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['The aim of this study was to evaluate the relationship between 18F-fluoride bone metabolic measures obtained by nonlinear regression (NLR), Patlak analysis, and standardized uptake value (SUV) for a wide range of normal and pathologic bone conditions. In patients imaged twice, changes in metabolic rates were determined using the different quantitation methods.', 'In 33 patients 2-51 mo after resection of a bone tumor of the limbs, a total of 42 dynamic PET scans were performed after injection of 250-350 MBq 18F-fluoride. SUV, fluoride bone influx rate obtained by Patlak analysis (KPat), and fluoride bone influx rate obtained by NLR (KNLR) were calculated in each patient for the bone graft, the contralateral normal side, and the spine, if within the field of view.', 'SUV ranged from 0.4 to 9.9, KPat from 0.0035 to 0.0742 mL/min/mL, and KNLR from 0.0027 to 0.0737 mL/min/mL. Significant linear correlations were found between KPat and KNLR (r = 0.99), KPat and SUV (r = 0.95), and KNLR and SUV (r = 0.93). Eight patients have been imaged twice within 6 mo. Changes in metabolic values of the grafts were significantly correlated for KPat and KNLR (r = 0.96), KPat and SUV (r = 0.88), and KNLR and SUV (r = 0.79). The 95% ranges of normal change in limb bones were +/-58.0% for SUV, +/-23.0% for KPat, and +/-20.2% for KNLR; the corresponding 95% ranges in the spine were +/-8.6%, +/-7.6%, and +/-19.6%.'] |
['Prior to listing patients for Orthotopic liver transplantation (OLT) an abstention period of 6 months is required. Ethyl glucuronide in the hair is a new reliable marker for the assessment of alcohol consumption. Here, the diagnostic value of determining the ethyl glucuronide concentration in the hair of liver transplant candidates was evaluated.', 'In 63 transplant candidates with alcoholic liver cirrhosis and 25 control patients with cirrhosis of other aetiologies alcohol markers, i.e. hEtG, urine EtG, blood ethanol, methanol and carbohydrate deficient transferrin were determined in parallel to an interview with a psychologist.', 'A total of 19 (30%) transplant candidates admitted alcohol consumption within the last 6 months, while 39/63 (62%) were positive for at least one alcohol marker. In 52% of the 44 candidates denying alcohol consumption, abstention was disproved by detecting at least one positive alcohol marker, in 83% of cases by a positive hEtG result. In the control patients stating abstention from alcohol all hEtG tests were negative. No impact of renal or liver function on hEtG results was detected. A specificity of 98% and a positive predictive value of 92% were calculated for testing hEtG in proximal hair segment and applying a cut-off of 30 pg/mg.'] |
['To investigate whether transvaginal power Doppler imaging of the vascularity improves the ultrasound detection rate of endometrial polyps in symptomatic and asymptomatic patients.', 'Forty-one patients with endometrial polyps confirmed by operative hysteroscopy and histologic examination. They were all examined with grey-scale and subsequent power Doppler enhanced ultrasound preoperatively according to the same protocol. Double layer endometrium and detailed endometrial morphology were described at grey scale scan. With power Doppler imaging pattern of endometrial vascularity. In the presence of a single feeding artery the ultrasound diagnosis of an endometrial polyp was made.', 'With grey-scale imaging 20 polyps (49%) were recognized, while the subsequent application of power Doppler diagnosed the remaining 21 polyps increasing the overall detection rate to 10% (P < 0.01). The grey-scale detection rate for the polyp was 11/30 (0.37) in the asymptomatic patients and 9/11 (82%) in the symptomatic patients. No difference in endometrial thickness was observed. With power Doppler imaging, the detection rate for the feeding arteries was 97% (29/30) in the asymptomatic polyps and a similar 91% (10/11) in the symptomatic polyps. In the 21 polyps, where imaging of the vascularity was the only diagnostic marker, all but two were asymptomatic.'] |
['We evaluated the adequacy of nutrient intake in comparison with the Indonesian Estimated Average Requirement (EARs) among pregnant Indonesian women and explain the short-term effect of economic crisis on nutrient intake and iron status.', 'Cross-sectional study.', 'Purworejo District, Central Java, located 60 km west of Yogyakarta Province, Indonesia.', 'During the period from 1996 to 1998, up to six 24 h recalls were performed during the second trimester of pregnancy among 450 women. Nutrient intake and iron status was evaluated in relation to date of data collection relative to the economic crisis that emerged in August 1997. A computer program (Inafood) was developed to calculate nutrient intake.', ': Forty percent of the pregnant women were at risk of inadequate intake of energy and protein, and 70% were at risk of inadequate intake of vitamin A, calcium and iron even before the crisis. Our results also demonstrate an effect of short-term economic crisis on nutrient intake and iron status. When the crisis emerged, urban poor experienced a decrease in intake of most nutrients. During the crisis, rich women experienced a significant decrease in fat (P<0.05). Negative changes in fat density during crisis were experienced by the rich and the rural, poor, and access to rice field subgroups (P<0.01). A significant increase in carbohydrate densities was seen for the rich and rural, poor, and access to rice fields groups (P<0.05). Urban poor experienced decreased serum ferritin concentration (P<0.05), whereas rich women experienced a significant increase (P<0.05).'] |
['Major depressive disorder is a common disease with serious morbidity, including increased risk of death from suicide. Major depressive disorder is treated with antidepressants. However, the molecular targets of antidepressants remained ill-defined and require further elucidation.', 'Mice were treated with corticosterone to induce stress, amitriptyline and the p38-kinase (p38K) inhibitor SB239063 or a combination of these drugs. Phosphorylation of p38K in hippocampal neurons was determined by immunostaining with a phospho-specific antibody, neuronal proliferation using BrdU-labelling and behaviour employing a set of behavioural tests.', 'Corticosterone induced phosphorylation/activation of p38K in the hippocampus in vivo. Antidepressants reversed the effect of corticosterone on p38K activation in wildtype mice, but had no effect in acid sphingomyelinase-deficient animals. Corticosterone also reduced neurogenesis and triggered depression-like behavioural changes, effects that were prevented by pharmacological inhibition of p38K.'] |
['The objective of this study was to determine if fixed-site high-frequency transcutaneous electrical nerve stimulation (FS-TENS) is effective in treating chronic low back and lower extremity pain.', 'Transcutaneous electrical nerve stimulation is widely used for treatment of chronic pain. General-purpose transcutaneous electrical nerve stimulation devices are designed for stimulation anywhere on the body and often cannot be used while the user is active or sleeping. FS-TENS devices are designed for placement at a pre-determined location, which enables development of a wearable device for use over extended time periods.', 'Study participants with chronic low back and/or lower extremity pain self-administered an FS-TENS device for 60 days. Baseline, 30-, and 60-day follow-up data were obtained through an online questionnaire. The primary outcome measure was the patient global impression of change. Pain intensity and interference were assessed using the Brief Pain Inventory. Changes in use of concomitant pain medications were evaluated with a single-item global self-rating.', 'One hundred and thirty participants were enrolled, with 88 completing the 60-day follow-up questionnaire. Most participants (73.9%) were 50 years of age or older. At baseline, low back pain was identified by 85.3%, lower extremity pain by 71.6%, and upper extremity pain by 62.5%. Participants reported widespread pain, at baseline, with a mean of 3.4 (standard deviation 1.1) pain sites. At the 60-day follow-up, 80.7% of participants reported that their chronic pain had improved and they were classified as responders. Baseline characteristics did not differentiate non-responders from responders. There were numerical trends toward reduced pain interference with walking ability and sleep, and greater pain relief in responders. There was a large difference in use of concomitant pain medications, with 80.3% of responders reporting a reduction compared to 11.8% of non-responders.'] |
['Small-animal models have been used in traumatic brain injury (TBI) research to investigate the basic mechanisms and pathology of TBI. Unfortunately, successful TBI investigations in small-animal models have not resulted in marked improvements in clinical outcomes of TBI patients.', 'To develop a clinically relevant immature large-animal model of pediatric neurocritical care following TBI.', 'Eleven 4-week-old piglets were randomly assigned to either rapid axial head rotation without impact (n = 6) or instrumented sham (n = 5). All animals had an intracranial pressure monitor, brain tissue oxygen tension (Pbto(2)) probe, and cerebral microdialysis probe placed in the frontal lobe and data collected for 6 hours following injury.', 'Injured animals had sustained elevations in intracranial pressure and lactate-pyruvate ratio (LPR), and decreased Pbto(2) compared with sham. Pbto(2) and LPR from separate frontal lobes had strong linear correlation in both sham and injured animals. Neuropathologic examination demonstrated significant axonal injury and infarct volumes in injured animals compared with sham at 6 hours postinjury. Averaged over time, Pbto(2) in both injured and sham animals had a strong inverse correlation with total injury volume. Average LPR had a strong correlation with total injury volume.'] |
["Rimmed vacuoles (RVs) are round-oval cytoplasmic inclusions, detected in muscle cells of patients with myopathies, such as inclusion body myositis (IBM) and distal myopathy with RVs (DMRV). Granulovacuolar degeneration (GVD) bodies are spherical vacuoles containing argentophilic and hematoxyphilic granules, and are one of the pathological hallmarks commonly found in hippocampal pyramidal neurons of patients with aging-related neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. These diseases are common in the elderly and share some pathological features. Therefore, we hypothesized that mechanisms of vacuolar formation in RVs and GVD bodies are common despite their role in two differing pathologies. We explored the components of RVs by immunohistochemistry, using antibodies for GVD markers.", 'Subjects included one AD case, eight cases of sporadic IBM, and three cases of DMRV. We compared immunoreactivity and staining patterns for GVD markers. These markers included: (1) tau-modifying proteins (caspase 3, cyclin-dependent kinase 5 [CDK5], casein kinase 1δ [CK1δ], and c-jun N-terminal kinase [JNK]), (2) lipid raft-associated materials (annexin 2, leucine-rich repeat kinase 2 [LRRK2], and flotillin-1), and (3) other markers (charged multi-vesicular body protein 2B [CHMP2B] and phosphorylated transactive response DNA binding protein-43 [pTDP43]) in both GVD bodies and RVs. Furthermore, we performed double staining of each GVD marker with pTDP43 to verify the co-localization.', 'GVD markers, including lipid raft-associated proteins and tau kinases, were detected in RVs. CHMP2B, pTDP43, caspase 3, LRRK2, annexin 2 and flotillin-1 were detected on the rim and were diffusely distributed in the cytoplasm of RV-positive fibers. CDK5, CK1δ and JNK were detected only on the rim. In double staining experiments, all GVD markers colocalized with pTDP43 in RVs.'] |
['Traditionally, the administration of aspirin is stopped seven days before coronary artery bypass surgery to reduce the risk of postoperative bleeding. The aim of this study was to evaluate the effect of preoperative aspirin on bleeding in these patients.', 'A prospective nonrandomized unblinded study was carried out at the King Abdullah University Hospital in Jordan/Irbid from June 2005 to December 2009 in 756 patients. Patients were divided into 2 groups: Group 1 (n\u2009=\u2009400) consisted of patients on aspirin, 100\u2009mg/day, until the day of surgery; Group 2 (n\u2009=\u2009356) consisted of patients who stopped taking aspirin seven days before surgery. The groups were compared to evaluate the effect of preoperative aspirin on bleeding in patients undergoing elective coronary artery bypass surgery. Data were collected and compared and included total amount of postoperative chest tube drainage, number of transfused units of blood and blood products, and numbers of patients who required reexploration for bleeding. Results were considered significant when P\u2009<\u20090.05.', 'There was no significant increase in the amount of blood loss, units of transfused blood products, or the incidence of reexploration between the two groups ( P\u2009>\u20090.05).'] |
['To assess trends in mortality after burn injuries treated in a regional specialist burns service between 1982 and 2008.', 'Patient and burn-specific information and mortality were collated from written admission ledgers and the hospital coding department for 11,109 patients. The data set was divided into age cohorts (0-14, 15-44, 45-64, and >65 years) and time cohorts (1982-1991, 1992-2000, and 2000-2008). Lethal area 50 (LA50) was calculated by logistic regression and probit analysis. Mortality was related to the Baux score (age + total % burned surface area) by logistic regression.', 'In the time period 2000 to 2008, the LA50 values with approximate 95% confidence intervals (CIs) were 100% (CI, 85.5-100%) in the 0 to 14 cohort (LA10, 78.3%; CI, 64.1-92.5%), 76.4% (CI, 69.1-83.8%) in the 15 to 44 cohort, 58.6% (CI, 50.8-66.5%) in the 45 to 64 cohort, and 30.8% (CI, 24.7-36.9%) in the >65 cohort. The point of futility (the Baux Score at which predicted mortality is 100%) was 160 and the Baux50 (the Baux score at which predicted mortality is 50%) was 109.6 (CI, 105.9-113.4) in the 2000 to 2008 cohort.'] |
['Plasma exchange (PE) is the first-line treatment for primary acquired thrombotic thrombocytopenic purpura (aTTP) with severe deficiency of ADAMTS13 activity (ADAMTS13:AC). Some patients are poor responders to PE, raising concern over multiple pathogenetic pathways.', 'Based on 52 aTTP patients in our national cohort study, we monitored plasma levels of ADAMTS13, clinical and laboratory findings, and outcomes. In a representative poor responder to PE, we examined an ADAMTS13 inhibitor (ADAMTS13:INH) complex in plasma milieu, by means of a large-pore isoelectric focusing (IEF) analysis.', 'Of 52 aTTP patients, 20 were good responders and 32 were poor responders. In the latter group, plasma ADAMTS13:AC levels never increased to more than 10% of normal during 14 days after PE initiation. Mean (±SD) plasma ADAMTS13:INH titers (Bethesda unit/mL) were 5.7 (±4.5) before PE, but decreased to 1.4 (±0.8) on the fourth PE day and then remarkably increased to 14.8 (±10.0) on the 10th PE day, termed "inhibitor boosting," and then slowly decreased to undetectable level over 1 month. On admission, none of the routinely available clinical and laboratory markers differentiated these two groups. However, elevated pre-PE levels of ADAMTS13:INH were correlated with a poor response. We visualized an ADAMTS13:INH (immunoglobulin G) complex in a patient plasma by an IEF analysis and found proteolytic fragment of ADAMTS13 antigen by a two-dimensional IEF and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis.'] |
['Thoracic aortic aneurysm repair with the stented elephant trunk technique seems to be associated with an increased risk of spinal cord injury. We investigated whether severe atherosclerosis of the distal landing zone or extensive deployment of the stented elephant trunk is associated with increased risk of spinal cord injury.', 'Twenty-five patients underwent thoracic aortic aneurysm repair with the stented elephant trunk technique. The study population included 19 men and had a mean age of 73 +/- 7 years. All patients underwent a median sternotomy with cardiopulmonary bypass and selective cerebral perfusion. The elephant trunk was fixed with a Z-stent distal to the aneurysm during hypothermic circulatory arrest. Thirteen patients underwent concomitant total aortic arch replacement.', 'Six (24%) patients had spinal cord injury. The presence of severe atherosclerosis at the distal landing zone demonstrated a tendency to increase the incidence of spinal cord injury (36% vs 9%, P = .1218). More distal deployment of the stented elephant trunk was significantly associated with increased risk of spinal cord injury (T8.0 +/- 0.6 vs T6.5 +/- 1.1, P = .0043). Univariate logistic regression analysis identified a history of abdominal aortic aneurysm repair (P = .0296) and the vertebral level of the distal landing zone (P = .0249) as significant independent risk factors for spinal cord injury, and only the latter was significant in multivariate analysis (P = .0396). The combination of a distal landing zone of T7 or greater and a history of abdominal aortic aneurysm repair was the strongest predictor for spinal cord injury (71% vs 6%, P = .0047).'] |
