correlation coefficients and corresponding P values were calculated for the PNS threshold measurements against simple physiologic measurements taken of the subjects, including weight, height, girth, and average body fat percentage, in order to determine if there were any easily observable dependencies. No convincing correlations between threshold parameters and gross physiologic measurements were observed. | The purpose of this study was to determine the role of matrix metalloproteinases (MMP) in Pseudomonas aeruginosa keratitis. Gene array and selective real-time PCR examined MMP expression in the cornea of susceptible (C57BL/6, B6) versus resistant (BALB/c) mice before and after infection; zymography tested enzyme activity for MMP-2 and -9. Clinical score, Langerhans cell (LC), and Neutrophil (PMN) quantitation were done in recombinant (r) MMP-9, antibody neutralized, and MMP-9(-/-) mice. The chemotactic potential of MMP-9 was tested in a Boyden chamber assay; light and transmission microscopy and immunostaining for collagen IV and MMP-9 were used to examine the effects and the source of MMP-9 after infection. ELISA was used to assess IL-1beta and MIP-2 levels. Gene array (confirmed by PCR) revealed sixfold more MMP-9, and zymography showed greater enzyme activity in the infected cornea of B6 over BALB/c mice. rMMP-9 injection of BALB/c mice enhanced, whereas MMP-9 antibody neutralization in B6 mice and its absence in MMP-9(-/-) mice decreased corneal disease. MMP-9(-/-) and antibody neutralized mice had fewer LCs in cornea; rMMP-9-treated mice had more. A myeloperoxidase (MPO) assay showed a similar pattern for PMN. MMP-9 was not chemotactic for LC or PMN. The basement membrane was more intact in MMP-9(-/-) over wild-type infected mice and correlated with staining for collagen IV; PMN was a source of MMP-9. IL-1beta and MIP-2 were increased in rMMP-9 but decreased in MMP-9 antibody neutralized and MMP-9(-/-) over control groups. |
Is vitamin D deficiency at melanoma diagnosis associated with higher Breslow thickness? | Epidemiological evidence shows that people with thicker, or higher stage, melanomas have lower vitamin D status compared to those with thinner tumours. Evidence from experimental studies is inconsistent, but some suggest that administration of vitamin D metabolites can decrease tumour aggressiveness. Determine the relationship between vitamin D status at diagnosis and melanoma thickness (as an indicator of prognosis), in a subtropical setting with high melanoma incidence. We recruited 100 melanoma patients in Brisbane, Australia within days of their diagnosis. Data on factors previously associated with melanoma risk or prognosis were collected by questionnaire and physical examination. Serum for 25-hydroxyvitamin D3 [25(OH)D] levels was collected prior to wider excision biopsy; histological indicators of prognosis were obtained from pathology reports. We used multivariable logistic regression models to analyse the association between Breslow thickness (≥0.75 mm compared to <0.75 mm), Clark level (2-5 compared to 1) and presence of mitoses, and vitamin D status. Serum 25(OH)D <50 nmol/L (versus ≥50 nmol/L) was associated with a nearly four-fold increase in risk of having a thicker tumour (Adjusted OR = 3.82, 95% CI: 1.03, 14.14; p = 0.04, adjusted for age, sex, skin phototype, body mass index and season at diagnosis). There was no significant association with Clark level or presence of mitosis. Serum 25(OH)D levels in the highest quartile (≥69.8 nmol/L) were not associated with a more favourable prognosis. | The ADAMTS13-von Willebrand factor (vWF) axis has been suggested to play a critical role in the pathophysiology of ischemia-reperfusion injury (IRI) in the heart or brain. Therefore, we aimed to investigate whether this axis was involved in the pathophysiology of IRI-induced acute kidney injury. We performed renal IRI in ADAMTS13 knockout (KO) or wild type (WT) mice. Functional and histological kidney damage, and inflammation were compared and the effect of anti-vWF antibodies in ADAMTS13 KO mice was assessed. Following IRI, the blood and kidney ADAMTS13 levels were significantly decreased. vWF expression was significantly upregulated in both the medulla and cortex of injured kidneys as shown by immunohistochemistry and western blot analyses. There was also an increased level of vWF dimers after IRI. In ADAMTS13 KO mice, kidney vWF levels were further increased and this was associated with greater endothelial and epithelial injury compared to WT mice, suggesting an important role of vWF in renal IRI. In addition, the number of Gr-1 |
Do [ The preliminary study of the origin characters of snore in simple snorers ]? | to investigate the origin characters of snore in simple snorers and provide the basis for its treatment. Thirty-two simple snorers diagnosed by polysomnography were induced to sleep by propofol and dexmedetomidine, then we observed the vibration sites, pattern and concomitant collapse of soft tissue in pharyngeal cavity by nasendoscopy. Thirteen cases showed palatal fluttering only, and 1 case showed vibration of epiglottis only. Six cases showed palatal fluttering with vibration of epiglottis, and 2 cases showed palatal fluttering with vibration of epiglottis and tongue base. Five cases showed palatal fluttering with vibration of pharyngeal lateral wall, and 5 cases showed palatal fluttering with vibration of lateral wall, epiglottis and tongue base together. Palate and pharyngeal lateral wall vibrated strongly and always collapsed with vibrating, but epiglottis and tongue base usually vibrated slightly and seldom collapsed. | In approximately two-thirds of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) no suitable related donor can be identified but an unrelated HLA-matched donor can be found through international donor registries. HSCT grafts from unrelated donors are commonly collected at distant sites. Therefore, graft storage and transportation becomes crucial in the HSCT process. We aimed to study the impact of graft quality on clinical outcome and identify factors affecting graft quality. We investigated the influence of graft quality on the clinical outcome in 144 HSCT patients. Graft quality was assessed by determining the viability (7-aminoactinomycin D [7AAD]) on a frozen-thawed sample from the peripheral blood stem cell (PBSC) graft. Patients receiving PBSCs with inferior quality (i.e., viability < 64% in the frozen-thawed sample) more frequently developed acute graft-versus-host disease (aGVHD) Grades I to IV than patients receiving grafts with better quality (p = 0.025). The transplant-related mortality (TRM) was higher in the group receiving grafts with lower viability (p = 0.03). The viability of the frozen-thawed samples was highly variable (median, 64%; range, 24%-96%). No correlation could be observed when comparing the viability in newly arrived PBSC grafts to frozen-thawed vials. Grafts with white blood cell (WBC) count of more than 300 × 10(9) /L had lower viability than those with lower WBC counts (p < 0.001). |
