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All Benign and Malignant Apocrine Breast Lesions Over-Express Claudin 1 and 3 and Are Negative for Claudin 4. Invasive apocrine carcinoma of the breast is an uncommon triple negative tumour that lacks a specific therapeutic target. Apocrine metaplasia of the breast shares common morphological features with apocrine carcinoma, and was previously found to consistently over-express claudin 1 and to lack claudin 4. This study was aimed at finding whether apocrine carcinoma, and other related apocrine breast lesions, have similar claudin profile. The immunohistochemical expression of claudin 1, 3 and 4 was studied in 11 cases of in situ and invasive apocrine breast carcinoma, 7 benign apocrine lesions and 45 consecutive morphologically non-apocrine triple negative breast carcinomas. All cases were also immunostained for Gross Cystic Disease Fluid Protein-15 (GCDFP-15), a marker for apocrine differentiation. Apocrine breast lesions maintained their expression pattern from benign through DCIS to invasive carcinoma; all showing strong expression of claudin 1 and 3 and absence of claudin 4. The same pattern of expression was seen in 2 out of the 45 morphologically non-apocrine tumours, but both showed strong positive staining for GCDFP-15. It is concluded that all benign and malignant apocrine lesions of the breast have a consistent pattern of claudin 1, 3 and 4 expression, suggesting the presence of a specific pathway for the development of invasive apocrine carcinoma. The over-expression of claudin 1 and 3 may have therapeutic implications as targets for managing apocrine cancers.
The role of intercalated water in multilayered graphene oxide. A detailed in situ infrared spectroscopy analysis of single layer and multilayered graphene oxide (GO) thin films reveals that the normalized infrared absorption in the carbonyl region is substantially higher in multilayered GO upon mild annealing. These results highlight the fact that the reduction chemistry of multilayered GO is dramatically different from the single layer GO due to the presence of water molecules confined in the ∼1 nm spacing between sheets. IR spectroscopy, XPS analysis, and DFT calculations all confirm that the water molecules play a significant role interacting with basal plane etch holes through passivation, via evolution of CO(2) leading to the formation of ketone and ester carbonyl groups. Displacement of water from intersheet spacing with alcohol significantly changes the chemistry of carbonyl formation with temperature.
Proton spectroscopic imaging: a tool for studying intracerebral tumor models in rat. Water-suppressed 2D 1H spectroscopic imaging was used with surface coils to study in vivo the cerebral metabolism changes in rat brain induced by a glial tumor growing in situ. To achieve slice selection without a chemical-shift artifact, we exploited the depth pulse properties of a spin-echo sequence. In order to give a spectral response which is independent of the position, the water suppression was achieved by using a spin-locking excitation and a binomial refocusing pulse. Spectroscopic images were obtained with an in-plane resolution of 1.1 X 1.1 mm and a slice thickness of roughly 3 mm. The growing of the tumor induced dramatic modifications in the proton spectra, including a nearly complete loss of N-acetyl aspartate, an increase of the 1.3-ppm peak, an increase in choline, and a decrease in creatine. The results demonstrate the potential of spectroscopic imaging in the study of intracranial tumor models in rats.
Manufacture of fine spherical granules by an extrusion/spheronization method. Fine spherical granules of uniform particle size less than 500 microm are desired for easy handling in dispensing pharmacy. These fine particles have been produced by layering an active ingredient and excipients on a core; however, several technical problems have been difficult to overcome, e.g., the amount of layered ingredients is limited and often granules themselves agglomerate during the layering process and affect the quality of the finished product. Here, we studied the feasibility of the manufacture of fine spherical granules by an extrusion/spheronization method. A screen with a pore size of 0.4mm or smaller was used for extrusion, and reduction of the extrusion pressure at the screen was necessary to prevent the screen from breaking. In light of the reduction of the screen pressure, we found low substituted hydroxypropylcellulose (L-HPC), croscarmellose sodium (Ac-Di-Sol) and carmellose calcium (ECG-505), markedly decreased the screen pressure. It is suggested that the high swelling property of these excipients is closely related to screen pressure reduction. In the spheronization process, it was found that L-HPC gave the highest sphericity, while Ac-Di-Sol and ECG-505 were unsatisfactory. It is concluded that L-HPC is the most appropriate excipient for the manufacture of fine spherical granules of less than 500 microm diameter by the extrusion/spheronization method.
Gene array identification of osteoclast genes: differential inhibition of osteoclastogenesis by cyclosporin A and granulocyte macrophage colony stimulating factor. Treatment of adherent peripheral blood mononuclear cells (PBMCs) with macrophage colony stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL) stimulates the formation of multinucleate osteoclast-like cells. Treatment with M-CSF alone results in the formation of macrophage-like cells. Through the use of Atlas human cDNA expression arrays, genes regulated by RANKL were identified. Genes include numerous cytokines and cytokine receptors (RANTES and CSF2R proportional, variant ), transcription factors (nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and GA binding protein transcription factor alpha (GABPalpha)), and ribosomal proteins (60S L17 and 40S S20). Real-time PCR analysis showed significant correlation (R2 of 0.98 P < 0.01) with array data for all genes tested. Time courses showed differential activation patterns of transcription factors with early induction of FUSE binding protein 1 (FBP) and c-Jun, and later steady upregulation of NFATc1 and GABP by RANKL. Treatment with cyclosporin A, a known NFATc1 inhibitor, resulted in a blockade of osteoclast formation. The mononuclear cells resulting from high cyclosporin treatment (1,000 ng/ml) were cathepsin K (CTSK) and tartrate-resistant acid phosphatase (TRAP) positive but expression of calcitonin receptor (CTR) was downregulated by more than 30-fold. Constant exposure of M-CSF- and RANKL-treated cells to GM-CSF resulted in inhibition of osteoclast formation and the downregulation of CTSK and TRAP implicating the upregulation of CSF2R in a possible feedback inhibition of osteoclastogenesis.
Detailed 3D models of the induced electric field of transcranial magnetic stimulation coils. Previous models neglected contributions from current elements spanning the full geometric extent of wires in transcranial magnetic stimulation (TMS) coils. A detailed account of TMS coil wiring geometry is shown to provide significant improvements in the accuracy of electric field (E-field) models. Modeling E-field dependence based on the TMS coil's wire width, height, shape and number of turns clearly improved the fit of calculated-to-measured E-fields near the coil body. Detailed E-field models were accurate up to the surface of the coil body (within 0.5% of measured) where simple models were often inadequate (up to 32% different from measured).
Reduced memory and attention performance in a population-based sample of young adults with a moderate lifetime use of cannabis, ecstasy and alcohol. Regular use of illegal drugs is suspected to cause cognitive impairments. Two substances have received heightened attention: 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') and delta-9-tetrahydrocannabinol (THC or 'cannabis'). Preclinical evidence, as well as human studies examining regular ecstasy consumers, indicated that ecstasy use may have negative effects on learning, verbal memory and complex attentional functions. Cannabis has also been linked to symptoms of inattention and deficits in learning and memory. Most of the published studies in this field of research recruited participants by means of newspaper advertisements or by using word-of-mouth strategies. Because participants were usually aware that their drug use was critical to the research design, this awareness may have caused selection bias or created expectation effects. Focussing on attention and memory, this study aimed to assess cognitive functioning in a community-based representative sample that was derived from a large-scale epidemiological study. Available data concerning drug use history allowed sampling of subjects with varying degrees of lifetime drug experiences. Cognitive functioning was examined in 284 young participants, between 22 and 34 years. In general, their lifetime drug experience was moderate. Participants completed a neuropsychological test battery, including measures for verbal learning, memory and various attentional functions. Linear regression analysis was performed to investigate the relationship between cognitive functioning and lifetime experience of drug use. Ecstasy and cannabis use were significantly related to poorer episodic memory function in a dose-related manner. For attentional measures, decrements of small effect sizes were found. Error measures in tonic and phasic alertness tasks, selective attention task and vigilance showed small but significant effects, suggesting a stronger tendency to experience lapses of attention. No indication for differences in reaction time was found. The results are consistent with decrements of memory and attentional performance described in previous studies. These effects are relatively small; however, it must be kept in mind that this study focussed on assessing young adults with moderate drug use from a population-based study.
An introduction to quality of life assessment in oncology: the value of measuring patient-reported outcomes. This article provides an introduction to the concepts of quality of life (QOL) research, including the documented uses and benefits of patient-reported outcomes. Health-related QOL data have been useful in clinical care studies, clinical trials, and cost-effectiveness studies. In the area of cancer treatment, such health-related QOL data have been influential on treatment decisions and cancer care. In addition, this article addresses the challenges resulting from more frequent use of patient-reported outcomes by researchers and physicians. In particular, the impact of the response-shift phenomenon is examined, as well as the time pressure, clinical constraints, and suboptimal communication skills that may hinder the transfer of information from patient to physician and/or researcher.
Developing nursing leaders: an overview of trends and programs. Nurses need to acquire new leadership skills to meet the demands of their positions. Until recently, the healthcare industry has focused on continuing education to meet licensure requirements and to achieve advanced clinical certifications. Given increasingly complex leadership challenges, we are seeing the emergence of leadership development programs designed to enhance leadership effectiveness in the service of broader strategic objectives. By learning more about these opportunities, nurse executives can make better decisions for themselves and other nursing colleagues.
Glial cells form boundaries for developing insect olfactory glomeruli. Like many other first-order olfactory centers, the olfactory lobe of the moth brain is organized into histologically conspicuous synaptic glomeruli delimited by glial cells. These glomeruli in the moth offer an advantageous system in which to study the parcellation of central neuropils during development. In this article, we review the evidence that glial cells play an essential role in the induction of glomeruli by olfactory sensory axons, and we present new evidence that leads us to propose that a major role for glia in the development of glomeruli is to define for ingrowing dendrites of second-order olfactory neurons edges that lead to the formation of these cells' characteristic morphology.
Clinicopathologic assessment of Candida colonization of oral leukoplakia. Leukoplakia is the most common premalignant lesion of the oral mucosa. We studied the colonization of Candida in oral leukoplakia using direct microscopy, culture and histopathology to determine if there is a statistical correlation between Candida invasion and the clinical appearance and presence of epithelial dysplasia in leukoplakia. Samples were collected from 40 patients with oral leukoplakia and 21 controls. The swabs collected were used to inoculate Sabouraud's dextrose agar slant and for direct microscopy with Gram's stain. Culture growths were subjected to germ tube and corn meal agar tests to differentiate between Candida albicans and non-albicans groups. Biopsies were also done in all patients for histopathological confirmation; Gomori's methanamine silver stain was used to identify fungal invasion of lesional epithelium. Nineteen cases of leukoplakia showed Candida on direct smears, compared to 3 controls. Eighteen cases and one control showed growth of Candida on culture. Non-homogenous leukoplakia showed a higher positivity rate on microscopy and culture than homogenous lesions. All these correlations were statistically significant. Forty percent of leukoplakia cases were simultaneously positive for Candida on direct microscopy, culture and histopathologic evaluation. No significant difference was found between non-dysplastic and distinctly dysplastic lesions with respect to Candida detection on microscopy or culture.
Integrative Medicine and Health Coaching in Polytrauma Rehabilitation. Veterans Health Administration (VHA) has embarked on a journey of cultural transformation focused on creating a personalized and patient-driven experience with health care service. In addition to training thousands of providers in the principles of whole health and expanding availability of complementary medicine, VHA also pursues developing the evidence for such care. The Polytrauma Integrative Medicine Pilot explored the feasibility of implementing health coaching in polytrauma care. The qualitative and quantitative data collected on 547 participants in the pilot shows high satisfaction with the health coaching services received and statistically significant positive changes in domains of life satisfaction and well-being.
Esophageal Ulcer as a Cause of Death: A Population-Based Study. Mortality of Esophageal Ulcer Disease. This study aimed at defining the mortality and the nature of fatal complications that arise out of esophageal ulcer for one clearly defined geographical area. In this national, population-based study, the occurrence of fatal esophageal ulcer or ulcer requiring hospital treatment between January 1987 and December 2000 was assessed by the use of Finland's administrative databases. Medical records provided etiology of fatal ulcer and agonal symptoms. Due to an esophageal ulcer, 2,242 patients received treatment in Finnish hospitals, at an annual frequency of 3.2/100,000. Ulcer with hemorrhage (53.5%), perforation (38.4%), or aspiration pneumonia (2.3%) was the cause of death in 86 patients for an annual mortality of 0.12/100,000. Based on the number of ulcers treated, 3.8% cases ended fatally. Gastroesophageal reflux disease (GERD) seemed to be the etiologic factor for ulcer in 68 (79.0%) patients. The most common agonal symptoms were hematemesis (41.8%), abdominal pain (25.6%), melaena (22.1%), and dyspnea (17.4%). Twenty (23.3%) patients were found dead at home. The rarity of the disease, related disorders, and the diversity of symptoms make the complicated esophageal ulcer a diagnostic challenge. Effective monitored treatment for severe GERD may be an important step to prevent fatal outcome.
Mosaic origin of the heme biosynthesis pathway in photosynthetic eukaryotes. Heme biosynthesis represents one of the most essential metabolic pathways in living organisms, providing the precursors for cytochrome prosthetic groups, photosynthetic pigments, and vitamin B(12). Using genomic data, we have compared the heme pathway in the diatom Thalassiosira pseudonana and the red alga Cyanidioschyzon merolae to those of green algae and higher plants, as well as to those of heterotrophic eukaryotes (fungi, apicomplexans, and animals). Phylogenetic analyses showed the mosaic character of this pathway in photosynthetic eukaryotes. Although most of the algal and plant enzymes showed the expected plastid (cyanobacterial) origin, at least one of them (porphobilinogen deaminase) appears to have a mitochondrial (alpha-proteobacterial) origin. Another enzyme, glutamyl-tRNA synthase, obviously originated in the eukaryotic nucleus. Because all the plastid-targeted sequences consistently form a well-supported cluster, this suggests that genes were either transferred from the primary endosymbiont (cyanobacteria) to the primary host nucleus shortly after the primary endosymbiotic event or replaced with genes from other sources at an equally early time, i.e., before the formation of three primary plastid lineages. The one striking exception to this pattern is ferrochelatase, the enzyme catalyzing the first committed step to heme and bilin pigments. In this case, two red algal sequences do not cluster either with the other plastid sequences or with cyanobacterial sequences and appear to have a proteobacterial origin like that of the apicomplexan parasites Plasmodium and Toxoplasma. Although the heterokonts also acquired their plastid via secondary endosymbiosis from a red alga, the diatom has a typical plastid-cyanobacterial ferrochelatase. We have not found any remnants of the plastidlike heme pathway in the nonphotosynthetic heterokonts Phytophthora ramorum and Phytophthora sojae.