['Indirect methods to predict the presence of esophageal varices (EV) in patients with cirrhosis are not sensitive enough to be used as a surrogate for endoscopy. We tested the effectiveness of liver stiffness measurement (LSM) by transient elastography and the presence of insulin resistance (IR), a marker associated with fibrosis progression, in the noninvasive prediction of portal hypertension. One hundred four consecutive patients with newly diagnosed Child A hepatitis C virus (HCV) cirrhosis underwent upper gastrointestinal endoscopy to search for EV. Clinical, anthropometric, biochemical, ultrasonographic, and metabolic features, including IR by the homeostasis model assessment (HOMA), and LSM by transient elastography, were recorded at the time of endoscopy. EVs were detected in 63 of 104 patients (60%). In 10 patients (16%), the EVs were medium-large (>or=F2). By multivariate analysis, the presence of EVs was independently associated with a low platelet count/spleen diameter ratio (OR, 0.998; 95% CI, 0.996-0.999) and a high HOMA-IR score (OR, 1.296; 95%CI, 1.018-1.649), not with LSM (OR, 1.009; 95%CI, 0.951-1.070). It is noteworthy that nine of ten patients with medium-large EVs had a platelet/spleen ratio of less than 792 or an HOMA-IR of greater than 3.5. The independent association between low platelet count/spleen diameter ratio (OR, 0.998; 95%CI, 0.996-1.000), high HOMA-IR score (OR, 1.373; 95%CI, 1.014-1.859) and presence of EV was confirmed in the subgroup of 77 nondiabetic subjects.'] |
['This study aimed at investigating whether the orphan nuclear receptor NR4A2 is significantly associated with clinicopathologic features and overall survival of patients with nasopharyngeal carcinoma (NPC).', 'Immunohistochemistry was performed to determine NR4A2 protein expression in 84 NPC tissues and 20 non-cancerous nasopharyngeal (NP) tissues. The prognostic significance of NR4A2 protein expression was evaluated using Cox proportional hazards regression models and Kaplan-Meier survival analysis.', 'We did not find a significant association between total NR4A2 expression and clinicopathological variables in 84 patients with NPC. However, we observed that high cytoplasmic expression of NR4A2 was significantly associated with tumor size (T classification) (P = 0.006), lymph node metastasis (N classification) (P = 0.002) and clinical stage (P = 0.017). Patients with higher cytoplasmic NR4A2 expression had a significantly lower survival rate than those with lower cytoplasmic NR4A2 expression (P = 0.004). Multivariate Cox regression analysis analysis suggested that the level of cytoplasmic NR4A2 expression was an independent prognostic indicator for overall survival of patients with NPC (P = 0.033).'] |
['Early human milk feeding is beneficial for gut and brain development. Persistent ductus arteriosus (PDA) and indomethacin may compromise enteral function in preterm infants. For many years enteral milk feedings have continued in preterm infants receiving indomethacin for PDA. The aim of this study was to investigate whether this strategy is efficient in terms of risks and tolerance to early enteral feeding.', 'This retrospective study included 64 inborn infants of <29 wk gestational age (GA), 32 infants who received indomethacin for symptomatic PDA (case infants) and 32 matched controls. Case infants had a mean (SD) GA of 26.3 wk (1.3) and body weight 839 g (203) versus controls GA 26.4 wk (1.2) and body weight 896 g (213) (p = 0.82 and 0.27, respectively). Case infants had higher respiratory morbidity; 90.6% versus 50% of controls needed mechanical ventilation (p = 0.000).', 'Case infants received human milk from a median (range) age of 4.0 h (1.5-27.5), and controls from 5.3 h (2.0-38.0) (p = 0.092). The first dose of indomethacin was given at a mean age of 1.7 d (1.0). There were no differences between the two groups in feeding volumes or gastric residuals on days 1 to 7. Mean (SD) feeding volume on day 7 was 64 ml/kg (31) in case infants and 76 ml/kg (30) in controls (p = 0.23). Four infants developed necrotizing enterocolitis: two case infants and two controls (p = 1.00).'] |
['Since 1982, specific serotypes of Shiga toxin-producing Escherichia coli (STEC) have been recognized as significant foodborne pathogens acquired from contaminated beef and, more recently, other food products. Cattle are the major reservoir hosts of these organisms, and while there have been advancements in food safety practices and industry standards, STEC still remains prevalent within beef cattle operations with cattle hides implicated as major sources of carcass contamination. To investigate whether the composition of hide-specific microbial communities are associated with STEC prevalence, 16S ribosomal RNA (rRNA) bacterial community profiles were obtained from hide and fecal samples collected from a large commercial feedlot over a 3-month period. These community data were examined amidst an extensive collection of prevalence data on a subgroup of STEC that cause illness in humans, referred to as enterohemorrhagic E. coli (EHEC). Fecal 16S rRNA gene OTUs (operational taxonomic units) were subtracted from the OTUs found within each hide 16S rRNA amplicon library to identify hide-specific bacterial populations.', 'Comparative analysis of alpha diversity revealed a significant correlation between low bacterial diversity and samples positive for the presence of E. coli O157:H7 and/or the non-O157 groups: O26, O111, O103, O121, O45, and O145. This trend occurred regardless of diversity metric or fecal OTU presence. The number of EHEC serogroups present in the samples had a compounding effect on the inverse relationship between pathogen presence and bacterial diversity. Beta diversity data showed differences in bacterial community composition between samples containing O157 and non-O157 populations, with certain OTUs demonstrating significant changes in relative abundance.'] |
['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.'] |
['The role of bile acids for insulin resistance in cholestatic liver disease is unknown.', 'The effect of taurolithocholic acid-3 sulfate (TLCS) on insulin signaling was studied in cultured rat hepatocytes and perfused rat liver.', 'TLCS induced insulin resistance at the level of insulin receptor (IR) beta Tyr(1158) phosphorylation, phosphoinositide (PI) 3-kinase activity and protein kinase (PK)B Ser(473) phosphorylation in cultured hepatocytes. Consistently, the insulin stimulation of the PI 3-kinase-dependent K(+) uptake, hepatocyte swelling and proteolysis inhibition was blunted by TLCS in perfused rat liver. The PKC inhibitor Go6850 and tauroursodeoxycholate (TUDC) counteracted the suppression of insulin-induced IRbeta and PKB phosphorylation by TLCS. Rapamycin and dibutyryl-cAMP, which inhibited basal signaling via mammalian target of rapamycin (mTOR), restored insulin-induced PKB- but not IRbeta phosphorylation. In livers from 7 day bile duct-ligated rats PKB Ser(473) phosphorylation was decreased by about 50%.'] |
['To examine the association between diabetes-related lower-extremity amputation (LEA) and ethnicity, age, source of payment, geographic location, diabetes severity, and health condition in adults with diabetes mellitus type 2 living in border and non-border counties in Texas, United States of America, and to assess intra-border region geographic differences in post-LEA treatment.', 'This correlational study was based on secondary data from the 2003 Texas Inpatient Hospital Discharge Data. The sample consisted of individuals 45 years of age and older with type 2 diabetes who had undergone a nontraumatic LEA (n = 5,865). Descriptive statistics and logistic regression analyses were applied.', 'The following characteristics were predictors of LEA: being Hispanic or African American, male, ≥ 55 years old, and a Medicare or Medicaid user, and living in a border county. Persons with moderate diabetes and those who suffered from cardiovascular disease or stroke also had higher odds of undergoing an LEA. Post-LEA occupational therapy was significantly less prevalent among border residents (9.5%) than non-border residents (15.3%) (P < 0.001).'] |
['Melanoma progression occurs through three major stages: radial growth phase (RGP), confined to the epidermis; vertical growth phase (VGP), when the tumor has invaded into the dermis; and metastasis. In this work, we used suppression subtractive hybridization (SSH) to investigate the molecular signature of melanoma progression, by comparing a group of metastatic cell lines with an RGP-like cell line showing characteristics of early neoplastic lesions including expression of the metastasis suppressor KISS1, lack of alphavbeta3-integrin and low levels of RHOC.', 'Two subtracted cDNA collections were obtained, one (RGP library) by subtracting the RGP cell line (WM1552C) cDNA from a cDNA pool from four metastatic cell lines (WM9, WM852, 1205Lu and WM1617), and the other (Met library) by the reverse subtraction. Clones were sequenced and annotated, and expression validation was done by Northern blot and RT-PCR. Gene Ontology annotation and searches in large-scale melanoma expression studies were done for the genes identified.', 'We identified 367 clones from the RGP library and 386 from the Met library, of which 351 and 368, respectively, match human mRNA sequences, representing 288 and 217 annotated genes. We confirmed the differential expression of all genes selected for validation. In the Met library, we found an enrichment of genes in the growth factors/receptor, adhesion and motility categories whereas in the RGP library, enriched categories were nucleotide biosynthesis, DNA packing/repair, and macromolecular/vesicular trafficking. Interestingly, 19% of the genes from the RGP library map to chromosome 1 against 4% of the ones from Met library.'] |
['Recent evidence suggests axonal injury after aneurysmal subarachnoid haemorrhage (aSAH). The microtubule-associated protein, tau, has been shown to be elevated in the cerebrospinal fluid after aSAH, however, brain extracellular tau levels and their relation to long-term neurological and cognitive outcomes have not been investigated.', 'Serial cerebral microdialysis (CMD) samples were collected from 22 consecutive aSAH patients with multimodal neuromonitoring to determine CMD-total-tau by ELISA. CMD-total-tau was analysed considering other brain metabolic parameters, brain tissue oxygen tension (PbtO2), and functional and neuropsychological outcome at 12\u2005months. All outcome models were analysed using generalised estimating equations with an autoregressive working correlation matrix to account for multiple measurements of brain extracellular proteins per subject.', 'CMD-total-tau levels positively correlated with brain extracellular fluid levels of lactate (r=0.40, p<0.001), glutamate (r=0.45, p<0.001), pyruvate (r=0.26, p<0.001), and the lactate-pyruvate ratio (r=0.26, p<0.001), and were higher in episodes of hypoxic (PbtO2<20\u2005mm\u2005Hg) brain extracellular lactate elevation (>4\u2005mmol/L) (p<0.01). More importantly, high CMD-total-tau levels were associated with poor functional outcome (modified Rankin Scale ≥4) 12\u2005months after aSAH even after adjusting for disease severity and age (p=0.001). A similar association was found with 3/5 neuropsychological tests indicative of impairments in cognition, psychomotor speed, visual conceptualisation and frontal executive functions at 1\u2005year after aSAH (p<0.01).'] |
['Colorectal cancer (CRC) is the second most common cancer in the Kingdom of Saudi Arabia with ever increasing incidence rates. DNA methylation is a common event in CRC where it is now considered an important phenomenon in CRC carcinogenesis and useful for the classification and prognosis of CRC.', 'To gain insight into the molecular mechanisms underpinning CRC in Saudi Arabian patients, we profiled the DNA methylation frequency of key genes (MLH1, MSH2, RASSF1A, SLIT2, HIC1, MGMT, SFRP1, MYOD1, APC, CDKN2A, as well as five CIMP markers) in 120 sporadic CRC cases. CRC tumors originating from the rectum, left, and right colons are represented in this cohort of formalin-fixed paraffin-embedded tissues.', 'The most common methylation frequency was detected in the polycomb group target genes (PCGT) including SFRP1 (70%), MYOD1 (60.8%), HIC1 (61.7%), and SLIT2 (56.7%). In addition, MGMT methylation was detected at a high frequency (68.3%). RASSF1A, APC, and CDKN2A methylation frequencies were 42.5%, 25%, and 32.8%, respectively. K-means clustering analysis of the methylation events results in the clustering of the CRC samples into three groups depending on the level of methylation detected.'] |
['This study evaluated the impact of an eight-session training program for aged care staff in managing dementia-related challenging behaviours. Participation in the training program with an additional five-session peer support group was compared with both participation in training only and a wait-list control condition.', 'Outcomes were evaluated for 90 participating staff members and 113 residents with challenging behaviours from six aged care facilities. Measures of staff attitudes and the behaviours of staff and residents were collected pre- and post-intervention, and at six month follow-up.', 'Staff members in both dementia training groups reported improved attitudes regarding their knowledge and skills in managing residents with challenging behaviours, immediately after the training and six months later. Facility supervisors rated the nursing performance of trained staff more positively, particularly those who participated in a peer support group. The dementia training programs, whether with or without the inclusion of peer support, did not impact on levels of staff burnout or substantially reduce the level of challenging behaviours among aged care residents.'] |
['Scutellaria barbata D.Don has been applied to treat cancers, inflammation and urinary disease. However, its antitumor mechanism still remains unclear.', 'With methylene chloride fraction of Herba Scutellariae barbatae (MCSB), apoptosis-related experiments were carried out on human U937 leukemia cells by (a) 2,3-bis[2-4-nitro-5-sulphophenyl]2H-tetrazolium-5-carboxanilide (XTT) assay for cytotoxicity; (b) terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) assay for morphological changes; (c) cell cycle analysis; (d) Western blot analysis of poly(ADP-ribose) polymerase (PARP), caspase-8, caspase-9, caspase-3 and Bax, Bcl-2 and cytochrome c expressions for apoptosis signaling pathway.', 'MCSB inhibited the proliferation of human U937 leukemia cells in a dose-dependent manner (IC50 = approximately 10 microg/ml). MCSB dose-dependently increased the sub-G1 DNA contents by cell cycle analysis. DNA fragments indicating induction of apoptosis were observed in MCSB-treated U937 cells by TUNEL assay. Caspase-9 and caspase-3 were activated while caspase-8 was intact by MCSB. Similarly, MCSB effectively cleaved PARP, increased the ratio of Bax/Bcl-2 and released the cytochrome c from mitochondria during apoptosis in U937 cells.'] |
["The strong predilection for thyrotoxic periodic paralysis (TPP) to occur in males suggests androgen may contribute to its pathogenesis. We therefore sought to determine if serum total and free testosterone (TT and FT) concentrations differed among patients with TPP during episodes of paralysis, patients with TPP between episodes of paralysis, and patients with Graves' disease (GD) not having TPP.", 'A total of 105 Chinese men were included in the study, and were divided into three groups. Group 1 consisted of men with TPP who were studied during episodes of paralysis; group 2 consisted of men with TPP who were studied between episodes of paralysis; group 3 consisted of men with GD not having TPP. Patients in each were different persons. Serum electrolytes, free triiodothyronine (FT3), free thyroxine (FT4), TT, and FT were measured. Multiple regression analyses and analysis of covariance were performed to analyze the relationship of serum parameters, group status, and age.', 'One multiple regression analysis was used to determine if serum TT concentrations were associated with age, FT3, FT4, or group status. This analysis indicated that age, FT4 level, and group status were significantly and independently associated with serum TT concentrations. With regard to group status, patients in group 1 had serum TT concentrations 0.92 ng/mL higher than patients in group 3 (p=0.033). As to FT4 level, TT concentrations increased by 0.016 ng/mL for each additional pmol/L of FT4 (p=0.002). Another multiple regression analysis was used to determine if serum FT concentrations were associated with age, FT3, FT4, group status, or serum TT concentrations. This analysis revealed that serum TT concentrations and group status were significantly and independently associated with serum FT concentrations. In terms of group status, patients in group 1 had serum FT concentrations of 2.11 pg/mL greater on average than patients in group 3 (p=0.006).'] |
['The glomerular filtration rate (GFR) estimating equation incorporating both cystatin C and creatinine perform better than those using creatinine or cystatin C alone in patients with reduced GFR. Whether this equation performs well in kidney transplant recipients cross-sectionally, and more importantly, over time has not been addressed.', 'We analyzed four GFR estimating equations in participants of the Angiotensin II Blockade for Chronic Allograft Nephropathy Trial (NCT 00067990): Chronic Kidney Disease Epidemiology Collaboration equations based on serum cystatin C and creatinine (eGFR (CKD-EPI-Creat+CysC)), cystatin C alone (eGFR (CKD-EPI-CysC)), creatinine alone (eGFR (CKD-EPI-Creat)) and the Modification of Diet in Renal Disease study equation (eGFR (MDRD)). Iothalamate GFR served as a standard (mGFR).', 'mGFR, serum creatinine, and cystatin C shortly after transplant were 56.1 ± 17.0 ml/min/1.73 m(2), 1.2 ± 0.4 mg/dl, and 1.2 ± 0.3 mg/l respectively. eGFR (CKD-EPI-Creat+CysC) was most precise (R(2) = 0.50) but slightly more biased than eGFR (MDRD); 9.0 ± 12.7 versus 6.4 ± 15.8 ml/min/1.73 m(2), respectively. This improved precision was most evident in recipients with mGFR >60 ml/min/1.73 m(2). For relative accuracy, eGFR (MDRD) and eGFR (CKD-EPI-Creat+CysC) had the highest percentage of estimates falling within 30% of mGFR; 75.8 and 68.9%, respectively. Longitudinally, equations incorporating cystatin C most closely paralleled the change in mGFR.'] |