Do the overlap syndrome of depression and delirium in older hospitalized patients? | To measure the prevalence, predictors, and posthospitalization outcomes associated with the overlap syndrome of coexisting depression and incident delirium in older hospitalized patients. Secondary analysis of prospective cohort data from the control group of the Delirium Prevention Trial. General medical service of an academic medical center. Follow-up interviews at 1 month and 1 year post-hospital discharge. Four hundred fifty-nine patients aged 70 and older who were not delirious at hospital admission. Depressive symptoms assessed at hospital admission using the 15-item Geriatric Depression Scale (cutoff score of 6 used to define depression), daily assessments of incident delirium from admission to discharge using the Confusion Assessment Method, activities of daily living at admission and 1 month postdischarge, and new nursing home placement and mortality determined at 1 year. Of 459 participants, 23 (5.0%) had the overlap syndrome, 39 (8.5%) delirium alone, 121 (26.3%) depression alone, and 276 (60.1%) neither condition. In adjusted analysis, patients with the overlap syndrome had higher odds of new nursing home placement or death at 1 year (adjusted odds ratio (AOR)=5.38, 95% confidence interval (CI)=1.57-18.38) and 1-month functional decline (AOR=3.30, 95% CI=1.14-9.56) than patients with neither condition. | Formation of branching tubes is a fundamental step in the development of glandular organs. To identify extracellular cues that orchestrate epithelial tubulogenesis, we employed an in vitro assay in which EpH4-J3B1A mammary epithelial cells form spheroidal cysts when grown in collagen gels under serum-free conditions, but form branching tubules in the presence of fetal calf serum (FCS). Initial experiments showed that the tubulogenesis-inducing activity of FCS was markedly increased by heating (70 degrees C) or transient acidification to pH3. We therefore hypothesized that the tubulogenic agent was transforming growth factor-beta (TGF-beta), a cytokine that is present in serum in latent form and can be activated by heat or acid treatment. We found indeed that the tubulogenic activity of acidified FCS is abrogated by addition of either SB-431542, a selective inhibitor of the TGF-beta type I receptor, or a neutralizing antibody to TGF-beta-1. On the other hand, addition of low concentrations (20-100 pg/ml) of exogenous TGF-beta-1 recapitulated the effect of acidified FCS in inducing morphogenesis of hollow tubes. In contrast, higher concentrations of TGF-beta-1 induced the formation of thin cellular cords devoid of a detectable lumen. To gain insight into the mechanisms underlying TGF-beta-1-induced tube formation, we assessed the potential role of matrix metalloproteinases (MMPs). By western blot and gelatin zymography, we observed a dose-dependent increase in MMP-9 upon TGF-beta-1 treatment. Tube formation was suppressed by a synthetic broad-spectrum metalloproteinase inhibitor, by recombinant tissue inhibitor of metalloproteinases-2 (TIMP-2) and by a selective inhibitor of MMP-9, indicating that this morphogenetic process requires the activity of MMP-9. |
Do surgeon 's expectations predict the outcome of a total knee arthroplasty? | It is fascinating for both the patient and the surgeon to predict the outcome of a TKA at an early stage. Satisfaction after TKA is primarily determined by the preoperative expectations of the patient. The purpose of this study was to investigate if the peri-operative expectations of the surgeon predicted the outcome of a TKA. A prospective study of 53 primary TKAs was performed. Preoperatively, the surgeon described the assessment of the difficulty of the TKA on a VAS. Immediately postoperative, the surgeon gave his satisfaction VAS about the procedure. After 1 year the surgeon's satisfaction VAS, the patient's satisfaction VAS and the KSCRS were determined. The Spearman's correlation coefficients between the preoperative difficulty assessment, the immediate postoperative satisfaction and the outcome measurements after 1 year were all very poor (-0.01 to 0.23). | Oxidative stress is implicated in the pathogenesis of atherosclerosis, and Nrf2 is the transcriptional factor central in cellular antioxidant responses. In the present study, we investigate the effect of a dihydrolipoic acid derivative lipoicmethylenedioxyphenol (LMDP) on the progression of atherosclerosis and test whether its effect on atherosclerosis is mediated by Nrf2. Both magnetic resonance imaging (MRI) scanning and en face analysis reveal that 14 weeks of treatment with LMDP markedly reduced atherosclerotic burden in a rabbit balloon vascular injury model. Myograph analyses show decreased aortic contractile response to phenylephrine and increased aortic response to acetylcholine and insulin in LMDP-treated animals, suggesting that LMDP inhibits atherosclerosis through improving vascular function. A role of Nrf2 signaling in mediating the amelioration of vascular function by LMDP was supported by increased Nrf2 translocation into nuclear and increased expression of Nrf2 target genes. Furthermore, chemotaxis analysis with Boydem chamber shows that leukocytes isolated from LMDP-treated rabbits had reduced chemotaxis, and knock-down of Nrf2 significantly reduced the effect of LMDP on the chemotaxis of mouse macrophages. |
Does hydrogen sulfide inhibit formaldehyde-induced endoplasmic reticulum stress in PC12 cells by upregulation of SIRT-1? | Formaldehyde (FA), a well-known environmental pollutant, has been classified as a neurotoxic molecule. Our recent data demonstrate that hydrogen sulfide (H2S), the third gaseous transmitter, has a protective effect on the neurotoxicity of FA. However, the exact mechanisms underlying this protection remain largely unknown. Endoplasmic reticulum (ER) stress has been implicated in the neurotoxicity of FA. Silent mating type information regulator 2 homolog 1 (SIRT-1), a histone deacetylases, has various biological activities, including the extension of lifespan, the modulation of ER stress, and the neuroprotective action. We hypothesize that the protection of H2S against FA-induced neurotoxicity involves in inhibiting ER stress by upregulation of SIRT-1. The present study attempted to investigate the protective effect of H2S on FA-induced ER stress in PC12 cells and the contribution of SIRT-1 to the protection of H2S against FA-induced injuries, including ER stress, cytotoxicity and apoptosis. We found that exogenous application of sodium hydrosulfide (NaHS; an H2S donor) significantly attenuated FA-induced ER stress responses, including the upregulated levels of glucose-regulated protein 78, C/EBP homologous protein, and cleaved caspase-12 expression. We showed that NaHS upregulates the expression of SIRT-1 in PC12 cells. Moreover, the protective effects of H2S on FA-elicited ER stress, cytotoxicity and apoptosis were reversed by Sirtinol, a specific inhibitor of SIRT-1. | Restenosis occurs in 40-50% of patients treated with percutaneous transluminal coronary angioplasty (PTCA). Some data indicate that platelet derived growth factor (PDGF) plays a pathogenetic role. The aims of the present study were to measure the plasma levels of PDGF across the coronary circulation during PTCA and relate them to the development of restenosis. Blood samples from the aortic root and coronary sinus were drawn simultaneously before, and after completed PTCA in 26 patients. Plasma levels of PDGF and beta-thromboglobulin (BTG), as well as platelet counts were measured. Restenosis was evaluated by quantitative coronary angiography after 6 months. Significant increases both in PDGF and BTG were encountered in the aortic root after PTCA in patients who developed restenosis as compared to patients without restenosis. Patients who developed restenosis also had significantly higher platelet counts compared to those without. |
