Role of cephamycins in obstetrics and gynecology.
Infections of the female upper genital tract are usually polymicrobic, often involving mixed aerobic (facultative) and anaerobic bacteria. Optimal therapy provides coverage against aerobes (both gram positive and gram negative and especially the Enterobacteriaceae) and anaerobes (especially the beta-lactamase-producing gram-negative species, such as Bacteroides). A variety of antibiotics provide the broad spectrum of activity needed for these infections, including clindamycin plus an aminoglycoside, cephalosporins and cephamycins, imipenem, extended-spectrum penicillins and the beta-lactam agents combined with a beta-lactamase inhibitor. The cephamycins--cefoxitin, cefotetan and cefmetazole--have been shown to have a high rate of clinical efficacy and bacteriologic response. The cephalosporins are usually used for prophylaxis at the time of obstetric and gynecologic surgery. The cephamycins have recently undergone extensive evaluation for prophylaxis and have demonstrated comparable microbiologic and clinical efficacy. A pharmacokinetic comparison of cefoxitin, cefotetan and cefmetazole points to cefmetazole as a cost-effective alternative to cefoxitin and cefotetan for both prophylaxis and treatment of pelvic infections.


Both Ser361 phosphorylation and the C-arrestin domain of thioredoxin interacting protein are important for cell cycle blockade at the G1/S checkpoint.
Thioredoxin interacting protein (TXNIP) is a novel tumor suppressor that is down-regulated in several cancer tissues and tumor cell lines. Overexpression of TXNIP causes cell cycle arrest at the G1/S checkpoint in the hepatocellular carcinoma cell line HuH-7. TXNIP contains putative phosphorylation sites, but the effects of its phosphorylation have not been fully characterized. TXNIP also contains two α-arrestin domains (N-arrestin and C-arrestin) whose functions are not fully understood. Here, we reveal an association between TXNIP and cell cycle regulatory proteins (p27kip1, Jun activation domain-binding protein 1 (JAB1), Cdk2, and cyclin E), suggesting its participation in cell cycle regulation. We observed phosphorylation of TXNIP and used both in vivo and in vitro kinase assays to demonstrate that TXNIP can be phosphorylated by p38 mitogen-activated protein kinase. Furthermore, we also identified Ser361 in TXNIP as one of the major phosphorylation sites. Cell cycle analysis showed that Ser361 phosphorylation participates in TXNIP-mediated cell cycle arrest. In addition, the C-arrestin domain may also play an important role in cell cycle arrest. We also showed that phosphorylation at Ser361 may be important for the association of TXNIP with JAB1 and that the C-arrestin domain is necessary for the nuclear localization of this molecule. Collectively, these studies reveal that TXNIP participates in cell cycle regulation through association with regulatory proteins, especially JAB1, and that C-arrestin-dependent nuclear localization is important for this function. This work may facilitate the development of a new cancer therapy strategy that targets TXNIP as a key molecule inhibiting cancer cell growth via cell cycle blockade at the G1/S checkpoint.


Surface rheology of PEO-PPO-PEO triblock copolymers at the air-water interface: comparison of spread and adsorbed layers.
The dilatational rheological properties of monolayers of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide)-type block copolymers at the air-water interface have been investigated by employing an oscillating ring trough method. The properties of adsorbed monolayers were compared to spread layers over a range of surface concentrations. The studied polymers were PEO26-PPO39-PEO26 (P85), PEO103-PPO40-PEO103 (F88), and PEO99-PPO65-PEO99 (F127). Thus, two of the polymers have similar PPO block size and two of them have similar PEO block size, which allows us to draw conclusions about the relationship between molecular structure and surface dilatational rheology. The dilatational properties of adsorbed monolayers were investigated as a function of time and bulk solution concentration. The time dependence was found to be rather complex, reflecting structural changes in the layer. When the dilatational modulus measured at different concentrations was replotted as a function of surface pressure, one unique master curve was obtained for each polymer. It was found that the dilatational behavior of spread (Langmuir) and adsorbed (Gibbs) monolayers of the same polymer is close to identical up to surface concentrations of approximately 0.7 mg/m2. At higher coverage, the properties are qualitatively alike with respect to dilatational modulus, although some differences are noticeable. Relaxation processes take place mainly within the interfacial layers by a redistribution of polymer segments. Several conformational transitions were shown to occur as the area per molecule decreased. PEO desorbs significantly from the interface at segmental areas below 20 A(2), while at higher surface coverage, we propose that segments of PPO are forced to leave the interface to form a mixed sublayer in the aqueous region.


Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development.
We have generated Cbfa1-deficient mice. Homozygous mutants die of respiratory failure shortly after birth. Analysis of their skeletons revealed an absence of osteoblasts and bone. Heterozygous mice showed specific skeletal abnormalities that are characteristic of the human heritable skeletal disorder, cleidocranial dysplasia (CCD). These defects are also observed in a mouse Ccd mutant for this disease. The Cbfa1 gene was shown to be deleted in the Ccd mutation. Analysis of embryonic Cbfa1 expression using a lacZ reporter gene revealed strong expression at sites of bone formation prior to the earliest stages of ossification. Thus, the Cbfa1 gene is essential for osteoblast differentiation and bone formation, and the Cbfa1 heterozygous mouse is a paradigm for a human skeletal disorder.


Systemic Lupus Erythematosus: Clinical Updates in Women's Health Care Primary and Preventive Care Review.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease most commonly involving skin, joints, and kidneys. Usually, it presents in women in puberty or early adulthood. This monograph provides an overview of the role of an obstetrician-gynecologist (ob-gyn) in the treatment of SLE patients. An ob-gyn is uniquely placed in the health care continuum throughout the life cycle of a woman. Notably, an ob-gyn often is the first physician to notice SLE-related rash, swollen joints, cytopenias, or proteinuria in a patient and is the first to provide initial management. Obstetrician-gynecologists must be familiar with SLE effects on reproductive issues, such as SLE effects on the choice of birth control, pregnancy outcomes, and the risks of hormone therapy use, as well as the pregnancy effects on the risk of lupus nephritis flares. Human papillomavirus and associated cancer also are of concern in patients with SLE. Providing care to women with SLE is multifaceted; therefore, ob-gyns often will need to liaise with rheumatologists and other specialists.


Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice.
Impairment of myocardial fatty acid substrate metabolism is characteristic of late-stage heart failure and has limited treatment options. Here, we investigated whether inhibition of G-protein-coupled receptor kinase 2 (GRK2) could counteract the disturbed substrate metabolism of late-stage heart failure. The heart failure-like substrate metabolism was reproduced in a novel transgenic model of myocardium-specific expression of fatty acid synthase (FASN), the major palmitate-synthesizing enzyme. The increased fatty acid utilization of FASN transgenic neonatal cardiomyocytes rapidly switched to a heart failure phenotype in an adult-like lipogenic milieu. Similarly, adult FASN transgenic mice developed signs of heart failure. The development of disturbed substrate utilization of FASN transgenic cardiomyocytes and signs of heart failure were retarded by the transgenic expression of GRKInh, a peptide inhibitor of GRK2. Cardioprotective GRK2 inhibition required an intact ERK axis, which blunted the induction of cardiotoxic transcripts, in part by enhanced serine 273 phosphorylation of Pparg (peroxisome proliferator-activated receptor γ). Conversely, the dual-specific GRK2 and ERK cascade inhibitor, RKIP (Raf kinase inhibitor protein), triggered dysfunctional cardiomyocyte energetics and the expression of heart failure-promoting Pparg-regulated genes. Thus, GRK2 inhibition is a novel approach that targets the dysfunctional substrate metabolism of the failing heart.


Osteoporosis-related life habits and knowledge about osteoporosis among women in El Salvador: a cross-sectional study.
Osteoporosis is a systemic skeletal disorder, characterized by reduced bone mass, deterioration of bone structure, increased bone fragility, and increased fracture risk. It is more frequent to find among women than men at a 4:1 ratio. Evidence suggests that to adopt changes on some life habits can prevent or delay development of osteoporosis. Several osteoporosis-risk factors have been confirmed in the US and western Europe, but in El Salvador there are neither reliable epidemiological statistics about this skeletal disorder nor studies addressing osteoporosis-risk factors in women. The aim of this study was to determinate the extent of osteoporosis knowledge, the levels of both daily calcium intake and weight-bearing physical activity, and the influence of several osteoporosis-risk factors on these variables in three age groups of Salvadorean women. In this exploratory cross-sectional study, an osteoporosis knowledge assessment questionnaire including a food frequency and a physical activity record section were used to collect data and it was delivered through a face-to-face interview. A convenience sample (n = 197) comprised of three groups of women aged 25-35 years, 36-49 years, and over 49 years was taken. Among-group comparisons of means were analyzed by two-way ANOVA. To determinate the overall influence of osteoporosis-risk factors, the multivariate analysis was used. Study results indicated that better educated women had more knowledge about osteoporosis than women with a low education level, regardless of age, even though this knowledge was rather fair. Older women got more weight-bearing physical activity at home and less at place of employment than reported by the younger women; however, neither group performed sufficient high-intensity WBPA to improve bone mass. Regardless of age, the most women consumed 60% or less than the Dietary Reference Intake of calcium and depend on household income, lactose intolerance and coffee rather than milk consumption. In summary, the majority of women in this study have modest knowledge on osteoporosis. The knowledge base is not linked to preventive health habits, including sufficient calcium intake and performance of weight-bearing physical activities. They are thus at increased risk for low bone mass.


Value of monoenergetic dual-energy CT (DECT) for artefact reduction from metallic orthopedic implants in post-mortem studies.
The aim of this ex vivo study was to assess the performance of monoenergetic dual-energy CT (DECT) reconstructions to reduce metal artefacts in bodies with orthopedic devices in comparison with standard single-energy CT (SECT) examinations in forensic imaging. Forensic and clinical impacts of this study are also discussed. Thirty metallic implants in 20 consecutive cadavers with metallic implants underwent both SECT and DECT with a clinically suitable scanning protocol. Extrapolated monoenergetic DECT images at 64, 69, 88, 105, 120, and 130 keV and individually adjusted monoenergy for optimized image quality (OPTkeV) were generated. Image quality of the seven monoenergetic images and of the corresponding SECT image was assessed qualitatively and quantitatively by visual rating and measurements of attenuation changes induced by streak artefact. Qualitative and quantitative analyses showed statistically significant differences between monoenergetic DECT extrapolated images and SECT, with improvements in diagnostic assessment in monoenergetic DECT at higher monoenergies. The mean value of OPTkeV was 137.6 ± 4.9 with a range of 130 to 148 keV. This study demonstrates that monoenergetic DECT images extrapolated at high energy levels significantly reduce metallic artefacts from orthopedic implants and improve image quality compared to SECT examination in forensic imaging.