['Exposure of human pre-osteoclasts to the MDM2 antagonist Nutlin-3 activated the p53 pathway and significantly decreased the entry of pre-osteoclasts in the S phase in response to RANKL. Moreover, repeated exposure to Nutlin-3 suppressed osteoclastic differentiation, without affecting cell survival at any culture time.', 'The p53 oncosuppressor coordinates an intracellular network involved in protection from malignant transformation and cell cycle control; its activation is tightly regulated by the murine double minute 2 (MDM2) gene and p53-MDM2 interaction can be disrupted by selective small molecule inhibitors, the Nutlins. Although the ability of Nutlins to suppress the growth of wildtype p53 tumors has been clearly established, their biological activity in normal cells and tissues has not been extensively studied.', 'Peripheral blood mononuclear cell pre-osteoclasts were cultured with macrophage-colony stimulating factor (M-CSF) + RANKL or co-cultured with SaOS-2 osteosarcoma cells in the presence of IL-1beta to induce osteoclastic differentiation. Cell cycle was analyzed by BrdU incorporation. The degree of osteoclastic differentiation was monitored at different culture times by TRACP and DAPI staining, as well as by TRACP-5b ELISA. Finally, the role of p53 in mediating the biological activity of Nutlin-3 was studied using specific siRNA.', 'Exposure of human pre-osteoclasts to RANKL induced an early (24 h) increase in the percentage of cells in the S phase, followed by the exit from the cell cycle at later time-points. The simultaneous addition of Nutlin-3 and RANKL dose-dependently decreased the percentage of pre-osteoclasts in the S phase and induced a rapid accumulation of p53 protein coupled with the induction of p53 target genes. Unexpectedly, the administration of Nutlin-3 to pre-osteoclasts at early culture times significantly suppressed the final output of osteoclasts at day 14 of culture. The role of p53 in mediating this biological activity of Nutlin-3 was underscored by gene knockdown experiments, in which the anti-osteoclastic activity of Nutlin-3 was significantly counteracted by siRNA specific for p53. Nutlin-3 also significantly decreased the formation of osteoclasts in a co-culture system of SaOS-2 osteosarcoma and pre-osteoclastic cells.'] |
['The current Society for Vascular Surgery Clinical Practice Guidelines suggest urgent (<24\xa0hours) thoracic endovascular aortic repair for grade (G) II to G IV blunt thoracic aortic injuries (BTAIs). The purpose of this study was to determine whether some patients may require more emergency treatment.', 'We reviewed imaging variables of prospectively collected BTAI patients between 1999 and 2014. We used computed tomographic angiography to classify BTAIs into four categories: G I, intimal tear; G II, intramural hematoma; G III, aortic pseudoaneurysm; and G IV, free rupture. Specific examination of G III injuries was undertaken in an effort to predict aortic-related mortality (ARM) before repair. For this subset, we examined pseudoaneurysm size, lesion/normal aortic diameter ratio, and mediastinal hematoma location and size.', 'Among 331 patients with BTAIs, 86 died before imaging. Admission computed tomographic angiography was available for 205 patients (71.2% male; mean age, 39.3\xa0years) with BTAIs (24\xa0G I, 49\xa0G II, 124\xa0G III, 8\xa0G IV). The mean Injury Severity Score was 35.6, and 22.4% had hypotension (<90\xa0mm Hg). Overall mortality was 11.2% (G I/G II, 4.1%; G III/G IV, 15.3%; P\xa0= .02). ARM was 2.4% (G I/G II, 0%; G III/G IV, 3.8%; P\xa0= .09). ARM was significantly greater in G IV (3 of 8 [37.5%]) than G III (2 of 124 [1.6%]) vs G I/II (0 of 73 [0%]) injuries (P\xa0< .0001). Medical management alone was used in 53 (20\xa0G I, 18\xa0G II, 13\xa0G III, and 2\xa0G IV). Open repair was performed in 51 (3\xa0G I, 9\xa0G II, 36\xa0G III, and 3\xa0G IV) at a mean time to repair (TTR) of 10.6\xa0hours. Thoracic endovascular aortic repair was conducted for 101 patients (1\xa0G I, 22\xa0G II, 75\xa0G III, and 3\xa0G IV) at a mean TTR of 9.4\xa0hours. Median TTR for the overall population of BTAI patients was 24.0\xa0hours from admission. (G I, 64.5\xa0hours; G II, 24.0\xa0hours; G III, 19.7\xa0hours; and G IV, 3.5\xa0hours). ARM occurred in four of five patients before planned repair (2\xa0G III and 2\xa0G IV), 7.0\xa0± 3.6\xa0hours from admission. No G I/II ARM occurred. Among eight G IV injuries, there were three ARMs. Focus on G III injuries through regression analysis demonstrated that early clinical/imaging variables (eg, mediastinal hematoma dimensions and lesion/normal aortic diameter ratio) were not significant predictors of ARM.'] |
['To determine the impact of the peak E(2) level and its midluteal decline on IVF-ET outcome in a group of normal- and high-responding patients.', 'Retrospective analysis of IVF-ET data.', 'Tertiary-care, university-affiliated teaching hospital.', 'A total of 100 patients aged </=38 years and receiving up to three embryos per transfer who underwent a similar standard controlled ovarian hyperstimulation for IVF-ET.', 'Morning blood was collected on days 0 (hCG day), +9, and +14.', 'Treatment cycle hormonal characteristics and percent midluteal E(2) decline in conception and nonconception cycles.', 'Among all cycles, a mean decline of 95.0% in serum E(2) was observed at the midluteal phase. No significant differences were found in various parameters comparing conception with nonconception cycles. Occurrence of conception did not correlate with the absolute E(2) level or with percent E(2) decline in good and high responders. Early spontaneous abortion occurred more frequently in high responders with >98% E(2) decline; however, the difference did not reach statistical significance.'] |
['Four Italian regions have cost coding for outpatient capsule-endoscopy. Elsewhere it is performed in ordinary hospital admission. To identify, in a cohort of patients of a Gastroenterology Unit, those feasible for outpatient versus inpatient treatment; to analyze costs distribution in both management areas.', 'We retrospectively analysed 100 clinical records of admissions to A.O. San-Carlo-Borromeo, Milan between 2005-2008. Hospitalization criteria (at least 3): 1) occult/obscure gastrointestinal bleeding; 2) hemoglobin ≤ 8 gr/dL; 3) indication for blood transfusions; 4) urgent hospital admission.', 'A total of 62 patients had urgent admission, 60 blood transfusions, 81 underwent EGD and colonoscopy, 8 enteroscopy and 5 surgery. Mean haemoglobin value was 8.67 g/dL. Capsule-endoscopy was positive in 70, uncertain in 8, negative in 22. Positive cases: 33 angiodyplasia, 18 ulcers/erosions, 13 polyps/masses, 5 overt bleeding, 1 celiac disease. 47/100 were appropriate as outpatient, saving 432 days of hospital stays. Admission coding was grouped into 7 DRGs (overall expense: 98,366 Euros). Considering EGD/colonoscopy outpatient costs and 1.100 euros as estimated value for capsule-endoscopy, the total expense could be 53.919.'] |
['p53 abnormality and aneuploidy often coexist in human tumors, and tetraploidy is considered as an intermediate between normal diploidy and aneuploidy. The purpose of this study was to investigate whether and how p53 influences the transformation from tetraploidy to aneuploidy.', 'Live cell imaging was performed to determine the fates and mitotic behaviors of several human and mouse tetraploid cells with different p53 status, and centrosome and spindle immunostaining was used to investigate centrosome behaviors. We found that p53 dominant-negative mutation, point mutation, or knockout led to a 2∼ 33-fold increase of multipolar mitosis in N/TERT1, 3T3 and mouse embryonic fibroblasts (MEFs), while mitotic entry and cell death were not significantly affected. In p53-/- tetraploid MEFs, the ability of centrosome clustering was compromised, while centrosome inactivation was not affected. Suppression of RhoA/ROCK activity by specific inhibitors in p53-/- tetraploid MEFs enhanced centrosome clustering, decreased multipolar mitosis from 38% to 20% and 16% for RhoA and ROCK, respectively, while expression of constitutively active RhoA in p53+/+ tetraploid 3T3 cells increased the frequency of multipolar mitosis from 15% to 35%.'] |
['Mycophenolate Mofetil (MMF) has been shown to significantly decrease the number of acute rejection episodes in renal transplant recipients during the 1st year. A beneficial effect of MMF on long-term graft survival has been more difficult to demonstrate. This beneficial effect has not been detected, despite the impact of acute rejection on the development of chronic allograft nephropathy and experimental evidence that MMF may have a salutary effect on chronic allograft nephropathy independent of that of rejection.', 'Data on 66,774 renal transplant recipients from the U.S. renal transplant scientific registry were analyzed. Patients who received a solitary renal transplant between October 1, 1988 and June 30, 1997 were studied. The Cox proportional hazard regression was used to estimate relevant risk factors. Kaplan-Meier analysis was performed for censored graft survival.', 'MMF decreased the relative risk for development of chronic allograft failure (CAF) by 27% (risk ratio [RR] 0.73, P<0.001). This effect was independent of its outcome on acute rejection. Censored graft survival using MMF versus azathioprine was significantly improved by Kaplan-Meier analysis at 4 years (85.61% v. 81.9%). The effect of an acute rejection episode on the risk of developing CAF seems to be increasing over time (RR=1.9, 1988-91; RR=2.9, 1992-94; RR=3.7, 1995-97).'] |
['Heat stress induces various physiological changes and so could influence ocular circulation. This study examined the effect of heat stress on ocular blood flow.', "Ocular blood flow, end-tidal carbon dioxide (P(ET)CO2) and blood pressure were measured for 12 healthy subjects wearing water-perfused tube-lined suits under two conditions of water circulation: (1) at 35 °C (normothermia) for 30 min and (2) at 50 °C for 90 min (passive heat stress). The blood-flow velocities in the superior temporal retinal arteriole (STRA), superior nasal retinal arteriole (SNRA), and the retinal and choroidal vessels (RCV) were measured using laser-speckle flowgraphy. Blood flow in the STRA and SNRA was calculated from the integral of a cross-sectional map of blood velocity. PETCO2 was clamped at the normothermia level by adding 5% CO2 to the inspired gas. Passive heat stress had no effect on the subjects' blood pressures. The blood-flow velocity in the RCV was significantly lower after 30, 60 and 90 min of passive heat stress than the normothermic level, with a peak decrease of 18 ± 3% (mean ± SE) at 90 min. Blood flow in the STRA and SNRA decreased significantly after 90 min of passive heat stress conditions, with peak decreases of 14 ± 3% and 14 ± 4%, respectively."] |
['The possible association between coronary artery disease (CAD) and Chlamydia pneumoniae (C pneumoniae) infection is controversial. On the basis of the recent suggestion that mannose-binding lectin (MBL) variant alleles are related to an increased risk of severe atherosclerosis, and on the in vitro interaction of MBL with C pneumoniae, we asked whether MBL might contribute to CAD in conjunction with C pneumoniae.', 'Antibodies to C pneumoniae were measured by immunofluorescence and MBL alleles were determined by polymerase chain reaction technique in samples from 210 patients with CAD and 257 healthy subjects from Hungary collected between 1995 and 1996. A higher percentage of patients with CAD were anti-C pneumoniae positive as compared with the control group (P=0.058). However, at logistic regression analysis adjusted to age, sex, and serum lipid levels, this difference was confined only to subjects carrying MBL variant alleles (P=0.035, odds ratio 2.63, [95% CI: 1.07 to 6.45]). In contrast, no significant difference was seen in those homozygous for the normal MBL allele (P=0.412). During a 65+/-5.8-month follow-up period, major outcomes (new myocardial infarction, and/or bypass operation or cardiovascular death) occurred in 11 C pneumoniae positive and 3 C pneumoniae negative patients. In the C pneumoniae positive group, the odds ratio of development of outcomes was 3.27 (95% CI: 1.10 to 9.71, P=0.033) in the carriers of the MBL variant alleles compared with the homozygous carriers of the normal MBL allele.'] |
['Reperfusion injury is a vital problem in non-heart-beating donor (NHBD) organs. The sodium-hydrogen inhibitor cariporide is thought to improve cellular integrity after ischemia and reperfusion. Recently, we demonstrated the possibility of preserving hearts with in situ perfusion after circulatory death. The purpose of this study was to determine whether cariporide improves in situ heart protection.', 'We studied 20 pigs (18 +/- 2 kg). Hearts in the conventional group (CON, n = 6) underwent cardioplegic arrest with University of Wisconsin solution and then were explanted and stored for 150 minutes on ice. In the other groups, a catheter was placed in each ascending aorta and right atrium. After disconnecting the ventilator, hypoxia caused circulatory arrest within 7 +/- 2 minutes. The aorta was endoclamped, and continuous in situ perfusion of the aortic root was maintained for 60 minutes with University of Wisconsin solution (UW, n = 7) or with UW solution and cariporide (CAR, n = 7). After explantation, the hearts were stored on ice for 90 minutes. In all groups, hearts were reperfused with homologous, whole pig blood in an isolated working heart model for 45 minutes. We monitored stroke-work index on-line, intermittently measured troponin I and malondialdehyde, and compared light microscopic examinations among the groups.', 'Stroke-work index was higher in the CAR group compared with the UW group during the last 20 minutes of reperfusion (10(3)dynes x cm x beats(-1)x gm(-1), 6.6 +/- 1.4 vs 4.5 +/- 2.0, p < 0.05), troponin I was lower in the CAR group compared with the UW group (161 +/- 32 ng/ml vs 277 +/- 35 ng/ml, p < 0.05). Results of malondialdehyde and light microscopic examinations were slightly better in the CAR group, without reaching statistical significance.'] |
['Clinical characteristics and control of the infection of patients with culture-negative (CN) prosthetic joint infection (PJI) have not been well assessed. Prior use of antimicrobial therapy has been speculated but not proven as a risk factor for CNPJI.', 'We therefore determined whether prior use of antimicrobial therapy, prior PJI, and postoperative wound healing complications were associated with CN PJI.', 'We performed a retrospective case-control study of 135 patients with CN PJI treated between January 1, 1985, and December 31, 2000 matched with 135 patients with culture-positive (CP) PJIs (control patients) during the study period. The time to failure of therapy compared between cases and control patients using a Kaplan-Meier analysis.', 'The use of prior antimicrobial therapy and postoperative wound drainage after index arthroplasty were associated with increased odds of PJI being culture-negative (odds ratio, 4.7; 95% CI, 2.8-8.1 and odds ratio, 3.5; 95% CI, 1.5-8.1, respectively). The percent (+/- SE) cumulative incidence free of treatment failure at 2 years followup was similar for CN and CP PJI: 75% (+/- 4%) and 79% (+/- 4%), respectively.'] |
['Taspine, isolated from Radix et Rhizoma Leonticis has demosntrated potential proctiective effects against cancer. Tas13D, a novel taspine derivative synthetized by structure-based drug design, have been shown to possess interesting biological and pharmacological activities. The current study was designed to evaluate its antiproliferative activity and underlying mechanisms.', 'Antiproliferative activity of tas13D was evaluated by xenograft in athymic mice in vivo, and by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and cell migration assays with human liver cancer (SMMC-7721) cell lines in vitro. Docking between tas13D and VEGFR and EGFR was studied by with a Sybyl/Surflex module. VEGF and EGF and their receptor expression was determined by ELISA and real-time PCR methods, respectively.', 'Our present study showed that tas13D inhibited SMMC-7721 xenograft tumor growth, bound tightly with the active site of kinase domains of EGFR and VEGFR, and reduced SMMC-7721 cell proliferation (IC=34.7 μmol/L) and migration compared to negative controls. VEGF and EGF mRNAs were significantly reduced by tas13D treatment in a dose-dependent manner, along with VEGF and EGF production.'] |
['The COLIA1 gene is a strong candidate for susceptibility to osteoporosis. The causal genetic variants are currently unclear, but the most likely are functional polymorphisms in the promoter and intron 1 of COLIA1.', 'The objective of the study was to determine whether promoter and intron 1 polymorphisms of COLIA1 or haplotypes defined by these polymorphisms regulate bone mineral density (BMD) in women.', 'This was a population-based association study involving 3270 women from the United Kingdom who took part in a regional osteoporosis screening program.', 'BMD at the lumbar spine (LS-BMD) and femoral neck (FN-BMD) was measured on two occasions approximately 6 yr apart, in relation to polymorphisms and haplotypes defined by polymorphisms within the COLIA1 intron 1 (+1245G/T; rs1800012) and promoter (-1997G/T; rs1107946; -1663IndelT; rs2412298).', 'The polymorphisms were in strong linkage disequilibrium, and three haplotypes accounted for more than 95% of alleles at the COLIA1 locus. The individual polymorphisms were associated with BMD, but the most consistent associations were with haplotypes defined by all three polymorphisms. Homozygote carriers of haplotype 2 (-1997G/-1663delT/+1245T) had reduced BMD at baseline (P = 0.007 for LS-BMD; P = 0.008 for FN-BMD), whereas homozygotes for haplotype 3 (-1997T/-1663insT/+1245G) had increased BMD (P = 0.007 for LS-BMD). Similar associations were observed at follow-up for haplotype 3, but the association with haplotype 2 was weaker due to increased uptake of hormone replacement therapy in homozygotes for this haplotype.'] |