Is transfemoral aortic valve implantation of Edwards SAPIEN XT without predilatation feasible? | Transcatheter aortic valve implantation (TAVI) without predilatation has fewer procedural steps and thereby potentially fewer complications. This has been demonstrated for the antegrade transapical access; however, whether TAVI can be safely performed without predilatation using the retrograde transfemoral route is unknown. We postulated that TAVI is feasible with a balloon-expandable device without predilatation using the retrograde transfemoral route. Twenty-six consecutive patients with stenosis of the native aortic valve (AV) undergoing transfemoral TAVI with the Edwards SAPIEN XT prosthesis without predilatation were enrolled in this retrospective study and compared with 30 patients treated previously with predilatation. The procedure was successfully performed in all 26 patients, irrespective of the AV area and the extent of AV calcification. At baseline mean AV area, mean AV gradient, and median left ventricular ejection fraction were 0.7 ± 0.2 cm(2) , 36.0 ± 17.3 mm Hg, and 55.0% (interquartile range [IQR], 35.0-60.0], respectively; prior to discharge these values were 1.7 ± 0.3 (P < 0.001), 9.8 ± 6.1 mm Hg (P < 0.001), and 57.5% (IQR, 38.7-60.0) (P = not significant). Postdilatation was required in 3 patients due to aortic regurgitation > 2°; this was reduced by the procedure to < 2° in all cases. Radiation dose and amount of contrast dye were significantly reduced in comparison with the predilatation group. No periprocedural neurological adverse events occurred. Mortality at 30 days was 0%. | Anaemia is a major cause of morbidity and mortality for children in Africa. The plasma protein haptoglobin (Hp) binds avidly to free haemoglobin released following malaria-induced haemolysis. Haptoglobin polymorphisms result in proteins with altered haemoglobin-binding capacity and different antioxidant, iron-recycling, and immune functions. Previous studies examined the importance of haptoglobin polymorphism in malaria and iron homeostasis, but it is unknown whether haptoglobin genotype might be a risk factor for anaemia in children in a malaria-endemic area. A cohort of 780 rural Gambian children aged 2-6 y was surveyed at the start and end of the malaria season. Samples were taken to assess haemoglobin (Hb) concentration, iron status (ferritin, zinc protoporphyrin, transferrin saturation, and soluble transferrin receptor concentration), haptoglobin concentration, alpha-1-antichymotrypsin (a measure of inflammation), and malaria parasites on blood film. We extracted DNA and genotyped for haptoglobin, sickle cell, and glucose-6-phosphate (G6PD) deficiency. Mean Hb levels fell over the malaria season. Children with the haptoglobin 2-2 genotype (17%) had a greater mean drop in Hb level over the malaria season (an 8.9 g/l drop; confidence interval [CI] 5.7, 12.1) compared to other children (a 5.1 g/l drop; CI 3.8, 6.4). In multivariate regression analysis, controlling for baseline Hb level, age group, village, malaria parasites on blood film, iron status, haptoglobin concentration, and G6PD deficiency, haptoglobin genotype predicted Hb level at the end of the malaria season (p = 0.0009, coefficient = -4.2). Iron status was not influenced by haptoglobin genotype. |
Does ultrasound-mediated microbubble destruction enhance the therapeutic effect of intracoronary transplantation of bone marrow stem cells on myocardial infarction? | The combination of intracoronary transplantation and ultrasound-mediated microbubble destruction may promote effective and accurate delivery of bone marrow stem cells (BMSCs) into the infarct zone. To test this hypothesis in this study we examined the effectiveness of ultrasound-mediated microbubble destruction in combination with intracoronary transplantation of BMSCs for the treatment of myocardial infarction in canine model of acute myocardial infarction. The dogs were randomly assigned to four groups: PBS, ultrasound-mediated microbubble destruction, BMSCs, BMSCs together with ultrasound-mediated microbubble destruction. At 28 days post-surgery, cardiac function and the percentage of perfusion defect area to total left ventricular perfusion area (DA%) were determined by myocardial contrast echocardiography. Nitro blue tetrazolium staining was performed to determine myocardial infarct size, hematoxylin and eosin staining for assessing microvascular injury, Masson's staining for analyzing myocardial tissue collagen, immunohistochemical analysis of α-actin to measure cardiac contractile function and of BrdU-labeled myocardial cells to measure the number of the BMSCs homing to the infarcted region. The transplantation of BMSCs significantly improved heart function and DA% (P < 0.05). The group that received ultrasound-mediated microbubble destruction with BMSCs transplantation showed the most improvement in heart function and DA% (P < 0.05). This group also showed a denser deposition of BMSCs in the coronary artery and more BrdU positive cells in the infarcted region, had the maximum number of α-actin positive cells, showed the smallest myocardial infarct area compared to other groups (P< 0.05). | Recent studies have reported the association of gamma-glutamyltransferase (GGT) or ferritin with metabolic disorders. However, there has been no large population-based study assessing the interrelationship of these two biomarkers and their association with insulin resistance. A population-based cross-sectional study was carried out in the Chinese Liangshan Yi ethnic group. 756 eligible subjects, aged 20 - 74 years, were included. Demographic characteristics, medical history, and lifestyle data were collected through questionnaires. An oral glucose tolerance test was performed. Laboratory tests, including GGT and ferritin measurements, were conducted. Spearman's rank-order correlation and multiple linear regression were used to calculate the correlation of GGT with ferritin and their relationship to the insulin resistance index determined by the homeostasis model assessment (HOMA-IR). A significant correlation between serum GGT and ferritin levels was found (r = 0.393, p < 0.05). GGT was independently correlated with ferritin after adjustment for age, gender, place of residence, education, income, leisure-time physical activity, drinking, smoking, body mass index, systolic pressure, diastolic pressure, hepatitis B surface antigen, anti-hepatitis C virus, aspartate aminotransferase, alanine aminotransferase, total cholesterol, low density lipoprotein-cholesterol, triglyceride, high density lipoprotein-cholesterol, fasting plasma glucose, 2-hour postprandial plasma glucose, uric acid, and urinary albumin to creatinine ratio (p < 0.05). Positive correlations were established between HOMA-IR and GGT (standard β = 0.252) or ferritin (standard β = 0.181) after adjustment for multiple confounders (p < 0.05). |