Network reset: a simplified overarching theory of locus coeruleus noradrenaline function. Unraveling the functional role of neuromodulatory systems has been a major challenge for cognitive neuroscience, giving rise to theories ranging from a simple role in vigilance to complex models concerning decision making, prediction errors or unexpected uncertainty. A new, simplified and overarching theory of noradrenaline function is inspired by an invertebrate model: neuromodulators in crustacea abruptly interrupt activity in neural networks and reorganize the elements into new functional networks determining the behavioral output. Analogously in mammals, phasic activation of noradrenergic neurons of the locus coeruleus in time with cognitive shifts could provoke or facilitate dynamic reorganization of target neural networks, permitting rapid behavioral adaptation to changing environmental imperatives. Detailed analysis and discussion of extensive electrophysiological data from the locus coeruleus of rats and monkeys in controlled behavioral situations is provided here to support this view. This simplified 'new look' at locus coeruleus noradrenaline function redirects the challenge of understanding neuromodulatory systems towards their target networks, particularly to the dynamics of their interactions and how they organize adaptive behavior.
A monoclonal antibody, MN13, that recognizes specifically a novel substance between the postacrosomal sheath and the overlying plasma membrane in the mammalian sperm head. Monoclonal antibody MN13 raised against mouse spermatozoa specifically recognizes the postacrosomal region of the sperm head in several mammalian species. Colloidal gold-immunoelectron microscopy of demembranated mouse spermatozoa indicated that the antigen is associated with the outer layer of the periodic substructure apparently linking the postacrosomal sheath to the overlying plasma membrane. The antigen recognized by MN13 may contribute to the intimate association of the postacrosomal sheath with the overlying plasma membrane.
Resting lymphocyte kinase (Rlk/Txk) phosphorylates the YVKM motif and regulates PI 3-kinase binding to T-cell antigen CTLA-4. CTLA-4 and CD28 are differentially expressed on T-cells. They bind to a common ligand B71/2 (CD80/86), however with different avidities. Unlike CD28 which augments the T-cell response, CTLA-4 operates predominately as a negative regulator of T-cell proliferation. The mechanism by which CTLA-4 can generate these intracellular signals is unclear. Little is known regarding the identity of the protein-tyrosine kinase(s) responsible for CTLA-4 phosphorylation and thus creating conditions for the reported binding to PI 3-kinase and the protein tyrosine phosphatase SHP-2. In this study, we demonstrate that Rlk (resting lymphocyte kinase) is capable of phosphorylating CTLA-4 at the YVKM motif. Consistent with this finding, Rlk is capable of providing conditions for the binding of the SH2 domains of PI 3-kinase to the receptor. CTLA-4 is therefore the first known substrate for Rlk suggesting the possibility that this kinase may participate in CTLA-4 function.
Resonance Raman spectra of manganese myoglobin and its azide complex. Assignment of a new charge-transfer band to azide (pi) to porphyrin (pi) transition. The enhancement of bound azide vibrations at 650 [depolarized (dp), bending] and 2039 cm-1 (dp, antisymmetric stretch) upon excitation at approximately 400-460 nm indicates the existence of a new charge-transfer transition in manganese(III) myoglobin-azide complex. The assignments of these two vibrational modes are based on the agreement of their 15N3 isotope shifts (22 and 70 cm-1) with the calculated values (22 and 69 cm-1), the depolarized nature, and their close proximity to the corresponding vibrations in ionized azide. The Mn-(III)-N3 stretch has not been observed in the present study although the Fe(III)-N3 stretch at 413 cm-1 (polarized) was reported [Asher, S. A., Vickery, L. E., Schuster, T. M., & Sauer, K. (1977) Biochemistry 16, 5849]. The RR spectra of MnIIIMb-azide between 150 and 300 cm-1 differ dramatically from those of FeIIIMb-azide exicted in the 640-nm charge-transfer band or near the Soret band. There are lines at 170 and 282 cm-1 (both polarized) in the MnIIIMb-azide spectra which exhibit extremely large resonance enhancements and are unshifted by 15N3 isotope substitution. These two lines, having no analogue in other heme protein spectra, may be tentatively assigned to the out-of-plane porphyrin ring vibrations, with the latter involving significant Mn(III)-N(pyrrole) stretch. The enhancement of non totally symmetric azide modes suggests that the charge-transfer state may be mixed with other excited electronic states (possibly band Va or band VI) via Herzberg-Teller vibronic couplings. The lack of enhancement of the Mn(III)-N3 stretch leads to our present assignment of azide (pi) to porphyrin (pi) charge-transfer transition rather than azide (pi) to metal (dz2) or azide (n) to metal (dz2).
Minimising collateral damage: family peer support and other strategies. The impact on family members of mental illness in a young person is intensely distressing. Symptoms that they cannot understand, and the stigma surrounding mental illness may lead to families feeling isolated in their distress. Family carers are reassured by talking with other families who have experienced the same or similar situations. The "Families Helping Families" program at ORYGEN Youth Health trains family peer-support workers, who are employed to provide information and support to families new to the service. Medical practitioners need to appreciate the importance of ensuring that families receive information and emotional support to help them cope effectively. Difficulties in helping family carers, often around perceived confidentiality restraints, need to be overcome so that collateral damage--family breakdown, persistence of symptoms, and behavioural maladjustments--can be reduced. Families who are supported can become advocates for improvements to mental health services for young people.
Charmed baryonium. We reanalyze the published data on the Y(4630)-->Lambda(c) Lambda(c) and the Y(4660)-->psi(2S)pi pi with a consistent ansatz and we find that the two observations are likely to be due to the same state Y(B), produced via initial state radiation (ISR), with M(Y(B))=4660.7+/-8.7 MeV and Gamma(Y(B))=61+/-23 MeV. Under this hypothesis and reanalyzing the e+e- -->J/psi pi pi gamma(ISR) spectrum we find B(Y(B))-->Lambda(c) Lambda(c))/B(Y(B))-->psi(2S)pi pi)=117+/-44, B(Y(B))-->J/psi pi pi)/B(Y(B))-->psi(2S)pi pi)<0.46@90% C.L., B(Y(4350)-->J/psi pi pi)/B(Y(4350)-->psi(2S)pi pi)<3.4x10(-3)@90% C.L., and B(Y(B))-->psi(2S)sigma)/B(Y(B))-->psi(2S)f0)=2.0+/-0.3. These conclusions strongly support the hypothesis of Y(B) being the first observation of a charmed baryonium constituted by four quarks. Analyzing the mass spectrum we show that Y(4350) and Y(B) are, respectively, consistent with the ground state and first radial excitation of the l=1 state.
[Pharmacovigilance update]. The main pharmacovigilance updates in 2015are reviewed. Sofosbuvir amiodarone interaction: risk of severe bradycardia. Dasabuvir clopidogrel interaction: increased dasabuvir concentrations and potential risk of QTprolongation. SGLT2 inhibitors: risks of diabetic acidocetosis and bone fracture. Dabigatran: therapeutic drug monitoring may improve benefit-risk ratio. Ibuprofen: at higher dosage, vascular risks are comparable to coxibs. Pregabaline, gabapentine: potential for abuse and addiction. Varenicline: potentiates alcohol's effects. Codeine: contra-indicated as cough medicine under the age of twelve. Valproate: strengthened warnings on the risks of valproate use in pregnancy. Dimethylfumarate: rare observations of progressive multifocal leucoencephalopathy. Ustekinumab: rare observations of erythrodermia.
Molecular characterization of the Epstein-Barr virus DNA in three new Burkitt's lymphoma-derived cell lines. Three new Epstein-Barr virus DNA populations have been isolated from the recently established Burkitt's lymphoma-derived cell lines, LY47, LY91 and BL8. Each of these lines carries one of the specific chromosome translocations associated with Burkitt's lymphoma but few if any other chromosomal abnormalities. An outline of their molecular organization, as determined by restriction enzyme analysis, is presented. Two of the isolates, LY47 and BL8, give patterns broadly similar to Epstein-Barr virus DNA molecules studied to date. The third, LY91, shows a highly unusual molecular organization, in particular within BamHI subfragments of the EcoRI A fragment, indicative of the presence of a major defective molecular species within this line. All three cell lines produce virions that are capable of transforming immature B-lymphocytes.
N-substituted 4beta-methyl-5-(3-hydroxyphenyl)-7alpha-amidomorphans are potent, selective kappa opioid receptor antagonists. In a previous study, we identified (-)-N-[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(1-piperidinyl)propanamide (5a, KAA-1) as the first potent and selective kappa opioid receptor antagonist from the 5-(3-hydroxyphenyl)morphan class of opioids. In this study we report an improved synthesis of this class of compounds. The new synthetic method was used to prepare analogues 5b-r where the morphan N-substituent and 7alpha-amido group were varied. Most of the analogues showed sub-nanomolar potency for the kappa opioid receptor and were highly selective relative to the mu and delta opioid receptors. (-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-{(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-[2-(2-methylphenyl)ethyl]-2-azabicyclo[3.3.1]non-7-yl}propanamide (5n, MTHQ) is at least as potent and selective as nor-BNI as a kappa opioid receptor antagonist in the [35S]GTP-gamma-S in vitro functional test.
Semiconductor diode laser photocoagulation in retinal vascular disease. The authors successfully performed clinical transpupillary retinal photocoagulation in 30 eyes of 26 patients with retinal vascular disease using a gallium-aluminium-arsenide (GaAlAs) diode laser emitting at 805 nm. Retinal photocoagulation was performed at treatment powers of 300 to 1300 mW and exposure durations of 0.2 to 0.5 seconds with a 200-microns diameter treatment spot. Patients treated with both diode and argon green lasers required 4.5 +/- 1.8 times greater mean laser energy with diode compared with argon to create ophthalmoscopically similar lesions. Parallel experimental retinal photocoagulation in Chinchilla rabbits required 3.1 +/- 0.9 times more power to create ophthalmoscopically similar lesions with the diode laser than with the argon laser. Intraoperative subretinal hemorrhage occurred rarely in patients with an incidence of 4 (0.44%) of 9021 treatment spots. Patients complained of moderate-to-marked pain in 10 (43%) of 23 treatments initiated under topical anesthesia. A transpupillary diode laser may be used clinically to perform therapeutic retinal photocoagulation.
Secreted AGR2 promotes invasion of colorectal cancer cells via Wnt11-mediated non-canonical Wnt signaling. Human anterior gradient-2 (AGR2), a member of protein disulfide isomerase (PDI) family, is present in both intracellular and extracellular compartments. Although AGR2 is overexpressed in various human cancers and reported to promote aggressive tumor features, little is known regarding AGR2's extracellular functions during tumorigenesis. Here, we demonstrate that secreted AGR2 promotes cell migration and metastasis of colorectal cancer (CRC) in vitro and in vivo. Mechanistically, secreted AGR2 elevated Wnt11 expression, triggering non-canonical Wnt signaling: the Ca2+/Calmodulin-dependent protein kinase II (CaMKII) and c-jun amino-terminal kinase (JNK) pathways. Knockdown of Wnt11 or pretreatment with CaMKII and JNK inhibitors reversed the secreted AGR2's migration-promoting effect. Further studies revealed that AGR2 antagonized canonical Wnt/β-catenin signaling via activating CaMKII. Collectively, our study uncovers a critical role of Wnt11-mediated non-canonical Wnt signaling (CaMKII and JNK pathways) in secreted AGR2's promoted migration of CRC cells. These results raise the possibility that secreted AGR2 may be a potential therapeutic target towards inhibiting CRC metastasis.
Comparison of chemotherapeutic agents as a myeloablative conditioning with total body irradiation for pediatric acute lymphoblastic leukemia: A study from the pediatric ALL working group of the Japan Society for Hematopoietic Cell Transplantation. As a partner of total body irradiation (TBI) in hematopoietic stem cell transplantation (HSCT) for pediatric acute lymphoblastic leukemia (ALL), various cytotoxic agents are used, but the optimal combination is still unclear. We retrospectively analyzed 767 children who received TBI-based myeloablative allogeneic HSCT in complete remission (CR), using nationwide registry data of the Japan Society for Hematopoietic Cell Transplantation. Combinations of chemotherapy were categorized as follows: cyclophosphamide (CY) (n = 74), melphalan (L-PAM) (n = 139), CY + etoposide (VP16) (n = 408), CY + cytarabine (AraC) (n = 73), and others (n = 73). Event-free survival (EFS) at 5 years after HSCT was 62.2% for CY, 71.4% for L-PAM, 67.6% for CY + VP16, 52.6% for CY + AraC, and 59.1% for others (P = 0.009). Further detailed comparison of LPAM and CY + VP16 demonstrated superior EFS for LPAM (83.2 ± 6.7%), with a marked difference compared with CY + VP16 (66.7 ± 4.9%) when limited to HSCT from a matched related donor (MRD), and this result was reproduced regardless of disease status (CR1 or CR2). However, EFS for CY + VP16 (68.3 ± 2.8%) was comparable to that for LPAM (64.5 ± 5.7%, P = 0.37) in HSCT from alternative donors, because higher non-relapse mortality attenuated the advantage of LPAM. For pediatric ALL in remission, LPAM could provide superior EFS for HSCT from MRD; however, compared to LPAM, CY + VP16 has similar EFS for HSCT from an alternative donor.