['The DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents, and its loss in cancer cells is associated with hypermethylation of the MGMT CpG island. Thus, methylation of MGMT has been correlated with the clinical response to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in primary gliomas. Here, we investigate whether the presence of MGMT methylation in gliomas is also a good predictor of response to another emergent alkylating agent, temozolomide.', 'Using a methylation-specific PCR approach, we assessed the methylation status of the CpG island of MGMT in 92 glioma patients who received temozolomide as first-line chemotherapy or as treatment for relapses.', 'Methylation of the MGMT promoter positively correlated with the clinical response in the glioma patients receiving temozolomide as first-line chemotherapy (n = 40). Eight of 12 patients with MGMT-methylated tumors (66.7%) had a partial or complete response, compared with 7 of 28 patients with unmethylated tumors (25.0%; P = 0.030). We also found a positive association between MGMT methylation and clinical response in those patients receiving BCNU (n = 35, P = 0.041) or procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (n = 17, P = 0.043) as first-line chemotherapy. Overall, if we analyze the clinical response of all of the first-line chemotherapy treatments with temozolomide, BCNU, and procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea as a group in relation to the MGMT methylation status, MGMT hypermethylation was strongly associated with the presence of partial or complete clinical response (P < 0.001). Finally, the MGMT methylation status determined in the initial glioma tumor did not correlate with the clinical response to temozolomide when this drug was administered as treatment for relapses (P = 0.729).'] |
['Obesity is an increasing burden affecting developed and emerging societies since it is associated with an increased risk of diabetes and consequent cardiovascular complications. Increasing evidence points towards a pivotal role of inflammation in the etiology of vascular dysfunction. Our study aimed to investigate signs of inflammation and their relation to vascular dysfunction in rats receiving a high fat diet.', 'Diet-induced obese (DIO) rats were used as a model since these rats exhibit a human pre-diabetic pathology. Oral glucose and insulin tolerance tests were conducted on DIO rats and their controls prior to the development of insulin resistance. Furthermore, the plasma contents of selected cytokines [macrophage chemoattractant protein (MCP-1), interleukin-6 (IL-6), and interleukin-1 (IL-1)] and the concentration of adiponectin were measured. Using wire myography, we tested the vascular function of isolated small mesenteric arteries.', 'DIO animals had significantly (p < 0.05) increased body weight (721.2 ± 6.3 g) compared to age- and sex-matched controls (643.4 ± 14.6 g), as well as a significant increase (p < 0.01) in body fat percentage (29.7 ± 1.7% and 22.7 ± 0.97%, respectively). No significant difference in fasting plasma insulin levels could be detected between the two groups (chow-fed group 141.5 ± 15.1 pmol/l; high fat-fed group 125.9 ± 18.8 pmol/l). However, the levels of MCP-1 (89.7 ± 4.2 pg/ml vs. 60.8 ± 7.7 pg/ml) and IL-6 (61.6 ± 3.1 pg/ml vs. 41.6 ± 7.4 pg/ml) were significantly elevated in DIO animals (p < 0.05) as compared to controls. Adiponectin levels were also significantly increased (p < 0.01) in DIO rats (10.8 ± 0.7 ng/ml) versus controls (6.9 ± 0.5 ng/ml). No difference in vascular or endothelial function was evident as determined by responses to acetylcholine, sodium nitroprusside, endothelin-1, and calcitonin gene-related peptide.'] |
['Dendritic cell activation through ligation of pattern recognition receptors leading to full functional maturation causes induction of CD8(+) T-cell immunity through increased delivery of costimulatory signals instead of tolerance. Here we investigate whether organ-resident antigen-presenting cells, such as liver sinusoidal endothelial cells (LSECs), also switch from tolerogenic to immunogenic CD8(+) T-cell activation upon such stimulation.', 'Murine LSECs were isolated by immunomagnetic separation and analyzed for functional maturation upon triggering pattern recognition receptors or viral infection employing gene expression analysis and T cell coculture assays. In vivo relevance of the findings was confirmed with bone-marrow chimeric animals.', 'LSECs expressed numerous pattern recognition receptors that allowed for sentinel function, but ligand-induced activation of these receptors was not sufficient to overcome tolerance induction of CD8(+) T cells. Importantly, viral infection with murine cytomegalovirus caused functional maturation of antigen-presenting LSECs and was sufficient to promote antigen-specific differentiation into effector CD8(+) T cells in the absence of dendritic cells and independent of CD80/86.'] |
['Patients with gastro-oesophageal reflux disease (GERD) frequently report excessive belching but it is not known what determines the severity of these complaints.', 'To determine what causes troublesome belching symptoms in GERD patients.', 'We included 90 consecutive patients who were referred for ambulatory 24-h pH-impedance measurement as part of the analysis of reflux symptoms. Overall severity of belching was reported by the patients using a 3-point scale. Furthermore, each belch perceived during the ambulatory measurement was reported by the patients using a symptom diary.', 'No significant differences in frequency of gastric belches or combined liquid reflux and gastric belches were observed. However, the number of supragastric belches was significantly higher in patients with severe belching complaints compared to patients with moderate and none to mild complaints. Moreover, the number of supragastric belches which coincided with a liquid reflux episode was significantly higher in patients with severe complaints than in those with moderate and none to mild complaints. Per-patient analysis showed that belches coinciding with a liquid reflux event were more often symptomatic than isolated belches.'] |
['Diabetes is considered a risk factor in the osseointegration of dental implants, which suggests that these patients might benefit from anabolic therapies. Preclinical studies, including investigations by this research group, revealed that intermittent administration of parathyroid hormone (PTH) stimulates bone formation on the surface of titanium implants under physiological conditions. However, the anabolic effect of PTH on osseointegration under the hyperglycemic condition of diabetes is unknown.', 'The ability of PTH to stimulate osseointegration was investigated in 40 female Wistar rats that were randomly divided into the following treatment groups: diabetes, diabetes plus PTH, control, and control plus PTH. Diabetes was induced by intraperitoneal injection of streptozotocin (45 mg/kg) at 1 week before implantation. Rats received PTH at a dose of 60 μg/kg or a vehicle by subcutaneous injection starting at the day of implant insertion into the tibia. Histomorphometric analysis was performed after 4 weeks.', 'The medullary peri-implant bone area significantly increased in rats receiving PTH in comparison with the control group (41±12% to 20±12%; P<0.01). Moreover, there was an increased bone-to-implant contact (BIC) area in animals treated with PTH (47±18% to 27±16%; P<0.05). In contrast, diabetic rats failed to benefit from the anabolic treatment. A similar peri-implant bone area occurred in the diabetes group, independent of treatment with PTH (13±9% to 15±6%; P>0.05). Moreover, PTH did not affect the BIC area under hyperglycemic conditions (16±12% to 16±8%; P>0.05). No significant changes were observed in the cortical compartment of all groups.'] |
['As hypertension (HT) is one of the risk factors for lower urinary tract symptoms, we investigated the effect of an angiotensin II type I receptor blocker, olmesartan, on bladder dysfunction in the spontaneously hypertensive rat (SHR).', 'Twelve-week-old male SHRs were administered perorally with olmesartan (0, 1, or 3 mg/kg/day) or nifedipine (30 mg/kg/day) for 6 weeks. Wistar rats were used as normotensive controls. The effects of olmesartan or nifedipine on blood pressure (BP), bladder blood flow (BBF), urodynamic parameters, tissue levels of malondialdehyde (MDA), nuclear factor erythroid 2-related factor 2 (Nrf2), and nerve growth factor (NGF) were measured in the bladder. Localization of 4-hydroxy-2-nonenal (4-HNE), Nrf2, and NGF in the bladder was shown by immunohistochemistry.', 'The SHRs showed significant increase in BP, micturition frequency, and expression of MDA, 4-HNE, Nrf2, and NGF when compared to the control Wistar rats. Conversely, there was a decrease in BBF and single voided volume in SHRs when compared to Wistar rats. Treatment with olmesartan and nifedipine significantly improved BP. However, only olmesartan significantly ameliorated urodynamic parameters and oxidative damage compared to the non-treated SHR. The immunoreactivities of 4-HNE, Nrf2, and NGF in SHR urothelium and blood vessels were increased compared to the control. Treatment with a high dose of olmesartan decreased the expressions of 4-HNE, Nrf2, and NGF in the bladder.'] |
['Visfatin is an insulin-mimetic adipokine. In non-rheumatoid arthritis (RA) patients circulating levels of visfatin are correlated with the amount of visceral fat. Recent studies have disclosed an implication of visfatin in inflammation. Chronic systemic inflammation is of major importance in the development of atherosclerosis in RA. In the present study we investigated whether inflammation, obesity or metabolic syndrome are potential determinants of circulating visfatin concentrations in a group of RA patients on periodical treatment with the TNF-alpha blocker infliximab due to severe disease. We also assessed whether the infusion of infliximab may alter circulating visfatin concentrations in patients with severe RA.', 'We investigated 33 non-diabetic patients with RA on periodical treatment with infliximab. Serum visfatin levels were determined immediately prior to and after infliximab infusion.', 'There was no correlation between body mass index of RA patients and baseline serum level of visfatin. Also, no significant correlations between baseline visfatin levels and the age at the time of the study or at the onset of the disease, disease duration, ESR and CRP levels, DAS28, lipids, insulin sensitivity, resistin or the cumulative prednisone dose at the time of the study were found. Visfatin levels did not change upon infliximab infusion.'] |
['Newborns display distinct immune responses that contribute to susceptibility to infection and reduced vaccine responses. Toll-like receptor (TLR) agonists may serve as vaccine adjuvants, when given individually or in combination, but responses of neonatal leukocytes to many TLR agonists are diminished. TLR8 agonists are more effective than other TLR agonists in activating human neonatal leukocytes in vitro, but little is known about whether different TLR8 agonists may distinctly activate neonatal leukocytes. We characterized the in vitro immuno-stimulatory activities of a novel benzazepine TLR8 agonist, VTX-294, in comparison to imidazoquinolines that activate TLR8 (R-848; (TLR7/8) CL075; (TLR8/7)), with respect to activation of human newborn and adult leukocytes. Effects of VTX-294 and R-848 in combination with monophosphoryl lipid A (MPLA; TLR4) were also assessed.', 'TLR agonist specificity was assessed using TLR-transfected HEK293 cells expressing a NF-κB reporter gene. TLR agonist-induced cytokine production was measured in human newborn cord and adult peripheral blood using ELISA and multiplex assays. Newborn and adult monocytes were differentiated into monocyte-derived dendritic cells (MoDCs) and TLR agonist-induced activation assessed by cytokine production (ELISA) and co-stimulatory molecule expression (flow cytometry).', 'VTX-294 was ≈ 100x more active on TLR8- than TLR7-transfected HEK cells (EC50, ≈ 50 nM vs. ≈ 5700 nM). VTX-294-induced TNF and IL-1β production were comparable in newborn cord and adult peripheral blood, while VTX-294 was 1 log more potent in inducing TNF and IL-1β production than MPLA, R848 or CL075. Combination of VTX-294 and MPLA induced greater blood TNF and IL-1β responses than combination of R-848 and MPLA. VTX-294 also potently induced expression of cytokines and co-stimulatory molecules HLA-DR and CD86 in human newborn MoDCs.'] |
['This study compared insulin lispro (IL) pharmacokinetics (PK) and pharmacodynamics (PD) delivered via microneedle intradermal (ID) injection with subcutaneous (SC) injection under euglycemic glucose clamp conditions.', 'Ten healthy male volunteers were administered 10 international units (IU) of IL at 3 microneedle lengths (1.25, 1.50, or 1.75 mm) in a randomized, crossover fashion on Days 1-3 followed by a repetitive ID 1.5-mm microneedle dose (Day 4) and an SC dose (Day 5).', 'Microneedle ID delivery resulted in more rapid absorption of IL, with decreased time to maximum insulin concentration (ID vs. SC: 36.0-46.4 vs. 64.3 min, P < 0.05) and higher fractional availability at early postinjection times. ID produced more rapid effects on glucose uptake with shorter times to maximal and early half-maximal glucose infusion rates (GIRs) (ID vs. SC: time to maximum GIR, 106-112 vs. 130 min, P < 0.05; early half-maximal GIR, 29-35 vs. 42 min), increased early GIR area under the curve (AUC), and faster offset of insulin action (shorter time to late half-maximal GIR: 271-287 vs. 309 min). Relative total insulin bioavailability (AUC to 360 min and AUC to infinite measurement) did not significantly differ between administration routes. ID PK/PD parameters showed some variation as a function of needle length. Delivery of ID IL was generally well tolerated, although transient, localized wheal formation and redness were observed at injection sites.'] |
['The aim of the study was to clinically and histologically evaluate the healing of human intrabony defects treated with open flap surgery (OFD) and application of a new, resorbable, fully synthetic, unsintered, nanocrystalline, phase-pure hydroxyapatite (nano-HA).', 'Six patients, each of them displaying very advanced intrabony defects around teeth scheduled for extraction due to advanced chronic periodontitis and further prosthodontic considerations, were included in the study. Following local anaesthesia, mucoperiosteal flaps were reflected; the granulation tissue was removed, and the roots were meticulously debrided by hand and ultrasonic instruments. A notch was placed at the most apical extent of the calculus present on the root surface or at the most apical part of the defect (if no calculus was present) in order to serve as a reference for the histological evaluation. Following defect fill with nano-HA, the flaps were sutured by means of mattress sutures to allow primary intention healing. At 7 months after regenerative surgery, the teeth were extracted together with some of their surrounding soft and hard tissues and processed for histological analysis.', 'The postoperative healing was uneventful in all cases. At 7 months following surgery, mean PPD reduction and mean CAL gain measured 4.0\u2009±\u20090.8 and 2.5\u2009±\u20090.8 mm, respectively. The histological analysis revealed a healing predominantly characterized by epithelial downgrowth. Limited formation of new cementum with inserting connective tissue fibers and bone regeneration occurred in three out of the six biopsies (i.e. 0-0.86 and 0-1.33 mm, respectively). Complete resorption of the nano-HA was found in four out of the six biopsies. A few remnants of the graft particles (either surrounded by newly formed mineralized tissue or encapsulated in connective tissue) were found in two out of the six biopsies.'] |
['To evaluate the impact of surgery on gastrointestinal lymphoma.', 'The Surveillance, Epidemiology, and End Results (SEER) database was queried from 1973 to 2005.', 'A total of 17,222 cases of PGIL were identified. The overall incidence of PGIL was approximately 1.505 cases per 100,000. A significantly increasing incidence for PGIL was observed (APC = +4.67, P < 0.05). In the cases for which treatment data was available, resection occurred in roughly half of the patients. In univariate analysis, surgical extirpation did not improve survival (47 months vs. 76 months, P < 0.001), while radiation treatment improved median survival (77 months vs. 59 months, P < 0.001). Multivariate analysis revealed increasing age and male gender as independent predictors of decreased overall survival. Tumor location also was a significant predictor of outcome. Large B-cell lymphoma type PGIL had a poorer prognosis than marginal zone B-cell lymphoma. By multivariate analysis, surgery was not found to increase the risk of death (HR = 0.99).'] |
['Cerebral white matter hyperintensities on magnetic resonance imaging (MRI) scans have been associated with vascular disease and late-life depression, both in the general population and in psychiatric patients. Therefore, a cerebrovascular etiology for late-onset depression has been hypothesized. However, longitudinal studies on the causal role of white matter hyperintensities in the development of depressive symptoms in elderly adults are lacking.', 'To investigate the relation between white matter hyperintensities and depressive symptoms in elderly subjects at risk of cardiovascular disease.', 'In the Dutch sample of the PROSPER (PROspective Study of Pravastatine in the Elderly at Risk of cardiovascular disease) cohort, 527 non-demented elderly, all aged 70 years or older, received a cranial MRI scan and the 15-item Geriatric Depression Scale, at baseline and 33 months (SD 1.6) later.', 'Presence of white matter hyperintensities at baseline was not related to baseline depressive symptoms nor to the development of depressive symptoms during follow-up. Moreover, no association was found between progression of white matter lesion volume and progression of depressive symptoms.'] |