Does dry lab practice lead to improved laparoscopic performance in the operating room? | Research has demonstrated that practice in surgical simulators leads to improved performance in that simulator. Our hypothesis is that skills acquired in simulators are transferable to the operating room. Twenty-three laparoscopically naïve surgical interns performed two standardized tasks in a simulator: pegboard transfer and intracorporeal knot tying. Performance was measured using a validated scoring system. On the same day as this initial assessment, subjects were videotaped performing two tasks in a live porcine model: running the small bowel and intracorporeal knot tying. Performance in the porcine model was measured using a modified version of a validated skills assessment tool by two blinded experts. Following a 6-wk proficiency-based dry lab laparoscopic training course, task performance was re-evaluated. No interval live operative laparoscopic experience occurred between the first and second assessment. After training, mean pegboard transfer scores increased from 118.7 to 181.8 (theoretical maximum = 300; P < 0.01). Dry lab knot tying scores increased from 294.7 to 459.0 (theoretical maximum = 600, P < 0.01). In the porcine model, scores for the bowel running task increased from 8.5 to 13.5 (maximum score = 20 for both porcine tasks, P < 0.01). Knot tying scores increased from 7.3 to 14.3 (P < 0.01). | Statin disposition and response are greatly determined by the activities of drug metabolizing enzymes and efflux/ uptake transporters. There is little information on the regulation of these proteins in human cells after statin therapy. In this study, the effects of atorvastatin and simvastatin on mRNA expression of efflux (ABCB1, ABCG2 and ABCC2) and uptake (SLCO1B1, SLCO2B1 and SLC22A1) drug transporters in Caco-2 and HepG2 cells were investigated. Quantitative real-time PCR was used to measure mRNA levels after exposure of HepG2 and Caco-2 cells to statins. Differences in mRNA basal levels of the transporters were as follows: ABCC2>ABCG2>ABCB1>SLCO1B1>>>SLC22A1>SLC O2B1 for HepG2 cells, and SLCO2B1>>ABCC2>ABCB1>ABCG2>>>SLC22A1 for Caco-2 cells. While for HepG2 cells, ABCC2, ABCG2 and SLCO2B1 mRNA levels were significantly up-regulated at 1, 10 and 20 micromol/L after 12 or 24 h treatment, in Caco-2 cells, only the efflux transporter ABCB1 was significantly down-regulated by two-fold following a 12 h treatment with atorvastatin. Interestingly, whereas treatment with simvastatin had no effect on mRNA levels of the transporters in HepG2 cells, in Caco-2 cells the statin significantly down-regulated ABCB1, ABCC2, SLC22A1, and SLCO2B1 mRNA levels after 12 or 24 h treatment. |
Does recurrent recessive mutation in deoxyguanosine kinase cause idiopathic noncirrhotic portal hypertension? | Despite advances in the diagnosis and management of idiopathic noncirrhotic portal hypertension, its pathogenesis remains elusive. Insight may be gained from study of early-onset familial idiopathic noncirrhotic portal hypertension, in which Mendelian mutations may account for disease. We performed exome sequencing of eight subjects from six kindreds with onset of portal hypertension of indeterminate etiology during infancy or childhood. Three subjects from two consanguineous families shared the identical rare homozygous p.N46S mutation in DGUOK, a deoxyguanosine kinase required for mitochondrial DNA replication; haplotype sharing demonstrated that the mutation in the two families was inherited from a remote common ancestor. All three affected subjects had stable portal hypertension with noncirrhotic liver disease for 6-16 years of follow-up. This mutation impairs adenosine triphosphate binding and reduces catalytic activity. Loss-of-function mutations in DGUOK have previously been implicated in cirrhosis and liver failure but not in isolated portal hypertension. Interestingly, treatment of patients with human immunodeficiency viral infection with the nucleoside analogue didanosine is known to cause portal hypertension in a subset of patients and lowers deoxyguanosine kinase levels in vitro; the current findings implicate these effects on deoxyguanosine kinase in the causal mechanism. | To determine whether the number and location of positive surgical margins (PSMs) in radical prostatectomy (RP) surgical specimens affect biochemical recurrence (BCR) rates. The locations of PSMs were recorded for 1308 consecutive men who underwent RP between October 2000 and December 2006. BCR was defined as three consecutive prostate-specific antigen (PSA) level rises with the peak level >or=0.15 ng/mL. Multivariate regression analyses were used to identify preoperative predictors of PSMs and BCR. The estimated 5-year risk of BCR was calculated using the Kaplan-Meier method. In all, 128 (9.8%) men had one or more PSMs. The mean body mass index, mean preoperative serum PSA level, the distributions of clinical stage and biopsy Gleason scores, and the presence or absence of biopsy perineural invasion were significantly different between men with or with no PSMs. In multivariate analysis, baseline serum PSA level, Gleason score and perineural invasion were independent preoperative predictors of PSMs. The 5-year actuarial BCR rates were dependent on the site of the PSM (P = 0.035) and not the number of PSMs (P = 0.18). The rank order of estimated 5-year BCR rates according to the site of PSMs were base > anterior > posterolateral > apex approximately posterior. |
Does inflammatory signaling pathway containing TRAF6 contribute to neointimal formation via diverse mechanisms? | The purpose of this study was to investigate the contribution of inflammatory signaling containing tumor necrosis factor receptor-associated factor 6 (TRAF6) to neointimal formation in a balloon injury model of rabbit carotid artery. Male Japanese white rabbits fed a normal diet were used. We transferred the dominant negative (DN) form of TRAF6 to a rabbit carotid artery that was subjected to balloon injury by in vivo electroporation method, and then evaluated its effect on intimal lesion formation after balloon injury. An expression plasmid vector containing the TRAF6 DN sequence was successfully transferred to arterial wall cells, and its inhibitory effect on inflammatory signaling was confirmed by the marked suppression of nuclear factor-kappaB (NFkappaB) activity after injury. Morphometric analyses revealed significant inhibition of intimal lesion formation at 7 days after injury. Cell replication and accumulation of macrophages in the media were significantly decreased, and apoptosis was enhanced on day 2. Cell migration to the intima was suppressed on day 4. Extracellular signal-regulated kinase1/2 (ERK1/2) activity at 2 h after injury was also down-regulated. Interestingly, intimal cell replication was significantly blocked when TRAF6 DN was transfected at 7 days after injury. | Our objective was to describe the association between voriconazole concentrations and CYP2C19 diplotypes in pediatric cancer patients, including children homozygous for the CYP2C19*17 gain-of-function allele. A linear mixed effect model compared voriconazole dose-corrected trough concentrations (n = 142) among CYP2C19 diplotypes in 33 patients (aged 1-19 years). Voriconazole pharmacokinetics was described by a two-compartment model with Michaelis-Menten elimination. Age (p = 0.05) and CYP2C19 diplotype (p = 0.002) were associated with voriconazole concentrations. CYP2C19*17 homozygotes never attained therapeutic concentrations, and had lower dose-corrected voriconazole concentrations (median 0.01 μg/ml/mg/kg; p = 0.02) than CYP2C19*1 homozygotes (median 0.07 μg/ml/mg/kg). Modeling indicates that higher doses may produce therapeutic concentrations in younger children and in those with a CYP2C19*17/*17 diplotype. |
