Effect of cotrimoxazole on causes of death, hospital admissions and antibiotic use in HIV-infected children.
Cotrimoxazole prophylaxis reduces morbidity and mortality in HIV-1-infected children, but mechanisms for these benefits are unclear. CHAP was a randomized trial comparing cotrimoxazole prophylaxis with placebo in HIV-infected children in Zambia where background bacterial resistance to cotrimoxazole is high. We compared causes of mortality and hospital admissions, and antibiotic use between randomized groups. Of 534 children (median age, 4.4 years; 32% 1-2 years), 186 died and 166 had one or more hospital admissions not ending in death. Cotrimoxazole prophylaxis was associated with lower mortality, both outside hospital (P = 0.01) and following hospital admission (P = 0.005). The largest excess of hospital deaths in the placebo group was from respiratory infections [22/56 (39%) placebo versus 10/35 (29%) cotrimoxazole]. By 2 years, the cumulative probability of dying in hospital from a serious bacterial infection (predominantly pneumonia) was 7% on cotrimoxazole and 12% on placebo (P = 0.08). There was a trend towards lower admission rates for serious bacterial infections in the cotrimoxazole group (19.1 per 100 child-years at risk versus 28.5 in the placebo group, P = 0.09). Despite less total follow-up due to higher mortality, more antibiotics (particularly penicillin) were prescribed in the placebo group in year one [6083 compared to 4972 days in the cotrimoxazole group (P = 0.05)]. Cotrimoxazole prophylaxis appears to mainly reduce death and hospital admissions from respiratory infections, supported further by lower rates of antibiotic prescribing. As such infections occur at high CD4 cell counts and are common in Africa, the role of continuing cotrimoxazole prophylaxis after starting antiretroviral therapy requires investigation.


Strain-induced violation of temperature uniformity in mesoscale liquids.
Thermo-elasticity couples the deformation of an elastic (solid) body to its temperature and vice-versa. It is a solid-like property. Highlighting such property in liquids is a paradigm shift: it requires long-range collective interactions that are not considered in current liquid descriptions. The present microthermal studies provide evidence for such solid-like correlations. It is shown that ordinary liquids emit a modulated thermal signal when applying a low frequency (Hz) mechanical shear stress. The liquid splits in several tenths microns wide hot and cold thermal bands, all varying synchronously and separately with the applied stress wave reaching a sizable amplitude of ± 0.2 °C. Thermomechanical coupling challenges fluid dynamics: it reveals that the liquid does not dissipate the energy of shear waves at low frequency, but converts it in non-uniform thermodynamic states. The dynamic thermal changes work in an adiabatic way supporting the hypothesis of the excitation of macroscopic elastic correlations whose range is limited to several tens of microns, in accordance with recent non-extensive theoretical models. The proof of thermomechanical coupling opens the way to a new generation of energy-efficient temperature converters.


Light-induced translocation of RGS9-1 and Gβ5L in mouse rod photoreceptors.
The transducin GTPase-accelerating protein complex, which determines the photoresponse duration of photoreceptors, is composed of RGS9-1, Gβ5L and R9AP. Here we report that RGS9-1 and Gβ5L change their distribution in rods during light/dark adaptation. Upon prolonged dark adaptation, RGS9-1 and Gβ5L are primarily located in rod inner segments. But very dim-light exposure quickly translocates them to the outer segments. In contrast, their anchor protein R9AP remains in the outer segment at all times. In the dark, Gβ5L's interaction with R9AP decreases significantly and RGS9-1 is phosphorylated at S(475) to a significant degree. Dim light exposure leads to quick de-phosphorylation of RGS9-1. Furthermore, after prolonged dark adaptation, RGS9-1 and transducin Gα are located in different cellular compartments. These results suggest a previously unappreciated mechanism by which prolonged dark adaptation leads to increased light sensitivity in rods by dissociating RGS9-1 from R9AP and redistributing it to rod inner segments.


Isolated Systolic Hypertension and its Determinants - A Cross-sectional Study in the Adult Population of Lucknow District in North India.
1) To determine the prevalence of isolated systolic hypertension (ISH) in the adult population of Lucknow district. 2) To study the determinants of ISH especially the relationship with age. A community-based cross-sectional study was conducted in four randomly selected areas of Lucknow district. A total of 800 subjects, aged 20 years and above, 400 from urban and 400 from rural area of Lucknow district were included in the study. The statistical tools used for analysis were Pearson's Chi-square test and multiple logistic regression. The prevalence of ISH according to JNC-7 criteria was 4.3%, which was 5.1% in men and 3.6% in women. A significant increase in the prevalence of ISH was seen with an increase in age. Multivariate logistic regression analysis of the determinants showed that age, BMI and smoking were significant independent risk factors of ISH. Given the risk of cardiovascular disease associated with ISH, the findings of this study emphasize the need for further research to document the impact of modifiable risk factors of ISH and the effect of hypertension screening and specific health promotion in bringing down the burden of ISH and related cardiovascular morbidity.