['Intermediate early graft function is associated with increased incidence of graft loss and worse long-term graft function in kidney transplantation.', 'Delayed graft function (DGF) is associated with premature graft loss, increased rate of allograft function decline, and greater incidence of acute rejection episodes (ARE). Regarding early intermediate graft function (IGF), these prognostic observations have not been clearly made. Our objective was to investigate the impact of IGF as compared with excellent graft function (EGF) on these outcomes.', 'Retrospective analysis included all patients who underwent transplantation in a tertiary care center between 1989 and 2009. Definitions are as follows: DGF, need for dialysis in the first 7 days posttransplantation; EGF, serum creatinine (sCr) <3 mg/dL at 5 days posttransplantation; IGF, absence of dialysis need but with a sCr >3 mg/dL at 5 days posttransplantation. For univariate analysis we performed Student t test, Mann- Whitney test, or Chi-square test, as appropriate. For survival analysis we performed Kaplan-Meier method to determine survival curves and we used the log-rank test for comparison. Multivariate logistic regression analysis was used to determine independent predictors of IGF and of graft survival.', 'Five hundred seventy patients were included: 69.0% had EGF, 22.6% had IGF, and 8.4% had DGF. Patients with IGF had worse graft survival at 5 and 10 years posttransplantation (75% vs 92% and 69% vs 85%, respectively; P < .001 for both comparisons) and higher incidence of ARE (41% vs 27%; P = .001), compared with EGF. In multivariate analysis, IGF was independently associated with an increased risk of graft loss compared with EGF (odds ratio [OR], 2.40; 95% confidence interval [CI], 1.32-4.35; P = .004]. Donor age (OR, 1.03 per year; 95% CI, 1.02-1.05; P < .001) was the strongest predictor of the occurrence of IGF. IGF was also associated with worse long-term graft function until 7 years posttransplantation (mean glomerular filtration rate [GFR] 48.3 ± 18.9 vs 57.4 ± 20.4 mL/min/1.73 m(2); P = .008).'] |
['We previously reported that 48 weeks of combination therapy with pegylated interferon-alpha2b (PEG-IFN-alpha2b) and adefovir dipivoxil (ADV) in patients with chronic hepatitis B led to marked decreases of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) (-2.4 log10 copies/ml). Combination therapy was followed by 96 weeks of ADV monotherapy.', 'Here, we report on the final outcome after 144 weeks of sequential antiviral treatment. Twenty-four patients were analysed, triplet liver biopsies (taken at baseline, week 48 and week 144) were available from 16 patients.', 'At week 144, 12/15 patients positive for hepatitis B virus e antigen (HBeAg) had lost HBeAg, alanine transaminase (ALT) levels were normal in 23 patients (96%), median serum HBV DNA had decreased by -4.9 log10 copies/ml and was undetectable (<100 copies/ml) in 11/24 individuals (46%). Median total intrahepatic HBV DNA had decreased by -2.2 log. Although no further significant cccDNA changes occurred between week 48 and week 144, two years of ADV monotherapy proved capable of controlling cccDNA levels in most patients. Analysis of intrahepatic HBV DNA species demonstrated that combination therapy with PEG-IFN-alpha2b and ADV inhibited viral productivity by 99% and subsequent ADV monotherapy by 76%, respectively. Virus suppression to undetectability within the first 12 weeks of treatment was strongly associated with long-term virological response and HBeAg and hepatitis B virus surface antigen HBsAg seroconversion. Histological improvement was determined in 11/16 patients at week 144. Two patients developed ADV resistance during the third year of treatment.'] |
['We explain why traits of interest to behavioral scientists may have a genetic architecture featuring hundreds or thousands of loci with tiny individual effects rather than a few with large effects and why such an architecture makes it difficult to find robust associations between traits and genes.', "We conducted a genome-wide association study at 2 sites, Harvard University and Union College, measuring more than 100 physical and behavioral traits with a sample size typical of candidate gene studies. We evaluated predictions that alleles with large effect sizes would be rare and most traits of interest to social science are likely characterized by a lack of strong directional selection. We also carried out a theoretical analysis of the genetic architecture of traits based on R.A. Fisher's geometric model of natural selection and empirical analyses of the effects of selection bias and phenotype measurement stability on the results of genetic association studies.", 'Although we replicated several known genetic associations with physical traits, we found only 2 associations with behavioral traits that met the nominal genome-wide significance threshold, indicating that physical and behavioral traits are mainly affected by numerous genes with small effects.'] |
['Classical effects of oestrogen involve activation of target genes after binding nuclear receptors. Oestrogenic effects too rapid for DNA transcription (non-genomic) are known to occur. The effect of oestrogen on colonic motility is unknown despite the prevalence of gastrointestinal symptoms in pregnant and premenopausal women.', 'Histologically normal colon was obtained from proximal resection margins of colorectal carcinoma specimens. Circular smooth muscle strips were microdissected and suspended in organ baths under 1 g of tension. After equilibration, they were exposed to 17beta-oestradiol (n = 8) or bovine serum albumin (BSA)-conjugated 17beta-oestradiol (n = 8). Fulvestrant, an oestrogen receptor antagonist, was added to some baths (n = 8). Other strips were exposed to calphostin C or cycloheximide. Carbachol was added in increasing concentrations and contractile activity was recorded isometrically.', 'Oestrogen inhibited colonic contractility (mean difference 19.7 per cent; n = 8, P < 0.001). In keeping with non-genomic, rapid-onset steroid action, the effect was apparent within minutes and reversible. It was observed with both 17beta-oestradiol and BSA-conjugated oestrogen, and was not altered by cycloheximide. Effects were inhibited by fulvestrant, suggesting receptor mediation.'] |
['Thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS) share many clinical features and have been difficult to separate into distinct entities. Histologic examination of organs from autopsied patients suggested that TTP and HUS have dissimilar lesions of different severity and distribution.', 'To perform a retrospective observational review of autopsied patients with TTP or HUS to compare the nature and severity of the lesions found.', 'To examine the pathologic features of these conditions, we reviewed all cases among 51 350 indexed autopsies at The Johns Hopkins Hospital (Baltimore, Md) diagnosed with TTP or HUS, and included those showing multiple arteriolar thrombi or their sequela.', 'The 56 cases that met the inclusion criteria fell into 2 distinct groups, based on distribution and severity of arteriolar lesions. In 25 patients classified as having TTP, platelet-rich thrombi were present-in decreasing severity-in heart, pancreas, kidney, adrenal gland, and brain. In 31 patients with HUS, fibrin/red cell-rich thrombi were present, largely confined to the kidney and often severe, and only 6 cases showed pancreas involvement, 4 adrenal gland involvement, 2 brain involvement, and 1 heart involvement.'] |
["Cortactin activates the actin-related 2/3 (Arp2/3) complex promoting actin polymerization to remodel cell architecture in multiple processes (e.g. cell migration, membrane trafficking, invadopodia formation etc.). Moreover, it was called the Achilles' heel of the actin cytoskeleton because many pathogens hijack signals that converge on this oncogenic scaffolding protein. Cortactin is able to modulate N-WASP activation in vitro in a phosphorylation-dependent fashion. Thus Erk-phosphorylated cortactin is efficient in activating N-WASP through its SH3 domain, while Src-phosphorylated cortactin is not. This could represent a switch on/off mechanism controlling the coordinated action of both nucleator promoting factors (NPFs). Pedestal formation by enteropathogenic Escherichia coli (EPEC) requires N-WASP activation. N-WASP is recruited by the cell adapter Nck which binds a major tyrosine-phosphorylated site of a bacterial injected effector, Tir (translocated intimin receptor). Tir-Nck-N-WASP axis defines the current major pathway to actin polymerization on pedestals. In addition, it was recently reported that EPEC induces tyrosine phosphorylation of cortactin.", 'Here we demonstrate that cortactin phosphorylation is absent on N-WASP deficient cells, but is recovered by re-expression of N-WASP. We used purified recombinant cortactin and Tir proteins to demonstrate a direct interaction of both that promoted Arp2/3 complex-mediated actin polymerization in vitro, independently of cortactin phosphorylation.'] |
['This study was designed to assess whether a new method of cardiopulmonary resuscitation (CPR), termed active compression-decompression CPR, or ACD-CPR, improves organ perfusion when compared with standard (S) CPR in a dog model of ventricular fibrillation.', 'ACD-CPR has recently been shown to improve hemodynamic and respiratory parameters during cardiac arrest when compared with standard CPR. However, to our knowledge, the effects of ACD-CPR on tissue perfusion have not been investigated.', 'Ventricular fibrillation was induced in eight anesthetized, intubated animals. ACD-CPR and standard CPR were each performed twice in alternating order. All interventions were preceded by 1 min of ventricular fibrillation, in which no CPR was performed, and consisted of 6 min of CPR with either technique during which tissue perfusion was measured. Compressions were performed at 80/min with a 50 percent duty cycle and 175 to 200 N downward force applied to the chest wall for both techniques. Epinephrine was administered at the beginning of each 6-min CPR interval. Hemodynamic monitoring of aortic and right atrial pressure was performed continuously and myocardial, cerebral, and renal blood flows were measured using the radiolabeled microsphere technique at baseline and during all interventions.', 'Baseline organ perfusion and hemodynamics were similar for all dogs. Baseline left ventricular, brain, and renal blood flows were 62.0 +/- 5.5, 14.1 +/- 2.1, and 476.3 +/- 55.5 ml/min/100 g, respectively (mean +/- SEM). Compared with standard CPR, ACD-CPR resulted in higher global left ventricular (22.5 +/- 6.2 vs 14.1 +/- 4.0 ml/min/100 g, p < 0.01), cerebral (12.0 +/- 2.4 vs 8.5 +/- 2.3 ml/min/100 g, p < 0.01), and renal cortical (27.8 +/- 5.0 vs 17.5 +/- 5.0 ml/min/100 g, p < 0.05) blood flows. Regional flows to the epicardium, endocardium, and midmyocardium as well as to the frontal, parietal, and occipital lobes of the brain were all significantly improved by ACD-CPR. Aortic systolic (61.7 +/- 4.1 vs 49.5 +/- 3.1 mm Hg, p < 0.01), aortic mean (31.6 +/- 2.8 vs 27.2 +/- 2.2 mm Hg, p = 0.001), and myocardial perfusion pressure (12.9 +/- 3.4 vs 10.4 +/- 3.4 mm Hg, ACD-CPR vs standard CPR, p < 0.01) were all higher during ACD-CPR than during standard CPR.'] |
['We tested the hypothesis that ventilation in the prone position might improve homogenization of tidal ventilation by reducing time-constant inequalities, and thus improving alveolar ventilation. We have recently reported in ARDS patients that these inequalities are responsible for the presence of a "slow compartment," excluded from tidal ventilation at supportive respiratory rate.', 'In 11 ARDS patients treated by ventilation in the prone position because of a major oxygenation impairment (PaO(2)/FIO(2)</=100 mm Hg) we studied mechanical and blood gas changes produced by a low PEEP (6+/-1 cm H(2)O), ventilation in the prone position, and the two combined.', 'Ventilation in the prone position significantly reduced the expiratory time constant from 1.98+/-0.53 s at baseline with ZEEP to 1.53+/-0.34 s, and significantly decreased PaCO(2) from 55+/-11 mm Hg at baseline with ZEEP to 50+/-7 mm Hg. This improvement in alveolar ventilation was accompanied by a significant improvement in respiratory system mechanics, and in arterial oxygenation, the latter being markedly increased by application of a low PEEP (PaO(2)/FIO(2) increasing from 64+/-19 mm Hg in supine position with ZEEP to 137+/-88 mm Hg in prone with a low PEEP).'] |
['The spatial relationship of glioblastoma (GBM) to the subventricular zone (SVZ) is associated with inferior patient survival. However, the underlying molecular phenotype is largely unknown. We interrogated an SVZ-dependent transcriptome and potential location-specific prognostic markers.', 'mRNA microarray data of a discovery set (n\u2009=\u200936 GBMs) were analyzed for SVZ-dependent gene expression and process networks using the MetaCore™ workflow. Differential gene expression was confirmed by qPCR in a validation set of 142 IDH1 wild-type GBMs that was also used for survival analysis.', "Microarray analysis revealed a transcriptome distinctive of SVZ+ GBM that was enriched for genes associated with Notch signaling. No overlap was found to The Cancer Genome Atlas's molecular subtypes. Independent validation of SVZ-dependent expression confirmed four genes with simultaneous prognostic impact: overexpression of HES4 (p\u2009=\u20090.034; HR 1.55) and DLL3 (p\u2009=\u20090.017; HR 1.61) predicted inferior, and overexpression of NTRK2 (p\u2009=\u20090.049; HR 0.66) and PIR (p\u2009=\u20090.025; HR 0.62) superior overall survival (OS). Additionally, overexpression of DLL3 was predictive of shorter progression-free survival (PFS) (p\u2009=\u20090.043; HR 1.64). Multivariate analysis revealed overexpression of HES4 to be independently associated with inferior OS (p\u2009=\u20090.033; HR 2.03), and overexpression of DLL3 with inferior PFS (p\u2009=\u20090.046; HR 1.65)."] |
['We compared two rapid MR imaging T2-weighted pulse sequences with high-resolution turbo spin-echo for the diagnosis of adenomyosis, and we evaluated interobserver variability.', 'Fifty-six consecutive patients referred for hysterectomy prospectively underwent MR imaging. Two fast pulse sequences using a breath-hold technique-true fast imaging with steady-state free precession (FISP) and turbo inversion recovery-and turbo spin-echo T2-weighted images of the pelvis were obtained in each patient. The images were analyzed in a blinded manner and independently by three reviewers with different levels of experience for the accuracy of adenomyosis diagnosis, image quality, anatomic visualization, and image artifacts. The accuracy for the diagnosis of adenomyosis on turbo spin-echo T2-weighted imaging combined with one or two fast pulse sequences was evaluated for each reviewer.', 'Twenty-four patients (42.9%) had a histologic diagnosis of adenomyosis. The accuracy for the diagnosis of adenomyosis for reviewers 1, 2, and 3 using turbo spin-echo T2-weighted, true FISP, and turbo inversion recovery sequences was 83.9%, 67.8%, 75%; 83.9%, 67.8, 78.5%; and 87.5%, 73.2%, and 75%, respectively. A difference in the accuracy rate was found among the observers for the three sequences (p < 0.001). Whatever the pulse sequence, the accuracy rate was higher for the reviewer with more experience in gynecologic imaging. The combination of turbo spin-echo T2-weighted imaging with at least one rapid sequence increased the accuracy of observers with little experience in gynecology. With turbo inversion recovery sequences, the image quality score was low for the three reviewers compared with turbo spin-echo T2-weighted and true FISP sequences. The combination of turbo spin-echo T2-weighted and true FISP sequences gave the highest image quality scores.'] |
['To study whether N-terminal probrain natriuretic peptide (NT-proBNP) is a short-term independent predictor of both all-cause and cardiovascular (CV) mortality in type 2 diabetic patients and to establish whether albuminuria and C-reactive protein (CRP) affect this relationship.', 'The prospective study included 1,825 type 2 diabetic patients from the population-based cohort of the Casale Monferrato study. CV risk factors, preexisting CVD, and NT-proBNP levels were evaluated at baseline. All-cause and CV mortality were assessed 5.5 years after baseline examination. Multivariate Cox proportional hazards modeling was used to estimate mortality hazard ratios (HRs).', 'During the follow-up period, 390 people died (175 for CVD) out of 9,101 person-years of observations. A significantly increased mortality risk by quartiles of NT-proBNP was observed (test for trend, P < 0.001). NT-proBN P values >91 pg/mL conferred HRs of 2.05 (95% CI 1.47-2.86) for all-cause and 4.47 (2.38-8.39) for CV mortality, independently of CV risk factors, including CRP and albumin excretion rate (AER). The association was also significant for modest rises in NT-proBNP levels and in patients without microalbuminuria and CVD at baseline (upper quartiles HRs 3.82 [95% CI 1.24-13.75]) and 3.14 [1.00-9.94]). Albuminuria and NT-proBNP had an additive effect on mortality, though the association was stronger for NT-proBNP.'] |
['Vascular and valvular calcifications are a common finding in chronic kidney disease (CKD) patients and are associated with increased morbidity and mortality. We investigated the hypothesis that calcification of the cardiac valves is a marker of coronary artery calcification (CAC) and thoracic aorta calcification (AoC) in hemodialysis (CKD-5) patients.', 'This was a cross-sectional study of 145 maintenance CKD stage 5 (CKD-5) patients. All patients underwent electron beam tomography for quantification of CAC and AoC score via the Agatston score. The presence of calcification of the cardiac valves was assessed by standard bi-dimensional echocardiography.', 'Eighty-four of the study patients (58%) had echocardiographic evidence of valvular calcification. A significant and graded association between valvular calcification and CAC as well as AoC was detected. Patients with 1 or 2 calcified valves had a significantly greater likelihood of having a CAC score >1,000 (odds ratio [OR] = 5.94; 95% confidence interval [95% CI], 1.91-18.44; p=0.002; and OR=3.27; 95%CI, 1.36-7.88; p=0.007, respectively). Similarly, the presence of 1 or 2 calcified valves was associated with an eightfold and threefold increased probability of an AoC score greater than the third quartile, respectively.'] |