The Variations in Care and Real-world Outcomes in Individuals With Rectal Cancer: Protocol for the Ontario Rectal Cancer Cohort.
Individuals with rectal cancer require a number of pretreatment investigations, often require multidisciplinary treatment, and require ongoing follow-ups after treatment is completed. Due to the complexity of treatments, large variations in practice patterns and outcomes have been identified. At present, few comprehensive, population-level data sets are available for assessing interventions and outcomes in this group. Our study aims to create a comprehensive database of individuals with rectal cancer who have been treated in a single-payer, universal health care system. This database will provide an excellent resource that investigators can use to study variations in the delivery of care to and real-world outcomes of this population. The Ontario Rectal Cancer Cohort database will include comprehensive details about the management and outcomes of individuals with rectal cancer who have been diagnosed in Ontario, Canada (population: 14.6 million), between 2010 and 2019. Linked administrative data sets will be used to construct this comprehensive database. Individual and care provider characteristics, investigations, treatments, follow-ups, and outcomes will be derived and linked. Surgical pathology details, including the stage of disease, histopathology characteristics, and the quality of surgical excision, will be included. Ethics approval for this study was obtained through the Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board. Approximately 20,000 individuals who meet the inclusion criteria for this study have been identified. Data analysis is ongoing, with an expected completion date of March 2023. This study was funded through the Canadian Institute of Health Research Operating Grant. The Ontario Rectal Cancer Cohort will include a comprehensive data set of individuals with rectal cancer who received care within a single-payer, universal health care system. This cohort will be used to determine factors associated with regional variability and adherence to recommended care, and it will allow for an assessment of a number of understudied areas within the delivery of rectal cancer treatment. RR1-10.2196/38874.


Subconjunctival Delivery of Dorzolamide-Loaded Poly(ether-anhydride) Microparticles Produces Sustained Lowering of Intraocular Pressure in Rabbits.
Topical medications that inhibit the enzyme carbonic anhydrase (CAI) are widely used to lower intraocular pressure in glaucoma; however, their clinical efficacy is limited by the requirement for multiple-daily dosing, as well as side effects such as blurred vision and discomfort on drop instillation. We developed a biodegradable polymer microparticle formulation of the CAI dorzolamide that produces sustained lowering of intraocular pressure after subconjunctival injection. Dorzolamide was ion paired with sodium dodecyl sulfate (SDS) and sodium oleate (SO) with 0.8% and 1.5% drug loading in poly(lactic-co-glycolic acid) (PLGA), respectively. Encapsulating dorzolamide into poly(ethylene glycol)-co-poly(sebacic acid) (PEG3-PSA) microparticles in the presence of triethylamine (TEA) resulted in 14.9% drug loading and drug release that occurred over 12 days in vitro. Subconjunctival injection of dorzolamide-PEG3-PSA microparticles (DPP) in Dutch belted rabbits reduced IOP as much as 4.0 ± 1.5 mmHg compared to untreated fellow eyes for 35 days. IOP reduction after injection of DPP microparticles was significant when compared to baseline untreated IOPs (P < 0.001); however, injection of blank microparticles (PEG3-PSA) did not affect IOP (P = 0.9). Microparticle injection was associated with transient clinical vascularity and inflammatory cell infiltration in conjunctiva on histological examination. Fluorescently labeled PEG3-PSA microparticles were detected for at least 42 days after injection, indicating that in vivo particle degradation is several-fold longer than in vitro degradation. Subconjunctival DPP microparticle delivery is a promising new platform for sustained intraocular pressure lowering in glaucoma.


Novel roles of Caenorhabditis elegans heterochromatin protein HP1 and linker histone in the regulation of innate immune gene expression.
Linker histone (H1) and heterochromatin protein 1 (HP1) are essential components of heterochromatin which contribute to the transcriptional repression of genes. It has been shown that the methylation mark of vertebrate histone H1 is specifically recognized by the chromodomain of HP1. However, the exact biological role of linker histone binding to HP1 has not been determined. Here, we investigate the function of the Caenorhabditis elegans H1 variant HIS-24 and the HP1-like proteins HPL-1 and HPL-2 in the cooperative transcriptional regulation of immune-relevant genes. We provide the first evidence that HPL-1 interacts with HIS-24 monomethylated at lysine 14 (HIS-24K14me1) and associates in vivo with promoters of genes involved in antimicrobial response. We also report an increase in overall cellular levels and alterations in the distribution of HIS-24K14me1 after infection with pathogenic bacteria. HIS-24K14me1 localization changes from being mostly nuclear to both nuclear and cytoplasmic in the intestinal cells of infected animals. Our results highlight an antimicrobial role of HIS-24K14me1 and suggest a functional link between epigenetic regulation by an HP1/H1 complex and the innate immune system in C. elegans.


Cardiovascular event-free survival after adjuvant radiation therapy in breast cancer patients stratified by cardiovascular risk.
The objective of this study was to estimate the risk of a cardiovascular event or death associated with modern radiation in a population of elderly female breast cancer patients with varying baseline cardiovascular risk. The data used for this analysis are from the linked Surveillance, Epidemiology, and End-Results (SEER)-Medicare database. The retrospective cohort study included women aged 66 years and older with stage 0-III breast cancer diagnosed between 2000 and 2005. Women were grouped as low, intermediate, or high cardiovascular risk based on the presence of certain clinical diagnoses. The risk for the combined outcome of a hospitalization for a cardiovascular event or death within 6 months and 24 months of diagnosis was estimated using a multivariable Cox model. The median follow-up time was 24 months. Among the 91,612 women with American Joint Committee on Cancer (AJCC) stage 0-III breast cancer: 39,555 (43.2%) were treated with radiation therapy and 52,057 (56.8%) were not. The receipt of radiation therapy in the first 6 months was associated with a statistically significant increased risk for the combined outcome in women categorized as high risk (HR = 1.510; 95% CI, 1.396-1.634) or intermediate risk (HR = 1.415; 95% CI, 1.188-1.686) but not low risk (HR = 1.027; 95% CI, 0.798-1.321). Women with a prior medical history of cardiovascular disease treated with radiation therapy are at increased risk for an event and should be monitored for at least 6 months following treatment with radiation therapy.


Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau.
Formation of neurofibrillary tangles (NFTs) is a common neuropathological feature found in several neurodegenerative diseases, including Alzheimer's disease. We have developed a transgenic (Tg) mouse expressing mutant human tau (V337M), derived from frontotemporal dementia parkinsonism-17. V337M Tg mice revealed tau aggregations in the hippocampus, which fulfills the histological criteria for NFTs in human neurodegenerative diseases. Concurrent with the accumulation of RNA and phosphorylated tau, neurons exhibited morphological characteristics of degenerating neurons, which include a loss of microtubules, accumulation of ribosomes, plasma and nuclear membrane ruffling, and swelling of the Golgi network. Thus, mutant tau induces neuronal degeneration associated with the accumulation of RNA and phosphorylated tau. The functional consequences of this neuronal degeneration was evidenced by the reduction of hippocampal neural activity and behavioral abnormality in Tg mice.


Examination of cervical spine kinematics in complex, multiplanar motions after anterior cervical discectomy and fusion and total disc replacement.
The biomechanical behavior of total disc replacement (TDR) and anterior cervical discectomy and fusion (ACDF) incomplex multiplanar motion is incompletely understood. The purpose of this study was to determine whether ACDF or TDR significantly affects in vitro kinematics through a range of complex, multiplanar motions. Seven human cervical spines from C4-7 were used for this study. Intact cervical motion segments with and without implanted TDR and ACDF were tested by use of unconstrained pure bending moment testing fixtures in 7 mechanical modes: axial rotation (AR); flexion/extension (FE); lateral bending (LB); combined FE and LB; combined FE and AR; combined LB and AR; and combined FE, LB, and AR. Statistical testing was performed to determine whether differences existed in range of motion (ROM) and stiffness among spinal segments and treatment groups for each mechanical test mode. ACDF specimens showed increased stiffness compared with the intact and TDR specimens (P < .001); stiffness was not found to be different between TDR and intact specimens. ACDF specimens showed decreased ROM in all directions compared with TDR and intact specimens at the treated level. For the coupled motion test, including AR, LB, and FE, the cranial adjacent level (C4/C5) for the intact specimens (2.7°) showed significantly less motion compared with both the TDR (6.1°, P = .009) and ACDF (6.8°, P = .002) treatment groups about the LB axis. Testing of the C4/C5 and C6/C7 levels in all other test modes yielded no significant differences in ROM comparisons, although a trend toward increasing ROM in adjacent levels in ACDF specimens compared with intact and TDR specimens was observed. This study compared multiplanar motion under load-displacement testing of subaxial cervical motion segments with and without implanted TDR and ACDF. We found a trend toward increased motion in adjacent levels in ACDF specimens compared with TDR specimens. Biomechanical multiplanar motion testing will be useful in the ongoing development and evaluation of spinal motion-preserving implants.


No priming for global motion in crowding.
There is psychophysical evidence that low-level priming, e.g., from oriented gratings, as well as high-level semantic priming, survives crowding. We investigated priming for global translational motion in crowded and noncrowded conditions. The results indicated that reliable motion priming occurs in the noncrowded condition, but motion priming does not survive crowding. Crowding persisted despite variations in the direction of the flankers with respect to the prime's direction. Motion priming was still absent under crowding when 85% of the flankers moved in the same direction as the prime. Crowding also persisted despite variations in the speed of the flankers relative to the prime even when the flankers' speed was four times slower than the speed of the prime. However, a priming effect was evident when the prime's spatial location was precued and its distance to the flankers increased, suggesting a release from crowding. These results suggest that transient attention induced by precueing the spatial location of the prime may improve subjects' ability to discriminate its direction. Spatial cueing could act to decrease the integration field, thereby diminishing the influence of nearby distracters. In an additional experiment in which we used fewer flankers, we found a priming effect under conditions in which the interelement distance varied between flankers and prime. Overall, the results suggest that motion priming is strongly affected by crowding, but transient attention can partially retrieve such facilitation.