Do cep70 and Cep131 contribute to ciliogenesis in zebrafish embryos? | The centrosome is the cell's microtubule organising centre, an organelle with important roles in cell division, migration and polarity. However, cells can divide and flies can, for a large part of development, develop without them. Many centrosome proteins have been identified but the roles of most are still poorly understood. The centrioles of the centrosome are similar to the basal bodies of cilia, hair-like extensions of many cells that have important roles in cell signalling and development. In a number of human diseases, such Bardet-Biedl syndrome, centrosome/cilium proteins are mutated, leading to polycystic kidney disease, situs inversus, and neurological problems, amongst other symptoms. We describe zebrafish (Danio rerio) embryos depleted for two uncharacterised, centrosome proteins, Cep70 and Cep131. The phenotype of these embryos resembles that of zebrafish mutants for intraflagellar transport proteins (IFTs), with kidney and ear development affected and left-right asymmetry randomised. These organs and processes are those affected in Bardet-Biedl syndrome and other similar diseases. Like these diseases, the root cause of the phenotype lies, in fact, in dysfunctional cilia, which are shortened but not eliminated in several tissues in the morphants. Centrosomes and basal bodies, on the other hand, are present. Both Cep70 and Cep131 possess a putative HDAC (histone deacetylase) interacting domain. However, we could not detect in yeast two-hybrid assays any interaction with the deacetylase that controls cilium length, HDAC6, or any of the IFTs that we tested. | Acute pain can lead to immune dysfunction, which can be partly ameliorated by successful pain management. Opioids, which are widely used for analgesia, can result in the deterioration of immune function. This study aimed to investigate the influence of morphine with or without flurbiprofen as post-operative analgesics on the immune systems of patients undergoing gastric cancer surgery. 60 patients undergoing gastric cancer surgery were equally randomized into two groups. They received post-operative patient-controlled intravenous (IV) analgesia using morphine either with or without flurbiprofen. Visual analogue scale (VAS) scores, Bruggemann comfort scale (BCS) scores, morphine consumption, time of first flatus, incidence of nausea/vomiting, and T-lymphocyte subsets (CD3⁺, CD4⁺, and CD8⁺) and natural killer cells (CD3⁻CD16⁺CD56⁺) were evaluated. No significant difference was observed in the VAS scores, BCS scores, and nausea/vomiting incidence between groups. Less morphine was consumed and the time of first flatus was earlier in patients receiving morphine with flurbiprofen than morphine alone. The expression of CD3⁺, CD4⁺, CD4⁺/CD8⁺, and CD3⁻CD16⁺CD56⁺ decreased at 2 hours after incision and, except for CD3⁻CD16⁺CD56⁺, returned to baseline at 120 hours after surgery. Moreover, the expression of CD3⁻CD16⁺CD56⁺ at 2 hours after incision and the expression of CD3⁺, CD4⁺, CD4⁺/CD8⁺, and CD3⁻CD16⁺CD56⁺ at 24 hours after surgery were higher in patients receiving morphine with flurbiprofen than morphine alone. |
Is increased tidal volume variability in children a better marker of opioid-induced respiratory depression than decreased respiratory rate? | During opioid administration, decreasing respiratory rate is typically used as a predictor of respiratory depression. Prior to opioid-induced apnea, progressively irregular breathing patterns have been noticed. We hypothesize that opioid administration to children will increase tidal volume variability (TV(var)) and that this will be a better predictor of respiratory depression than a decrease in respiratory rate. We recruited 32 children aged 2-8 years scheduled to undergo surgery. During spontaneous ventilation, flow rates and respiratory rates were continuously recorded, while remifentanil was infused at stepwise increasing doses each lasting 10 min. The infusion was continued until the patient showed signs of respiratory depression. Flow data from each dose was used to calculate tidal volumes, from which TV(var) was calculated. The respiratory rate and TV(var) during the last (D(last)), second to last (D-2), and third to last (D-3), administered doses were compared to those during baseline (fourth to last dose). We chose a threshold of TV(var) increase and compared it to a decrease in respiratory rate below 10 breaths per min as predictors of respiratory depression. Compared to baseline, the TV(var) increased by 336% and 668% during D(-2) and D(last), respectively, whereas respiratory rate decreased by 14.3%, 31.7%, and 55.5% during D(-3), D(-2), and D(last), respectively. A threshold increase in TV(var) of 150% over baseline correctly predicted respiratory depression in 41% of patients, compared to a drop in respiratory rate correctly predicting 22% of patients. | Type 1 diabetes mellitus (DM) is an autoimmune disorder with disturbed glucose/insulin metabolism, which has no medical treatment other than life-long insulin therapy, despite which 30% of subjects develop organ failure. Herein we have reported the use of human adipose-tissue-derived, insulin-making mesenchymal stem cells (h-AD-MSC) transfused with unfractionated cultured bone marrow (CBM) in 5 insulinopenic DM patients. Five (M:F, 2:3) insulinopenic DM patients of 0.6 to 10 years' duration, ages 14 to 28 years under treatment insulin (Human with 14-70 U/d) showed postprandial blood sugars between 156 to 470 mg%, glycosylated hemoglobin 6.8% to 9.9% and c-peptide levels of 0.02 to 0.2 ng/mL. They underwent intraportal administration of xenogeneic-free h-AD-MSC (mean dose = 1.5 mL; cell counts, 2.1 x 10(3)/muL). The CD45-/90+/73(+) cells (29.8/16.8%) showed c-peptide levels of 3.08 ng/mL, insulin level of 1578 micro IU/mL. The aliquot was supplemented with CBM (mean dose 94 mL with cell counts: 18.7 x 10(3)/microL) containing CD45-/34+ elements of 0.93%. The Institutional Review Board approved the study protocol and consent forms. All patients were successfully infused CBM plus h-AD-MSC without any untoward effects and showed 30% to 50% decreased insulin requirements with 4- to 26-fold increased serum c-peptide levels, with a mean follow-up of 2.9 months. |
Does sepsis-induced lung injury in rats increase alveolar epithelial vulnerability to stretch? | Previous in vitro models have shown that cellular deformation causes dose-dependent injury and death in healthy rat alveolar epithelial cells (AECs). We compared the viability of AECs from septic rats with those from nonseptic rats after 1 hr of cyclic equibiaxial stretch. We hypothesized that sepsis would increase stretch-induced cell death. Laboratory investigation. University research laboratory. Thirty-seven male Sprague-Dawley rats weighing 240-260 g. Anesthetized rats were subjected to cecal ligation and double puncture (2CLP) or sham laparotomy without cecal ligation or puncture (sham). After 24 or 48 hrs, AECs were isolated, seeded in custom wells, and maintained in culture for 48 hrs before study. AECs were stretched cyclically (15/min) to a 0%, 12%, 25%, or 37% change in surface area (DeltaSA) for 1 hr. Cell viability, phenotypic markers, and nuclear factor-kappaB intracellular localization were assessed using fluorescent immunocytochemistry. Phase and fluorescent images were evaluated for all studies. Response to stretch was the same at 24 and 48 hrs after 2CLP. Relative to sham, 2CLP significantly increased cell death at 25 and 37% DeltaSA (p<.003, analysis of variance). Relative to sham, 2CLP did not alter expression of type I or type II phenotypic markers. Nuclear factor-kappaB within the nuclear compartment was observed after 2CLP