['Although it is known that Müller cells express the glial fibrillary acidic protein (GFAP) in response to acute retinal damage, the regulatory mechanism is not completely understood. α(2)-Macroglobulin (α(2)M) and its receptor, low-density lipoprotein receptor-related protein 1 (LRP1), have also been found in injured retinas. Herein, the authors examined the involvement of the α(2)M/LRP1 system in GFAP expression in Müller cells using in vitro and in vivo experimental models.', 'Using Western blot analysis and immunocytochemistry, the authors evaluated the effect of α(2)M* on GFAP expression in the Müller cell line MIO-M1, which constitutively expresses LRP1. Intracellular signaling pathways activated by α(2)M* were examined by Western blot analysis. The effect of α(2)M* on GFAP expression in the mouse retina was examined by intravitreal microinjection of α(2)M* in mouse eyes.', 'These data demonstrate that α(2)M* induced GFAP expression in the MIO-M1 cell line, which was selectively blocked by RAP, an antagonist of LRP1 binding ligands. In addition, α(2)M* induced JAK/STAT pathway activation, determined by STAT3 phosphorylation (p-STAT3), which was also blocked by RAP. Finally, the authors showed that GFAP was expressed in the retinas of mice, preferentially in Müller cells at 3 and 6 days after a single intravitreal α(2)M* injection, whereas p-STAT3 staining increased at day 1 in both the ganglion cell layer and the inner nuclear layer.'] |
['Tissue organization during embryonic development and wound healing depends on the ability of cells on the one hand to exchange adhesive bonds during active rearrangement and on the other to become fixed in place as tissue homeostasis is reached. Cells achieve these contradictory tasks by regulating either cell-cell adhesive bonds, mediated by cadherins, or cell-extracellular matrix (ECM) connections, regulated by integrins. Integrin alpha5beta1 and soluble fibronectin (sFN) are key players in cell-ECM force generation and in ECM polymerization. Here, we explore the interplay between integrin alpha5beta1 and sFN and its influence on tissue mechanical properties and cell sorting behavior.', 'We generated a series of cell lines varying in alpha5beta1 receptor density. We then systematically explored the effects of different sFN concentrations on aggregate biomechanical properties using tissue surface tensiometry. We found previously unreported complex behaviors including the observation that interactions between fibronectin and integrin alpha5beta1 generates biphasic tissue cohesion profiles. Specifically, we show that at constant sFn concentration, aggregate cohesion increases linearly as alpha5beta1 receptor density is increased from low to moderate levels, producing a transition from viscoelastic-liquid to pseudo viscoelastic-solid behavior. However, further increase in receptor density causes an abrupt drop in tissue cohesion and a transition back to viscoelastic-liquid properties. We propose that this may be due to depletion of sFn below a critical value in the aggregate microenvironment at high alpha5beta1 levels. We also show that differential expression of alpha5beta1 integrin can promote phase-separation between cells.'] |
['The pathogenesis of immune dysfunction in chronic HIV-1 infection is unclear, and a potential role for oxidized lipids has been suggested. We hypothesize that both oxidized HDL and LDL (HDLox and LDLox) contribute to HIV-1-related immune dysfunction.', 'In the AIDS Clinical Trials Group A5260, 234 HIV-infected antiretroviral therapy (ART)-naive participants were randomized to receive tenofovir-emtricitabine and protease inhibitors or raltegravir and had HIV-1 RNA less than 50 copies/ml by week 24 and thereafter.', 'Associations between biomarkers of inflammation (IL-6, high-sensitivity C-reactive protein and D-dimer), immune activation (sCD163, sCD14, soluble IL-2 receptor, CD38 and HLA-DR), inflammatory monocytes (CD14CD16), T-cell senescence (CD28 and CD57) and exhaustion (PD1), and HDLox, LDLox were assessed at entry and after ART (week 96) with Spearman (partial) correlations.', 'HDLox declined and LDLox increased over 96 weeks of ART. Positive associations were observed at baseline and over time between HDLox (but not consistently for LDLox) and most markers of inflammation and immune activation (but not senescence/exhaustion), even after adjustment for multiple comparisons, demographics, entry CD4 cell count and HIV-1 RNA. HDLox was positively associated with IL-6 (r\u200a=\u200a0.19\u200a-\u200a0.29, P\u200a<\u200a0.01) and sCD163 (r\u200a=\u200a0.14\u200a-\u200a0.41, P\u200a≤\u200a0.04) at all time points.'] |
['Malaria and human immunodeficiency virus (HIV) infection during pregnancy affect the transplacental transfer of antibodies against several pathogens from mother to fetus, although the effect of malaria and HIV infection on the transfer of antimalarial antibodies remains unclear.', 'Levels of total immunoglobulin G (IgG), immunoglobulin M (IgM), and IgG subtypes against the following Plasmodium falciparum antigens were measured in 187 pairs of mother-cord plasma specimens from Mozambique: 19-kDa fragment of merozoite surface protein 1 (MSP119), erythrocyte binding antigen 175 (EBA175), apical membrane antigen 1 (AMA1), and parasite lysate. Placental antibody transfer was defined as the cord-to-mother ratio (CMR) of antibody levels.', 'Maternal malaria was associated with reduced CMR of EBA175 IgG (P = .014) and IgG1 (P = .029), AMA1 IgG (P = .002), lysate IgG1 (P = .001), and MSP1 IgG3 (P = .01). Maternal HIV was associated with reduced CMR of MSP1 IgG1 (P = .022) and IgG3 (P = .023), lysate IgG1 (P = .027) and IgG3 (P = .025), AMA1 IgG1 (P = .001), and EBA175 IgG3 (P = .001). Decreased CMR was not associated with increased adverse pregnancy outcomes or augmented risk of malaria in the infant during the first year of life.'] |
['Angiotensin II (Ang II) is a potent stimulus of vascular smooth muscle cell (VSMC) growth. Activation of extracellular signal-regulated kinase (ERK), the archetypal mitogen-activated protein (MAP) kinase, and phosphatidylinositol 3 (PI3) kinase are critical steps in Ang II-induced mitogenic signaling. However, the mechanism involved in the activation of these kinases upon binding of Ang II to its receptor is poorly understood.', 'In the present study, we examined the role of the epidermal growth factor receptor (EGFR) in Ang II signaling in VSMCs employing immunoprecipitation, Western blot analysis, kinase immunocomplex assay, and [3H]-thymidine incorporation.', 'A time-dependent tyrosine phosphorylation of the EGFR in response to Ang II was observed that was mediated by the Ang II type 1 receptor. This transactivation of the EGFR was blocked in the presence of PP1, an inhibitor of the intracellular Src-like tyrosine kinases. The tyrphostin AG 1478, a selective EGFR antagonist, inhibited both Ang II- and EGF-induced tyrosine phosphorylation of the EGFR. Furthermore, Ang II induced the binding of the adaptor protein Shc to the EGFR, leading to phosphorylation of Shc. In addition, the same nanomolar concentrations of AG 1478 that were effective in EGF signaling blocked the Ang II-induced activation of ERK and PI3 kinase in a dose-dependent manner. Proliferation of VSMCs, detected by measurements of DNA synthesis, following stimulation with Ang II was potently inhibited in the presence of AG 1478 or PP1.'] |
['With the increased use of nanoparticles in biomedical applications there is a growing need to understand the effects that nanoparticles may have on cell function. Identifying these effects and understanding the mechanism through which nanoparticles interfere with the normal functioning of a cell is necessary for any therapeutic or diagnostic application. The aim of this study is to evaluate if gold nanoparticles can affect the normal function of neurons, namely their activity and coding properties.', 'We synthesized star shaped gold nanoparticles of 180\xa0nm average size. We applied the nanoparticles to acute mouse hippocampal slices while recording the action potentials from single neurons in the CA3 region. Our results show that CA3 hippocampal neurons increase their firing rate by 17% after the application of gold nanostars. The increase in excitability lasted for as much as 50\xa0minutes after a transient 5\xa0min application of the nanoparticles. Further analyses of the action potential shape and computational modeling suggest that nanoparticles block potassium channels responsible for the repolarization of the action potentials, thus allowing the cell to increase its firing rate.'] |
['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).'] |
['This article reports our preliminary observation regarding the diagnostic ability of dynamic helical biphasic computed tomography (CT) for proximal arterioportal shunting in hepatoma patients as compared with that of conventional angiography.', 'Three hundred and sixty patients with clinically-suspected liver lesions received both dynamic helical biphasic CT scan and conventional angiography of the liver. The criteria for diagnosis of proximal arterioportal (AP) shunting in dynamic helical biphasic CT included early and strong enhancement of main portal vein or its major branches approaching the density of the aorta, or enhancement of the portal vein earlier than opacification of the splenic vein and superior mesenteric vein in the arterial phase. The angiographic diagnosis of proximal AP shunting was made if there was early opacification of the main portal vein or its major branches in the arterial phase. Peripheral subsegmental small AP shunting was excluded from our study. The existence and extent of AP shunting were compared in these two imaging modalities.', 'Dynamic helical biphasic CT scan demonstrated proximal AP shunting in 23 patients. All of these patients harbored hepatoma. Conventional angiography showed proximal AP shunting in 20 patients, which were all positive on dynamic helical CT. Dynamic helical biphasic CT demonstrated the presence of proximal AP shunting in 3 more patients than conventional angiography did. The extent of AP shunting was well correlated between these two imaging modalities in 17 patients.'] |
['Bivalirudin, a direct thrombin inhibitor, is a widely used adjunctive therapy in patients undergoing percutaneous intervention (PCI). Thrombin is a highly potent agonist of platelets and activates the protease-activated receptors, PAR1 and PAR4, but it is not known whether bivalirudin exerts antiplatelet effects in PCI patients. We tested the hypothesis that bivalirudin acts as an antiplatelet agent in PCI patients by preventing activation of PARs on the platelet surface.', 'The effect of bivalirudin on platelet function and systemic thrombin levels was assessed in patients undergoing elective PCI. Mean plasma levels of bivalirudin were 2.7±0.5 μmol/L during PCI, which correlated with marked inhibition of thrombin-induced platelet aggregation and significantly inhibited cleavage of PAR1. Unexpectedly, bivalirudin also significantly inhibited collagen-platelet aggregation during PCI. Collagen induced a conversion of the platelet surface to a procoagulant state in a thrombin-dependent manner that was blocked by bivalirudin. Consistent with this result, bivalirudin reduced systemic thrombin levels by >50% during PCI. Termination of the bivalirudin infusion resulted in rapid clearance of the drug with a half-life of 29.3 minutes.'] |
['Recent studies have shown that an increased bleeding tendency can be caused by Selective Serotonin Reuptake Inhibitors (SSRI) use. We aimed to investigate the occurrence and risk of blood transfusion in SSRI users compared to non-SSRI users in a cohort of patients admitted for hip-surgery.', 'We conducted a retrospective cohort study of patients who underwent planned or emergency hip surgery from 1996 to 2011 in the Academic Medical Center in Amsterdam. Primary outcome measure was risk of blood transfusion. Secondary outcome measures were pre- and postoperative hemoglobin level. Multivariate logistic regression was used to adjust for potential confounders.', 'One-hundred and fourteen SSRI users were compared to 1773 non-SSRI users. Risk of blood transfusion during admission was increased for SSRI users in multivariate analyses (OR 1.7 [95% CI 1.1-2.5]). Also, pre-operative hemoglobin levels were lower in SSRI users (7.8 ± 1.0 mmol/L) compared to non-SSRI users (8.0 ± 1.0 mmol/L) (p\u200a =\u200a 0.042)), as were postoperative hemoglobin levels (6.2 ± 1.0 mmol/L vs. 6.4 ± 1.0 mmol/L respectively) (p\u200a =\u200a 0.017)).'] |
['In adults, pencil-point spinal needles are believed to be less traumatic and therefore to be superior compared to cutting-point needles with respect to success rate and postpuncture complications. The aim of this randomised, parallel groups and prospective study was to record the success rate and to evaluate the incidence of complications following spinal anaesthesia with the two types of needles in children.', 'We studied 215 children aged 1 to 18 years. A 25-gauge needle was used in children up to 7 years (n=96) and a 27-gauge needle in older children (n=119). During lumbar puncture with either a cutting-point (n=109) or a pencil-point (n=106) spinal needle, we recorded puncture characteristics and the success of cerebrospinal fluid (CSF) aspiration. Hyperbaric bupivacaine 5 mg ml(-1) at a dose of 0.3-0.4 mg kg(-1) was used for the spinal anaesthesia. The incidence of postdural puncture complications was recorded from diaries completed by the children and parents one week after the lumbar puncture.', 'The success rate of the spinal anaesthesia was 97% without difference between the needles. The success rate was higher when the aspiration of CSF was easy compared to if it was difficult (98% vs. 88%, P=0.02). Two hundred and seven diaries were returned (97%). Twenty-four children developed a headache, 8 of which were classified as a postdural puncture headache (PDPH), 6 with the cutting-point needle and 2 with the pencil-point needle (n.s.). Nine children developed signs of transient radicular irritation with no difference between the needles.'] |
["Cerebral white matter lesions (WML) are known to increase with age, as is left ventricular (LV) diastolic dysfunction with normal contraction. Although aging is a common risk factor, the link between these diseases is not fully understood. The aim was to clarify this relationship, using the ratio between early diastolic mitral inflow and early diastolic mitral annular tissue velocity (E/E'). E/E' measured by tissue Doppler echocardiography offers an indicator of the severity of LV diastolic dysfunction, reflecting both diastolic LV stiffness and diastolic LV filling pressure.", 'Participants comprised 75 patients aged between 65 and 75 years with normal LV contraction and no signs or history of symptomatic heart failure, ischemic heart diseases, atrial fibrillation, stroke, or cognitive dysfunction. The volume of WML was quantified on brain magnetic resonance imaging.', "The participants were classified into three groups: Low E/E', E/E' ≤ 8; Middle E/E', 8 < E/E' < 15; and High E/E', E/E' ≥ 15. WML volume was 3.6 ± 3.0 mL in Low E/E', 5.4 ± 6.5 mL in Middle E/E' and 12.0 ± 11.0 mL in High E/E', increasing significantly with increased diastolic LV stiffness (Low vs High, P = 0.034; Middle vs High, P = 0.016). Linear regression analysis showed the positive association between the volume of WML and E/E' ratio (r = 0.377, P = 0.0009)."] |
['We sought to determine the etiologic mechanism of proinflammatory cytokine, interleukin-6 (IL-6), and statin as regulators of synthesis of plasminogen activator inhibitor-1 (PAI-1), the physiological fibrinolysis inhibitor and an acute-phase reactant.', "Transient transfection and luciferase assay in HepG2 human hepatoma-derived cells demonstrated that IL-6 increased PAI-1 promoter activity and mevastatin decreased IL-6-inducible response. Systematic deletion assay of the promoter demonstrated that the region (-239 to -210 bp) containing a putative CCAAT/enhancer-binding protein (C/EBP) binding site was necessary. Point mutation in this site abolished the IL-6-inducible response. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that C/EBPalpha, C/EBPbeta, and C/EBPdelta were involved in protein-DNA complex formation in intact cells. Deoxyribonuclease (DNase) I footprinting analysis revealed that 5' flanking region (-232 to -210 bp) is acute-phase response protein-binding site. C/EBPdelta binding activity was increased by IL-6 and attenuated by mevastatin. Mevastatin attenuated IL-6-mediated increase of C/EBPdelta protein in the nuclear extracts. IL-6 also increased PAI-1 and C/EBPdelta mRNA in mouse primary hepatocytes."] |
['Restenosis is an undesirable consequence following percutaneous vascular interventions. However, the current strategy for preventing restenosis is inadequate. The aim of this study was to investigate the role of low-voltage gated T-type calcium channels in regulating vascular smooth muscle cell (VSMC) proliferation during neointimal formation.', 'Wire injury of mice carotid arteries resulted in neointimal formation in the wild-type and Ca(v)3.2(-/-) but not Ca(v)3.1(-/-) mice, indicating a critical role of Ca(v)3.1 in neointimal formation. In addition, we found a significant increase of Ca(v)3.1 mRNA and protein in injured arteries. Ca(v)3.1 knockout or knockdown (shCa(v)3.1) reduced VSMC proliferation. Since T-channels are expressed predominantly in the G(1) and S phases in VSMCs, we examined whether an abnormal G(1)/S transition was the cause of the reduced cell proliferation in shCa(v)3.1 VSMCs. We found a disrupted expression of cyclin E in shCa(v)3.1 VSMCs, and calmodulin agonist CALP1 partially rescued the defective cell proliferation. Furthermore, we demonstrated that infusion of NNC55-0396, a selective T-channel blocker, inhibited neointimal formation in wild-type mice.'] |