Observation of high-energy astrophysical neutrinos in three years of IceCube data.
A search for high-energy neutrinos interacting within the IceCube detector between 2010 and 2012 provided the first evidence for a high-energy neutrino flux of extraterrestrial origin. Results from an analysis using the same methods with a third year (2012-2013) of data from the complete IceCube detector are consistent with the previously reported astrophysical flux in the 100 TeV-PeV range at the level of 10(-8) GeV cm-2 s-1 sr-1 per flavor and reject a purely atmospheric explanation for the combined three-year data at 5.7σ. The data are consistent with expectations for equal fluxes of all three neutrino flavors and with isotropic arrival directions, suggesting either numerous or spatially extended sources. The three-year data set, with a live time of 988 days, contains a total of 37 neutrino candidate events with deposited energies ranging from 30 to 2000 TeV. The 2000-TeV event is the highest-energy neutrino interaction ever observed.


Degradation of interleukin 1beta by matrix metalloproteinases.
Matrix metalloproteinases (MMPs) and interleukin 1 (IL-1) are implicated in inflammation and tissue destruction, where IL-1 is a potent stimulator of connective tissue cells to produce the extracellular matrix-degrading MMPs. Here, we report that IL-1beta, but not IL-1alpha, is degraded by MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), and MMP-9 (gelatinase B). This degradation was effectively blocked by tissue inhibitor of metalloproteinases (TIMP)-1. When IL-1beta was treated with MMPs it lost the ability to enhance the synthesis of prostaglandin E2 and pro-MMP-3 in human fibroblasts. The primary cleavage site of IL-1beta by MMP-2 was identified at the Glu25-Leu26 bond. These results suggest that IL-1beta stimulates connective tissue cells to produce MMPs, but activated MMPs in turn negatively regulate the activity of IL-1beta.


The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation.
Meckel-Gruber syndrome (MKS) is an autosomal recessive lethal malformation syndrome characterized by renal cystic dysplasia, central nervous system malformations (typically, posterior occipital encephalocele), and hepatic developmental defects. Two MKS genes, MKS1 and MKS3, have been identified recently. The present study describes the cellular, sub-cellular and functional characterization of the novel proteins, MKS1 and meckelin, encoded by these genes. In situ hybridization studies for MKS3 in early human embryos showed transcript localizations in agreement with the tissue phenotype of MKS patients. Both MKS proteins predominantly localized to epithelial cells, including proximal renal tubules and biliary epithelial cells. MKS1 localized to basal bodies, while meckelin localized both to the primary cilium and to the plasma membrane in ciliated cell-lines and primary cells. Meckelin protein with the Q376P missense mutation was unable to localize at the cell membrane. siRNA-mediated reduction of Mks1 and Mks3 expression in a ciliated epithelial cell-line blocked centriole migration to the apical membrane and consequent formation of the primary cilium. Co-immunoprecipitation experiments show that wild-type meckelin and MKS1 interact and, in three-dimensional tissue culture assays, epithelial branching morphogenesis was severely impaired. These results suggest that MKS proteins mediate a fundamental developmental stage of ciliary formation and epithelial morphogenesis.


Compact Cr:ZnS channel waveguide laser operating at 2,333 nm.
A compact mid-infrared channel waveguide laser is demonstrated in Cr:ZnS with a view to power scaling chromium laser technology utilizing the thermo-mechanical advantages of Cr:ZnS over alternative transition metal doped II-VI semiconductor laser materials. The laser provided a maximum power of 101 mW of CW output at 2333 nm limited only by the available pump power. A maximum slope efficiency of 20% was demonstrated.


Identification of autoantibodies against TRPM1 in patients with paraneoplastic retinopathy associated with ON bipolar cell dysfunction.
Paraneoplastic retinopathy (PR), including cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), is a progressive retinal disease caused by antibodies generated against neoplasms not associated with the eye. While several autoantibodies against retinal antigens have been identified, there has been no known autoantibody reacting specifically against bipolar cell antigens in the sera of patients with PR. We previously reported that the transient receptor potential cation channel, subfamily M, member 1 (TRPM1) is specifically expressed in retinal ON bipolar cells and functions as a component of ON bipolar cell transduction channels. In addition, this and other groups have reported that human TRPM1 mutations are associated with the complete form of congenital stationary night blindness. The purpose of the current study is to investigate whether there are autoantibodies against TRPM1 in the sera of PR patients exhibiting ON bipolar cell dysfunction. We performed Western blot analysis to identify an autoantibody against TRPM1 in the serum of a patient with lung CAR. The electroretinograms of this patient showed a severely reduced ON response with normal OFF response, indicating that the defect is in the signal transmission between photoreceptors and ON bipolar cells. We also investigated the sera of 26 patients with MAR for autoantibodies against TRPM1 because MAR patients are known to exhibit retinal ON bipolar cell dysfunction. Two of the patients were found to have autoantibodies against TRPM1 in their sera. Our study reveals TRPM1 to be one of the autoantigens targeted by autoantibodies in at least some patients with CAR or MAR associated with retinal ON bipolar cell dysfunction.


Clinical Features and Outcomes of Fusobacterium Species Infections in a Ten-Year Follow-up.
Although uncommon, Fusobacterium infections have a wide clinical spectrum, ranging from local pharyngeal infections to septic shock. Our aim was to characterize and analyze the clinical features and outcomes in patients with Fusobacterium infections, and determine which variables were able to predict a poor outcome. We conducted a retrospective, hospital-based study using the computerized records of a second-level Spanish general hospital, serving a population of 155,000 inhabitants. The cohort was enrolled among patients cared for at the hospital between 2007 and 2016. Demographic, clinical data, microbiological characterization and outcomes at discharge, were analyzed. We collected data for all 26 patients over a 10-year period (annual incidence of 1.78 per 100,000), with an incidence of bacteremia of 0.53 cases per 100,000 population per year. F. nucleatum and F. necrophorum were the most frequent isolations (53.8% and 38.5%, respectively). F. necrophorum was found to be associated with a younger population. Although we found no deaths attributable to Fusobacterium, 15 patients (57%) were found to have severe infections due to this pathogen, and 7 patients (26.9%) were admitted to the Intensive Care Unit (ICU). The only identifiable risk factor for a severe infection (sepsis, septic shock or ICU admission) was the presence of bacteremia. Fusobacterium infections are uncommon. F. necrophorum tends to cause infection in younger individuals, while F. nucleatum has a preference for older patients. The clinical spectrum is wide, ranging from local, nonsevere infections, such as sinusitis or pharyngitis, to abscess formation and life-threatening infections.


Epidemiologic and clinical parameters of West Nile virus infections in humans: a scoping review.
Clinical syndromes associated with West Nile virus (WNV) infection range from fever to neuroinvasive disease. Understanding WNV epidemiology and disease history is important for guiding patient care and healthcare decision-making. The objective of this review was to characterize the existing body of peer-reviewed and surveillance literature on WNV syndromes and summarize epidemiologic and clinical parameters. We followed scoping review methodology described by the Joanna Briggs Institute. Terms related to WNV epidemiology, hospitalization, and surveillance were searched in four bibliographic databases (MEDLINE, EMBASE, Scopus, and CINAHL) for literature published from January 1999 to December 2015. In total, 2334 non-duplicated titles and abstracts were screened; 92 primary studies were included in the review. Publications included one randomized controlled trial and 91 observational studies. Sample sizes ranged from under 25 patients (n = 19) to over 400 patients (n = 28). Eight studies were from Canada, seven from Israel, and the remaining (n = 77) from the United States. N = 17 studies were classified as outbreak case investigations following epidemics; n = 37 with results of regional/national surveillance and monitoring programs. Mean patient ages were > 40 years old; three studies (3%) focused on the pediatric population. Patients with encephalitis fared worse than patients with meningitis and fever, considering hospitalization, length of stay, discharge, recovery, and case-fatality. Several studies examined risk factors; however, age was the only risk factor for neuroinvasive disease/death consistently identified. Overall, patients with acute flaccid paralysis or encephalitis fared worse than patients with meningitis and West Nile fever in terms of hospitalization and mortality. Among the included studies, proportion hospitalized, length of stay, proportion discharged home and case-fatality ranged considerably. Our review highlights the heterogeneity among reporting clinical WNV syndromes and epidemiologic parameters of WNV-related illness. Presently, there is potential for further synthesis of the risk factors of WNV-illness and mortality; undertaking further analysis through a systematic review and meta-analysis may benefit our understanding of risk factors for emerging mosquito-borne diseases. Future research on the burden of WNV can build on existing evidence summarized in this review, not only to support our understanding of endemic WNV, but also to strengthen research on emerging arboviruses with similar clinical manifestations.


Metabolic complications of in utero maternal HIV and antiretroviral exposure in HIV-exposed infants.
Despite a wide body of literature supporting the use of antenatal antiretrovirals (ARV) for the prevention of mother-to-child transmission, there remains a need for continued monitoring as the intrauterine interval is a critical period during which fetal programming influences the future health and development of the child. We conducted a systematic review of the current literature addressing potential metabolic complications of in utero HIV and ARV exposure. We describe studies evaluating metabolic outcomes such as intrauterine and early postnatal growth, bone health and mitochondrial toxicity. Overall, infants exposed to HIV/ARV do not appear to exhibit vastly compromised intrauterine or early postnatal growth. However, some studies on the effect of combination antiretroviral therapy on small for gestational age and low birth weight outcomes in low-middle income countries show a risk for small for gestational age/low birth weight while those in the United States do not. Postnatal growth to 1 year does not appear to be affected by intrauterine tenofovir exposure in African studies, but a US study found statistically significant differences in length for age z scores (LAZ) at 1 year. Little data exists on long-term bone health. Mitochondrial toxicity including abnormal mitochondrial morphology and DNA content, as well as neurologic deficits and death, have been demonstrated in HIV/ARV-exposed infants. Although gross measures of metabolic well-being appear to be reassuring, careful vigilance of even small risks for potential serious adverse effects to infants exposed to intrauterine HIV/ARVs is warranted as intrauterine fetal metabolic programming may substantially impact the future health of the child.