in unstretched cells and after 1 hr of cyclic stretch at 37% DeltaSA. In sham, nuclear factor-kappaB within the nuclear compartment was seen only after stretch. | Mild hyperhomocysteinaemia (HHC) is associated with an increased risk of premature atherothrombotic cerebrovascular disease. We investigated the clinical efficacy with regard to the incidence of cardiovascular events of treatment of mild HHC with vitamin B(6) plus folic acid. We studied 224 consecutive patients with clinically manifest atherothrombotic cerebrovascular disease with onset before the age of 56. Follow-up was obtained in 203 (90.6%) patients. At baseline, 52 (25.6%) were hyperhomocysteinaemic after methionine loading and started treatment with vitamin B(6) (250 mg) plus folic acid (5 mg); 151 (74.4%) were normohomocysteinaemic (reference group). During follow-up (median 57 months), 31 (20.5%) of the normo- and 11 (21.2%) of the hyperhomocysteinaemic patients had a new cardiovascular event. The crude incidence rate per person-year for any cardiovascular event was similar in both groups (0.043 [CI, 0.029-0.057] in the normo- vs. 0.045 [CI, 0.021-0. 069] in the hyperhomocysteinaemic group). Multivariate Cox-regression analyses showed that hypertension and cholesterol levels were associated with an increased risk of new cardiovascular events in the total group [relative risk [RR] (yes vs. no), 7.4 (3. 4-16.0) and RR (per 1 mmol/l), 1.9 (CI, 1.4-2.7)]. The adjusted RR for new cardiovascular events in the hyper- as compared to the normohomocysteinaemic patients was 0.96 (CI, 0.48-1.92). |
Does pain intensity attenuate movement control of the lumbar spine in low back pain? | Pain intensity attenuates muscular activity, proprioception, and tactile acuity, with consequent changes of joint kinematics. People suffering from low back pain (LBP) frequently show movement control impairments of the lumbar spine in sagittal plane. This cross-sectional, observational study investigated if the intensity of LBP attenuates lumbar movement control. The hypothesis was that lumbar movement control becomes more limited with increased pain intensity. The effect of LBP intensity, measured with a numeric rating scale (NRS), on lumbar movement control was tested using three movement control tests. The lumbar range of motion (ROM), the ratio of lumbar and hip ROM as indicators of direction specific movement control, and the recurrence and determinism of repetitive lumbar movement patterns were assessed in ninety-four persons suffering from LBP of different intensity and measured with an inertial measurement unit system. Generalized linear models were fitted for each outcome. Lumbar ROM (+ 0.03°, p = 0.24) and ratio of lumbar and hip ROM (0.01, p = 0.84) were unaffected by LBP intensity. Each one point increase on the NRS resulted in a decrease of recurrence and determinism of lumbar movement patterns (-3.11 to -0.06, p ⩽ 0.05). | Endothelial dysfunction is an initial and vascular smooth muscle cell (VSMC) apoptosis, a later step of atherosclerosis. Hypothyroidism accelerates atherosclerosis. However, the early events responsible for this pro-atherosclerotic effect are unclear. Rats were resistant to induction of atherosclerosis by high cholesterol diet alone, but became susceptible in hypothyroid state achieved by administration of propylthiouracil (PTU) for 6 weeks. VSMC dysfunction and apoptosis were obvious within 1 week after PTU treatment, without signs of endothelial dysfunction. This early VSMC damage was caused by hypothyroidism but not the high cholesterol diet. In ApoE knockout mice, PTU-induced hypothyroidism triggered early VSMC apoptosis, increased oxidative stress, and accelerated atherosclerosis development. Thyroid hormone supplementation (T4, 10, or 50 μg/kg) prevented atherogenic phenotypes in hypothyroid rats and mice. In rats, thyroidectomy caused severe hypothyroidism 5 days after operation, which also led to rapid VSMC dysfunction and apoptosis. In vitro studies did not show a direct toxic effect of PTU on VSMCs. In contrast, thyroid hormone (T3, 0.75 μg/L plus T4, 50 nmol/L) exerted a direct protection against VSMC apoptosis, which was reduced by knockdown of TRα1, rather than TRβ1 and TRβ2 receptors. TRα1-mediated inhibition of apoptotic signalling of JNKs and caspase-3 contributed to the anti-apoptotic action of thyroid hormone. |
Do geographical miss is associated with vulnerable plaque and increased major adverse cardiovascular events in patients with myocardial infarction? | To determine the incidence, characteristics, and outcomes associated with geographical miss (GM) of plaque. GM describes plaques that are incompletely covered following stenting, with GM thought to be associated with worse clinical outcomes. However, the incidence and characteristics of intravascular ultrasound (IVUS)-defined GM plaques have never been studied and the relationship between GM with both short and long-term clinical events is unknown. One hundred and seventy patients with stable angina (n = 100) or myocardial infarction (MI) (n = 70) underwent virtual-histology IVUS (VH-IVUS) prior to, and following, percutaneous coronary intervention (PCI). GM was defined as three consecutive uncovered VH frames, either proximal or distal to the stented segment with plaque burden >40%. MACE was defined as a composite of death, myocardial infarction, unplanned revascularization, or hospitalization for angina. In total, 245 plaques underwent PCI with 80 (32.7%) displaying evidence of GM (69 patients). GM was associated with increased plaque volume (p < 0.001), % necrotic core, and dense calcium (both p < 0.001) and VH-defined thin-cap fibroatheroma (VH-TCFA) (p = 0.01). GM was not associated with increased periprocedural MI (p = 0.15) or inflammatory cytokine release. At follow-up, 42 MACE occurred in 28 patients (median 1,115 days). MACE was attributable to 8/80 (10%) plaques with and 7/165 (4.2%) plaques without GM (log-rank p = 0.11). GM was associated with increased MACE in patients presenting with MI (p = 0.015), but not for those with stable angina (p = 0.94). | Anti-epileptic drugs (AEDs) and the ketogenic diet (KD) are often used concomitantly in children with refractory epilepsy. It has been hypothesised that certain AEDs may interfere with KD. The purpose of this study was to elucidate relationships between efficacy of KD and use of specific AEDs. A retrospective study was performed in 71 children with refractory epilepsy starting the KD between 2008 and 2014 in Erasmus University Hospital Sophia Children's Hospital. Efficacy of the KD (defined as 50% seizure reduction) was evaluated after three months of treatment and related to the AEDs used. The KD was successful after three months in 61% of the children (N=71). Efficacy was significantly reduced if children (n=16) used lamotrigine (31%) at diet initiation or in the course of the diet, compared to other antiepileptic drugs (69%) (p=0.006). In comparison to children using other antiepileptic drugs, the percentage of children that had adequate ketosis was significantly reduced in case of lamotrigine use (p=0.049). |