A pilot study examining the speed and accuracy of triage for simulated disaster patients in an emergency department setting: Comparison of a computerized version of Canadian Triage Acuity Scale (CTAS) and Simple Triage and Rapid Treatment (START) methods. To compare emergency department triage nurses' time to triage and accuracy of a simulated mass casualty incident (MCI) population using a computerized version of CTAS or START systems. This pilot study was a prospective trial using a convenience sample. A total of 20 ED triage nurses, 10 in each arm of the study, were recruited. The paper-based questionnaire contained nine simulated MCI vignettes. An expert panel arrived at consensuses on the wording of the vignettes and created a standard triage score from which to compare the study participants. Linear regression and chi-squared test were used to examine the time to triage and accuracy of triage, respectively. The mean triage time for computerized CTAS (cCTAS) and START were 138 seconds/patient and 33 seconds/patient, respectively. The effect size due to triage method was 108 seconds/patient (95% CI 83-134 seconds/patient). The cumulative triage accuracy for the cCTAS and START tools were 70/90 (77.8%) and 65/90 (72.2%), respectively. The percent difference between cumulative triage was 6% (95% CI -19-8%). Triage nurses completed START triage 105 seconds/patient faster when compared to cCTAS triage and a similar level of accuracy between the two methods was achieved. However, when the typing time is taken into consideration cCTAS took 45 seconds/patient longer. The use of either CTAS or START in the ED during a MCI may be reasonable but choosing one method over another is not justified from this investigation.
Solution-state dynamic nuclear polarization at high magnetic field. The goal of dynamic nuclear polarization (DNP) is to enhance NMR signals by transferring electron spin polarization to the nuclei. Although mechanisms such as the solid effect and thermal mixing can be used for DNP in the solid state, currently, the only practical mechanism in solutions is the Overhauser effect (OE), which usually arises due to dipolar relaxation between electrons and the nuclei. At magnetic fields greater than approximately 1 T, dipolar relaxation does not result in a useful enhancement and therefore the conventional wisdom is that DNP should not work in solutions at high magnetic fields. However, scalar relaxation due to time-dependent scalar couplings has a different magnetic field dependence and can lead to substantial OE enhancements. At room temperature and at a magnetic field of 5 T (211 MHz for protons, 140 GHz for electrons), we have observed that scalar relaxation between electrons and nuclei results in NMR signal enhancements of 180, 42, -36, and 8, for 31P, 13C, 15N, and 19F, respectively.
Tolerance and biocompatibility of micronized black pigment for keratopigmentation simulated pupil reconstruction. To study the tolerance and biocompatibility of new mineral micronized pigments for corneal cosmetic pigmentation in an experimental animal model. Central corneal intralamellar tattoos were performed with a black iron oxide mineral micronized pigment using an irrigating solution as a control. Animals were examined regularly under a slit lamp to detect any signs of inflammation, pigment diffusion, or color changes and neovascularization. The animals were divided into 2 groups, A and B. These groups were followed up at 1 and 3 months, respectively. At the end of this period, confocal microscopy examination was performed before the animals were killed, and their eyes were processed for histopathological examination to determine the level of pigment diffusion and inflammation and the presence of neovascularization. Clinical findings included 2 cases of minimal inflammation that resolved within 2 weeks and a severe case of inflammation detected 20 days after the surgery. Confocal microscopy at the end of the follow-up revealed normal corneal structures in all the eyes examined, with a layer of highly reflective material in the mid stroma because of the presence of mineral pigment particles. Histopathological examination corroborated clinical results regarding inflammation. No pigment diffusion or changes in color occurred throughout the study, and there were no cases of corneal neovascularization. Central keratopigmentation presented good cosmetic appearance without adverse effects. These results suggest the adequacy of mineral micronized pigments for successful keratopigmentation. The hen animal model is a suitable model for assaying the biocompatibility and tolerance of micronized pigments in central keratopigmentation.
[An analysis of the possible mechanism of the ulcerostatic action of 1-ethoxysilatrane]. Stimulating effect of 1-ethoxysilatrane on healing processes of experimental stomach ulcers was studied in rats. 1-ethoxysilatrane inhibited lipid peroxidation in blood and stomach wall tissues, interacted with artificial membranes, and affected the rate of mitochondrial respiration in liver. A hypothesis is put forward on the membranotropic effect of 1-ethoxysilatrane which underlies its ulcerostatic effect.
Syntheses of 6-sulfo sialyl Lewis X glycans corresponding to the L-selectin ligand "sulfoadhesin". [structure: see text] Divergent syntheses of sulfated sialyl Lewis X oligosaccharides corresponding to the core 1 and core 6 branches of the L-selectin ligand are reported. These synthetic targets incorporate a selectively protected serine residue at the reducing terminus, providing a functional handle for further conjugation.
[Preoperative radiotherapy of bladder cancer]. Based on the observation of 58 patients with carcinoma of the bladder the effect of preoperative irradiation is reported. After application of 3500 Rad in about four weeks the examination of the surgery preparations revealed histological absence of tumor cells in one third of the cases approximately. The irradiation technique used is described and also the effects and side-effects of synchronization induced by 5-fluorouracil in a part of the group. Consequences for the therapeutic proceeding with regard to the carcinoma of the bladder are discussed.
[Are there guidelines for treatment of metacarpal fractures? Personal results and literature analysis of the last 12 years]. As the treatment of metacarpal fractures is today still a controversial subject, we conducted an analysis of the literature in order to present the different therapy guidelines, indications, and their results. The data from the follow-up of 1602 patients was taken from literature which dated from 1 January 1984 to 31 March 1996. A total of 522 patients who underwent surgery received K-wires, screws or external minifixateur. The conservative approaches ranged from immobilization to various methods of mobilization with different aids or without fixation of the fracture. The mobilization in a brace provided good to excellent results in 95% of the cases; however, the failure rate of therapy was 23% because of local bruises and skin necrosis (3%). The mobilization with handcast, tape etc. attained good to excellent results in 94% of the cases. Here, no complications occurred. Both the immobilization treatment and the surgery provided good to excellent results in 85% of the cases. The reposition of fractures of the fifth metacarpal was successful in only 15% of the cases. Fractures with dislocations below 30 degrees, a shortening of less than 5 mm, no rotational displacement or that below 10 degrees, no articular incongruency, and no relevant soft tissue trauma do not need surgery according to our results and should be treated with early mobilization as suggested by the survey. Beyond these limits a primary surgical therapy is justified. The immobilization of metacarpal fractures over a period of more than 3-4 weeks is not necessary.
Essential role of Rac1/NADPH oxidase in nerve growth factor induction of TRPV1 expression. Nerve growth factor (NGF) regulates the nociceptive properties of a subset of small diameter sensory neurons by increasing the expression of the heat-sensing transient receptor potential (TRP) channel, TRPV1. This action involves activation of the tyrosine kinase receptor (Trk) A/p38 MAPK pathway. Recent studies indicate that activation of TrkA promotes superoxide generation via NADPH oxidase. In this study, we determined whether the NADPH oxidase pathway is involved in NGF-stimulated TRPV1 expression using a rat pheochromocytoma 12 line and rat dorsal root ganglion neurons. Treatment of these cells with NGF (100 ng/mL) increased TRPV1 protein expression (approx. twofold) but not mRNA. This increase was mimicked by H(2)O(2) and attenuated by catalase and inhibitors of NADPH oxidase. NGF stimulated NADPH oxidase activity, while 24 h exposure further increased expression of the Rac1 and gp91(phox) subunits of the holoenzyme. Inhibition of NADPH oxidase by transient transfection of a dominant negative Rac1 mutant (RacN17) plasmid blocked NGF-stimulated TRPV1 protein expression, while expression of a constitutively active Rac1 increased basal and NGF-stimulated TRPV1 levels. Inhibition of NADPH oxidase activity also attenuated NGF-dependent p38 MAPK activation. We conclude that the Rac1/NADPH oxidase pathway regulates p38 activation and TRPV1 expression which aids in the maintenance of peripheral neuron integrity and pain perception.
Lettuce Salad as a Carrier of Microorganisms of Public Health Significance 1. Culture, distribution, and preparation of lettuce for salad offers opportunities for contamination with and growth of microorganisms. Protection and preservation methods, even when appropriate, may likewise be favorable for the contaminants. Fresh lettuce, as commercially available, was studied to determine the magnitude of contamination and the nature of representative contaminants. Specific contaminants of public health interest were added to test portions to determine their fate during storage of lettuce as a salad at room temperature. Storage of lettuce in bowls on ice resulted in very little cooling of most of the lettuce. Microbial plate counts on fresh lettuce commonly were over 105/g and the diversity of the microflora indicated a generally favorable microenvironment for many types of bacteria. Inocula of Salmonella typhimurium , Escherichia coli , and Staphylococcus aureus fared well on lettuce salad and were able to grow at room temperature storage. Commmercial "whitener" added to lettuce to preserve freshness reduced the total microflora and indicator organisms of public health significance.
CIUSuite 2: Next-Generation Software for the Analysis of Gas-Phase Protein Unfolding Data. Ion mobility-mass spectrometry (IM-MS) has become an important addition to the structural biology toolbox, but separating closely related protein conformations remain challenging. Collision-induced unfolding (CIU) has emerged as a valuable technique for distinguishing iso-cross-sectional protein and protein complex ions through their distinct unfolding pathways in the gas phase. The speed and sensitivity of CIU analyses, coupled with their information-rich data sets, have resulted in the rapid growth of CIU for applications, ranging from the structural assessment of protein complexes to the characterization of biotherapeutics. This growth has occurred despite a lag in the capabilities of informatics tools available to process the complex data sets generated by CIU experiments, resulting in laborious manual analysis remaining commonplace. Here, we present CIUSuite 2, a software suite designed to enable robust, automated analysis of CIU data across the complete range of current CIU applications and to support the implementation of CIU as a true high-throughput technique. CIUSuite 2 uses statistical fitting and modeling methods to reliably quantify features of interest within CIU data sets, particularly in data with poor signal quality that cannot be interpreted with existing analysis tools. By reducing the signal-to-noise requirements for handling CIU data, we are able to demonstrate reductions in acquisition time of up to 2 orders of magnitude over current workflows. CIUSuite 2 also provides the first automated system for classifying CIU fingerprints, enabling the next generation of ligand screening and structural analysis experiments to be accomplished in a high-throughput fashion.
Interleukin-6 autoantibodies: possible biological and clinical significance. The pleiotropic cytokines, interleukin (IL)-1 alpha, type I interferons and IL-6 also act on cells involved in antibody production. Somehow the immunologic tolerance to these cytokines is often spontaneously broken--even in healthy individuals. Thus, relatively high concentrations of high affinity IgG antibodies against IL-1 alpha and IL-6 frequently occur in the circulation of healthy adults. The autoantibodies specifically antagonize the respective cytokines in vitro. Thermodynamic estimations strongly suggest that autoimmunity can play a significant role in the regulation of certain cytokines. In the light of IL-6 autoantibodies the possible biological and clinical significance of cytokine autoimmunity is discussed.
The importance of the practicing nurse in nursing research. Most research findings never reach the practicing nurse. However, many scientific findings would enhance quality of care if nurses knew about them and incorporated them into their practice. To make nursing research practice based, medical-surgical nurses must identify pertinent questions for research and use the findings in practice and evaluate subsequent outcomes.
Cognitive and motor performance of narcoleptic and normal subjects living in temporal isolation. Six unmedicated narcoleptic subjects and nine normal controls lived in a temporal isolation laboratory for 18-22 days. They were permitted to "free-run" for the last 9-13 days. Brief cognitive and motor performance tests were repeated on average six times per subjective day. They consisted of serial search, complex verbal reasoning tasks and manual dexterity of each hand. Only minor differences in performance were found between the narcoleptic subjects and controls. Narcoleptic subjects showed mild impairment of accuracy on the search task that could be explained by occasional lapses and an afternoon dip in performance. Narcoleptic subjects also tended to perform some tasks more slowly, but the group differences were not significant. Neither speed nor accuracy of performance of narcoleptic subjects decreased over the course of the experiment. By one standard of performance, therefore, all or nearly all of the sleep need of these subjects was met by the sleep they obtained in the laboratory. That amount, in turn, did not exceed the total sleep obtained by the normal controls. Significant time-of-day effects were found in narcoleptic subjects for speed of verbal reasoning (progressive slowing over the course of the day), manual dexterity (fluctuations in speeds) and accuracy of serial search (afternoon dip). These variations in performance could not be attributed to changes in core body temperature or to occurrences of naps or meals.
Chemical characterization of a protein-4-hydroxy-2-nonenal cross-link: immunochemical detection in mitochondria exposed to oxidative stress. We have previously shown that incubation of the model protein glucose-6-phosphate dehydrogenase (Glu-6-PDH) from the bacterium Leuconostoc mesenteroides with 4-hydroxy-2-nonenal (HNE), a major product of lipid peroxidation, results in the formation of cross-linked protein. HNE-modified protein is resistant to proteolytic degradation and acts as an inhibitor of the multicatalytic proteinase. It was therefore important to establish the chemistry of the cross-linking reaction. The formation of cross-linked Glu-6-PDH is associated with the nearly exclusive loss of lysine residues. For this reason the reaction of N-acetyllysine with HNE has been investigated. The epsilon-amino group of lysine reacts with the double bond (C3) and the carbonyl (C1) functions of HNE via Michael addition and Schiff base formation resulting in the production of a 2:1 amino acid-HNE cross-link. Chromatographic detection of this adduct in the acid hydrolysate of HNE-treated Glu-6-PDH reveals that this chemistry is responsible for the formation of cross-linked protein. Antibody to the reduced form of the 2:1 lysine-HNE adduct was prepared. The antibody was used to demonstrate that exposure of isolated liver mitochondria to oxidative stress led to the formation of intra- and intermolecular protein-HNE cross-links. The results of the present study indicate that modifications to protein by lipid peroxidation products may be physiologically relevant and could contribute to the disease- and age-related buildup of damaged protein.