Disposition of 14C-mescaline by rabbit lung.
Metabolism of mescaline by several rabbit tissues was examined in vitro. Mescaline-oxidizing activity (micromoles per milligram of protein/15 min) of lung homogenates was 4 times greater than that of either liver or kidney. Brain and plasma each had comparatively little capacity to metabolize mescaline. Mescaline metabolism in vitro was sensitive to inhibition by semicarbazide. Removal of mescaline from the medium perfusing the isolated rabbit lung was explained by intrapulmonary metabolism. Semicarbazide (10(-3) M pargyline. Semicarbazide-treated lungs accumulated more mescaline than did untreated lungs. Mescaline efflux from lung was slower than that of its metabolite. These results indicate that the intact lung removes perfused mescaline and may be important in the disposition of circulating mescaline in vivo.


Electrospray soft-landing for the construction of non-covalent molecular nanostructures using charged droplets under ambient conditions.
An electrospray soft-landing (SL) technique was utilized to create 2D nano-networks on HOPG under ambient conditions. A 2,3,6,7,10,11-hexahydroxy-triphenylene close-packing structure was observed by STM instead of unorganized clusters, as well as amine and acid nanostructures. On C18H37NH2 networks, C18H37NH3+ was identified by XPS analysis revealing retaining of charges on the SL-modified surface.


Blood oxidative stress and post-exercise recovery are unaffected byhypobaric and hypoxic environments.
Hypobaria and hypoxia exert independent effects on oxidative stress during exercise, while combined effectson the post-exercise recovery period remain unclear.Accordingly, this study examined the recovery period during lab-simulated hypoxic and hypobaric conditions following exercise-induced oxidative stress. Participants (n=13) performed 60-minutes of cycling (70% watts max) in a normobaric normoxic environment followed by a four-hour recovery under three conditions; 1000m normobaric normoxia (NN, 675mmHg), 4400m normobaric hypoxia (NH, 675mmHg), or 4400m hypobaric hypoxia (HH, 440mmHg). Blood samples collected at Pre, Post, 2-Hours (2-HR), and 4-Hours (4-HR) post-exercise were analyzed fora potential increase in biochemical modifications of proteins(protein carbonyls, PC; 3-nitrotyrosines, 3NT) lipids (lipid hydroperoxides, LOOH; 8-isoprostanes, 8-ISO), and antioxidant capacity (FRAP, TEAC). Gene transcripts (EPAS, HMOX1, SOD2, NFE2L2) were quantified by qRT-PCR from muscle biopsies taken Pre and Post exercise. Hypoxia and hypobaria had no effect throughout recovery. Post-exercise TEAC (p=0.041), FRAP (p=0.013), and 8-ISO (p=0.044) increased, while PC (p=0.002) and 3-NT (p=0.032) were decreased. LOOH was lower in Post (p=0.018) NH trial samples. Exercise-dependent increases occurred in NFE2L2 (p=0.003), HMXO1 (p<0.001), SOD2 (p=0.046), and EPAS (p=0.038). Exercise recovery under conditions of NH and HH did not impact blood oxidative stress or redox-sensitive gene transcripts.