Is resistance to thrombomodulin associated with de novo portal vein thrombosis and low survival in patients with cirrhosis? | Portal vein thrombosis (PVT) is frequently observed in cirrhosis and may be a clinically important complication. In vitro assays for endogenous thrombin potential (ETP) demonstrated that in cirrhosis plasma has intrinsic resistance to the anticoagulant action of thrombomodulin (TM-R). This study retrospectively explores the association of TM-R with de novo PVT and its clinical impact on cirrhosis. Fifty-three patients with cirrhosis were tested for ETP-ratio with/without thrombomodulin. Clinical, endoscopic variables, presence/absence of PVT by Doppler-US and/or CT examination were collected at baseline and up to 4 years from baseline. The de novo PVT was the primary clinical end-point. Portal hypertension (PHT)-related complications and transplantation free survival were secondary end-points. ETP-ratio higher than the 95° percentile of the distribution in 173 healthy controls defined TM-R. During 48 months of follow-up, 11 patients developed de novo PVT, with preference for the 36 patients with TM-R after adjusting for Child-Pugh class (HR: 8.354; 90%CI:1.475 - 47.305; P = 0.009). Seventeen patients experienced PHT-related complications, 23 either died or underwent liver transplantation. PHT complications and transplantation free survival were associated with TM-R, but were independently predicted by Child-Pugh class, only. Same results were obtained by considering the MELD score. | Sleep disturbances have been thought to augment pain. Sleep deprivation has been proven to produce hyperalgesic effects. It is still unclear whether these changes are truly specific to pain and not related to general changes in somatosensory functions. The aim of the present study was to evaluate the effect of total sleep deprivation on thermal pain thresholds (heat, cold) and pain complaints. Thermal detection thresholds (warmth, cold) were included as covariates to determine the contribution of somatosensory functions to changes in pain processing. Twenty healthy volunteers were randomly assigned either to two nights of total sleep deprivation or to two nights of undisturbed night sleep. Sleep deprivation nights were separated by two days with normal night sleep. Heat and cold pain thresholds as well as warmth and cold detection thresholds were measured by use of a peltier thermode in the evening before and the morning after each deprivation or control night. Pain complaints were examined by use of a questionnaire in parallel. During treatment nights, sleep deprivation produced a significant overnight decrease in heat pain thresholds. Cold pain thresholds tended to decrease also during sleep deprivation, whereas the warmth and cold detection thresholds remained unaffected. Accordingly, no substantial contributions of the changes in thermal detection thresholds to the changes in thermal pain thresholds were determined by regression analyses. Pain complaints were not induced by sleep deprivation. |
Is the relation between hostility and concurrent levels of inflammation sex , age , and measure dependent? | Hostility may be associated with greater systemic inflammation. However, contradictory evidence exists. Certain individuals or dimensions of hostility may be more susceptible to these effects. Main and interactive effects of hostility with sex and/or age were evaluated on markers of inflammation, independently of traditional risk factors for coronary artery disease. 199 healthy men (81) and women (118), aged 20-64 years (M=41 ± 11 years) were recruited. Hostility was assessed using the Cook-Medley Hostility Inventory (CMHo) and ecological momentary assessments (EMA) of quarrelsome behavior and angry affect in daily living. Blood samples were drawn to measure inflammatory activity (Il-6, TNF-α, hsCRP, Il-8, Il-10, Il-18, MCP-1) and lipid oxidation (Myeloperoxidase; MPO). Correlations and hierarchical regression analyses were performed controlling for pertinent behavioral, psychological, medical, and socio-demographic factors. Significant univariate associations emerged between CMHo and Il-6, TNF-α, MCP-1 (p<.05). Hierarchical regressions showed interactions of hostility with sex (Il-6, TNF-α; p<.05) and age (hsCRP, Il-6, TNF-α; p<.05). For example, in simple slope analyses, hostility was positively related to TNF-α in women (b=0.009, p=0.006) but not men. Greater hostility was also related to greater Il-6 levels among younger women (b=. 027, p=0.000). | To evaluate the long-term success rate and complications of nonpenetrating deep sclerectomy with collagen implant in open-angle glaucoma. Clinical, prospective, monocentric, nonrandomized, unmasked study on 105 patients with medically uncontrolled glaucoma. A standard procedure deep sclerectomy with collagen implant was performed. Complete examinations were performed before surgery and postoperatively at 1 and 7 days; 1, 2, 3, 6, 9, and 12 months and then every 6 months during the 10 following years. The mean follow-up was 101.5+/-43.1 (3 to 144) months [mean+/-SD, (range)]. The preoperative intraocular pressure (IOP) was 26.8+/-7.7 (14 to 52) mm Hg and the best-corrected visual acuity 0.71+/-0.33 (0.02 to 1.5). Ten years after surgery IOP was 12.2+/-4.7 (6 to 20) mm Hg and best-corrected visual acuity 0.63+/-0.34 (0.01 to 1.2) (number of remaining patients=52). The mean number of medications per patient went from 2.3+/-0.7 (1 to 4) down to 1.3+/-1.1 (0 to 3). An IOP <or=21 mm Hg without medication was achieved in 47.7% patients and in 89% with or without treatment. One major complication was reported. Goniopuncture was performed in 61 eyes (59.8%), 5-fluorouracil treatment given to 25 patients postoperatively and included needling (n=5). |
Does zinc replenishment reverse overexpression of the proinflammatory mediator S100A8 and esophageal preneoplasia in the rat? | Zinc deficiency is implicated in the pathogenesis of human esophageal cancer. In the rat esophagus, it induces cell proliferation, modulates genetic expression, and enhances carcinogenesis. Zinc-replenishment reverses proliferation and inhibits carcinogenesis. The zinc-deficient rat model allows the identification of biological differences affected by zinc during early esophageal carcinogenesis. We evaluated gene expression profiles of esophageal epithelia from zinc-deficient and replenished rats vs zinc-sufficient rats using microarray analysis. We characterized the role of the top-up-regulated gene S100A8 in esophageal hyperplasia/reversal and in chemically induced esophageal carcinogenesis in zinc-modulated animals by immunohistochemistry and real-time quantitative polymerase chain reaction. The hyperplastic-deficient esophagus has a distinct expression signature with the proinflammation genes S100 calcium binding protein A8 (S100A8) and A9 (S100A9) up-regulated 57-fold and 5-fold, respectively. Zinc replenishment rapidly restored to control levels the expression of S100A8/A9 and 27 other genes and reversed the hyperplastic phenotype. With its receptor for advanced glycation end products (RAGE), colocalization and overexpression of S100A8 protein occurred in the deficient esophagus that overexpressed nuclear factor kappaBeta p65 and cyclooxygenase-2 (COX-2) protein. Zinc replenishment, but not a COX-2 inhibitor, reduced the overexpression of these 4 proteins. Additionally, esophageal S100A8/A9 messenger RNA levels were associated directly with the diverse tumorigenic outcome in zinc-deficient and zinc-replenished rats. | The microcirculation supplies oxygen (O2) and nutrients to all cells with the red blood cell (RBC) acting as both a deliverer and sensor of O2. In sepsis, a proinflammatory disease with microvascular complications, small blood vessel alterations are associated with multi-organ dysfunction and poor septic patient outcome. We hypothesized