An Unmet Need Meets an Untapped Resource: Pharmacist-Led Pathways for Hypertension Management for Emergency Department Patients. The purpose of this review is to describe the role of the pharmacist in innovative pathways of care for hypertension (HTN) management for emergency department (ED) patients, particularly in under-resourced communities. Due to intersecting socioeconomic and personal health risk factors, these patients bear a disproportionate share of cardiovascular disease, yet often have limited access to high-quality primary care. Recent meta-analyses demonstrate a clear advantage associated with pharmacist-physician collaborative models over traditional physician-only care in achieving blood pressure control. However, no prior study has evaluated use of pharmacist-led follow-up for ED patients with uncontrolled blood pressure (BP). Thus, we developed a pharmacist-driven transitional care clinic (TCC) that utilizes a collaborative practice agreement with ED physicians to improve HTN management for ED patients. We have successfully implemented the TCC in a high-volume urban ED and in a pilot study have shown clinically relevant BP reductions with our collaborative model. The use of pharmacist-led follow-up for HTN management is highly effective. Novel programs such as our TCC, which extend the reach of such a model to ED patients, are promising, and future studies should focus on implementation through larger, multicenter, randomized trials. However, to be most effective, policy advocacy is needed to expand pharmacist prescriptive authority and develop innovative financial models to incentivize this practice.
Use of rK39 for diagnosis of post kala-azar dermal leishmaniasis in Nepal. A recently developed nitrocellulose-based dipstick test, rK39, has been widely used for the diagnosis of kala-azar. In this study, we evaluated its use for the diagnosis of post kala-azar dermal leishmaniasis (PKDL). We also investigated the time taken by patients to develop PKDL after apparent cure of kala-azar (visceral leishmaniasis, VL) and the time taken by patients to come to the hospital after the appearance of symptoms of PKDL. A majority of patients developed the disease within three years after the apparent cure of kala-azar (KA). A majority of patients sought treatment within five years after the onset of PKDL. The amastigotes of Leishmania donovani bodies (LDBs) were demonstrated in 70, 20, and 20% of slit-skin smears (SSS) prepared, respectively, from nodular, papular, and macular forms. The presence of highest density (6+) LDBs in the SSS of 20% of nodular PKDL patients indicated that they may have acted as reservoir in the community. Other reservoirs are not known in Nepal. Only 8% cases were detected by aldehyde test. Although this test is obsolete it is still used in rural parts of Nepal. The dipstick (rK39) was 96% sensitive and 100% specific to diagnose PKDL. Its positive predictive value, negative predictive value, and diagnostic efficacy were 100, 91, and 97% respectively. Due to the advantage of cost compared with the direct agglutination test (DAT), and being easy to use and store in field conditions, rK39 is a good tool to diagnose PKDL in rural situations. All the PKDL patients were cured of the disease after treatment by SAG.
C-C chemokine receptor 2 expression by circulating monocytes influences atherosclerosis in patients on chronic hemodialysis. Mortality from cardiovascular or cerebrovascular disease due to atherosclerosis is increased in patients on chronic hemodialysis. Monocyte chemoattractant protein-1 and its receptor, C-C chemokine receptor 2, play an important role in recruiting monocytes to atherosclerotic lesions. The relationship between atherosclerosis in hemodialysis patients and C-C chemokine receptor 2 expression is unknown. Fifty-six patients on chronic hemodialysis and 27 age- and sex-matched controls were enrolled. Serum levels of monocyte chemoattractant protein-1 and expression of C-C chemokine receptor 2 by circulating monocytes were determined. Atherosclerosis was evaluated from the carotid intima-media thickness and cardio-ankle vascular index. Serum levels of monocyte chemoattractant protein-1 and expression of C-C chemokine receptor 2 by monocytes were significantly higher in the hemodialysis patients than the controls. Multiple regression analysis showed a positive correlation between receptor expression and both indexes of atherosclerosis. C-C chemokine receptor 2 expression by circulating monocytes influences atherosclerosis in patients on chronic hemodialysis.
Comparison of Graphene Oxide and Reduced Graphene Oxide for DNA Adsorption and Sensing. Fluorescently labeled DNA adsorbed on graphene oxide (GO) is a well-established sensing platform for detecting a diverse range of analytes. GO is a loosely defined material and its oxygen content may vary depending on the condition of preparation. Sometimes, a further reduction step is intentionally performed to decrease the oxygen content, and the resulting material is called reduced GO (rGO). In this study, DNA adsorption and desorption from GO and rGO is systematically compared. Under the same salt concentration, DNA adsorbs slightly faster with a 2.6-fold higher capacity on rGO. At the same time, DNA adsorbed on rGO is more resistant to desorption induced by temperature, pH, urea, and organic solvents. Various lengths and sequences of DNA probes have been tested. When its complementary DNA is added as a model target analyte, the rGO sample has a higher signal-to-background and signal-to-noise ratio, whereas the GO sample has a slightly higher absolute signal increase and faster signaling kinetics. DNAs adsorbed on GO or rGO are still susceptible to nonspecific displacement by other DNA and proteins. Overall, although rGO adsorbs DNA more tightly, it allows efficient DNA sensing with an extremely low background fluorescence signal.
[Automated perimetry in ptosis and blepharochalasis]. First, we were looking if a correlation between the extent of ptosis and superior visual field defect exists. In a second step visual fields in blepharochalasis were compared with those in ptosis. Pre- and postoperative visual fields in 20 patients with blepharochalasis, 6 patients with congenital and 9 with acquired ptosis were tested using program 7 of Octopus 500 automated perimeter. The degree of ptosis was separated in mild, medium and severe. According to the extent of visual field defect the same parameters as in ptosis were used also grading blepharochalasis in mild, medium and severe. We found that the amount of upper visual field defect clearly correlated with the extent of ptosis. In addition, patients with congenital ptosis showed less visual field defect compared to those with acquired ptosis. Comparable to ptosis surgery blepharoplasty also lead in severe and medium cases to a clear gain of upper visual field. Using perimetry and the same grading system as for ptosis makes it possible to study the functional defect occurring to the blepharochalasis patient.
Electron paramagnetic resonance studies of the membrane fluidity of the foodborne pathogenic psychrotroph Listeria monocytogenes. Listeria monocytogenes is a foodborne psychrotrophic pathogen that grows at refrigeration temperatures. Previous studies of fatty acid profiles of wild-type and cold-sensitive, branched-chain fatty acid deficient mutants of L. monocytogenes suggest that the fatty acid 12-methyltetradecanoic (anteiso-C(15:0)) plays a critical role in low-temperature growth of L. monocytogenes, presumably by maintaining membrane fluidity. The fluidity of isolated cytoplasmic membranes of wild-type (SLCC53 and 10403S), and a cold-sensitive mutant (cld-1) of L. monocytogenes, grown with and without the supplementation of 2-methylbutyric acid, has been studied using a panel of hydrocarbon-based nitroxides (2N10, 3N10, 4N10, and 5N10) and spectral deconvolution and simulation methods to obtain directly the Lorentzian line widths and hence rotational correlation times (tau(c)) and motional anisotropies of the nitroxides in the fast motional region. tau(c) values over the temperature range of -7 degrees C to 50 degrees C were similar for the membranes of strains SLCC53 and 10403S grown at 10 degrees C and 30 degrees C, and for strain cld-1 grown with 2-methylbutyric acid supplementation (which restores branched-chain fatty acids) at 30 degrees C. However, strain cld-1 exhibited a threefold higher tau(c) when grown without 2-methylbutyric acid supplementation (deficient in branched-chain fatty acids) compared to strains SLCC53, 10403S, and supplemented cld-1. No evidence was seen for a clear lipid phase transition in any sample. We conclude that the fatty acid anteiso-C(15:0) imparts an essential fluidity to the L. monocytogenes membrane that permits growth at refrigeration temperatures.
Influence of protein transduction domains on intracellular delivery of macromolecules. As the plasma membrane and blood-brain barrier selectively restrict the entry of most compounds into cells to < 500 Da, delivering macromolecules into cells was, until recently, little more than a goal. However, with significant effort to capitalise on therapeutic targets available in the post-genomic era, novel approaches for delivering therapeutic macromolecules are being rapidly developed. The discovery of small cationic peptides, termed peptide/protein transduction domains or cell-penetrating peptides, which cross biological membranes, has emerged as a venerable Trojan horse to transport large, biologically active molecules, such as peptides, proteins and oligonucleotides, into mammalian cells in vitro, as well as in preclinical models and clinical trials in vivo. This review discusses the implications of peptide/protein transduction domain-mediated delivery of macromolecules and their possible uses as important primary drug delivery agents.
Coracoclavicular ligament reconstruction: coracoid tunnel diameter correlates with failure risk. The current study compared tunnel diameter as an independent risk factor for fixation failure from the coracoid after transcoracoid coracoclavicular reconstruction. The effect of variation in coracoid size and scapular bone density on fixation failure was also studied. Sixty-two cadaveric scapulae were randomized into 1 of 4 groups: a control group with no coracoid hole, a group with a 4-mm transcoracoid tunnel, a group with a 6-mm transcoracoid tunnel, and a group with a socket technique using a 6-mm hole superiorly with a 4-mm hole inferiorly. Bone density measures for all specimens were performed. Coracoid dimensions were quantified. Using a cortical button device, all specimens were loaded to failure with an Instron servohydraulic testing machine (Instron Corp, Canton, Massachusetts). All drilled specimens failed by button pullout, and all control specimens failed by coracoid fracture. Average pullout strength for each tunnel subgroup was as follows: 4 mm, 296.9 N; 6 mm, 146.2 N; 6-4 socket, 261.8 N; control, 762.9 N. No difference was found with respect to tunnel subgroups in base height (P=.25) or bone density (P=.44). Load to failure for the control group was significantly higher than for the other 3 techniques. The 4-mm tunnel load to failure was significantly higher than that for the 6-mm tunnel (P=.006). No difference was found between the 4-mm tunnel and the 6-4 socket technique (P=.853). Although it was not statistically significant, a very strong trend was seen toward increased strength of the 6-4 socket over the 6-mm tunnel (P=.051). The study results show that when employing a transcoracoid reconstruction technique, a 4-mm tunnel technique is significantly stronger than a 6-mm tunnel technique. None of the coracoids drilled with the various tunnels approached the strength of the native coracoid controls using a looped wire technique.
The interplay between glottis and vocal tract during the male passaggio. The transition between 'chest' and 'head' register is essential for male opera singers in order to reach the higher pitches. The 'passaggio', which is a scale passage where this transition takes place, but also a maneuver of register equalization, is typically difficult to learn. Studies on parameters for a definition of this transition are restricted to a small number of singers so far. Audio, electroglottographic, and equivalent subglottic pressure signals of 11 male opera singers were recorded while singing scales on open back vowels and passing the register transition. A spectrum analysis of the audio signal revealed that the second harmonic (H2) dominates in 'chest', resonated by the first formant (F1), together with the fourth harmonic (H4), supported by the second formant (F2). During the passaggio, H2 level decreases because it loses the resonance of F1, while the third harmonic (H3) gains the resonance of F2. At this point the H4 level drops because that harmonic is no longer supported by F2. The transition from 'chest' to 'head' register is marked by characteristic changes in the amplitude patterns of the partials H2, H3, and H4, and the frequency progressions of the first two formants, defining an objective distinction between the two registers.
Evolution of Entanglement Spectra under Generic Quantum Dynamics. We characterize the early stages of the approach to equilibrium in isolated quantum systems through the evolution of the entanglement spectrum. We find that the entanglement spectrum of a subsystem evolves with three distinct timescales. First, on an o(1) timescale, independent of system or subsystem size and the details of the dynamics, the entanglement spectrum develops nearest-neighbor level repulsion. The second timescale sets in when the light cone has traversed the subsystem. Between these two times, the density of states of the reduced density matrix takes a universal, scale-free 1/f form; thus, random-matrix theory captures the local statistics of the entanglement spectrum but not its global structure. The third time scale is that on which the entanglement saturates; this occurs well after the light cone traverses the subsystem. Between the second and third times, the entanglement spectrum compresses to its thermal Marchenko-Pastur form. These features hold for chaotic Hamiltonian and Floquet dynamics as well as a range of quantum circuit models.
[Catamenial pneumothorax: easy to see, difficult to manage]. Catamenial pneumothorax (PNO) is a real clinical occurrence. Several cases are reported in the literature as a spontaneous PNO occurring during the catamenial period among women in their thirties. There is no consensus about management and the recurrence rate is very high whatever the initial treatment. Among 310 cases of spontaneous PNO operated in our institution in 10 years, we identified five cases of catamenial PNO. A retrospective study of these cases was used to study the initial operating data, including the existence of intrathoracic lesions and the choice of technique of pleurodesis. Patient follow-up was clinically and radiologically. Adjuvant hormonal therapies, recurrence of PNO and treatment modalities have been studied. These five patients of average age 37.6 years (37,38) who had 2.6 (2.3) episodes of right catamenial PNO before hospitalization in surgery department. No patient was smoker. Two of them had a known thoracic or pelvic endometriosis. The initial surgery was video assisted thoracic surgery with a parietal pleurectomy and twice a mesh upon the diaphragm. There were no immediate postoperative complications, and the average length of stay was 6.6 days (5.9). Two patients had adjuvant hormonal therapy. All patients had at least one recurrence and three of them had redo surgery. The diagnosis of catamenial PNO must be mentioned in any woman who has a spontaneous pneumothorax right in catamenial period. Endometriosis should be systematically sought. A standardized therapeutic approach to establish the role of surgery and the most appropriate technique as well as the appropriateness and duration of peroperative hormonal therapy remains to be defined.
Dispersion of reactivity of copper proteins in solutions. The redox reactions of superoxide dismutase and ceruloplasmin fit the simple kinetic schemes if the dispersion of their reactivities is accounted for by the time-dependent rate constants of the form k(t) = Bt alpha-1, 0 less than alpha less than or equal to 1. The lower the value of alpha the greater is the dispersion of reactivity. The limit of classical kinetics corresponds to alpha = 1.
[Doppler echocardiography of ventricular diastole]. Non-invasive studies of left ventricular relaxation and filling by means of doppler-echocardiography are of considerable interest owing to easy recording and good reproducibility. However, such physiological parameters as site of measurement, heart rate and, chiefly, age may interfere with the curves obtained. The interpretation of tracings must also take into account the presence of mitral valve pathology (stenosis or regurgitation), aortic stenosis, disorders of atrioventricular (prolonged PR complex) or intraventricular (left bundle branch block) conduction and medication (e.g. vasodilators). In clinical practice, one of the main advantages of the technique is that it makes it possible to distinguish between the physiological left ventricular hypertrophy (LVH) of top-class sportsmen (without impaired ventricular filling) and the pathological LVH of hypertrophic cardiomyopathy. The purpose of this study, with a review of the literature, was to take stock of the value and limitations of the doppler indices.