Physiological sharp wave-ripples and interictal events in vitro: what's the difference?
Sharp wave-ripples and interictal events are physiological and pathological forms of transient high activity in the hippocampus with similar features. Sharp wave-ripples have been shown to be essential in memory consolidation, whereas epileptiform (interictal) events are thought to be damaging. It is essential to grasp the difference between physiological sharp wave-ripples and pathological interictal events to understand the failure of control mechanisms in the latter case. We investigated the dynamics of activity generated intrinsically in the Cornu Ammonis region 3 of the mouse hippocampus in vitro, using four different types of intervention to induce epileptiform activity. As a result, sharp wave-ripples spontaneously occurring in Cornu Ammonis region 3 disappeared, and following an asynchronous transitory phase, activity reorganized into a new form of pathological synchrony. During epileptiform events, all neurons increased their firing rate compared to sharp wave-ripples. Different cell types showed complementary firing: parvalbumin-positive basket cells and some axo-axonic cells stopped firing as a result of a depolarization block at the climax of the events in high potassium, 4-aminopyridine and zero magnesium models, but not in the gabazine model. In contrast, pyramidal cells began firing maximally at this stage. To understand the underlying mechanism we measured changes of intrinsic neuronal and transmission parameters in the high potassium model. We found that the cellular excitability increased and excitatory transmission was enhanced, whereas inhibitory transmission was compromised. We observed a strong short-term depression in parvalbumin-positive basket cell to pyramidal cell transmission. Thus, the collapse of pyramidal cell perisomatic inhibition appears to be a crucial factor in the emergence of epileptiform events.


Protective role of zinc against the toxicity induced by exposure to cadmium during gestation and lactation on testis development.
To assess the effects of exposure to Cd and Zn on rat testicular development, offspring, from mothers receiving either tap water, Cd, Zn or Cd+Zn during gestation and lactation periods, were observed on gestational day (GD) 20 and on postnatal days (PND) 12, 21 and 35. During gestation, Cd induced maternal hypozincemia and less transfer of Zn to the fetus. During lactation, progressive Cd accumulation and Zn depletion in testis at PND12 and PND21 were noted. An increase of abnormal seminiferous tubules and a decrease in testis weight and plasmatic testosterone concentration were also observed at PND21 and PND35 respectively. Interestingly, Zn supply induced a significant protection against Cd toxicity. These results suggest that the toxic effects of Cd observed during development are mediated by the disruption of Zn metabolism, which is established in mothers during pregnancy causing Zn deficiency in fetuses and continues to become more pronounced during lactation.


Phylogenetic and morphological diversity of cyanobacteria in soil desert crusts from the Colorado plateau.
We compared the community structures of cyanobacteria in four biological desert crusts from Utah's Colorado Plateau developing on different substrata. We analyzed natural samples, cultures, and cyanobacterial filaments or colonies retrieved by micromanipulation from field samples using microscopy, denaturing gradient gel electrophoresis, and sequencing of 16S rRNA genes. While microscopic analyses apparently underestimated the biodiversity of thin filamentous cyanobacteria, molecular analyses failed to retrieve signals for otherwise conspicuous heterocystous cyanobacteria with thick sheaths. The diversity found in desert crusts was underrepresented in currently available nucleotide sequence databases, and several novel phylogenetic clusters could be identified. Morphotypes fitting the description of Microcoleus vaginatus Gomont, dominant in most samples, corresponded to a tight phylogenetic cluster of probable cosmopolitan distribution, which was well differentiated from other cyanobacteria traditionally classified within the same genus. A new, diverse phylogenetic cluster, named "Xeronema," grouped a series of thin filamentous Phormidium-like cyanobacteria. These were also ubiquitous in our samples and probably correspond to various botanical Phormidium and Schizothrix spp., but they are phylogenetically distant from thin filamentous cyanobacteria from other environments. Significant differences in community structure were found among soil types, indicating that soil characteristics may select for specific cyanobacteria. Gypsum crusts were most deviant from the rest, while sandy, silt, and shale crusts were relatively more similar among themselves.


Phonological and orthographic approaches to the treatment of word retrieval in aphasia.
We present a preliminary report on a study of the treatment of word finding difficulties in aphasia using phonological and orthographic cues. These techniques although often used to cue word finding in the immediate term have been little evaluated in terms of therapy designed to improve word retrieval in the long term. The first phase using cued word retrieval in a picture naming task was followed by a second phase designed to facilitate use of treated words in real-life contexts. The results from both phases were encouraging with improved word retrieval for three out of the four participants. The implications for clinical practice are discussed.


Cooperation across the histocompatibility barrier: H2d T cells primed to antigen in an H-2d environment can cooperate with H-2k B cells.
H-2d spleen cells derived from either tetraparental or semiallogeneic radiation bone marrow chimeras can be primed to antigen within H-2d recipients to generate helper T cells capable of cooperating in a secondary response with equal efficiency with H-2d or H-2k B cells. Thus it would seem that the cooperative act between T and B cells does not require that the T cell interacts with its target B cells by either cell interaction genes or via an altered self mechanism involving both antigen and the target B-cell I-region products. This does not preclude a requirement for associative recognition or altered self in the interaction of helper T cells with accessory cells.


Metabolism, bioaccumulation, and incorporation of diethanolamine into phospholipids.
Diethanolamine (DEA) is a major industrial chemical which has low acute toxicity, but, on repeat exposure, has significant cumulative toxicity. The present work suggests that the cumulative toxicity can be attributed to the fact that, unlike most small polar molecules, DEA accumulates to high concentrations in certain tissues following repeat exposure. The highest concentrations of DEA were seen in liver, kidney, spleen, and brain. Investigations described here have determined that DEA is metabolized by biosynthetic routes common to ethanolamine and is conserved, O-phosphorylated, N-methylated, and incorporated into phosphoglyceride and sphingomyelin analogues as the parent compound and as its N-methyl and N,N-dimethyl derivatives. This is the first report of the conjugation of a xenobiotic headgroup with a natural ceramide to form aberrant sphingomyelins. DEA-derived phosphoglycerides constituted the majority of aberrant phospholipid following acute administration. On repeat administration, DEA bioaccumulated to plateau levels at approximately 8 weeks. This bioaccumulation was accompanied by an increasing degree of methylation and accumulation of aberrant sphingomylenoid lipids in tissues. Uptake and incorporation of DEA into ceramide derivatives in human liver slices were also demonstrated in the present studies. It is speculated that the cumulative toxicity observed on repeat administration of DEA to rats is caused in part by increasing levels of aberrant phospholipids derived from this unnatural alkanolamine.


Partial Splenic Embolization Is a Safe and Effective Alternative in the Management of Portal Hypertension in Children.
There are multiple approaches to manage the clinical complications of portal hypertension (PHTN) to treat/prevent spontaneous hemorrhage by mitigating thrombocytopenia. No single approach is ideal for all patients given the heterogeneity of this population. Our goal was to determine whether partial splenic embolization (PSE) was safe and effective in the pediatric population. This is a retrospective review of our single-center experience for all patients ages 0 to 21 who underwent PSE between January 2010 and August 2017. The embolized splenic volume targeted was 60% to 70%. Twenty-six patients underwent PSE due to thrombocytopenia and/or recurrent variceal bleeding. Patients ranged in age from 18 months to 20 years (mean 13.1 years). The median platelet count before PSE was 53.0 (×10/L). The platelet count improved after PSE with values >100,000 in 21 patients (80.8%). Children with prior esophageal varices showed improvement after PSE with only 9 (34.6%) requiring further endoscopic therapy. After PSE, patients developed transient abdominal pain, distention, fever, and perisplenic fluid collections. Serious complications such as splenic abscess, splenic rupture, bleeding, pancreatic infarction, opportunistic infection, or death were not observed. One patient experienced thrombotic complications after PSE and was later diagnosed with myelodysplastic syndrome. PSE is a safe and effective alternative in the management of pediatric PHTN in select populations. PSE may be a favorable alternative to splenectomy and portal systemic shunting because it preserves functional spleen mass and avoids postprocedure accelerated liver disease or encephalopathy.


Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus.
Ceftaroline (PPI 0903, formerly TAK-599), the active metabolite of a N-phosphono prodrug, ceftaroline fosamil, has been approved by the US Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This antimicrobial agent binds to penicillin binding proteins (PBP) inhibiting cell wall synthesis and has a high affinity for PBP2a, which is associated with methicillin resistance. Ceftaroline is consistently active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus, including methicillin-resistant, vancomycin-intermediate, linezolid-resistant, and daptomycin-nonsusceptible strains. It possesses variable activity against Enterobacteriaceae and good activity against oral anaerobes. The drug is usually administrated intravenously at 600 mg every 12 h. Ceftaroline has low protein binding and is excreted by the kidneys and thus requires dose adjustments in individuals with renal failure. Clinical trials have demonstrated noninferiority when compared with vancomycin in the treatment of acute bacterial skin and skin structure infections and noninferiority when compared with ceftriaxone in the treatment of community-acquired bacterial pneumonia. Ceftaroline demonstrated a safety profile similar to that of comparator drugs in clinical trials.


Effects of wine on blood pressure, glucose parameters, and lipid profile in type 2 diabetes mellitus: A meta-analysis of randomized interventional trials (PRISMA Compliant).
Previous studies identified conflicting results about the effects of wine intake on glucose parameters and the risk of cardiovascular diseases in type 2 diabetes mellitus (T2DM). The present study further investigated the association between wine digestion and these outcomes in T2DM patients. A search of PubMed, Embase, and Scopus databases (up to November 2018) was performed for randomized interventional trials which evaluated the effect of wine on blood pressure (BP), glucose parameters and lipid profiles in T2DM people. We used a variety of tests: fixed and random effects models, Q Cochrane test and I index, Egger and Begg tests, forest plots, and sensitivity analysis in our study. A total of 9 randomized interventional studies were included in this meta-analysis. Overall, significant association between wine intake with diastolic BP (weighted mean difference [WMD] = 0.10; 95% confidence interval [95% CI]: -0.01 to 0.20, P = .03 I = 13%) and total cholesterol (TC) (WMD = 0.16, 95% CI: 0.02-0.31, P = .03, I = 6%), whereas no noticeable differences in glucose parameters, systolic BP, low-density lipoprotein cholesterol (LDLC), triglyceride (TG) and high-density lipoprotein cholesterol (HDLC) were identified between wine and controls groups (fasting glucose [FG],WMD = -0.00, 95% CI: -0.58 to 0.58; fasting insulin [FI], -0.22, -2.09 to 1.65; HbAc1%, -0.16, -0.40 to 0.07; systolic blood pressure, 0.12, -0.05 to 0.28; LDLC, -0.02, -0.25 to 0.21; TG, -0.34, -1.31 to 0.64; HDLC, 0.22, -0.08 to 0.53]. This meta-analysis revealed that moderate wine consumption among T2DM patients could reduce the level of diastolic blood pressure and TC, but not glucose parameters and other cardiovascular risk factors.