that microvascular autoregulation-existing at three levels: over the entire capillary network, within a capillary and within the erythrocyte-was impaired during onset of sepsis. This study had three objectives: 1) measure capillary response time within hypoxic capillaries, 2) test the null hypothesis that RBC O2-dependent adenosine triphosphate (ATP) efflux was not altered by sepsis and 3) develop a framework of a pathophysiological model. This was an animal study, comparing sepsis with control, set in a university laboratory. Acute hypotensive sepsis was studied using cecal ligation and perforation (CLP) with a 6-hour end-point. Rat hindlimb skeletal muscle microcirculation was imaged, and capillary RBC supply rate (SR = RBC/s), RBC hemoglobin O2 saturation (SO2) and O2 supply rate (qO2 = pLO2/s) were quantified. Arterial NOx (nitrite + nitrate) and RBC O2-dependent ATP efflux were measured using a nitric oxide (NO) analyzer and gas exchanger, respectively. Sepsis increased capillary stopped-flow (p = 0.001) and increased plasma lactate (p < 0.001). Increased plasma NOx (p < 0.001) was related to increased capillary RBC supply rate (p = 0.027). Analysis of 30-second SR-SO2-qO2 profiles revealed a shift towards decreased (p < 0.05) O2 supply rates in some capillaries. Moreover, we detected a three- to fourfold increase (p < 0.05) in capillary response time within hypoxic capillaries (capillary flow states where RBC SO2 < 20 %). Additionally, sepsis decreased the erythrocyte's ability to respond to hypoxic environments, as normalized RBC O2-dependent ATP efflux decreased by 62.5 % (p < 0.001). |
Does human herpesvirus 6B inhibit cell proliferation by a p53-independent pathway? | Various forms of cellular stress can activate the tumour suppressor protein p53, an important regulator of cell cycle arrest, apoptosis, and cellular senescence. Cells infected by human herpesvirus 6B (HHV-6B) accumulate aberrant amounts of p53. The aim of this study was to investigate the role of p53 accumulation in the HHV-6B-induced cell cycle arrest. The role of p53 was studied using the p53 inhibitor pifithrin-a, and cells genetically deficient in functional p53 by homologous recombination. In response to HHV-6B infection, epithelial cells were arrested in the G1/S phase of the cell cycle concomitant with an aberrant accumulation of p53. However, the known p53-induced mediator of cell cycle arrest, p21, was not upregulated. Approximately 90% of the cells expressed HHV-6B p41, indicative of viral infection. The presence of pifithrin-a, a p53 inhibitor, did not reverse the HHV-6B-induced cell cycle block. In support of this, HHV-6B infection of p53(-/-) cells induced a cell cycle block before S-phase with kinetics similar to or faster than that observed by infection in wt cells. | Chagas heart disease (CHD) patients may have a reduced functional capacity (FC). Field tests, as the Incremental Shuttle Walk Test (ISWT), can estimate peak oxygen uptake (VO2 peak). However, the relationship between the ISWT and the Cardiopulmonary Exercise Testing (CPET), the gold standard in the assessment of FC, is not well established in CHD patients. This study aimed to evaluate the FC of CHD patients by ISWT with direct measurement of VO2 peak and to compare these findings with data obtained from CPET. A secondary goal was to derive a regression equation to calculate the VO2 peak by ISWT. Cross-sectional and correlative study. Research laboratory setting. Thirty-two CHD patients (58.8±9.0 years, 81.3% women) participated in this study. Eligible patients underwent clinical evaluation, echocardiography, CPET by ramp protocol and ISWT according to current guidelines. The distance walked in ISWT showed a positive correlation with VO2 peak from CPET and ISWT (r=0.456, P=0.009 and r=0.869, P<0.001, respectively). In the agreement analysis, the values of the differences between VO2 peak from CPET and ISWT showed absence of bias (mean bias ±95% CI and mean -1.29±5.09 mL.kg.min). Based in real values of VO2 obtained from ISWT, one equation including sex, functional class and distance walked was provided to predict the VO2 values in this test. |
Is d-dimer a significant prognostic factor in patients with suspected infection and sepsis? | The aim of the study was to determine whether C-reactive protein (CRP), procalcitonin (PCT), and d-dimer (DD) are markers of mortality in patients admitted to the emergency department (ED) with suspected infection and sepsis. We conducted a prospective cohort in a university hospital in Medellín, Colombia. Patients were admitted between August 1, 2007, and January 30, 2009. Clinical and demographic data and Acute Physiology and Chronic Health Evaluation II and Sepsis Organ Failure Assessment scores as well as blood samples for CRP, PCT, and DD were collected within the first 24 hours of admission. Survival was determined on day 28 to establish its association with the proposed biomarkers using logistic regression and receiver operating characteristic curves. We analyzed 684 patients. The median Acute Physiology and Chronic Health Evaluation II and Sepsis Organ Failure Assessment scores were 10 (interquartile range [IQR], 6-15) and 2 (IQR, 1-4), respectively. The median CRP was 9.6 mg/dL (IQR, 3.5-20.4 mg/dL); PCT, 0.36 ng/mL (IQR, 0.1-3.7 ng/mL); and DD, 1612 ng/mL (IQR, 986-2801 ng/mL). The median DD in survivors was 1475 ng/mL (IQR, 955-2627 ng/mL) vs 2489 ng/mL (IQR, 1698-4573 ng/mL) in nonsurvivors (P=.0001). The discriminatory ability showed area under the curve-receiver operating characteristic for DD, 0.68; CRP, 0.55; and PCT, 0.59. After multivariate analysis, the only biomarker with a linear relation with mortality was DD, with an odds ratio of 2.07 (95% confidence interval, 0.93-4.62) for values more than 1180 and less than 2409 ng/mL and an odds ratio of 3.03 (95% confidence interval, 1.38-6.62) for values more than 2409 ng/mL. | MiR-138 is frequently downregulated in different cancer types and is thought to be involved in the progression of tumorigenesis. However, the molecular mechanism of miR-138 involvement in gallbladder carcinoma still remains unknown. The expression of miR-138 in 49 gallbladder carcinoma samples and paired normal gallbladder samples was analyzed using quantitative reverse transcription-polymerase chain reaction. The biological functions of miR-138 and Bag-1 (Bcl-2-associated athanogene-1) on cell proliferation were examined using 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide and apoptosis assays. Targets of miR-138 were predicted using bioinformatics and validated using luciferase reporter and Western blot analyses. The in vivo effects of miR-138 were examined using subcutaneous inoculation of gallbladder carcinoma cells in Balb/c nude mice. Compared with their paired normal gallbladder samples, the gallbladder carcinoma samples had decreased expression of miR-138 and increased expression of Bag-1. Overexpression of miR-138 inhibited the proliferation of gallbladder carcinoma cells. Bag-1 was defined as a novel target of miR-138. Both the inhibition of Bag-1 by miR-138 and the silencing of Bag-1 by siRNA led to alterations of apoptosis-related proteins such as Bcl-2 and Bax. Restoring expression of Bag-1 eliminates the effects of miR-138 on cell proliferation and apoptosis. Furthermore, overexpression of miR-138 markedly inhibited the growth of tumors in the gallbladder carcinoma xenograft model in nude mice. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.