['Statins (hydroxymethylglutaryl coenzyme A reductase inhibitors) are effective in reducing the risk of cardiovascular morbidity and mortality in patients with hyperlipidemia, hypertension, or type II diabetes. Next to their cholesterol-lowering activity, statins have immunomodulatory properties. Based on these properties, we hypothesized that statin use may eventually lead to dysregulation of immune responses, possibly resulting in autoimmunity. We have recently shown in an observational study that statin use was associated with an increased risk of developing rheumatoid arthritis. Our objective was to investigate whether a causal relationship could be established for this finding.', 'The mouse collagen type II (CII)-induced arthritis (CIA) model was used, with immunization, challenge, and euthanasia at days 0, 21, and 42, respectively. Statins were given orally before (day -28 until day 21) or after (day 21 until day 42) CIA induction. Atorvastatin (0.2 mg/day) or pravastatin (0.8 mg/day) was administered. Arthritis was recorded three times a week. Serum anti-CII autoantibodies and cytokines in supernatants from Concanavalin-A-stimulated lymph node cells and CII-stimulated spleen cells were measured.', 'Statin administration accelerated arthritis onset and resulted in 100% arthritic animals, whereas only seven out of 12 nonstatin control animals developed arthritis. Atorvastatin administration after CIA induction resulted in earlier onset than atorvastatin administration before induction, or than pravastatin administration before or after induction. The arthritic score of animals given pravastatin before CIA induction was similar to that of the nonstatin controls, whereas the other groups that received statins showed higher arthritic scores. Atorvastatin administration, especially before CIA induction, increased anti-CII autoantibody production. IL-2 and IL-17 production by lymph node and spleen cells was higher in CIA animals than in PBS controls, but was not affected by statin administration. While IFNγ production was not affected by CIA induction, atorvastatin administration before CIA induction increased the production of this cytokine.'] |
['Euthyroid sick syndrome is a common finding in critically ill patients with nonthyroidal illness, characterized by low serum levels of free triiodothyronine (fT3) with a peculiar increase in reverse T3 (rT3) and normal-to-low free thyroxine (fT4) as well as thyroid-stimulating hormone (TSH) levels. This condition has been proposed as a prognostic factor of worse outcome in critically ill patients, while no conclusive data are available in burns.', 'Since thyroid function testing is contained in our baseline laboratory tests at admission, we retrospectively evaluated fT3, fT4 and TSH in 295 consecutive burn patients admitted to the Burn Center of Turin from January 2002 to December 2006, comparing hormone levels in survivors and non-survivors.', "fT3 and TSH levels were significantly lower (p<or=0.0002) in non-survivors compared to survivors, while no significant difference between the two populations was found in fT4 concentrations. Excluding from the study 20 patients who received dopamine administration for more than 21h, serum fT3 levels fell further still (p=0.0003). In addition, fT3 concentrations showed a significant correlation with burn severity expressed by the Roi score (Spearman's correlation coefficient -0.37 with p<0.00001)."] |
["The comprehension of tense/aspect morphology by children with autism spectrum disorder (ASD) was assessed via Intermodal Preferential Looking (IPL) to determine whether this population's difficulties with producing these morphemes extended to their comprehension.", 'Four-year-old participants were assessed twice, 4 months apart. They viewed a video that presented side-by-side ongoing and completed events paired with familiar verbs with past tense and progressive morphology. Their eye movements were recorded and coded offline; the IPL measures included percentage of looking time at, and latency of first look to, the matching scene. Spontaneous speech samples were also obtained and coded for number of words, past tense, and progressive inflections.', 'Relative to their baseline preferences, these 4-year-old children with ASD looked more quickly to and longer at the matching scene for both morphemes. Children who produced more words, including progressive and past morphemes, and those who performed better on standardized language assessments demonstrated better comprehension of -ing.'] |
['New data suggest that glioma stem-like cells (GSCs) and neural stem/progenitor cells (NSCs) may share common origins. GSCs drive tumor proliferation and appear to be resistant to classic chemotherapy, while the effects of chemotherapy on NSCs are not well studied. As the role of NSCs in learning and memory is increasingly recognized, we need to identify drugs that reduce neurotoxicity but are still effective against glial tumors.', 'We treated 3 human NSC cultures and multiple low- and high-grade GSC cultures with the commonly used agents temozolomide (TMZ) and cisplatin (CIS), and with 2 newer, promising drugs: the proteasome inhibitor bortezomib (BTZ) and the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (ERL). We measured cell survival, proliferation, cell death induction, and drug resistance markers.', "TMZ decreased NSC viability, while minimally affecting GSCs. TMZ induced NSC death, which was partially compensated for by increased proliferation. CIS had similar effects. The NSC's sensitivity to TMZ and CIS correlated with low expression of the multidrug resistance gene ABCG2, but not of MGMT or MSH1/MLH2. BTZ caused an 80%decrease in GSCs, while minimally affecting NSCs. GSCs had lower proteasome levels and activity after BTZ treatment. ERL treatment also decreased GSC numbers, but not NSC viability, which correlated with low EGFR expression in NSCs compared to GSCs."] |
['Exogenous bone morphogenetic protein 4 (BMP-4) has been reported to inhibit ureteric branching morphogenesis and regulate the anterior-posterior axis of the developing kidney in vitro. We examined the role of BMP-4 on ureteric branching in vitro using three-dimensional image analysis software and statistical models. Additionally, in vivo ureteric branching was analyzed and the effect of reduced levels of BMP-4 in vivo on nephron number was examined.', 'Embryonic day 12.5 (E12.5) Balb/c mouse metanephroi cultured for 48 hours with or without 260 ng/mL recombinant human BMP-4 (rhBMP-4) were immunostained to identify the ureteric epithelium which was quantified in three dimensions. In vivo ureteric branching morphogenesis in Hoxb7/GFP mice was also analyzed. The effect of reduced in vivo levels of BMP-4 on nephron number was examined in BMP-4(+/-) and wild-type mice using an unbiased stereologic method.', 'Qualitative and quantitative studies identified a decrease in total ureteric length and branch number in wild-type mouse metanephroi cultured in the presence of BMP-4. A marked anterior-posterior asymmetry in both ureteric length and branch number was observed in BMP-4-treated metanephroi. A similar asymmetry was revealed in control metanephroi, both in vitro and in vivo. This asymmetry is the result of reduced ureteric branching morphogenesis in the posterior region of the kidney and appears to be due to slower growth rather than the adoption of an alternate branching pattern. Reduction of endogenous BMP-4 in BMP-4(+/-) mice resulted in no change in total nephron number in macroscopically normal kidneys.'] |
['Regional anesthesia has been shown to blunt the response to surgical stress and decrease the use of volatile anesthetics and the consumption of opioids, which may reduce immune compromise and potentially delay tumor recurrence. The goal of this study was to find a possible association between intraoperative regional anesthesia and decreased cancer recurrence.', 'Patients who underwent surgery for ovarian cancer between January 1, 2000, and October 1, 2006, were included. Subjects who had optimal surgical debulking (<1.0 cm of remaining tumor) were evaluated for time to tumor recurrence (carcinoantigen 125 >21 U/mL or computed tomography evidence of disease progression) and/or death.', 'One hundred eighty-two patients were evaluated; 127 did not receive epidural anesthesia/analgesia. Among the 55 who had epidural catheters placed, 26 were used intraoperatively and postoperatively; 29 were used only postoperatively. Cancer recurrence was documented in 121 patients. The median (interquartile range) time to recurrence was 40 (25-52) months. The intraoperative use epidural group had a mean (95% confidence interval) time to recurrence of 73 (56-91) months, which was longer than either the epidural postoperative group 33 (21-45) months (P = 0.002) or the no-epidural group 38 (30-47) months (P = 0.001). The postoperative-only and no-epidural groups were not different (P = 0.92). Intraoperative epidural significantly reduced (hazard ratio, 0.37 [95% confidence interval, 0.19-0.73]) tumor recurrence risk.'] |
['Departures from power law group size frequency distributions have been proposed as a useful tool to link individual behavior with population patterns and dynamics, although examples are scarce for wild animal populations.', 'We studied a population of Lesser kestrels (Falco naumanni) breeding in groups (colonies) from one to ca. 40 breeding pairs in 10,000 km(2) in NE Spain. A 3.5 fold steady population increase occurred during the eight-year study period, accompanied by a geographical expansion from an initial subpopulation which in turn remained stable in numbers. This population instability was mainly driven by first-breeders, which are less competitive at breeding sites, being relegated to breed solitarily or in small colony sizes, and disperse farther than adults. Colony size frequency distributions shifted from an initial power law to a truncated power law mirroring population increase. Thus, we hypothesized that population instability was behind the truncation of the power law. Accordingly, we found a power law distribution through years in the initial subpopulation, and a match between the power law breakpoint (at ca. ten pairs) and those colony sizes from which the despotic behavior of colony owners started to impair the settlement of newcomers. Moreover, the instability hypothesis was further supported by snapshot data from another population of Lesser kestrels in SW Spain suffering a population decline.'] |
['Isoflurane may be protective in preclinical models of lung injury, but its use in patients with lung injury remains controversial and the mechanism of its protective effects remains unclear. The authors hypothesized that this protection is mediated at the level of alveolar tight junctions and investigated the possibility in a two-hit model of lung injury that mirrors human acute respiratory distress syndrome.', 'Wild-type mice were treated with isoflurane 1\u2009h after exposure to nebulized endotoxin (n = 8) or saline control (n = 9) and then allowed to recover for 24\u2009h before mechanical ventilation (MV; tidal volume, 15\u2009ml/kg, 2\u2009h) producing ventilator-induced lung injury. Mouse lung epithelial cells were similarly treated with isoflurane 1\u2009h after exposure to lipopolysaccharide. Cells were cyclically stretched the following day to mirror the MV protocol used in vivo.', 'Mice treated with isoflurane following exposure to inhaled endotoxin and before MV exhibited significantly less physiologic lung dysfunction. These effects appeared to be mediated by decreased vascular leak, but not altered inflammatory indices. Mouse lung epithelial cells treated with lipopolysaccharide and cyclic stretch and lungs harvested from mice after treatment with lipopolysaccharide and MV had decreased levels of a key tight junction protein (i.e., zona occludens 1) that was rescued by isoflurane treatment.'] |
['Diabetes interferes with bone formation and impairs fracture healing, an important complication in humans and animal models. The aim of this study was to examine the impact of diabetes on mesenchymal stem cells (MSCs) during fracture repair.', 'Fracture of the long bones was induced in a streptozotocin-induced type 1 diabetic mouse model with or without insulin or a specific TNFα inhibitor, pegsunercept. MSCs were detected with cluster designation-271 (also known as p75 neurotrophin receptor) or stem cell antigen-1 (Sca-1) antibodies in areas of new endochondral bone formation in the calluses. MSC apoptosis was measured by TUNEL assay and proliferation was measured by Ki67 antibody. In vitro apoptosis and proliferation were examined in C3H10T1/2 and human-bone-marrow-derived MSCs following transfection with FOXO1 small interfering (si)RNA.', 'Diabetes significantly increased TNFα levels and reduced MSC numbers in new bone area. MSC numbers were restored to normal levels with insulin or pegsunercept treatment. Inhibition of TNFα significantly reduced MSC loss by increasing MSC proliferation and decreasing MSC apoptosis in diabetic animals, but had no effect on MSCs in normoglycaemic animals. In vitro experiments established that TNFα alone was sufficient to induce apoptosis and inhibit proliferation of MSCs. Furthermore, silencing forkhead box protein O1 (FOXO1) prevented TNFα-induced MSC apoptosis and reduced proliferation by regulating apoptotic and cell cycle genes.'] |
['To examine the effect of doxycycline on the activity of matrix metalloproteinases (MMPs) and oxidative stress in gastric tissues of rats following gastric injury.', 'Gastric ulcers were generated in rats by administration of 70% ethanol, and activity of doxycycline was tested by administration 30 min prior to ethanol. Similarly, the effect of doxycycline was tested in an indomethacin-induced gastric ulcer model. The activities and expression of MMPs were examined by zymography and Western blot analysis.', 'Gastric injury in rats as judged by elevated ulcer indices following exposure to ulcerogen, either indomethacin or ethanol, was reversed significantly by doxycycline. Indomethacin-induced ulcerated gastric tissues exhibited about 12-fold higher proMMP-9 activity and about 5-fold higher proMMP-3 activity as compared to control tissues. Similarly, ethanol induced about 22-fold and about 6-fold higher proMMP-9 and proMMP-3 activities, respectively, in rat gastric tissues. Both proMMP-9 and MMP-3 activities were markedly decreased by doxycycline in ulcerogen treated rat gastric tissues. In contrast, the reduced MMP-2 activity in ulcerated tissues was increased by doxycycline during ulcer prevention. On the other hand, doxycycline inhibited significantly proMMP-9, -2 and -3 activities in vitro. In addition, doxycycline reduced oxidative load in gastric tissues and scavenged H₂O₂ in vitro. Our results suggest a novel regulatory role of doxycycline on MMP-2 activity in addition to inhibitory action on MMP-9 and MMP-3 during prevention of gastric ulcers.'] |
['The use of patient-reported outcome measures to assess clinical outcomes after injury and surgery has become common in treating young athletes with orthopaedic injuries; however, normative data for these measures are limited and often include a wide range of ages and activity levels.', 'To provide normative data for the Knee Injury and Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) in a young and athletic population, and to compare scores between participants with a history of knee ligament injury and those with no history.', 'Cross-sectional study; Level of evidence, 3.', 'We administered the KOOS and WOMAC to 1177 college freshmen entering the United States Military Academy in June 2011. All participants were healthy and had been medically screened to meet the physical induction standards for military service. We calculated means, standard deviations, percentiles, ranges, and interquartile ranges for the KOOS and WOMAC by sex and injury history. We also compared median scale scores for those with a history of knee ligament injury with those with no history using the Kruskal-Wallis test.', 'Among the 1177 participants, 971 were male (age, 18.8 ± 0.9 years), and the remaining 206 were female (age, 18.7 ± 0.8 years). Normative median values and interquartile ranges (IQRs) for the KOOS scale scores among men with no history of knee ligament injury were the following: Symptoms (96.4; IQR, 10.7), Pain (100; IQR, 2.8), Functional Activities of Daily Living (ADL) (100; IQR, 0.0), Sports and Recreation Function (100; IQR, 5.0), and Knee-Related Quality of Life (QOL) (100; IQR, 12.5). For women with no history of knee ligament injury, the KOOS scale scores were the following: Symptoms (92.9; IQR, 14.3), Pain (100; IQR, 5.6), Functional ADL (100; IQR, 2.9), Sports and Recreation Function (100; IQR, 10.0), and Knee-Related QOL (93.8; IQR, 18.8). Among the men, 139 (14%) reported a history of knee ligament injury, while 33 (16%) women also reported a history of injury. All KOOS scale scores and the WOMAC Stiffness and Function scale scores were significantly lower (P < .05) for men who reported a history of knee ligament injury. Similarly, Symptoms, Pain, and Knee-Related QOL on the KOOS and Pain on the WOMAC were significantly lower among women with a history of knee ligament injury.'] |