Light effects on mitochondrial photosensitizers in relation to retinal degeneration.
The retina captures and converts light between 400-760 nm into electrical signals that are sent to the brain by way of the optic nerve and in the process helps to translate these electrical signals into what is known as vision. The same light that allows vision to occur is nevertheless also potentially toxic to retinal cells in certain situations. The shorter wavelengths of light are known to interact with chromophores in photoreceptors and pigment epithelial cells to cause oxidative stress and severe damage. Indeed it is generally accepted that short wavelength light effects is one cause for loss of photoreceptor function in age-related macular degeneration. Recent studies have demonstrated that light may be a contributing factor for the death of retinal ganglion cells in certain situations. Light as impinging on the retina, especially the short wavelength form, affect mitochondrial chromophores and can result in neurone death. Importantly ganglion cell axons within the eye are laden with mitochondria and unlike the outer retina are not protected from short wavelength light by macular pigments. It has therefore been proposed that when ganglion cell function is already compromised, as in glaucoma, then light impinging on their mitochondria might be a contributor to their eventual demise.


Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer.
To evaluate the toxicity, efficacy, and pharmacokinetics of docetaxel when combined with oral estramustine and dexamethasone in a phase I study in patients with progressive metastatic androgen-independent prostate cancer. Thirty-four men were stratified into minimally pretreated (MPT) and extensively pretreated (EPT) groups. Estramustine 280 mg PO tid was administered 1 hour before or 2 hours after meals on days 1 through 5, with escalated doses of docetaxel from 40 to 80 mg/m2 on day 2. Treatment was repeated every 21 days. Thirty-four patients were assessable for toxicity and 33 for response. In the MPT patients, dose-limiting myelosuppression was reached at 80 mg/m2, with six patients experiencing grade 3/4 granulocytopenia. In EPT patients, escalation above 70 mg/m2 was not attempted. Fourteen MPT (70%) and six EPT (50%) patients had a > or = 50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. The overall 50% PSA response rate was 63% (95% confidence interval [CI], 28% to 81%). Of the 18 patients with bidimensionally measurable disease, five (28%; 95% CI, 11% to 54%) achieved a partial response. At the time of entry onto the study, 15 patients required narcotic analgesics for bone pain; after treatment, eight (53%) discontinued their pain medications. The area under the curve for docetaxel increased linearly from 40 to 70 mg/m2. At 80 mg/m2, the measured area under the curve was 8.37 (standard deviation, 0.724), which was significantly higher than the previously reported values. The recommended phase II dose of docetaxel combined with estramustine is 70 mg/m2 in MPT patients and 60 mg/m2 in EPT patients. This combination is active in men with androgen-independent prostate cancer.


Intimate Partner Violence Perpetration and Victimization Among Young Adult Sexual Minorities.
Intimate partner violence (IPV) among sexual minority young adults has been understudied, and victimization and perpetration estimates are needed. Data on 13,653 women and men aged 24-32 who participated in Wave 4 of the National Longitudinal Study of Adolescent to Adult Health were used to examine associations between sexual orientation and IPV perpetration and victimization in respondents' current or most recent relationship. Logistic regression analyses were used to identify associations between respondent characteristics and three IPV categories (physical violence, threatened violence and forced sex). Some 94% of males and 80% of females identified as 100% heterosexual; 4% of males and 16% of females as mostly heterosexual; 1% of males and 2% of females as bisexual; and 2% of males and females as either mostly homosexual or 100% homosexual. Compared with their heterosexual counterparts, mostly heterosexual women were more likely to report having perpetrated or been a victim of physical IPV (odds ratios, 1.9 and 1.6, respectively), having threatened violence (2.0) and having been a victim of threatened violence and forced sex (1.6 for each); mostly heterosexual males were more likely to have been a perpetrator or victim of physical IPV (3.1 and 1.8, respectively) and a perpetrator of forced sex and threatened violence (2.0 and 1.8, respectively). Bisexual males had elevated odds of physical violence victimization (3.3) and forced sex victimization (4.9) and perpetration (5.0). Some sexual minority groups are disproportionately affected by IPV, indicating a need for increased prevention efforts and for studies exploring the mechanisms underlying these differences.


Indoor Spatial Updating With Impaired Vision.
Spatial updating is the ability to keep track of position and orientation while moving through an environment. We asked how normally sighted and visually impaired subjects compare in spatial updating and in estimating room dimensions. Groups of 32 normally sighted, 16 low-vision, and 16 blind subjects estimated the dimensions of six rectangular rooms. Updating was assessed by guiding the subjects along three-segment paths in the rooms. At the end of each path, they estimated the distance and direction to the starting location, and to a designated target. Spatial updating was tested in five conditions ranging from free viewing to full auditory and visual deprivation. The normally sighted and low-vision groups did not differ in their accuracy for judging room dimensions. Correlations between estimated size and physical size were high. Accuracy of low-vision performance was not correlated with acuity, contrast sensitivity, or field status. Accuracy was lower for the blind subjects. The three groups were very similar in spatial-updating performance, and exhibited only weak dependence on the nature of the viewing conditions. People with a wide range of low-vision conditions are able to judge room dimensions as accurately as people with normal vision. Blind subjects have difficulty in judging the dimensions of quiet rooms, but some information is available from echolocation. Vision status has little impact on performance in simple spatial updating; proprioceptive and vestibular cues are sufficient.


Delayed radioprotection by NFkappaB-mediated induction of Sod2 (MnSOD) in SA-NH tumor cells after exposure to clinically used thiol-containing drugs.
The ability of thiol-containing reducing agents to activate transcription factors leading to changes in gene expression and enzyme activities provides an additional mechanism to potentially protect against radiation-induced cell killing. Manganese superoxide dismutase (Sod2) is one such gene whose expression levels have been shown to be elevated after exposure to the thiol compounds WR-1065 and N-acetyl-L-cysteine (NAC), resulting in an increase in radiation resistance. To further characterize this effect, SA-NH sarcoma cells, both wild-type and a clone stably transfected with a plasmid containing an IkappaBalpha gene mutated at serines 32 and 36, which prevents the inducible phosphorylation of these residues and the subsequent activation of NFkappaB (SA-NH+mIkappaBalpha1), were grown to confluence and then exposed to amifostine's free thiol WR-1065 at a concentration of 4 mM for 30 min. Effects of thiol exposure on NFKB activation in SA-NH+mIkappaBalpha1 cells were determined by a gel shift assay, and changes in Sod2 protein levels in these cells 24 h after exposure to 40 microM or 4 mM WR-1065 were measured by Western blot analysis and compared with wild-type cells exposed to the NFkappaB inhibitor BAY 11-7082. Changes in radiation response, measured immediately after thiol exposure or 24 h later, were determined using a colony-forming assay and were correlated with NFKB activation and Sod2 protein levels. The effects of captopril, mesna and NAC, each at a dose of 4 mM, on radiation response were also determined and contrasted with those of WR-1065. Only WR-1065 and captopril protected SA-NH cells when present during irradiation, i.e. 1.57 and 1.31 times increase in survival at 2 Gy, respectively. All four thiols were protective if irradiation with 2 Gy occurred 24 h later; i.e. increases in survival of 1.40, 1.22, 1.35, and 1.25 times were found for WR-1065, captopril, mesna and NAC, respectively. This delayed radioprotective effect correlated with elevated Sod2 protein levels in wild-type SA-NH tumor cells but was not observed in SA-NH+mIkappaBalpha1 cells, indicating that interference with thiol-induced NFKB activation abrogates this delayed radioprotective effect. Because the delayed radioprotective effect is readily demonstrable at a radiation dose of 2 Gy 24 h after exposure to clinically approved thiol-containing drugs such as amifostine, captopril, mesna and NAC, it suggests a new potential concern regarding the issue of tumor protection and the use of these agents in cancer therapy.


H3K36ac Is an Evolutionary Conserved Plant Histone Modification That Marks Active Genes.
In eukaryotic cells, histones are subject to a large number of posttranslational modifications whose sequential or combinatorial action affects chromatin structure and genome function. We identified acetylation at Lys-36 in histone H3 (H3K36ac) as a new chromatin modification in plants. The H3K36ac modification is evolutionary conserved in seed plants, including the gymnosperm Norway spruce (Picea abies) and the angiosperms rice (Oryza sativa), tobacco (Nicotiana tabacum), and Arabidopsis (Arabidopsis thaliana). In Arabidopsis, H3K36ac is highly enriched in euchromatin but not in heterochromatin. Genome-wide chromatin immunoprecipitation sequencing experiments revealed that H3K36ac peaks at the 5' end of genes, mainly on the two nucleosomes immediately distal to the transcription start site, independently of gene length. H3K36ac overlaps with H3K4me3 and the H2A.Z histone variant. The histone acetyl transferase GCN5 and the histone deacetylase HDA19 are required for H3K36ac homeostasis. H3K36ac and H3K36me3 show negative crosstalk, which is mediated by GCN5 and the histone methyl transferase SDG8. Although H3K36ac is associated with gene activity, we did not find a linear relationship between H3K36ac and transcript levels, suggesting that H3K36ac is a binary indicator of transcription.


The use of feed additives to reduce the effects of aflatoxin and deoxynivalenol on pig growth, organ health and immune status during chronic exposure.
Three feed additives were tested to improve the growth and health of pigs chronically challenged with aflatoxin (AF) and deoxynivalenol (DON). Gilts (n = 225, 8.8 ± 0.4 kg) were allotted to five treatments: CON (uncontaminated control); MT (contaminated with 150 µg/kg AF and 1100 µg/kg DON); A (MT + a clay additive); B (MT + a clay and dried yeast additive); and C (MT + a clay and yeast culture additive). Average daily gain (ADG) and feed intake (ADFI) were recorded for 42 days, blood collected for immune analysis and tissue samples to measure damage. Feeding mycotoxins tended to decrease ADG and altered the immune system through a tendency to increase monocytes and immunoglobulins. Mycotoxins caused tissue damage in the form of liver bile ductule hyperplasia and karyomegaly. The additives in diets A and B reduced mycotoxin effects on the immune system and the liver and showed some ability to improve growth. The diet C additive played a role in reducing liver damage. Collectively, we conclude that AF and DON can be harmful to the growth and health of pigs consuming mycotoxins chronically. The selected feed additives improved pig health and may play a role in pig growth.