Association of sitting time and breaks in sitting with muscle mass, strength, function, and inflammation in community-dwelling older adults. The mechanisms through which excessive sitting time impacts health are important to understand. This study found that each hour of sitting per day was not associated with physical function, although associations with poor body composition were observed. Reducing sitting time for improved weight management in older adults needs further exploration. To examine the association of sitting time and breaks in sitting time with muscle mass, strength, function, and inflammation in older Australians. Data from the thigh-worn activPAL3™ monitor (7-day continuous wear) was used to derive time spent sitting (hours) and total number of sit-stand transitions per day. Body composition (dual energy X-ray absorptiometry), lower-body muscle strength, function (timed up-and-go [TUG], 4-m gait speed, four square step test, 30-second sit-to-stand), and serum inflammatory markers (interleukin-[IL-6], IL-8, IL-10, tumor necrosis factor-alpha [TNF-α], and adiponectin) were measured. Multiple regression analyses, adjusted for age, sex, ethnicity, education, employment status, marital status, number of prescription medications, smoking status, vitamin D, and stepping time, were used to assess the associations. Data from 123 community-dwelling older adults (aged 65-84 years, 63% female) were used. Total daily sitting time was associated with lower percentage lean mass (β [95%CI], - 1.70% [- 2.30, - 1.10]) and higher total body fat mass (2.92 kg [1.94, 3.30]). More frequent breaks in sitting time were associated with a 45% reduced risk of having pre-sarcopenia (OR = 0.55; 95% CI 0.34, 0.91; model 1), defined as appendicular lean mass divided by BMI. No significant associations were observed for sitting time or breaks in sitting with measures of muscle strength, function, or inflammation. In older community-dwelling adults, greater sitting time was associated with a lower percentage lean mass, while more frequent breaks in sitting time were associated with lower odds of having pre-sarcopenia. This suggests that reducing sedentary time and introducing frequent breaks in sedentary time may be beneficial for improving body composition in healthy older adults.
Impact of salinity on anaerobic microbial community structure in high organic loading purified terephthalic acid wastewater treatment system. To investigate the effect of salinity (1% sodium chloride) on anaerobic microbial community structure in high strength telephthalic wastewater treatment system, the performances of anaerobic-aerobic process and the shifts of microbial community in anaerobic tank were studied and determined. Results showed that the chemical oxygen demand (COD) removal in the whole process remained above 90%. And the effluent concentrations of targeted pollutants were lower than 10 mg/L, other than para-toluic acid (PT, 38.09 mg/L). However, methane production significantly decreased compared to no salinity situation. This might be due to the inhibition of salinity on methanogens, which hindered the conversion of acetate to methane. Furthermore, the dominant genus in bacterial level changed from Tepidisphaera to Syntrophus, which facilitated the syntrophic association with hydrogenotrophic methanogens. The prevailed archaea remained acetoclastic Methanothrix above 90%. Therefore, the salinity on anaerobic microbial community structure mainly reflects in the methanogen process, remarkably decreasing methane production.
Improved lung function tests on changing from topical timolol: non-selective beta-blockade impairs lung function tests in elderly patients. Fifty-two elderly glaucomatous patients, without a history of asthma or obstructive airways disease, who were using topical timolol for control of intraocular pressure were recruited. Their topical therapy was changed to either betaxolol or pilocarpine. The change was associated with improvement in mean peak flow from 278 l/min to 328 l/min (t = 5.73, p < 0.001), mean FEV1 from 1.66 l to 1.85 l (t = 7.09, p < 0.001) and mean FVC from 2.40 l to 2.64 l (t = 5.07, p < 0.001). Change to either betaxolol or pilocarpine was associated with improved lung function tests. Lung function tests in a control group of 20 showed no significant changes. Both drugs maintained control of intraocular pressure but betaxolol had fewer ocular side effects.
Lactate dehydrogenase activity and isoenzyme pattern in lungs, erythrocytes, and plasma of ozone-exposed rats and monkeys. The effect of low levels of ozone exposure (8 hr daily for 7 days) on lactate dehydrogenase (LDH) activity and isoenzyme pattern was studied in the lungs, plasma, and erythrocytes of rats and monkeys. Exposure to 0.8 or 0.5 ppm ozone resulted in a significant increase in total LDH activvity in the lungs but not in the plasma and erythrocytes of rats. The LDH-5 fraction of the LDH isoenzymes was significantly decreased in terms of percentage distribution in the lungs and plasma of rats exposed to 0.8 ppm ozone, whereas the LDH-4 in the lungs and plasma and LDH-3 in the lungs were increased. At 0.5 ppm ozone, the isoenzyme distribution was not significantly changed in lungs, plasma, or erythrocytes. In monkeys, no significant change in either total LDH activity or isoenzyme pattern was observed in lungs, plasma, or erythrocytes after exposure to 0.8 ppm ozone.
Histologic changes of doxycycline pleurodesis in rabbits. Effect of concentration and pH. The effects of doxycycline hyclate (DOXY) pleurodesis were compared with those of tetracycline hydrochloride (TCN) in 25 healthy New Zealand White rabbits. One group of rabbits received TCN (pH 2.0) in the left pleural space at a concentration of 35 mg/kg in 3.0 ml of saline solution. Four other groups of rabbits received DOXY in two concentrations (35 mg/kg or 10 mg/kg) and at two pHs (an acid of 2.0 and a NaOH neutralized pH of 7.6). No attempt was made to drain the pleural space after pleurodesis. At autopsy 2 weeks later, bloody fluid filled the pleural cavity and extensive intrapleural adhesions compressed the underlying lung. Microscopically, fibrin and collagen were diffusely deposited in the pleural connective tissue and in the intrapleural adhesions. The visceral pleural thickness increased from its normal value of 0.01 mm to values of 0.5 to 0.9 mm in the TCN and DOXY groups. Fibroblasts were the predominant inflammatory cell in the pleural connective tissue with few neutrophils or lymphocytes. No significant differences of histologic characteristics were observed between the TCN and DOXY groups. Alterations in pH or concentration in the DOXY groups produced similar changes in the gross and microscopic appearance of the pleural space. We conclude that DOXY is as effective as TCN in producing chemical pleurodesis. Doxycycline concentrations of 10 mg/kg were sufficient to substantially sclerose the pleural space in these healthy rabbits. Doxycycline pleurodesis was effective at neutral pH suggesting a mechanism of action independent of acid injury to the mesothelium.
Current treatment by United States and Canadian pediatric rheumatologists. To determine current treatment practices for 11 selected pediatric rheumatic diseases. A questionnaire was mailed to 224 US and Canadian physicians who were listed in membership directories that included pediatric rheumatologists. One hundred seventy-four questionnaires (78%) were returned. Board certified pediatricians accounted for 86% of respondents. Nonsteroidal antiinflammatory drugs were the most commonly used medicines for all forms of juvenile rheumatoid arthritis (JRA), seronegative enthesopathy and arthropathy syndrome (SEA), and Henoch-Schönlein purpura, whereas oral corticosteroids were most frequently used for systemic lupus erythematosus (SLE), juvenile dermatomyositis, polyarteritis nodosa, and sarcoidosis. Intraarticular corticosteroid injection was the second most common therapy for pauciarticular JRA, but methotrexate (MTX) was second for polyarticular and systemic onset forms of JRA, and sulfasalazine was second for SEA. For all diseases, MTX was administered orally roughly twice as often as subcutaneously. In treating SLE, cyclophosphamide was used more frequently than azathioprine, cyclosporin A, or intravenous immunoglobulin. The results from this survey should allow individual practitioners to compare their treatment patterns to pediatric rheumatologists in the US and Canada as a whole.
HAMLET: functional properties and therapeutic potential. Human α-lactalbumin made lethal to tumor cells (HAMLET) is the first member in a new family of protein-lipid complexes that kills tumor cells with high selectivity. The protein component of HAMLET is α-lactalbumin, which in its native state acts as a substrate specifier in the lactose synthase complex, thereby defining a function essential for the survival of lactating mammals. In addition, α-lactalbumin acquires tumoricidal activity after partial unfolding and binding to oleic acid. The lipid cofactor serves the dual role as a stabilizer of the altered fold of the protein and a coactivator of specific steps in tumor cell death. HAMLET is broadly tumoricidal, suggesting that the complex identifies conserved death pathways suitable for targeting by novel therapies. Sensitivity to HAMLET is defined by oncogene expression including Ras and c-Myc and by glycolytic enzymes. Cellular targets are located in the cytoplasmic membrane, cytoskeleton, mitochondria, proteasomes, lysosomes and nuclei, and specific signaling pathways are rapidly activated, first by interactions of HAMLET with the cell membrane and subsequently after HAMLET internalization. Therapeutic effects of HAMLET have been demonstrated in human skin papillomas and bladder cancers, and HAMLET limits the progression of human glioblastomas, with no evidence of toxicity for normal brain or bladder tissue. These findings open up new avenues for cancer therapy and the understanding of conserved death responses in tumor cells.
An Exploratory Study of the Knowledge of Personal Safety Skills Among Children with Developmental Disabilities and Their Parents. This study assessed the knowledge of personal safety skills among children with developmental disabilities and their parents' perceptions of children's knowledge. This exploratory study examined the mental health records of 37 children with developmental disabilities referred for an abuse risk reduction group in a community mental health setting. Qualitative analysis of children's responses to questions about personal safety skills (knowledge related to physical development and personal safety, an appropriate and inappropriate touch and safety skills to respond to an inappropriate touch) indicated participants' varied and inconsistent levels of knowledge. Consistent with the literature, the results indicate risk factors for sexual abuse among children with developmental disabilities, including children's difficulty distinguishing between an appropriate and inappropriate touch and the lack of knowledge regarding appropriate venues for disclosing an inappropriate touch. Among parents, a lack of certainty regarding their children's knowledge and the ability to keep themselves safe was identified. Results support the need for education about personal safety for children with developmental disabilities and their families.
The onset of diabetes and poor metabolic control increases gingival bleeding in children and adolescents with insulin-dependent diabetes mellitus. Gingival health (bleeding on probing) and oral hygiene (plaque percent) were assessed in 2 groups of children and adolescents with insulin-dependent diabetes mellitus (IDDM). 1st study group included 12 newly diagnosed diabetic children and adolescents (age range 6.3-14.0 years, 5 boys and 7 girls). They were examined on the 3rd day after initial hospital admission and at 2 weeks and 6 weeks after initiation of insulin treatment. Gingival bleeding decreased after 2 weeks of insulin treatment (37.8% versus 19.0%, p < 0.001, paired t-test), and remained at the same level when examined 1 month later while glucose balance was excellent. Another group (n = 80) of insulin-dependent diabetic children and adolescents (age range 11.7-18.4 years, 44 boys and 36 girls) with a mean duration of diabetes 6.0 years (range 0.3-15.0 years) were examined 2x at 3-month intervals. Subjects with poor blood glucose control (glycosylated haemoglobin, HbA1, values over 13%) had more gingival bleeding (46.3% on examination 1, 41.7% on examination 2) than subjects with HbA1 values less than 10% (mean gingival bleeding 35.2% and 26.9%, respectively) or subjects with HbA1 values between 10 to 13% (mean gingival bleeding 35.6% and 33.4%, respectively). Differences were significant on both examinations (p < 0.05, Anova), and remained significant after controlling the groups for differences in age, age at the onset of diabetes, duration of diabetes and pubertal stage (Ancova). Results were not related to differences or changes in dental plaque status, supporting the concept that imbalance of glucose metabolism associated with diabetes predisposes to gingival inflammation. An increase in gingival bleeding in association with hyperglycaemia suggests that hyperglycaemia-associated biological alterations, which lower host resistance toward plaque, have apparently taken place. Consequently, although not all gingivitis proceeds into a destructive periodontal disease, prevention of plaque-induced gingival inflammation should be emphasised, particularly in children and adolescents with poorly controlled diabetes.
Expression of anti-apoptosis genes alters lactate metabolism of Chinese Hamster Ovary cells in culture. In an effort to develop robust Chinese Hamster Ovary host cell lines, a variety of anti-apoptotic genes were over-expressed, either singly or in combination, followed by screening of transfectants for improved cell growth, extended longevity, reduced caspase 3/7 activity, and enhanced mitochondrial membrane potential (MMP). Two particular cell lines, one containing two anti-apoptotic genes, E1B-19K and Aven (EA167), and another containing three, E1B-19K, Aven, and a mutant of XIAP (EAX197), exhibited a reduction in caspase 3 activity of at least 60% and a 170% enhancement in mitochondrial membrane potential compared to controls when treated with staurosporine. In batch cell growth experiments, the peak viable cell densities and viabilities were higher resulting in a 186% increase in integrated viable cell densities. Analyses of metabolite utilization and formation of waste products indicated that the apoptotic resistant cell lines depleted all the lactate when grown in commercially available CD-CHO medium while significant levels (>1.8 g/L) accumulated in the host cell lines. When the lactate level was replenished daily in the apoptotic resistant cell lines, the cell lines consumed lactate and the culture longevity was extended up to four additional days compared to control cell lines. Furthermore, the anti-apoptosis cell lines also accumulated lower levels of ammonia. The ability of the apoptotic resistant cell lines to consume lactate was exploited by cultivating them in a "high" glucose medium containing 15 g/L (60 mM glucose) in which apoptotic resistant cell lines exhibited lower maximum lactate (1.8 g/L) compared to control cell lines which accumulated concentrations of lactate (2.2 g/L) that appeared to be deleterious for growth. The shaker flask titer of a therapeutic antibody product expressed in an apoptotic resistant cell line in "high" glucose medium reached 690 mg/L compared to 390 mg/L for a cell line derived from a control host cell line. These results represent to our knowledge the first example in the literature in which manipulation of the apoptosis pathway has altered the nutrient consumption profile of mammalian cells in culture; findings that underscore the interdependence of the apoptotic cellular machinery and metabolism and provide greater flexibility to mammalian bioreactor process development.
Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. Prostate safety is a primary concern when aging men receive testosterone replacement therapy (TRT), but little information is available regarding the effects of TRT on prostate tissue in men. To determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels. Randomized, double-blind, placebo-controlled trial of 44 men, aged 44 to 78 years, with screening serum testosterone levels lower than 300 ng/dL (<10.4 nmol/L) and related symptoms, conducted at a US community-based research center between February 2003 and November 2004. Participants were randomly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months. The primary outcome measure was the 6-month change in prostate tissue androgen levels (testosterone and dihydrotestosterone). Secondary outcome measures included 6-month changes in prostate-related clinical features, histology, biomarkers, and epithelial cell gene expression. Of the 44 men randomized, 40 had prostate biopsies performed both at baseline and at 6 months and qualified for per-protocol analysis (TRT, n = 21; placebo, n = 19). Testosterone replacement therapy increased serum testosterone levels to the mid-normal range (median at baseline, 282 ng/dL [9.8 nmol/L]; median at 6 months, 640 ng/dL [22.2 nmol/L]) with no significant change in serum testosterone levels in matched, placebo-treated men. However, median prostate tissue levels of testosterone (0.91 ng/g) and dihydrotestosterone (6.79 ng/g) did not change significantly in the TRT group. No treatment-related change was observed in prostate histology, tissue biomarkers (androgen receptor, Ki-67, CD34), gene expression (including AR, PSA, PAP2A, VEGF, NXK3, CLU [Clusterin]), or cancer incidence or severity. Treatment-related changes in prostate volume, serum prostate-specific antigen, voiding symptoms, and urinary flow were minor. These preliminary data suggest that in aging men with late-onset hypogonadism, 6 months of TRT normalizes serum androgen levels but appears to have little effect on prostate tissue androgen levels and cellular functions. Establishment of prostate safety for large populations of older men undergoing longer duration of TRT requires further study. Trial Registration clinicaltrials.gov Identifier: NCT00161304.
Explicit versus implicit fat-stigma. Human biologists are increasingly engaging with current global trends toward obesity. However, little is considered about how variation in cultural views of "fat" might shape the biology of obesity, such as through pathways related to socially induced stress. Recent research indicates elevated levels of explicit fat-stigma in middle income nations, suggesting potentially high levels of psychosocial stress around "being fat." We use the case of Paraguay to test if high levels of explicit prejudice around "being fat" also suggest internalization of those ideas in ways that might predict stress effects. Using a sample of women in Paraguay (N = 200), we test if the statement of anti-fat beliefs on standard scales correlates with similarly strong level of cognitive bias against fat based on an implicit association test. We confirm reasonable comparability of the findings to prior published studies by collecting data for U.S. undergraduates (N = 66) using the same set of tools. Women in Paraguay reveal high levels of explicit anti-fat bias in an interview on a standard (Attitudes to Obese People) scale, suggesting a shared cultural norm of fat-is-bad. However, Paraguayan women display, on average, no anti-fat stigma in cognitive testing. In contrast to what has been observed in industrialized nations, the high levels of explicit fat-stigma does not necessarily correlate with high levels of implicit fat-stigma. This means that pathways between obesity, psychosocial stress, and health outcomes may be very different across socioecological contexts.
Progress of immune checkpoint therapy in the clinic (Review). Cancer cells can escape antitumor immune responses by exploiting inhibitory immune checkpoints. Immune checkpoint therapy, mainly including anti‑CTLA‑4 therapy and anti‑PD‑1/PD‑L1 therapy, can enhance antitumor immune responses by blocking the inhibitory signals of the immune system. This therapy has produced clinical advances in a fraction of patients. Deeper insight into the tumor microenvironment and immune checkpoint inhibitors will improve this therapy. Here, we review immune checkpoint inhibitors that prevent tumor immune escape and recent clinical studies of immune checkpoint therapy. We also compare the efficacy of different combination immunotherapies, describe how the relationship between the gut microbiome and immune system can determine the therapeutic outcomes for immune checkpoint inhibitors and introduce several novel immune checkpoints that are potential targets for antitumor immunotherapy in the future.
Binding specificities of eight monoclonal antibodies to human glycophorin A--studies with McM, and MkEn(UK) variant human erythrocytes and M- and MNV-type chimpanzee erythrocytes. Four newly derived mouse monoclonal antibodies to human glycophorin A are described. Three of these antibodies bind preferentially to the N form of glycophorin A; the fourth recognizes a shared determinant of the M and N forms. All four antibodies are directed toward the 39 amino acid, amino-terminal portion of the protein, and the N-specific antibodies require for binding the presence of N-acetyl-neuraminic acid on the glycosidically linked oligosaccharides. Cross-reaction of the N-specific antibodies to homozygous MM erythrocytes appears to result from binding to glycophorin B. In addition, these antibodies together with four previously reported glycophorin monoclonal antibodies, including two that specifically recognize the M form of glycophorin A, were tested for binding to McM and MkEn(UK) variant human erythrocytes and M- and MNV-type chimpanzee erythrocytes. Results obtained for five of the six M- or N-specific monoclonal antibodies point to the general immunodominance of the amino-terminal serine-leucine polymorphism and the requirement for sialic acid. One of the two M-specific monoclonal antibodies, 9A3, discriminates between the M, N, and Mc forms of glycophorin A solely on the basis of the amino-terminal serine-leucine polymorphism. The other M-specific antibody, 6A7, requires a more complex determinant involving the glycine-glutamic acid polymorphism at the fifth position in the sequence as well. The epitopes for all three N-specific monoclonal antibodies include the amino terminal leucine that occurs in the N form of glycophorin A and may also include the glutamic acid that occurs at position five. Our studies support the proposed Lepore-type glycophorin A-B hybrid gene rearrangement for the En(UK) allele found in the English En(a-) family. The data also confirm the expression of the M-like glycoprotein on chimpanzee erythrocytes and the presence of a human glycophorin B-like antigen on the MNV-type cells.
Capillary electrophoresis for simultaneous quantification of human proinsulin, insulin and intermediate forms. Capillary electrophoresis (CE) for the simultaneous and precise quantification of human insulin (hI), proinsulin (hPI) and intermediate forms (des 31, 32; split 65-66 and des 64, 65), released in culture media by engineered cells, is described. Analytical conditions for standard proteins were optimized using a bare silica capillary (20 cm X 50 microm internal diameter). Proteins were monitored at 200 nm and separated at constant voltage. Culture supernatants (12-24 mL) were purified on Sep-Pak Vac C18 cartridges, recovered in 1 mL of acetonitrile:trifluoracetic acid mixture (60:40, v:v), concentrated, ultrafiltered and injected into CE. Protein recovery was 85+/-14% (n = 5, mean+/-standard deviation) with a sensitivity limit of 0.5 nmol/L in the culture media, corresponding to 2 fmol injected in 22 nL. Using the CE method, it was possible to detect and quantify, with precision and accuracy, the release of hPI, hI and intermediate forms directly in the cell culture media, and to compare the proteic pattern released from engineered cells transduced with different hPI gene constructs.
Functional and Mechanistic Insights into the Pathogenesis of P63-Associated Disorders. The p53 family member p63 is a master regulator of gene expression in stratified epithelia, such as the epidermis. One of the main functions of p63 is to sustain mechanical resistance, positively regulating several epidermal genes involved in cell-matrix adhesion and cell-cell adhesion (Ferone et al., 2015).
Oviposition stimulants for the beetle,Monochamus alternatus hope, in inner bark of pine. Field and laboratory ovipositional responses ofMonochamus alternatus Hope, respectively, to methanol and water extracts from pine inner bark were examined in comparison with those to pine inner bark, especially using a laboratory-built apparatus for the latter bioassay. Irrespective of the existence of volatiles from paraquat-induced lightwood, pine inner bark and its methanol and water extracts stimulated ovipositional response only in the presence of free moisture.
Prostanoids induce egr1 gene expression in cementoblastic OCCM cells. Prostanoids that activate protein kinase C signaling are potent anabolic stimulators of cementoblastic OCCM cells. Using cDNA subtractive hybridization, we identified early growth response gene-1 (egr1) as a prostanoid-induced gene. Egr1, a zinc-finger transcription factor expressed during tooth development, regulates cell growth and differentiation. We hypothesize that Egr1 may mediate part of the prostanoid-induced anabolic effect in cementoblasts. Our objective was to characterize prostanoid-induced egr1 gene expression in OCCM cells. Total RNA and proteins were assayed by northern blot and western immunoblot assays. Prostaglandin E2-, prostaglandin F2alpha- and fluprostenol-induced egr1 mRNA levels peaked at 0.5 h and returned to baseline by 4 h. Prostaglandin F2alpha and fluprostenol more potently induced egr1 compared with prostaglandin E2. The phorbol ester, phorbol 12-myristate 13-acetate, which activates protein kinase C signaling, induced egr1 mRNA levels 66-fold over the control, whereas forskolin (a cAMP-protein kinase A activator) and ionomycin (a calcium activator) had no effect. Protein kinase C inhibition significantly inhibited prostaglandin E2-, prostaglandin F2alpha- and fluprostenol-induced egr1 mRNA levels. Finally, prostanoids maximally induced Egr1 protein at 1 h. egr1 is a primary response gene induced by prostaglandin E2, prostaglandin F2alpha and fluprostenol in OCCM cells through protein kinase C signaling, suggesting that Egr1 may be a key mediator of anabolic responses in cementoblasts. Cementum is vital for periodontal organ maintenance and regeneration. Periodontal ligament fibers (Sharpey's fibers) insert into bone and cementum, thereby supporting the tooth in the alveolus (1). If the periodontal organ is lost, its regeneration requires cementoblast differentiation in order to form new cementum for periodontal ligament fiber insertion. Early attempts to regenerate cementum have proven difficult and rarely generate sufficient tissue (2). A better understanding of the molecular and cellular regulators that promote cementoblast differentiation is critical for developing targeted periodontal regeneration.
The molecular basis of transformation of lymphocytes by Theileria parva infection. The protozoan intracellular parasites, Theileria parva and Theileria annulata, infect cattle and cause severe and fatal leukocytic proliferative diseases. The proliferation is dependent on the presence of the parasites in the host cell cytoplasm. T. parva-infected cells proliferate permanently in cell culture and exhibit many features characteristic of tumor cells. The proliferation is reversible by treatment with parasite-specific drugs. Constitutive expression of interleukin-2, its receptor and their transcription factor, NF-kappa B, are dependent on the parasite and suggest autocrine growth. Cell-cell contact possibly via T cell adhesion molecules has been shown to stimulate proliferation.
Membrane potential gradient is carbon monoxide-dependent in mouse and human small intestine. The aims of this study were to quantify the change in resting membrane potential (RMP) across the thickness of the circular muscle layer in the mouse and human small intestine and to determine whether the gradient in RMP is dependent on the endogenous production of carbon monoxide (CO). Conventional sharp glass microelectrodes were used to record the RMPs of circular smooth muscle cells at different depths in the human small intestine and in wild-type, HO2-KO, and W/W(V) mutant mouse small intestine. In the wild-type mouse and human intestine, the RMP of circular smooth muscle cells near the myenteric plexus was -65.3 +/- 2 mV and -58.4 +/- 2 mV, respectively, and -60.1 +/- 2 mV and -49.1 +/- 1 mV, respectively, in circular smooth muscle cells at the submucosal border. Oxyhemoglobin (20 microM), a trapping agent for CO, and chromium mesoporphyrin IX, an inhibitor of heme oxygenase, abolished the transwall gradient. The RMP gradients in mouse and human small intestine were not altered by N(G)-nitro-l-arginine (200 microM). No transwall RMP gradient was found in HO2-KO mice and W/W(V) mutant mice. TTX (1 microM) and 1H-[1,2,4-]oxadiazolo[4,3-a]quinoxalin-1-one (10 microM) had no effect on the RMP gradient. These data suggest that the gradient in RMP across the thickness of the circular muscle layer of mouse and human small intestine is CO dependent.
Effect of Magic Johnson's HIV status on HIV-related attitudes and behaviors of an STD clinic population. This paper reports data on the effects that Earvin "Magic" Johnson's announced HIV infection had on the clients of an Philadelphia sexually-transmitted-disease (STD) clinic. Interviews conducted after Johnson's announcement (N = 148) included questions about whether respondents had heard his announcement and how this news had influenced their sexual attitudes and behaviors. The findings include comparisons of matched samples (N = 138) of respondents interviewed before and after the news. The comparisons focused on 3 areas related to the human immunodeficiency virus (HIV): 1) passive concern; 2) sense of personal risk; and 3) resolve to be tested for HIV in the next 6 months. A significantly greater percent (92%) of the postannouncement respondents reported planning HIV tests than did the preannouncement respondents (52%). Although the differences in perceived risk were not statistically significant, 25% of the preannouncement and 34% of the postannouncement respondents indicated high perceived risk for HIV. Forty-four percent of the postannouncement sample indicated that, as a result of the news, they were now using condoms; 32% reported no effect; and 54% reported a variety of behavior changes that included monogamy (21%), greater selectivity (10.6%), fewer sexual partners (9.2%), and abstinence (3.5%). Overall, the announcement by Magic Johnson that he had been infected with HIV was associated with increased concern about HIV and with attitude and behavior changes that would lead to reduced risk. This was especially true for those in the sample at relatively higher risk.
The AGL6-like gene OsMADS6 regulates floral organ and meristem identities in rice. Although AGAMOUS-LIKE6 (AGL6) MADS-box genes are ancient with wide distributions in gymnosperms and angiosperms, their functions remain poorly understood. Here, we show the biological role of the AGL6-like gene, OsMADS6, in specifying floral organ and meristem identities in rice (Oryza sativa L.). OsMADS6 was strongly expressed in the floral meristem at early stages. Subsequently, OsMADS6 transcripts were mainly detectable in paleas, lodicules, carpels and the integument of ovule, as well as in the receptacle. Compared to wild type plants, osmads6 mutants displayed altered palea identity, extra glume-like or mosaic organs, abnormal carpel development and loss of floral meristem determinacy. Strikingly, mutation of a SEPALLATA (SEP)-like gene, OsMADS1 (LHS1), enhanced the defect of osmads6 flowers, and no inner floral organs or glume-like structures were observed in whorls 2 and 3 of osmads1-z osmads6-1 flowers. Furthermore, the osmads1-z osmads6-1 double mutants developed severely indeterminate floral meristems. Our finding, therefore, suggests that the ancient OsMADS6 gene is able to specify "floral state" by determining floral organ and meristem identities in monocot crop rice together with OsMADS1.