Emergency department patient compliance with follow-up for outpatient exercise stress testing: a randomized controlled trial.
Numerous patients are assessed in the emergency department (ED) for chest pain suggestive of acute coronary syndrome (ACS) and subsequently discharged if found to be at low risk. Exercise stress testing is frequently advised as a follow-up investigation for low-risk patients; however, compliance with such recommendations is poorly understood. We sought to determine if compliance with follow-up for exercise stress testing is higher in patients for whom the investigation is ordered at the time of ED discharge, compared with patients who are advised to arrange testing through their family physician (FP). Low-risk chest pain patients being discharged from the ED for outpatient exercise stress test and FP follow-up were randomized into 2 groups. ED staff ordered an exercise stress test for the intervention group, and the control group was advised to contact their FP to arrange testing. The primary outcome was completion of an exercise stress test at 30 days, confirmed through both patient contact and stress test results. Patients were unaware that our primary interest was their compliance with the exercise stress testing recommendations. Two-hundred and thirty-one patients were enrolled and baseline characteristics were similar between the 2 groups. Completion of an exercise stress test at 30 days occurred in 87 out of 120 (72.5%) patients in the intervention group and 60 out of 107 (56.1%) patients in the control group. The difference in compliance rates (16.4%) between the 2 groups was statistically significant (Chi(2) = 6.69, p < 0.001) with a relative risk of 1.29 (95% confidence interval 1.18-1.40), and the results remained significant after a "worst case" sensitivity analysis involving 4 control group cases lost to follow-up. When subjects were contacted by telephone 30 days after the ED visit, 60% of those who were noncompliant patients felt they did not have a heart problem and that further testing was unnecessary. When ED staff order an outpatient exercise stress test following investigation for potential ACS, patients are more likely to complete the test if it is booked for them before ED discharge. After discharge, many low-risk chest pain patients feel they are not at risk and do not return to their FP for further testing in a timely manner as advised. Changing to a strategy of ED booking of exercise stress testing may help earlier identification of patients with coronary heart disease.


Impact of early treatment programs on HIV epidemics: An immunity-based mathematical model.
While studies on pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) have demonstrated substantial advantages in controlling HIV transmission, the overall benefits of the programs with early initiation of antiretroviral therapy (ART) have not been fully understood and are still on debate. Here, we develop an immunity-based (CD4+ T cell count based) mathematical model to study the impacts of early treatment programs on HIV epidemics and the overall community-level immunity. The model is parametrized using the HIV prevalence data from South Africa and fully analyzed for stability of equilibria and infection persistence criteria. Using our model, we evaluate the effects of early treatment on the new infection transmission, disease death, basic reproduction number, HIV prevalence, and the community-level immunity. Our model predicts that the programs with early treatments significantly reduce the new infection transmission and increase the community-level immunity, but the treatments alone may not be enough to eliminate HIV epidemics. These findings, including the community-level immunity, might provide helpful information for proper implementation of HIV treatment programs.


Correlation and studies of habitat selection: problem, red herring or opportunity?
With the advent of new technologies, animal locations are being collected at ever finer spatio-temporal scales. We review analytical methods for dealing with correlated data in the context of resource selection, including post hoc variance inflation techniques, 'two-stage' approaches based on models fit to each individual, generalized estimating equations and hierarchical mixed-effects models. These methods are applicable to a wide range of correlated data problems, but can be difficult to apply and remain especially challenging for use-availability sampling designs because the correlation structure for combinations of used and available points are not likely to follow common parametric forms. We also review emerging approaches to studying habitat selection that use fine-scale temporal data to arrive at biologically based definitions of available habitat, while naturally accounting for autocorrelation by modelling animal movement between telemetry locations. Sophisticated analyses that explicitly model correlation rather than consider it a nuisance, like mixed effects and state-space models, offer potentially novel insights into the process of resource selection, but additional work is needed to make them more generally applicable to large datasets based on the use-availability designs. Until then, variance inflation techniques and two-stage approaches should offer pragmatic and flexible approaches to modelling correlated data.


Proteomic analysis reveals CCT is a target of Fragile X mental retardation protein regulation in Drosophila.
Fragile X mental retardation protein (FMRP) is an RNA-binding protein that is required for the translational regulation of specific target mRNAs. Loss of FMRP causes Fragile X syndrome (FXS), the most common form of inherited mental retardation in humans. Understanding the basis for FXS has been limited because few in vivo targets of FMRP have been identified and mechanisms for how FMRP regulates physiological targets are unclear. We have previously demonstrated that Drosophila FMRP (dFMRP) is required in early embryos for cleavage furrow formation. In an effort to identify new targets of dFMRP-dependent regulation and new effectors of cleavage furrow formation, we used two-dimensional difference gel electrophoresis and mass spectrometry to identify proteins that are misexpressed in dfmr1 mutant embryos. Of the 28 proteins identified, we have identified three subunits of the Chaperonin containing TCP-1 (CCT) complex as new direct targets of dFMRP-dependent regulation. Furthermore, we found that the septin Peanut, a known effector of cleavage, is a likely conserved substrate of fly CCT and is mislocalized in both cct and in dfmr1 mutant embryos. Based on these results we propose that dFMRP-dependent regulation of CCT subunits is required for cleavage furrow formation and that at least one of its substrates is affected in dfmr1- embryos suggesting that dFMRP-dependent regulation of CCT contributes to the cleavage furrow formation phenotype.