Fundamentals of Health Economics.
Application of economics in the healthcare area is relatively new. Until recently, the public health scene has not understood the importance that the application of well-established economic concepts could have in this field. Fortunately, it is now well recognized that the introduction of economics in health (health economics) is of great importance. While other disciplines contribute to the understanding of factors that determine the health of an individual, health economics contributes to a better understanding of an individual's behavior that would ultimately have a strong influence on his health condition. A health economist explains individual behavior as a process in which an individual makes decisions by comparing current health condition, time and financial costs on one side and future health contributions such as a decrease of the probability of getting a disease or death, on the other side. Clarification of this issue, as well as numerous other issues concerning health economics applications are the central challenges for this field of research.


OA21 The power to choose: developing community capacity to provide palliative care in four first nations communities in canada.
First Nations people in Canada are ageing with a high burden of chronic, progressive, and life-limiting illness. The majority now die in urban hospitals or long term care homes far away from family and culture. Today, First Nations community leaders are working to build local community capacity to support people and their families who choose to die at home. This presentation describes a five year participatory action research project that has enhanced local palliative care capacity in four First Nations communities using innovative strategies for collaboration, education, and advocacy (www.eolfn.lakeheadu.ca). The process of community capacity development was locally driven and controlled. A local leader and advisory committee implemented a palliative care community assessment that identified resources and needs for community awareness, health provider education, service development and improved partnerships with external health care providers (physicians, hospitals etc) providing care to community members. Innovative strategies to address these needs were developed, implemented and evaluated. If services and community supports were available, 87% of the FN community participants would prefer to die at home. Each of the four participating FN communities developed a unique palliative care program model responsive to community culture and context. Culturally appropriate videos and print resources for education and community development were created to share internationally. First Nations communities have the desire and capacity to care for community members to the end of their lives. Community development and advocacy are required to support First Nations in addressing existing barriers and gaps in education, policy and service delivery.


The Polyphenol Altenusin Inhibits in Vitro Fibrillization of Tau and Reduces Induced Tau Pathology in Primary Neurons.
In Alzheimer's disease, the microtubule-associated protein tau forms intracellular neurofibrillary tangles (NFTs). A critical step in the formation of NFTs is the conversion of soluble tau into insoluble filaments. Accordingly, a current therapeutic strategy in clinical trials is aimed at preventing tau aggregation. Here, we assessed altenusin, a bioactive polyphenolic compound, for its potential to inhibit tau aggregation. Altenusin inhibits aggregation of tau protein into paired helical filaments in vitro. This was associated with stabilization of tau dimers and other oligomers into globular structures as revealed by atomic force microscopy. Moreover, altenusin reduced tau phosphorylation in cells expressing pathogenic tau, and prevented neuritic tau pathology induced by incubation of primary neurons with tau fibrils. However, treatment of tau transgenic mice did not improve neuropathology and functional deficits. Taken together, altenusin prevents tau fibrillization in vitro and induced tau pathology in neurons.


Rising standards for tuberculosis drug development.
Development of new drugs to treat tuberculosis (TB) faces even more constraints than the development of therapeutic agents for other diseases. This is due, in part, to intrinsic properties of the tubercle bacillus, such as its slow growth, phenotypic drug resistance during persistence and the need for compounds with a novel mode of action because of the increasing prevalence of primary resistance to the current TB drugs. Demographic changes to the population of TB patients are also a confounding factor; these now include co-infection with HIV, but other elements, such as the growing type-2 diabetes epidemic, should not be ignored. Consequently, a new TB drug will not only have to pass all the safety requirements associated with prolonged administration but also have to be compatible with antiretroviral therapy and, possibly, other medications. Here, we review the changing clinical landscape of TB and outline how this needs to be taken into consideration when defining the product profile for a new TB drug, before describing recent progress.


Efficient modularity optimization by multistep greedy algorithm and vertex mover refinement.
Identifying strongly connected substructures in large networks provides insight into their coarse-grained organization. Several approaches based on the optimization of a quality function, e.g., the modularity, have been proposed. We present here a multistep extension of the greedy algorithm (MSG) that allows the merging of more than one pair of communities at each iteration step. The essential idea is to prevent the premature condensation into few large communities. Upon convergence of the MSG a simple refinement procedure called "vertex mover" (VM) is used for reassigning vertices to neighboring communities to improve the final modularity value. With an appropriate choice of the step width, the combined MSG-VM algorithm is able to find solutions of higher modularity than those reported previously. The multistep extension does not alter the scaling of computational cost of the greedy algorithm.


Gallbladder Cancer Presenting with Jaundice: Uniformly Fatal or Still Potentially Curable?
Jaundice as a presenting symptom of gallbladder cancer has traditionally been considered to be a sign of advanced disease, inoperability, and poor outcome. However, recent studies have demonstrated that a small subset of these patients can undergo resection with curative intent. Patients with gallbladder cancer managed surgically from 2000 to 2014 in 10 US academic institutions were stratified based on the presence of jaundice at presentation (defined as bilirubin ≥4 mg/ml or requiring preoperative biliary drainage). Perioperative morbidity, mortality, and overall survival were compared between jaundiced and non-jaundiced patients. Of 400 gallbladder cancer patients with available preoperative data, 108 (27%) presented with jaundice while 292 (73%) did not. The fraction of patients who eventually underwent curative-intent resection was much lower in the presence of jaundice (n = 33, 30%) than not (n = 218, 75%; P < 0.001). Jaundiced patients experienced higher perioperative morbidity (69 vs. 38%; P = 0.002), including a much higher need for reoperation (12 vs. 1%; P = 0.003). However, 90-day mortality (6.5 vs. 3.6%; P = 0.35) was not significantly higher. Overall survival after resection was worse in jaundiced patients (median 14 vs. 32 months; P < 0.001). Further subgroup analysis within the jaundiced patients revealed a more favorable survival after resection in the presence of low CA19-9 < 50 (median 40 vs. 12 months; P = 0.003) and in the absence of lymphovascular invasion (40 vs. 14 months; P = 0.014). Jaundice is a powerful preoperative clinical sign of inoperability and poor outcome among gallbladder cancer patients. However, some of these patients may still achieve long-term survival after resection, especially when preoperative CA19-9 levels are low and no lymphovascular invasion is noted pathologically.


Effect of polytetrafluoroethylene (PTFE) phase transition at 19°C on the use of Spectralon as a reference standard for reflectance.
Sintered polytetrafluoroethylene (PTFE) is highly reflective and is widely used as a reference standard in remote sensing, radiometry, and spectroscopy. The relative change in output flux from a PTFE integrating sphere over the room temperature phase transition at 19°C has been measured at a monochromatic wavelength of 633 nm as 1.82±0.21%. The change in output flux was attributed to a small change of 0.09±0.02% in the total hemispherical reflectance of PTFE, caused by a change in its material density as a result of the phase transition. For the majority of users, this small change measured in total hemispherical reflectance is unlikely to impact significantly the accuracy of PTFE flat panel reflectors used as reference standards. However, owing to the multiple reflections that occur inside an integrating sphere cavity, the effect is multiplied and remedial action should be applied, either via a mathematical correction or through temperature stabilization of the integrating sphere when high accuracy (<5%) measurements of flux, irradiance, or radiance are required from PTFE-based integrating spheres at temperatures close to the phase transition at 19°C.


Effect of insulin dosage on glycemic response in dogs with diabetes mellitus: 221 cases (1993-1998).
To evaluate glycemic response to insulin treatment in dogs with diabetes mellitus. Retrospective study. 221 dogs with diabetes mellitus. Type and dosage of insulin used, minimum and maximum blood glucose concentrations, time of blood glucose concentration nadir, and optimal duration of action of insulin were determined on the basis of data obtained prior to initial examination at the teaching hospital (127 dogs), at the time of initial examination (212 dogs), at the time a second follow-up blood glucose curve was performed (59 dogs), and at the time of clinical control of diabetes mellitus (83 dogs). Prior to examination, 69 of 127 dogs (54%) received 1 s.c. insulin injection daily. Thirty-one dogs (24%) received a high dose of insulin (i.e., > 1.5 U/kg [0.7 U/lb] of body weight); 27 of these dogs (87%) received 1 injection/d. Eleven of 16 dogs (69%) that were hypoglycemic (blood glucose concentration < 80 mg/dl) also received 1 injection/d. However, optimal duration of action of insulin was > 12 hours in only 5 of 83 dogs (6%) evaluated at the time diabetes mellitus was clinically controlled. At that time, only 1 dog (1%) received a high dose of insulin, and the dog received 2 injections/d. Moreover, 8 of 10 dogs (80%) with hypoglycemia received 1 injection/d. Most dogs with diabetes mellitus are clinically regulated with 2 daily insulin injections. Administration of a high dose of insulin or development of hypoglycemia may be more common in diabetic dogs that receive insulin once daily, compared with dogs that receive insulin twice daily.


Light-directed, spatially addressable parallel chemical synthesis.
Solid-phase chemistry, photolabile protecting groups, and photolithography have been combined to achieve light-directed, spatially addressable parallel chemical synthesis to yield a highly diverse set of chemical products. Binary masking, one of many possible combinatorial synthesis strategies, yields 2n compounds in n chemical steps. An array of 1024 peptides was synthesized in ten steps, and its interaction with a monoclonal antibody was assayed by epifluorescence microscopy. High-density arrays formed by light-directed synthesis are potentially rich sources of chemical diversity for discovering new ligands that bind to biological receptors and for elucidating principles governing molecular interactions. The generality of this approach is illustrated by the light-directed synthesis of a dinucleotide. Spatially directed synthesis of complex compounds could also be used for microfabrication of devices.