A cross-border comparison of breast and cervical cancer screening uptake. This study investigated differences in uptake of breast and cervical cancer screening relating to socio-economic characteristics in the Republic and Northern Ireland. Multivariate analyses were performed using data from population-based surveys that detail breast and cervical cancer screening participation in the preceding 12 months in the two jurisdictions. Cervical screening rates were significantly higher in Northern Ireland where 536/1764 (30%) eligible women attended screening in comparison to the Republic where only 780/4472 (17%) eligible women attended screening. Differences in participation related to socio-economic group and education were also observed in screening programmes for cervical cancer (Wald: p = 0.000; p = 0.010) and related to education for breast cancer (Wald: p = 0.008) in the Republic of Ireland. Differences in participation across socio-economic groups in respect of breast and cervical cancer screening were not replicated in Northern Ireland. These differences may contribute to inequalities in treatment and outcomes across socio-economic groups in the Republic of Ireland.
A novel DNA microarray design for accurate and straightforward identification of Escherichia coli safety and laboratory strains. Escherichia coli K-12, B, C and W strains and their derivates are declared in biological safety guidelines as risk group 1 organisms as they are unable to colonise the human gut. Differentiation and identification of these safety strains is mainly based on pulsed-field gel electrophoresis (PFGE), phage sensitivity tests or PCR-based methods. However, these methods are either tedious and time consuming (phage sensitivity, PFGE) or based on single specific fragments (PCR) or patterns (PFGE) lacking additional information for further differentiation of the strains. In the current study, subtractive hybridisation techniques were applied to detect specific DNA fragments which were used to design a microarray (chip) for accurate and simple identification of these organisms, and to differentiate them from other E. coli strains. The chip can be used to identify E. coli safety strains and monitor them during ongoing experiments for changes in their genome and culture purity. The hybridisation layout of the microarray was arranged in such a way that the respective lineages of safety strains could be easily identified as distinct letters (K, B, C or W). Differentiation of single strains or subtyping was possible with further probes. In addition, a set of probes targeting genes coding for common virulence factors has been included, both to differentiate safety strains from pathogenic variants and to make sure that no transfer of these genes happens during handling or storage. The reliability of the approach has been tested on a comprehensive selection of E. coli laboratory strains and pathogenic representatives.
Degree of interocular synchrony required for maintenance of binocularity in kitten's visual cortex. 1. The importance of synchronous activation in maintaining cortical binocularity was studied physiologically in kittens that had been reared under different regimens of alternating monocular deprivation. 2. Three different techniques were employed to provide alternate monocular stimulation: a) mechanical shutters placed before the animals' eyes; b) goggles fitted with complementary colored cutoff filters, which restricted visual input to one eye at a time; and c) two rotating gratings that were 90 degrees out of phase. In the third technique, the gratings were always orthogonal to one another and viewed separately through cutoff filters. This allowed us to exploit the orientation selectivity of cortical cells and thereby stimulate them alternately through each eye without simultaneously affecting activity in the dorsal lateral geniculate nucleus (dLGN). 3. We based our conclusions on a sample of 691 neurons, which we recorded in 21 animals. Results with all techniques were remarkably consistent. Binocular cortical inputs predominated at normal or nearly normal levels, even when a number of seconds elapsed between successive exposures of each eye. 4. An interonset interval of at least 10 s was required to make a substantial reduction in binocularity. This interval can be separated into two parts--the duration of exclusive monocular stimulation and the time when neither channel receives input. Of these, the latter appeared to be less important. Blanking times of 0.15--1.0 s did not affect binocularity if the interonset interval was 1 or 10 s; and in one experiment where the blanking time was 9 s, the resulting disruption in binocularity was less than that found with shorter blanking times and the same interonset interval. 5. Our results imply that mechanisms responsible for the disappearance of binocular cortical inputs require independent stimulation of each eye for periods of at least a few seconds; this stimulation must be of a kind that is known to excite cortical cells. Our results with the rotating grafting show, in addition, that the mechanisms whose timing we have measured are intrinsic to the cortex.
Efficacy of micronized acellular dermal graft for use in interproximal papillae regeneration. The aim of this study was to evaluate interdental papillary reconstruction based on a micronized acellular dermal matrix allograft technique. Thirty-eight papillae in 12 patients with esthetic complaints of insufficient papillae were evaluated. Decreased gingival recession values were found postoperatively (P < .001). Chi-square analysis showed significantly higher postoperative Papilla Index values (chi-square = 43, P < .001), further supported by positive symmetry statistical analysis values (positive kappa and weighted kappa values). This procedure shows promise as a method for papillary reconstruction.
Zinc(II)-cyclen polyacrylamide gel electrophoresis for detection of mutations in short Ade/Thy-rich DNA fragments. We describe an improved gel-based method with an additive Zn(2+)-cyclen complex (cyclen, 1,4,7,10-tetraazacyclododecane), Zn(2+)-cyclen-PAGE, for mutation detection in DNA fragments by PCR that contain more than 65% Ade/Thy bases and fewer than 100base pairs (bp). Existing techniques have a problem in analyzing such short Ade/Thy-rich fragments because the duplexes are disrupted and are not detectable due to binding of Zn(2+)-cyclen to Thy bases. In this strategy using a PCR primer with a Gua/Cyt-lined sequence attached at its 5'-end, we successfully detected a mutation in an 86-bp Ade/Thy-rich region of the BRCA1 gene from formalin-fixed paraffin-embedded breast cancer-tissue sections.
Reye's syndrome in Bangalore. One hundred and twenty four cases of Reye's syndrome admitted to Vanivilas Children's Hospital, Bangalore were investigated. Clinical, biochemical and epidemiological details were obtained. The median age was five years, with no difference in sex ratio. This disease was frequent in winter months. Cases clustered in certain congested localities of the city among lower socio economic strata. Aspirin and varicella could not be associated as preceding factors. The clinical and biochemical features of the patients were suggestive of Reye's syndrome. Histopathological evaluation was done in 104 liver biopsy specimens. Virological studies for influenza and arbovirus were negative. Mortality was high (78%).
Superficial Siderosis and Dural Ectasia in a Patient with Marfan Syndrome.
Groundwater pesticides: interactive effects of low concentrations of carbamates aldicarb and methomyl and the triazine metribuzin on thyroxine and somatotropin levels in white rats. Using full-factorial design experiments for three variables at two levels each and center replicates, we examined the effects of common agricultural carbamate insecticides, aldicarb and methomyl, and a triazine herbicide, metribuzin, on hormone levels in Sprague-Dawley rats. Fifty-four female rats were sampled at 2 and 6 wk during a 6-wk exposure to individual chemicals or to combinations of them. Some main effects and interaction effects were significant. For example, rats treated with the herbicide (metribuzin) were hyperthyroid. The interactions of all three chemicals also significantly increased thyroxine levels. One year later, we repeated these experiments for 16 wk using 54 male rats; the results were very similar. Metribuzin alone significantly increased thyroxine throughout the second study (at 7, 13, and 16 wk). Somatotropin levels were significantly altered after 13 wk of exposure. The same concentrations and mixtures of these three pesticides have now been shown to be implicated in learning impairment and other neurological functions, immune parameter changes, and endocrine changes. These findings support the concept of the interconnectedness of the nervous, endocrine, and immune systems and raise the likelihood of impacts on all three systems if one is shown to be affected. Development, growth, and reproduction all depend on the proper function of these three systems. These results strongly suggest the need to reassess currently allowed "safe" levels of chemicals based on adult dosages that are accepted in ground-water and in our food supplies.
Increased risk of depressive disorder within 1 year after diagnosis with urinary calculi in Taiwan. This study investigated the risk of subsequent depressive disorders (DD) following a diagnosis of urinary calculi (UC) in Taiwan. In total, 67,917 adult patients newly diagnosed with UC were recruited, along with 153,951 age-matched enrollees who were used as a comparison group. A stratified Cox proportional hazard regression analysis revealed that the adjusted hazard of DD within a 1-year period following diagnosis with UC was 1.75 times greater for patients with UC than for comparison patients.
The very elderly dialysis patient: indication and discontinuation of dialysis. 1. When the current available data in the literature is summarized it becomes evident that the majority of it supports the position that it is, at least for medical reasons, not advisable to exclude patients over the age of 80 years from chronic dialysis. 2. It is correct to say that the refusal of dialysis therapy for elderly dialysis patients would lead to a not insignificant cutting of costs, although elderly patients are not as 'expensive' as younger dialysis patients. 3. The decision to exclude patients over 80 from dialysis treatment is difficult, in our opinion, to support ethically. 4. The refusal of therapy by a dialysis patient--independent of his age--can only occur with his/her consent, as long as the patient is clearly conscious of the decision. 5. Should the patient no longer be in the condition to exercise his/her autonomy, and there is no AD, the Surrogate's Court must be consulted. 6. AD can be seen as helpful, since they not only make the decisions for physicians easier, but also because they can be seen as an act of care for family members. 7. Whenever dialysis therapy is discontinued the problematic nature of so-called essential care should be carefully considered, especially if no clear position has been taken in an AD.
A new species of Isospora Schneider, 1881 (Apicomplexa: Eimeriidae) in Ruppell's agama Agama rueppelli (Vaillant) (Sauria: Agamidae) from East Africa, with a review of this genus in agamid lizards. Coprological examinations of eight Ruppell's agamas Agama rueppelli (Vaillant) revealed the presence of a coccidium of the genus Isospora Schneider, 1881 that represents a previously undescribed species. Oöcysts of Isospora farahi n. sp. are spherical or subspherical, 29.1 (26-31) x 28.8 (26-31) microm, with a shape-index of 1.01 (1-1.07). An oöcyst residuum, polar granules and micropyle are absent. The oöcyst wall is bilayered, brownish and smooth, c. 1.5-2 microm thick. The sporocysts are oval, 16.6 (15-18) x 11.4 (11-12) microm, with a shape-index of 1.46 (1.25-1.64) and both Stieda and substieda bodies. A sporocyst residuum is present as medium-sized granules scattered irregularly among the sporozoites. The sporozoites are vermiform, with a large posterior spherical refractile body. Endogenous development is intranuclear in the epithelial cells of the small intestine. Sporulation is unknown, as oöcysts were recovered from the faeces.
Weighted Transfer Learning for Improving Motor Imagery-Based Brain-Computer Interface. One of the major limitations of motor imagery (MI)-based brain-computer interface (BCI) is its long calibration time. Due to between sessions/subjects variations in the properties of brain signals, typically, a large amount of training data needs to be collected at the beginning of each session to calibrate the parameters of the BCI system for the target user. In this paper, we propose a novel transfer learning approach on the classification domain to reduce the calibration time without sacrificing the classification accuracy of MI-BCI. Thus, when only few subject-specific trials are available for training, the estimation of the classification parameters is improved by incorporating previously recorded data from other users. For this purpose, a regularization parameter is added to the objective function of the classifier to make the classification parameters as close as possible to the classification parameters of the previous users who have feature spaces similar to that of the target subject. In this paper, a new similarity measure based on the Kullback-Leibler divergence (KL) is used to measure the similarity between two feature spaces obtained using subject-specific common spatial patterns (CSP). The proposed transfer learning approach is applied on the logistic regression classifier and evaluated using three datasets. The results showed that compared with the subject-specific classifier, the proposed weighted transfer learning classifier improved the classification results, particularly when few subject-specific trials were available for training (p < 0.05). Importantly, this improvement was more pronounced for users with medium and poor accuracy. Moreover, the statistical results showed that the proposed weighted transfer learning classifier performed significantly better than the considered comparable baseline algorithms.
Iron-catalyzed redox radical cyclizations of 1,6-dienes and enynes. Treatment of 1,6-dienes and enynes with FeCl(3) or Fe(Pc) in the presence of NaBH(4) and air or O(2) causes radical cyclization to give five-membered carbo or heterocyclic compounds, into which a halogen atom or hydroxyl group was introduced.
Clinical Evaluation of Shaped Gel Breast Implant Rotation Using High-Resolution Ultrasound. Clinical trials have demonstrated through core and independent studies that anatomical devices are safe and effective with low complication rates. The rotation rate of shaped breast implants in the literature is 0 to 8.2%. Currently there are no studies evaluating the efficacy of in office ultrasound or clinical rotation vs actual rotation rates seen on high-resolution ultrasound (HRUS). The purpose of the study is to demonstrate the ease and reliability of HRUS for evaluating the rotation rate of 2 different brands of anatomic implants and to correlate this with the presumed clinical rate, as well as independent evaluators assessments. A total of 69 patients were followed up at routine intervals and were evaluated for rotation. Any implant rotated past >30° off of midline (outside 5-7 o’clock) was considered to be rotated. To determine if radiographic rotation was clinically evident, 20 composite patient photos were blindly evaluated. A random total of 69 patients underwent bilateral augmentation mammoplasty with form stable anatimic gel implants using 138 implants. Twenty-nine of the 69 (42%) patients and 37 of the 138 (27%) implants were found to be rotated-using HRUS. Eight of the 69 (12%) patients had bilateral rotations. Independent evaluators were able to identify two of 12 (17%) possible rotations, or 2 rotations in 40 (5%) total implants. Anatomic form stable gel implants are actually rotated up to 25 times more frequently than previously thought, but these rotations do not translate into clinically significant sequela. High-resolution ultrasound is a simple alternative for breast implant surveillance and is better accepted by patients than magnetic resonance imaging (MRI). The clinical value of HRUS is also discussed and recommendations for FDA implant labeling changes are provided in this article. 4
Antagomirzymes: oligonucleotide enzymes that specifically silence microRNA function. Many important cellular processes are regulated by small endogenous noncoding RNAs known as microRNAs (miRNAs). The precise molecular function of many miRNAs is unknown; different loss-of-function methods are required to gain insight into the biology of these small RNA molecules. Nucleic acid enzymes termed antagomirzymes are now shown to be valuable tools for the specific knockdown of miRNA in vitro and in vivo (see scheme).