PAR-TERRA is the main contributor to telomeric repeat-containing RNA transcripts in normal and cancer mouse cells.
Telomeric repeat-containing RNA (TERRA) molecules play important roles at telomeres, from heterochromatin regulation to telomerase activity control. In human cells, TERRA is transcribed from subtelomeric promoters located on most chromosome ends and associates with telomeres. The origin of mouse TERRA molecules is, however, unclear, as transcription from the pseudoautosomal PAR locus was recently suggested to account for the vast majority of TERRA in embryonic stem cells (ESC). Here, we confirm the production of TERRA from both the chromosome 18q telomere and the PAR locus in mouse embryonic fibroblasts, ESC, and various mouse cancer and immortalized cell lines, and we identify two novel sources of TERRA on mouse chromosome 2 and X. Using various approaches, we show that PAR-TERRA molecules account for the majority of TERRA transcripts, displaying an increase of two to four orders of magnitude compared to the telomeric 18q transcript. Finally, we present a SILAC-based pull-down screen revealing a large overlap between TERRA-interacting proteins in human and mouse cells, including PRC2 complex subunits, chromatin remodeling factors, DNA replication proteins, Aurora kinases, shelterin complex subunits, Bloom helicase, Coilin, and paraspeckle proteins. Hence, despite originating from distinct genomic regions, mouse and human TERRA are likely to play similar functions in cells.


RNA-RNA Interactomes of ProQ and Hfq Reveal Overlapping and Competing Roles.
Base pairing RNAs modulate gene expression in all studied organisms. In many bacteria, the base pairing between most small regulatory RNAs (sRNAs) and their targets is mediated by the Hfq RNA chaperone. However, recent studies have shown FinO-domain proteins also bind sRNAs. To examine the global contribution of the FinO-domain ProQ protein in Escherichia coli, we carried out RIL-seq to identify RNA pairs bound to this protein. The RNA-RNA interactome for ProQ contains hundreds of pairs. Intriguingly, a significant fraction of the ProQ-bound RNA pairs are also found associated with Hfq, indicating overlapping, complementary, or competing roles for the two proteins. Characterization of one novel RNA pair bound by both chaperones revealed that while Hfq is required for RNA sponge-mediated downregulation of the sRNA, ProQ can inhibit this regulation. Overall, our results uncover increased complexity in RNA regulatory networks involving RNA chaperone proteins, RNases, sRNAs, and mRNAs.


Normal or High Polyphenol Concentration in Orange Juice Affects Antioxidant Activity, Blood Pressure, and Body Weight in Obese or Overweight Adults.
The consumption of orange juice may lead to reduced oxidative stress and may enhance the antioxidant defense system. The aim was to evaluate the effects of the intake of orange juice containing either normal (NPJ) or high (HPJ) concentrations of polyphenols (299 and 745 mg/d, respectively) on the antioxidant defense system, oxidative stress biomarkers, and clinical signs of metabolic syndrome in 100 nonsmoking subjects who were either overweight or obese. A randomized, double-blind crossover study was conducted over two 12-wk periods with a 7-wk washout period. The effects on enzymatic and nonenzymatic blood antioxidant defense systems, urinary and plasma oxidative stress biomarkers, and clinical signs of metabolic syndrome were evaluated before and after an intervention with both of the orange juices. Paired t tests and linear mixed-effects models were used to evaluate the effects of juice, time, and interactions. The intake of either NPJ or HPJ led to a decrease in urinary 8-hydroxy-2'-deoxyguanosine (NPJ: 935 ± 134 to 298 ± 19 ng/mg creatinine; HPJ: 749 ± 84 to 285 ± 17 ng/mg creatinine), 8-iso-prostaglandin F2α (NPJ: 437 ± 68 to 156 ± 14 ng/mg creatinine; HPJ: 347 ± 43 to 154 ± 13 ng/mg creatinine), erythrocyte catalase, and glutathione reductase activities. A decrease was also observed in body mass index, waist circumference, and leptin (all P < 0.05). The NPJ intervention decreased systolic and diastolic blood pressures (systolic blood pressure: 128 ± 1 to 124 ± 2 mm Hg; diastolic blood pressure: 79 ± 1 to 76 ± 1 mm Hg), whereas the HPJ intervention increased erythrocyte superoxide dismutase (SOD) activity (17.7 ± 1.5 to 23.1 ± 1.7 U/mg hemoglobin). Our results show that the consumption of either NPJ or HPJ protected against DNA damage and lipid peroxidation, modified several antioxidant enzymes, and reduced body weight in overweight or obese nonsmoking adults. Only blood pressure and SOD activity were influenced differently by the different flavanone supplementations. This trial was registered at clinicaltrials.gov as NCT01290250.