Applying the InterVA-4 model to determine causes of death in rural Ethiopia.
In Ethiopia, most deaths take place at home and routine certification of cause of death by physicians is lacking. As a result, reliable cause of death (CoD) data are often not available. Recently, a computerized method for interpretation of verbal autopsy (VA) data, called InterVA, has been developed and used. It calculates the probability of a set of CoD given the presence of circumstances, signs, and symptoms reported during VA interviews. We applied the InterVA model to describe CoD in a rural population of Ethiopia. VA data for 436/599 (72.7%) deaths that occurred during 2010-2011 were included. InterVA-4 was used to interpret the VA data into probable cause of death. Cause-specific mortality fraction was used to describe frequency of occurrence of death from specific causes. InterVA-4 was able to give likely cause(s) of death for 401/436 of the cases (92.0%). Overall, 35.0% of the total deaths were attributed to communicable diseases, and 30.7% to chronic non-communicable diseases. Tuberculosis (12.5%) and acute respiratory tract infections (10.4%) were the most frequent causes followed by neoplasms (9.6%) and diseases of circulatory system (7.2%). InterVA-4 can produce plausible estimates of the major public health problems that can guide public health interventions. We encourage further validation studies, in local settings, so that InterVA can be integrated into national health surveys.


Poly-(ADP-Ribose) Polymerase-1 Promotes Prothrombin Gene Transcription and Produces Des-Gamma-Carboxy Prothrombin in Hepatocellular Carcinoma.
Although des-gamma-carboxy prothrombin (DCP) is a well-known tumor marker for hepatocellular carcinoma (HCC), the mechanism of DCP production is unclear. This study aimed to investigate the mechanism how DCP is produced in HCC cells. Levels of mRNA and DCP were analyzed by real-time polymerase chain reaction and electro-chemiluminescence immunoassay respectively. Secreted alkaline phosphatase (SEAP) expression vectors including deletion mutants of the prothrombin gene promoter were constructed for reporter gene assay. The transcription factors bound to DNA fragments were analyzed by mass spectrometry. An electrophoretic mobility shift assay (EMSA) was performed using a biotin end-labeled DNA. The prothrombin mRNA levels in all 5 DCP producing cell lines were appreciably high. However, those in 2 DCP non-producing cell lines were below detectable levels. A SEAP vector with -2985 to +27 showed a very high transcription activity in DCP-producing Huh-1 cells. However, transcription abruptly decreased when the vector with -2955 to +27 was transfected, and then remained at the similar levels with larger deletion mutants, indicating the existence of a cis-element at -2985 to -2955 (31-bp). Mass spectrometry analysis identified the protein that bound to the 31-bp DNA as poly-(ADP-ribose) polymerase-1 (PARP-1). Knockdown of the PARP-1 gene by small interfering RNA in Huh-1 cells induced marked inhibition of prothrombin gene transcription. The EMSA clearly showed that PARP-1 specifically binds to the 31-bp DNA fragment in the prothrombin gene promoter. Our data suggest that PARP-1 activates prothrombin gene transcription and that the excessive prothrombin gene transcription induces DCP production in DCP-producing HCC cells.


Genotypic response of detached leaves versus intact plants for chlorophyll fluorescence parameters under high temperature stress in wheat.
The genotypic response of wheat cultivars as affected by two methods of heat stress treatment (treatment of intact plants in growth chambers versus treatment of detached leaves in test tubes) in a temperature controlled water bath were compared to investigate how such different methods of heat treatment affect chlorophyll fluorescence parameters. A set of 41 spring wheat cultivars differing in their maximum photochemical efficiency of photosystem (PS) II (Fv/Fm) under heat stress conditions was used. These cultivars were previously evaluated based on the heat treatment of intact plants. The responses of the same cultivars to heat stress were compared between the two methods of heat treatment. The results showed that in detached leaves, all of the fluorescence parameters remained almost unaffected in control (20°C at all durations tested), indicating that the detachment itself did not affect the fluorescence parameters. In contrast, heat induced reduction in the maximum photochemical efficiency of PSII of detached leaves occurred within 2h at 40°C and within 30min at 45°C, and the response was more pronounced than when intact plants were heat stressed for three days at 40°C. The proportion of total variation that can be ascribed to the genetic differences among cultivars for a trait was estimated as genetic determination. During heat treatment, the genetic determination of most of the fluorescence parameters was lower in detached leaves than in intact plants. In addition, the correlation of the cultivar response in intact plants versus detached leaves was low (r=0.13 (with expt.1) and 0.02 with expt.2). The most important difference between the two methods was the pronounced difference in time scale of reaction, which may indicate the involvement of different physiological mechanisms in response to high temperatures. Further, the results suggest that genetic factors associated with cultivar differences are different for the two methods of heat treatment.


Surgery for ovarian cancer: rationale and guidelines.
Ovarian cancer is the second most common gynecologic cancer in women and the leading cause of death caused by gynecologic malignancy. Surgery plays a fundamental role in treating this challenging disease. Goals of primary surgery for ovarian cancer are to establish diagnosis, proper staging, determination of prognosis, and optimal cytoreduction of gross disease before chemotherapy for improved outcome. In addition to standard removal of the ovaries, uterus, omentum, and pelvic and para-aortic lymph nodes for early disease, extended surgical techniques used to debulk advanced disease include bowel resection, splenectomy, partial liver resection, peritoneal or diaphragmatic stripping, and use of laser or ultrasound (CUSA). Secondary surgery is used in a variety of situations. Second-look procedures were performed historically to determine response to chemotherapy to delineate duration of treatment, but now are best used in a research setting with the advent of improved chemotherapeutic agents. As a high percentage of patients have a gynecologic malignancy recurrence after primary treatment, many practitioners perform secondary cytoreductive procedures for recurrent disease. Additionally, in the recurrent setting, surgery may be necessary for relief of bowel obstruction and palliation of symptoms. Surgical management of ovarian cancer must be performed by surgeons, such as gynecologic oncologists, who have a firm understanding of the disease process, display good clinical judgment, and are adequately trained to perform the complex surgery that commonly is required for appropriate care.


The Developing Human Connectome Project: typical and disrupted perinatal functional connectivity.
The Developing Human Connectome Project is an Open Science project that provides the first large sample of neonatal functional MRI data with high temporal and spatial resolution. These data enable mapping of intrinsic functional connectivity between spatially distributed brain regions under normal and adverse perinatal circumstances, offering a framework to study the ontogeny of large-scale brain organization in humans. Here, we characterize in unprecedented detail the maturation and integrity of resting state networks (RSNs) at term-equivalent age in 337 infants (including 65 born preterm). First, we applied group independent component analysis to define 11 RSNs in term-born infants scanned at 43.5-44.5 weeks postmenstrual age (PMA). Adult-like topography was observed in RSNs encompassing primary sensorimotor, visual and auditory cortices. Among six higher-order, association RSNs, analogues of the adult networks for language and ocular control were identified, but a complete default mode network precursor was not. Next, we regressed the subject-level datasets from an independent cohort of infants scanned at 37-43.5 weeks PMA against the group-level RSNs to test for the effects of age, sex and preterm birth. Brain mapping in term-born infants revealed areas of positive association with age across four of six association RSNs, indicating active maturation in functional connectivity from 37 to 43.5 weeks PMA. Female infants showed increased connectivity in inferotemporal regions of the visual association network. Preterm birth was associated with striking impairments of functional connectivity across all RSNs in a dose-dependent manner; conversely, connectivity of the superior parietal lobules within the lateral motor network was abnormally increased in preterm infants, suggesting a possible mechanism for specific difficulties such as developmental coordination disorder, which occur frequently in preterm children. Overall, we found a robust, modular, symmetrical functional brain organization at normal term age. A complete set of adult-equivalent primary RSNs is already instated, alongside emerging connectivity in immature association RSNs, consistent with a primary-to-higher order ontogenetic sequence of brain development. The early developmental disruption imposed by preterm birth is associated with extensive alterations in functional connectivity.


Job strain as a risk factor for type 2 diabetes: a pooled analysis of 124,808 men and women.
The status of psychosocial stress at work as a risk factor for type 2 diabetes is unclear because existing evidence is based on small studies and is subject to confounding by lifestyle factors, such as obesity and physical inactivity. This collaborative study examined whether stress at work, defined as "job strain," is associated with incident type 2 diabetes independent of lifestyle factors. We extracted individual-level data for 124,808 diabetes-free adults from 13 European cohort studies participating in the IPD-Work Consortium. We measured job strain with baseline questionnaires. Incident type 2 diabetes at follow-up was ascertained using national health registers, clinical screening, and self-reports. We analyzed data for each study using Cox regression and pooled the study-specific estimates in fixed-effect meta-analyses. There were 3,703 cases of incident diabetes during a mean follow-up of 10.3 years. After adjustment for age, sex, and socioeconomic status (SES), the hazard ratio (HR) for job strain compared with no job strain was 1.15 (95% CI 1.06-1.25) with no difference between men and women (1.19 [1.06-1.34] and 1.13 [1.00-1.28], respectively). In stratified analyses, job strain was associated with an increased risk of diabetes among those with healthy and unhealthy lifestyle habits. In a multivariable model adjusted for age, sex, SES, and lifestyle habits, the HR was 1.11 (1.00-1.23). Findings from a large pan-European dataset suggest that job strain is a risk factor for type 2 diabetes in men and women independent of lifestyle factors.


Physicochemical and Antioxidant Properties of Honeys from the Sundarbans Mangrove Forest of Bangladesh.
This study evaluated the physicochemical, nutritional, antioxidant, and phenolic properties of ten honey samples from the Sundarbans mangrove forest, Bangladesh. The average pH, electrical conductivity, total dissolved solid, ash, moisture, hydroxymethyl furfural, titrable acidity, and absorbance were 4.3, 0.38 mS/cm, 187.5 ppm, 0.14%, 17.88%, 4.4 mg/kg, 37.7 meq/kg, and 483 mAU, respectively. In the honeys, the average contents of Ca, Cu, Fe, K, Mg, Mn, and Na were 95.5, 0.19, 6.4, 302, 39.9, 3.4, and 597 ppm, respectively, whereas Cd, Cr, Pb, and Ni were not found. The average contents of total sugar, protein, lipid, vitamin C, polyphenols, flavonoids, and anthocyanins in the honeys were 69.3%, 0.8%, 0.29%, 107.3 mg/kg, 757.2 mg gallic acid equivalent/kg, 43.1 mg chatechin equivalent/kg, and 5.4 mg/kg, respectively. The honeys had strong 1,1-diphenyl-2-picrylhydrazyl free radical scavenging activity, reducing power and total antioxidant capacity. High-performance liquid chromatography analysis of the honey fractions revealed the quantification of six polyphenols namely, (+)-catechin, (-)-epicatechin, p-caumeric acid, syringic acid, trans-cinnamic acid, and vanillic acid at 194.98, 330.34, 74.64, 218.97, 49.55, and 118.84 mg/kg, respectively. Therefore, the honeys in the Sundarbans are of excellent quality and a prospective source of polyphenols, and antioxidants.