['Sirtuin 3 (Sirt3), one of the seven Sirtuins family members, plays critical roles in the progression of multiple cancer types. However, its role in the prognosis of hepatocellular carcinoma (HCC) has not yet been investigated systematically.', 'The correlation of Sirtuins expression with prognosis of HCC was determined by immunohistochemistry (IHC) in a large HCC patient cohort (n = 342). Expression of Sirt3 in tumoral and peritumoral tissues of HCC patients were further determined by western blotting (WB).', 'IHC and WB studies both showed a decreased expression of Sirt3 in tumoral tissues compared with peritumoral tissues (P = 0.003 for IHC, P = 0.0042 for WB). Decreased expression of Sirt3 in both tumoral and peritumoral tissues was associated with increased recurrence probability and decreased overall survival rate by univariate analyses (intratumoral Sirt3: P = 0.011 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.017 for TTR, P = 0.023 for OS), the prognostic value was strengthened by multivariate analyses (intratumoral Sirt3: P = 0.031 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.047 for TTR, P = 0.031 for OS). Intratumoral Sirt3 also showed a favorable prognostic value in patients with BCLC stage A (TTR, P = 0.011; OS, P < 0.001). In addition, we found that IHC studies of other sirtuin members showed a decreased expression of Sirt2, Sirt4 and Sirt5 and an increased expression of Sirt1, Sirt6 and Sirt7 in intratumoral tissues compared with peritumoral tissues. In contrast to Sirt3, other members did not showed a remarkable correlation with HCC prognosis.'] |
['Human genome-wide association studies have identified genetic variants in the chromosome 9p21 region that confer increased risk of coronary artery disease and other age-related diseases. These variants are located in a block of high linkage disequilibrium with the neighboring Ink4/Arf tumor-suppressor locus (also named CDKN2A/CDKN2B). Since previous studies suggest an atheroprotective role of the Ink4/Arf locus, here we assessed whether gain-of-function of the encoded genes can be exploited therapeutically to reduce atherosclerosis.', 'Generation and characterization of apolipoprotein E-null mice carrying an additional transgenic copy of the entire Ink4/Arf locus (apoE-/-Super-Ink4/Arf) that reproduces the normal expression and regulation of the endogenous locus.', 'Although liver and aorta of apoE-/-Super-Ink4/Arf mice only showed a trend towards increased Ink4/Arf transcript levels compared to apoE-/- controls, cultured macrophages with increased Ink4/Arf gene dosage exhibited augmented apoptosis induced by irradiation with ultraviolet light, indicating that low level of transgene overexpression can lead to augmented Ink4/Arf function. However, increased Ink4/Arf gene dosage did not affect atherosclerosis development in different vascular regions of both male and female apoE-/- mice fed either normal or high-fat diet. Increased gene dosage of Ink4/Arf similarly had no effect on atheroma cell composition or collagen content, an index of plaque stability.'] |
['Future changes in environmental conditions may alter evolutionary processes, including hybridization in nature. Frequency of hybrids could be altered via range shifts by the parental species or by changes in prezygotic or postzygotic reproductive isolation. We examined the potential for range shifts and change in postzygotic isolation by determining effects of increasing and decreasing precipitation on leaf physiology and fitness components in the subalpine herbs Ipomopsis aggregata (Polemoniaceae), I. tenuituba¸ and their natural hybrids in a common garden in the habitat of I. aggregata.', 'Summer precipitation was experimentally doubled or halved over 3 yr in comparison with ambient conditions. We measured relative growth rate, specific leaf area, intrinsic water-use efficiency, survival to reproduction, biomass, number of flowers produced, and floral morphology.', 'Ipomopsis tenuituba increased relative growth rate with higher precipitation more so than did I. aggregata during the first summer, but this response did not result in changes across treatments in relative survival or final reproductive success of the two species. When precipitation was reduced, the relative success of hybrids was greater than that of the home species, I. aggregata. In dry conditions, hybrids increased water-use efficiency and fitness as indexed by number of flowers more so than the other plant types did.'] |
['To assess the impact of eliminating routine drain placement in patients undergoing robot-assisted laparoscopic prostatectomy (RALP) and pelvic lymph node dissection (PLND) on the risk of postoperative complications.', 'An experienced single surgeon performed RALP on 651 consecutive patients at our institution from 2008 to 2012. Before August 2011, RALP with or without PLND included a routine peritoneal drain placed during surgery. Thereafter, routine intraoperative placement of drains was omitted, except for intraoperatively noted anastomotic leakage. We used multivariable logistic regression to compare complication rates between study periods and the actual drain placement status after adjusting for standard prespecified covariates.', 'Most patients (92%) did not have ≥grade 2 complications after surgery and only two patients (0.3%) experienced a grade 4 complication. The absolute adjusted risk of a grade 2-5 complication was 0.9% greater among those treated before August 2011 (95% confidence interval [CI] -3.3%-5.1%; p=0.7), while absolute adjusted risk of a grade 3-5 complication was 2.8% less (-2.8%; 95% CI-5.3%-0.1%; p=0.061). RESULTS based on drain status were similar.'] |
['The Lancet recently sponsored a commission examining the role of surgery in global health. There is a paucity of published information on the cost-effectiveness of surgery in low- and middle-income countries, a key metric in the prioritisation of limited resources.', 'All patients undergoing emergency laparotomy, elective and emergency inguinal hernia repair, elective and emergency caesarean section, amputation, fracture manipulation, or fracture fixation over a 3 months period in a single district African hospital were assessed. World Health Organisation global burden of disease (GBD) methodology was used to calculate the disability-adjusted life years (DALYs) saved for each patient (using global and local life expectancy). Fully loaded costs were calculated for each patient’s care and providing the overall surgical service. Cost-effectiveness was calculated in year 2012 US$ per DALY saved for each procedure and overall.', 'A total of 428 patients were included, with an overall cost-effectiveness of $10.70 per DALY averted. The cost-effectiveness of individual procedures (global life expectancy) was: Amputation—$17.66; Emergency caesarean section—$7.42; Elective caesarean section—$20.50; Emergency laparotomy—$8.62; Elective hernia repair—$15.26; Emergency hernia repair—$4.36; Fracture/dislocation reduction—$69.03; Fracture/dislocation fixation—$225.89.'] |
["We have previously shown that toll-like receptor 3 (TLR3)-mediated signaling plays an important role in the induction of innate cytokine responses to Theiler's murine encephalomyelitis virus (TMEV) infection. In addition, cytokine levels produced after TMEV infection are significantly higher in the glial cells of susceptible SJL mice compared to those of resistant C57BL/6 mice. However, it is not known whether TLR3-mediated signaling plays a protective or pathogenic role in the development of demyelinating disease.", "SJL/J and B6;129S-Tlr3tm1Flv/J (TLR3KO-B6) mice, and TLR3KO-SJL mice that TLR3KO-B6 mice were backcrossed to SJL/J mice for 6 generations were infected with Theiler's murine encephalomyelitis virus (2 × 105 PFU) with or without treatment with 50 μg of poly IC. Cytokine production and immune responses in the CNS and periphery of infected mice were analyzed.", 'We investigated the role of TLR3-mediated signaling in the protection and pathogenesis of TMEV-induced demyelinating disease. TLR3KO-B6 mice did not develop demyelinating disease although they displayed elevated viral loads in the CNS. However, TLR3KO-SJL mice displayed increased viral loads and cellular infiltration in the CNS, accompanied by exacerbated development of demyelinating disease, compared to the normal littermate mice. Late, but not early, anti-viral CD4+ and CD8+ T cell responses in the CNS were compromised in TLR3KO-SJL mice. However, activation of TLR3 with poly IC prior to viral infection also exacerbated disease development, whereas such activation after viral infection restrained disease development. Activation of TLR3 signaling prior to viral infection hindered the induction of protective IFN-γ-producing CD4+ and CD8+ T cell populations. In contrast, activation of these signals after viral infection improved the induction of IFN-γ-producing CD4+ and CD8+ T cells. In addition, poly IC-pretreated mice displayed elevated PDL-1 and regulatory FoxP3+ CD4+ T cells in the CNS, while poly IC-post-treated mice expressed reduced levels of PDL-1 and FoxP3+ CD4+ T cells.'] |
['The aim of our study was to analyze whether there is a gender difference in the effects of maternal chocolate ingestion (80% cocoa) on the fetus, as expressed by the fetal heart rate (FHR).', 'One hundred pregnant women with uncomplicated term gestation, matched for age and parity, underwent computerized FHR recording before and after eating 30\u2009g of 80% cocoa chocolate; 46 carried a male fetus, and 54 carried a female. Computerized cardiotocography parameters (baseline FHR in beats per minute, number of contractions/hour, fetal movements/hour, accelerations of at least 15\u2009bpm for 15\u2009s, episodes of high variation/min and short-term variation in ms) were expressed as the mean and SD. We calculated the difference before and after maternal chocolate eating both in male and female fetuses and then compared the gender differences in the FHR variation. Statistical significance was set at p\u2009<\u20090.05.', 'While baseline FHR and number of contractions did not change, the number of: fetal movements/hour, accelerations, episodes of high variation/min, and the short-term variation significantly increased after chocolate ingestion. The percent variation of the movements (101.7\u2009±\u200989.23 males versus 252.0\u2009±\u2009297.6 females; p\u2009=\u20090.002), accelerations (70.90\u2009±\u200946.98 males versus 153.3\u2009±\u2009178.5 females; p\u2009=\u20090.004) and short-term FHR variation (21.47\u2009±\u200918.73 males versus 37.35\u2009±\u200927.46 females; p\u2009=\u20090.002) increased to a greater degree in the female fetuses than in the males.'] |
['Mitral valve repair (MVRr) has become the mainstay of surgical treatment for mitral valvular regurgitation. Evaluation of MVRr by intraoperative transesophageal echocardiography (IOE) has been routinely employed to guide the operation. While the main objective of IOE is to assess for residual mitral regurgitation, it is also important to exclude significant mitral stenosis. Utilisation of pressure half-time (PHT) to estimate mitral valve area (MVA) has been shown to be reliable in normal clinical situations. However, in MVRr, the accuracy of MVA calculation by PHT needs to be ascertained.', 'Data from IOE and post-MVRr transthoracic echocardiography (TTE) from the year 1998 to 2002 were analysed and when required, offline PHT measurements were made. The mean time interval between the two echocardiographic examinations was 10.6 (1 to 56) weeks. In our 36 cases, the IOE MVA was found to be 2.1+/-0.5 cm2, with the corresponding TTE MVA to be 2.7+/-1.0 cm2. MVA by PHT with IOE underestimated TTE findings by 0.6+/-0.9 cm2 (95% CI: -0.85 to -0.24, P=0.001). In 6 patients, the IOE MVA was moderately reduced. Subsequent TTE in these patients showed that the MVA was adequate and was significantly underestimated by IOE in 5 of these patients. In all these cases, IOE underestimated MVA by a margin, which may result in a need to revise the repair.'] |
['Degree of satisfaction with a knee arthroplasty is said to be correlated to reduced pain and better function. During a validation of the Swedish Knee Arthroplasty Register in 1997, previously operated patients were asked how satisfied they were with their knee. A subgroup of "satisfied" patients was identified who underwent revision within 2 years of having expressed satisfaction. Our aim was to study the revision diagnosis, to determine whether the problem leading to revision had been discovered as a result of routine follow-up, and also to find out when the symptoms leading to revision had started.', 'We retrospectively studied the medical records of 181 patients (181 knees), with a median age of 74 (31-88) years. 68% were women and the median time between primary operation and revision was 8 (3-21) years.', 'Aseptic loosening (74/181) was the most common diagnosis. 2 cases were revised as a result of routine follow-up. 44% of the medical records included reports of pain in the replaced knee prior to answering the satisfaction questionnaire.'] |
['To determine which respiratory function tests best predicted diaphragmatic strength in patients with amyotrophic lateral sclerosis.', 'Patients referred for pulmonary evaluation were included (n = 25) if they underwent measurement of transdiaphragmatic pressure (Pdi) and one or more of the following on the same day: upright FVC, supine FVC, upright FEV(1), supine FEV(1), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and PaCO(2). Abdominal paradox and use of accessory muscles were also assessed. Bivariate analyses were performed using simple linear regression. Sensitivity and specificity of the potential predictors to detect an abnormal Pdi (< 70 cm H(2)O) were calculated.', 'Pulmonary function laboratory of an academic medical center.', 'Upright FVC, FEV(1), and MEP were all significantly correlated with Pdi, while MIP and PaCO(2) were not. Supine FVC was the most highly correlated predictor of Pdi (R(2) = 0.76). A cutoff of supine FVC that was < 75% predicted was 100% sensitive and specific for predicting an abnormally low Pdi. Accessory muscle use and abdominal paradox were both significantly associated with Pdi, and the presence of accessory muscle use had a sensitivity of 84% and a specificity of 100% for detecting a low Pdi.'] |
['Previous studies showed that serum tartrate-resistant acid phosphatase 5b (TRACP5b) activity was increased in 70% to 94% of breast cancer (BC) patients with bone metastasis (BM). This study aims to determine whether serum TRACP5b is useful for identifying limited or extensive BM in BC patients.', 'Serum TRACP5b activity was measured in 168 BC patients, including 81 who were newly diagnosed with early BC, 20 with extraosseous metastasis, 24 with limited BM, and 43 with extensive BM. Serum TRACP5b activity was also measured monthly in 151 patients with early BC until they developed BM. Four hundred and twenty-seven (427) healthy women ages 18 to 90 served as control. One-way ANOVA was used to compare serum TRACP5b among groups. The sensitivity and specificity of serum TRACP5b as a marker for BM were estimated by receiver operator characteristic (ROC) curves.', 'Serum TRACP5b increased with age in healthy women ( P < 0.0001). It was significantly elevated in patients with extensive BM compared with all other groups ( P < 0.0001). ROC analysis established a cutoff value of 4.026 units/L to identify patients with extensive BM with a specificity of 98% and a sensitivity of 93% (area under the curve = 0.9807; 95% CI = 0.9698-0.9915). Among the 151 patients with early BC, 6 developed limited BM and 2 developed extensive BM during the follow-up period. Serum TRACP5b remained below the cutoff value in patients with limited BM, but became significantly increased in those whose BM became extensive.'] |
['Changing dietary and physical activity habits has the potential to postpone or prevent the development of type 2 diabetes. However, it needs to be assessed whether moderate interventions, in agreement with current guidelines for the general population, are effective. We evaluated the impact of a 2-year combined diet and physical activity intervention program on glucose tolerance in Dutch subjects at increased risk for developing diabetes.', 'Subjects with glucose intolerance were randomly assigned to either the lifestyle intervention group (INT) or control group (CON). The INT received regular dietary advice and was stimulated to increase their physical activity. The CON received a brief leaflet about healthy diet and increased physical activity. Primary outcome measure was the change in glucose tolerance.', 'In total, 88 subjects completed 2 years of intervention (40 subjects in the INT, 48 subjects in the CON, mean BMI 29.4 kg/m2). Subjects in the INT reduced their body weight, waist circumference, and (saturated) fat intake and improved their aerobic capacity. Two-hour plasma glucose concentration declined from 8.7 to 8.0 mM in the INT and rose from 8.6 to 9.4 mM in the CON (p < 0.01). Subjects adherent to both the diet and exercise intervention showed the largest reduction in 2-hour glucose levels.'] |
['The pressure in air-filled endotracheal cuffs increases steadily throughout general anesthesia with nitrous oxide (N2O). High cuff pressures can be responsible for local ischemia, which may induce tracheal mucosal injury. In this study, cuff pressure was monitored in anesthetized patients, and postanesthesia endotracheal lesions were assessed by endoscopy. Sixty-five patients undergoing general anesthesia with tracheal intubation >1 h in duration were randomized into two groups. The endotracheal tube cuff was inflated to 30-40 cm H2O with air in Group 1 (n = 33) and with a gas mixture (N2O 50% in oxygen) in Group 2 (n = 32). At the time of tracheal extubation, a fiberoptic examination via the endotracheal tube was performed by an independent observer. Aspects of trachea at the level of cuff contact area were scored as 0 = normal, 1 = mucosal erythema or edema, 2 = mucosal erosion or hemorrhage, 3 = mucosal erosion or hemorrhage on both anterior and posterior tracheal walls. Cuff pressure increased throughout the procedure (P<0.01) in Group 1 and remained stable in Group 2. In Group 1, tracheal lesions in the area of the cuff were more frequent than they were in Group 2 (79% vs. 37%; P<0.001). Tracheal injury was correlated to cuff pressure (r = 0.62, P<0.001). No postoperative respiratory complication was observed in any patient. In patients anesthetized with N2O, the inflation of the tracheal tube cuff with a gas mixture of the same composition as the inhaled mixture can prevent excessive cuff pressure and reduce the incidence of tracheal injury.'] |
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