[The characteristics of 123I-MIBG myocardial scintigraphy in patients with left ventricular pressure-overload diseases]. The purpose of this study was to clarify the clinical significance of 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy in patients with left ventricular pressure-overload diseases. MIBG scintigraphy was applied to 10 pts with aortic valve stenosis (AS group), 11 pts with hypertrophic obstructive cardiomyopathy (HOCM group), 17 pts with hypertrophic non-obstructive cardiomyopathy (HCM group) and 6 control cases (C group). Mean pressure gradient in AS and HOCM groups was 62 +/- 21 mmHg and 38 +/- 18 mmHg, respectively. Initial myocardial uptake of MIBG (MU) was higher in the AS (1.92 +/- 0.46%) and HOCM (2.27 +/- 0.47%) groups than those in the HCM (1.61 +/- 0.29%) and C (1.50 +/- 0.23) groups. Myocardial clearance of MIBG (MC) was higher in the AS (39 +/- 11%), HOCM (37 +/- 19%) and HCM (28 +/- 17%) groups than that in the C (14 +/- 6%) groups. Heart/mediastinum count ratio (H/M) of AS, HOCM, HCM and C groups was 1.87 +/- 0.29, 2.09 +/- 0.19, 1.98 +/- 0.26, and 2.20 +/- 0.10, respectively. In the cases of AS, positive correlation was observed between mean pressure gradient and MU (r = 0.618, p < 0.05). In conclusion, MU was increased in the case of left ventricular pressure-overload state (AS and HOCM).
Polymorphisms in MIR122, MIR196A2, and MIR124A Genes are Associated with Clinical Phenotypes in Inflammatory Bowel Diseases. Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial disorders that result from a dysregulated inflammatory response to environmental factors in genetically predisposed individuals. Recently, microRNAs (miRNAs) have been shown to be involved in the development of IBDs. We investigated common variants in five miRNA genes in a cohort of Italian IBD patients, to evaluate their possible role in the disease's susceptibility and phenotype manifestations. The analysis included 267 CD patients, 207 UC patients, and 298 matched healthy controls. Polymorphisms in the MIR122, MIR499, MIR146A, MIR196A2, and MIR124A genes were evaluated by allelic discrimination assay. We did not find associations between mir polymorphisms and IBD susceptibility. In both diseases, rs17669 and rs11614913 (MIR122 and MIR196A2) seem to contribute to clinical phenotypes: ileal location in CD (odds ratio [OR] = 1.82, p = 0.03; OR = 0.51, p = 0.01), and left-sided extent in UC (OR = 0.43, p = 0.05; OR = 0.28, p = 0.002). In CD, the MIR124A polymorphism (rs531564) contributed to colon location (p = 0.03, OR = 2.74). Finally, the variant allele of rs11614913 was associated with early age at onset in both diseases (p = 0.05 and p = 0.02). We showed for the first time that polymorphisms in MIR122, MIR196A2, and MIR124A could play a role in clinical phenotype modulation in IBD.
Safety and Efficacy of Microfocused Ultrasound in Tightening of Lax Elbow Skin. With the increased popularity of minimally invasive cosmetic treatments, this study evaluates the efficacy and safety of microfocused ultrasound with visualization (MFU-V) for tightening lax skin above the elbow. Subjects were treated bilaterally above the elbows with MFU-V using transducers with different focal depths. Photographs were taken before treatment and at 90- and 180-day follow-ups. Masked observer ratings and physician and subject global aesthetic improvement scales (PGAIS and SGAIS) were completed at follow-ups. Safety, based on adverse event (AE) incidence, was assessed. Masked blinded assessment was completed at 90 days; 56% showed aesthetic improvement. Overall improvement in SGAIS was 83% and 81% at 90 and 180 days, respectively. The overall improvement in PGAIS was 94% at both 90 and 180 days. Patient satisfaction questionnaires showed that 83% noticed improvements in elbow characteristics at 90 days, with 81% still indicating improvement at 180 days. No serious AEs or treatment-related AEs were reported. This pilot study suggests that MFU-V is a safe and promising nonsurgical option for the treatment of skin laxity above the elbow. Based on the positive results of this study, a larger trial is warranted together with testing different treatment densities to optimize this noninvasive approach.
Atorvastatin inhibits pyroptosis through the lncRNA NEXN-AS1/NEXN pathway in human vascular endothelial cells. Many clinical trials have demonstrated that statins convey protective effects against atherosclerosis independent of cholesterol-lowering capacities. Other evidence indicates that pyroptosis, a type of programmed cell death, is likely involved in atherosclerosis, but the effects and mechanisms of statins on pyroptosis must be further revealed. Here, we explored the effects and mechanisms of atorvastatin on pyroptosis in human vascular endothelial cells by quantitative real-time polymerase chain reaction and Western blot analyses. Atorvastatin upregulated long non-coding RNA (lncRNA) NEXN-AS1 and the expression of NEXN at both the mRNA and protein levels in a concentration- and time-dependent manner. Atorvastatin inhibited pyroptosis by decreasing the expression levels of the canonical inflammasome pathway biomarkers NLRP3, caspase-1, GSDMD, IL-1β, and IL-18 at both the mRNA and protein levels. The promotion effects of atorvastatin on NEXN-AS1 and NEXN expression could be significantly abolished by knockdown of lncRNA NEXN-AS1 or NEXN, and its inhibitory effects on pyroptosis were also markedly offset by knock-down of lncRNA NEXN-AS1 or interference of NEXN. These results demonstrated that atorvastatin regulated pyroptosis via the lncRNA NEXN-AS1-NEXN pathway, which provides a new insight into the mechanism of how atorvastatin promotes non-lipid-lower effects against the development of atherosclerosis and gives new directions on how to reverse atherosclerosis.
Effect of unilateral ovariectomy and subsequent ovum implantation in mice. Unilateral ovariectomy (ULO) was done on any stage of the cycle and the animals were mated within day 1 to day 21 to observe the acute and long term effect of ULO on ovum implantation. Implantation reduced in proportion to single ovary if the animals were mated within 24 hr of ULO. Increase in ovarian weight along with an increase in implantation number continued in mated mice and reached at peak on day 19-21 of ULO (sacrificed after 6 days i.e., 25-27 days of ULO). After ULO the remaining ovary compensated within day 5-6 of ULO even during pregnancy. Ovarian histology showed stimulation of small antral follicles in mice mated on day 3 of ULO (sacrificed after 6 days i.e., day 9 of ULO) along with a decrease of large antral follicles and pre-antral follicles. Preantral follicles were at peak on day 12-14. Large antral follicles attained a peak on day 4 which slowly decreased. The occurrence of implantation in such ULO conditions are discussed.
Clostridium sporogenes PA 3679 and its uses in the derivation of thermal processing schedules for low-acid shelf-stable foods and as a research model for proteolytic Clostridium botulinum. The putrefactive anaerobe Clostridium sporogenes PA 3679 has been widely used as a nontoxigenic surrogate for proteolytic Clostridium botulinum in the validation of thermal processes for low-acid shelf-stable foods, as a target organism in the derivation of thermal processes that reduce the risk of spoilage of such foods to an acceptable level, and as a research model for proteolytic strains of C. botulinum. Despite the importance of this organism, our knowledge of it has remained fragmented. In this article we draw together the literature associated with PA 3679 and discuss the identity of this organism, the phylogenetic relationships that exist between PA 3679 and various strains of C. sporogenes and proteolytic C. botulinum, the heat resistance characteristics of PA 3679, the advantages and limitations associated with its use in the derivation of thermal processing schedules, and the knowledge gaps and opportunities that exist with regard to its use as a research model for proteolytic C. botulinum. Phylogenetic analysis reviewed here suggests that PA 3679 is more closely related to various strains of proteolytic C. botulinum than to selected strains, including the type strain, of C. sporogenes. Even though PA 3679 is demonstrably nontoxigenic, the genetic basis of this nontoxigenic status remains to be elucidated, and the genetic sequence of this microorganism appears to be the key knowledge gap remaining to be filled. Our comprehensive review of comparative heat resistance data gathered for PA 3679 and proteolytic strains of C. botulinum over the past 100 years supports the practice of using PA 3679 as a (typically fail-safe) thermal processing surrogate for proteolytic C. botulinum.
[Hepatitis C and liver transplantation: fibrosis progression and treatment. Or how to improve management]. Hepatitis C virus-related end-stage liver disease, alone or in combination with alcohol, has become the leading indication for liver transplantation in most transplant programs accounting for approximately half of transplants performed in European centers. Hepatitis C virus infection recurs virtually in every post-transplant patient. The natural history of hepatitis C after liver transplantation is variable. Progression of chronic hepatitis C virus is more aggressive after liver transplantation with a cumulative probability of developing graft cirrhosis estimated to reach 30% at 5 years. Approximately 10% of the patients with recurrent disease will die or require re-transplantation within 5 years post-transplantation. Several factors, including those related to the virus, the host, the environment and the donor, are probably implicated in the outcome. The immune status represents the main significant variable in influencing disease severity in hepatitis C virus-infected patients; with higher HCV viral load and the significant association described between the degree of immunosuppression and disease severity. Interventions to prevent, improve, or halt the recurrence of hepatitis C virus infection have been evaluated by multiple small studies worldwide with similar overall rates of virological clearance of approximately 9-30%. Current consensus recommends combination therapy with pegylated interferon and ribavirin for those patients with histological recurrence of hepatitis C virus infection and fibrosis. Therapy is adjusted to tolerance and rescued with granulocyte colony-stimulating factor and erythropoietin for bone marrow suppression. In this article we present a comprehensive review of post-transplant hepatitis C virus infection; in particular fibrosis progression and the major challenges according to treatment.
Maternal serum placental growth factor isoforms 1 and 2 at 11-13, 20-24 and 30-34 weeks' gestation in late-onset pre-eclampsia and small for gestational age neonates. To compare the maternal serum concentrations of placental growth factor (PlGF)-1 and PlGF-2 in the first, second and third trimesters in normal pregnancies and in those complicated by pre-eclampsia (PE) or the delivery of small for gestational age (SGA) neonates after 37 weeks. Serum PlGF-1 and PlGF-2 were measured at 11-13, 20-24 and 30-34 weeks' gestation in 50 cases of PE, 99 cases of SGA and 298 controls. The values of PlGF-1 and PlGF-2 at 11-13 weeks were expressed as multiples of the median (MoM) after adjustment for maternal characteristics. The distributions of PlGF-1 and PlGF-2 in cases and controls at 20-24 and 30-34 weeks were converted to MoM of the values at 11-13 weeks and compared. Serum PlGF-1 and PlGF-2 levels were highly correlated and both increased with gestational age. At 30-34 weeks, the median MoM values for PlGF-1 and PlGF-2 in the late PE (4.2 and 4.3) and late SGA (7.2 and 6.0) groups were significantly lower than in the controls (12.8 and 9.9). Combining the two isoforms did not improve the prediction of late PE and late SGA provided by PlGF-1 alone. The performances of serum PlGF-1 and PlGF-2 in the prediction of late PE and late SGA are similar.
[Developmental disorders in the fourth edition of the American classification: diagnostic and statistical manual of mental disorders (DSM IV -- optional book)]. In 1991 the American Psychiatric Association proposed a draft version of the IV edition of the Diagnostic and Statistical Manual of Mental Disorders--the DSM IV Options Book. Authors of this version wanted to increase clarity of the criteria sets and to provide compatibility with the Tenth Edition of the International Classification of Diseases (ICD - 10). The purpose of this Options Book is to propose some changes in wording, diagnostic divisions and to discuss various options concerning the placement of sections and disorders within the classification. The "Disorders of Infancy, Childhood or Adolescence" section was renamed "Disorders Usually First Evident in Infancy, Childhood or Adolescence" and moved to the front of the classification and also was expended to 11 groups of disorders. Several suggestions have been made about including new diagnostic groupings such as: Rett's Disorder, Eating Disorders and Voice Disorder. The Options Book introduces a superior category for Attention Deficit Disorders (with and without hyperactivity) and for Conduct Disorder/Oppositional Defiant Disorder. Several options are proposed regarding The Anxiety Disorders of Childhood or Adolescence. There is no evidence for a distinction in this category according to the age criterion. One option would be to move these disorders into the adult anxiety section (similarly as in the Mood Disorders and Schizophrenia). In the new version the title "Specific Developmental Disorders" is omitted. The suggestion is to include Phonological Disorder (Articulation Disorders) and Elective Mutism into Speech and Language Disorders section.
Clinical significance of intestinal type fatty acid binding protein in patients undergoing coronary artery bypass surgery. The aim of this study was to determine whether serum levels of intestinal type fatty acid binding protein (I-FABP) are related to intestinal ischemia in patients undergoing coronary bypass surgery. The study was planned as prospective, observational. Elective coronary artery bypass candidate patients between ages of 50 and 70 were consecutively included in the study. Thirty-five patients scheduled for cardiopulmonary bypass (CPB) were identified as the CPB group and 16 patients not scheduled for CPB were identified as the off-pump coronary artery bypass surgery (OPCAB) group. The variables between and within the groups were analyzed with Student's t, Mann-Whitney U, Friedman and Wilcoxon tests respectively. In both CPB and OPCAB groups, I-FABP level at the end of the operation was significantly higher than that noted at the beginning of the operation (p<0.005). In the CPB group, there was a significant drop in I-FABP from the end of the operation to each of the postoperative time points (12(th) hour and 24(th) hour) (respectively p<0.001, p<0.001). In the OPCAB group, the I-FABP levels at both postoperative time points were lower than that at the end of the operation (p<0.001), and the level at 24-hour post-surgery was significantly lower than at both the end-of-operation I-FABP value (p<0.001) and the 12-hour post-surgery I-FABP value. Since we have not observed any intestinal ischemia through our research, slight changes of I-FABP measurements make us believe that I-FABP would be a valuable way to monitor for intestinal ischemia in patients who undergo cardiac surgery.

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