Women's empowerment and health: the role of institutions of power in Pakistan.
Women's right to health has been reiterated many times. However, there are social and cultural barriers in developing countries that hinder their empowerment. Women's low status, deprivation of education and lack of control over their own lives and bodies have a negative impact on their health status and that of their families. This paper discusses women's empowerment and health within the framework of the 4 institutions of power in a society-family, community, health care systems and the state--with special reference to the situation in Pakistan. It concludes that to improve women's health status, concerted efforts are needed by all these institutions of power to work towards gender equality and the greater empowerment of women.


The effect of dendrimer generations on the structure of Q(G) LLC mesophase and drug release.
In this paper the cosolubilization of 2nd, 3rd, and 4th generations of polypropyleneimine (PPI: PPI-G2, -G3, and -G4) dendrimers with sodium diclofenac (Na-DFC) into reverse gyroid cubic (Q(G)) liquid crystals is reported. Structural properties and interactions of PPI dendrimers with and without the drug were studied using small-angle X-ray scattering, attenuated total reflected Fourier transform infrared (ATR-FTIR) spectroscopy, and differential scanning calorimetry (DSC) measurements. Incorporation of PPI-G2 (without Na-DFC) into Q(G) mesophase led to a decrease of 78Å in the lattice parameter. Solubilization of higher PPI generations, G3 and G4, led to increases in the lattice parameter to 57Å and 64Å, respectively. At 25wt%, each of the dendrimers caused a phase transition Q(G)→reverse hexagonal (HII). According to ATR-FTIR and DSC, the large lattice parameter values of G3 and G4 (relative to G2) embedment were assigned to their interactions with the carboxyl groups of GMO at the interface in comparison to the strong interaction of PPI-G2 with the water. Cosolubilization of Na-DFC with PPI-G2 revealed enlargement of the lattice parameter (of the new HII mesophase), while in the case of G3 and G4 systems no significant influence was seen with Na-DFC. The release of Na-DFC from Q(G) and HII systems was followed by UV-vis spectroscopy and revealed generation-dependence on drug release. As dendrimer generation increased, the cumulative drug release decreased.


Marked increase in cerebrospinal fluid glial fibrillar acidic protein in neuromyelitis optica: an astrocytic damage marker.
Neuromyelitis optica (NMO) is a neurological inflammatory disease associated with autoimmunity to aquaporin 4, predominantly localised in astrocytic foot processes. Recent studies have revealed that loss of aquaporin 4 and glial fibrillar acidic protein (GFAP) is a prominent feature of NMO lesions, suggesting astrocytic impairment. To reveal a useful clinical biomarker of NMO. Enzyme-linked immunosorbent assays were carried out for astrocytic markers GFAP and S100B in CSFs, obtained from the patients with NMO (n = 10) and multiple sclerosis (MS) (n = 10) manifesting acute myelitis, acute disseminated encephalomyelitis (ADEM) (n = 3), spinal infarction (n = 3), and other neurological diseases (OND) (n = 5). The CSF-GFAP levels during relapse in NMO (7666.0 (SD 15 266.5) ng/ml) were significantly over several thousand times higher than those in MS (0.7 (1.5)) or OND (0.6 (0.3)), and considerably higher than those in spinal infarction (354.7 (459.0)) and ADEM (0.4 (0.2)). They returned close to normal levels along with clinical improvement soon after corticosteroid therapy in NMO. There were strong correlations between the CSF-GFAP or S100B levels and expanded disability status scales or spinal lesion length in NMO (r>0.9). CSF-GFAP and S100B may be clinically useful biomarkers in NMO, and astrocytic damage is strongly suggested in the acute phase of NMO.


Risk for osteoporosis in black women.
Models of involutional bone loss and strategies for the prevention of osteoporosis have been developed for white women. Black women have higher bone densities than white women, but as the black population ages there will be an increasingly higher population of black women with osteoporosis. Strategies should be developed to reduce the risk of black women for fragility fractures. Dual energy X-ray absorptiometry measurements of the total body, femur, spine, and radius were performed on 503 healthy black and white women aged 20-80 years. Indices of bone turnover, the calcitrophic hormones, and radioisotope calcium absorption efficiency were also measured to compare the mechanisms of bone loss.The black women had higher BMD values at every site tested than the white women throughout the adult life cycle. Black women have a higher peak bone mass and a slightly slower rate of adult bone loss from the femur and spine, which are skeletal sites comprised predominantly of trabecular bone. Indices of bone turnover are lower in black women as are serum calcidiol levels and urinary calcium excretion. Serum calcitriol and parathyroid hormone levels are higher in black women and calcium absorption efficiency is the same in black and white women, but dietary calcium intake is lower in black women. Black and white women have a similar pattern of bone loss, with substantial bone loss from the femur and spine prior to menopause and an accelerated bone loss from the total skeleton and radius after menopause. The higher values for bone density in black women as compared with white women are caused by a higher peak bone mass and a slower rate of loss from skeletal sites comprised predominantly of trabecular bone. Low-risk strategies to enhance peak bone mass and to lower bone loss, such as calcium and vitamin D augmentation of the diet, should be examined for black women. The risk vs. benefits of hormonal replacement therapy should be determined, especially in older women.


How is the client-dietitian relationship embedded in the professional education of dietitians? An analysis of curriculum documentation and program coordinators' perspectives in Australia.
How dietitians are trained to develop relationships with clients is not clearly articulated despite its importance being well-documented. This study aimed to describe how this relationship is expressed and addressed in curriculum documents of Australian dietetics education programs, and to explore program coordinators' perspectives of this description and how relationship development is actually taught. Data extracted from subject outlines included subject descriptions, learning outcomes, assessments, readings and the mode of delivery (eg, lectures). Guided by a pre-existing coding framework, deductive thematic analysis was utilised to explore qualitative themes from subject outline data. Semi-structured telephone interviews were conducted with 10 program coordinators and analysed using inductive thematic analysis. Subject outlines for 122 subjects across all 21 accredited Australian programs were analysed. The over-arching theme was the wide "variability" in the ways that the client-dietitian relationship was expressed across subject outlines. Program coordinators perceived that findings from the analysis of subject outlines made sense, however, acknowledged limitations of analysing data from curriculum documents. The relationship appeared ambiguously defined amongst programs and was described as occurring mostly in communication, counselling and medical nutrition therapy subjects and through theoretical and practical learning. The client-dietitian relationship appears inconsistently embedded in the curriculum of Australian dietetics education programs despite widespread acceptance of its importance to practice. Further research is needed to investigate if training programs should embed more consistent language around therapeutic relationships, and how this might be achieved to reflect current competency standards.


17β-trenbolone, an anabolic-androgenic steroid as well as an environmental hormone, contributes to neurodegeneration.
Both genetic and environmental factors contribute to neurodegenerative disorders. In a large number of neurodegenerative diseases (for example, Alzheimer's disease (AD)), patients do not carry the mutant genes. Other risk factors, for example the environmental factors, should be evaluated. 17β-trenbolone is a kind of environmental hormone as well as an anabolic-androgenic steroid. 17β-trenbolone is used as a growth promoter for livestock in the USA. Also, a large portion of recreational exercisers inject 17β-trenbolone in large doses and for very long time to increase muscle and strength. 17β-trenbolone is stable in the environment after being excreted. In the present study, 17β-trenbolone was administered to adult and pregnant rats and the primary hippocampal neurons. 17β-trenbolone's distribution and its effects on serum hormone levels and Aβ42 accumulation in vivo and its effects on AD related parameters in vitro were assessed. 17β-trenbolone accumulated in adult rat brain, especially in the hippocampus, and in the fetus brain. It altered Aβ42 accumulation. 17β-trenbolone induced apoptosis of primary hippocampal neurons in vitro and resisted neuroprotective function of testosterone. Presenilin-1 protein expression was down-regulated while β-amyloid peptide 42 (Aβ42) production and caspase-3 activities were increased. Both androgen and estrogen receptors mediated the processes. 17β-trenbolone played critical roles in neurodegeneration. Exercisers who inject large doses of trenbolone and common people who are exposed to 17β-trenbolone by various ways are all influenced chronically and continually. Identification of such environmental risk factors will help us take early prevention measure to slow down the onset of neurodegenerative disorders.


Is Drinking Contagious? An Analysis of the Collectivity of Drinking Behavior Theory Within a Multilevel Framework.
To analyze the effect of behavioral contagion regarding problematic adolescent alcohol use among countries with varying prevalence of problematic drinking. Nested data from 48,215 12 to 16-year olds from seventh to ninth grade of 25 European countries (48.5% male, M = 13.83 years) were studied using hierarchical general linear modeling sequences. Finally, an intercept-as-outcome model was built to test the main hypothesis. Multilevel analyses validated the significant effects of the individual risk factors of being older (OR = 2.02), being male (OR = 1.41) and being native born (OR = 1.32) on becoming a problematic alcohol user. Regarding the aggregated country-level predictor 'proportion of problematic alcohol users', the effect of behavioral contagion was also confirmed (OR = 1.05). The contagion effect regarding alcohol use behavior calls for a focus on environmental prevention efforts. By decreasing the public acceptance of (adolescent) alcohol use, the average proportion of problematic adolescent alcohol users in European countries may be reduced.


Fecal and rectal mucosal diacylglycerol concentrations and epithelial proliferative kinetics.
Fecal diacylglycerol (DAG) concentrations have been suggested as biomarkers for colonic neoplasia because of their potential to be absorbed in the colon and to stimulate epithelial cell proliferation. The interrelationships among nutrient intake, fecal and mucosal DAG, and colonic proliferative markers have not previously been studied. We designed a pilot study to evaluate the feasibility of evaluating these interrelationships in 12 volunteers who had a history of colonic adenomatous polyposis. Total mucosal DAG concentrations were not related to fecal DAG concentrations, but mucosal DAG correlated inversely with the whole crypt labeling index. Dietary intake did not alter fecal DAG concentrations. However, the percentage of calories from dietary fat correlated positively with the whole crypt labeling index. Fiber and calcium intake showed a positive correlation with the labeling index in the upper 40% of the crypt. The present pilot study failed to demonstrate a correlation between dietary components and fecal and total mucosal DAG. Additional studies relating fecal DAG with mucosal proliferation will require the evaluation of DAG concentrations in subcellular compartments of mucosal cells and/or measurement of fecal DAG fatty acid composition.