Financial Costs and Burden Related to Decisions for Breast Cancer Surgery.
Financial toxicity is a well-recognized adverse effect of cancer care, yet little is known about how women consider treatment costs when facing preference-sensitive decisions for breast cancer surgery or how surgical treatment choice affects financial harm. We sought to determine how financial costs and burden relate to decisions for breast cancer surgery. Women (≥ 18 years old) with a history of breast cancer were recruited from the Army of Women and Sisters Network to complete an 88-item electronic survey. Descriptive statistics and regression analysis were used to evaluate the impact of costs on surgical decisions and financial harm after breast cancer surgery. A total of 607 women with stage 0 to III breast cancer were included. Most were white (90%), were insured privately (70%) or by Medicare (25%), were college educated (78%), and reported household incomes of more than $74,000 (56%). Forty-three percent underwent breast-conserving surgery, 25% underwent mastectomy, 32% underwent bilateral mastectomy, and 36% underwent breast reconstruction. Twenty-eight percent reported that costs of treatment influenced their surgical decisions, and at incomes of $45,000 per year, costs were prioritized over breast preservation or appearance. Overall, 35% reported financial burden as a result of their cancer treatment, and 78% never discussed costs with their cancer team. When compared with breast-conserving surgery, bilateral mastectomy with or without reconstruction was significantly associated with higher incurred debt, significant to catastrophic financial burden, treatment-related financial hardship, and altered employment. Among the highest incomes, 65% of women were fiscally unprepared, reporting higher-than-expected (26%) treatment costs. Cancer treatment costs influenced decisions for breast cancer surgery, and comparably effective surgical treatments differed significantly in their risk of patient-reported financial burden, debt, and impact on employment. Cost transparency may inform preference-sensitive surgical decisions and improve patient-centered care.


The role of the estrogen in neuroprotection: implications for neurodegenerative diseases.
In trying to rectify the differences in the risk, onset, and progression of neurodegenerative diseases between men and women, the gonadal hormone estrogen has been the primary focus of investigation for many years. Although this gender difference may encompass disparate and overlapping reasons, estrogen and signaling events mediated by its receptor have been shown to be neuroprotective in a number of neurodegenerative disease models such as Alzheimer's, Parkinson's, and Schizophrenia. Although data from human studies remains highly controversial, a large body of research findings suggests that this hormone plays a pivotal role in retarding and preventing the formation of neurodegenerative diseases through its receptor. By activating common intracellular signaling pathways and initiating "cross talk" with neurotrophins, estrogen plays an influential role in neuronal survival from injuries induced by ischemia or other environmental insults. Gaining a better understanding of these estrogen receptor mediated neuroprotective mechanisms may lead to new therapeutic strategies for the treatment or prevention of neurodegenerative diseases.


The response of high and low polyamine-producing cell lines to aluminum and calcium stress.
The diamine putrescine (Put) has been shown to accumulate in tree leaves in response to high Al and low Ca in the soil, leading to the suggestion that this response may provide a physiological advantage to leaf cells under conditions of Al stress. The increase in Put is reversed by Ca supplementation in the soil. Using two cell lines of poplar (Populus nigra x maximowiczii), one with constitutively high Put (resulting from transgenic expression of a mouse ornithine decarboxylase--called HP cells) and the other with low Put (control cells), we investigated the effects of reduced Ca (0.2-0.8 mM vs. 4 mM) and treatment with 0.1 mM Al on several biochemical parameters of cells. We found that in the presence of reduced Ca concentration, the HP cells were at a disadvantage as compared to control cells in that they showed greater reduction in mitochondrial activity and a reduction in the yield of cell mass. Upon addition of Al to the medium, the HP cells, however, showed a reversal of low-Ca effects. We conclude that due to increased ROS production in the HP cells, their tolerance to low Ca is compromised. Contrary to the expectation of deleterious effects, the HP cells showed an apparent advantage in the presence of Al in the medium, which could have come from reduced uptake of Al, enhanced extrusion of Al following its accumulation, and perhaps a reduction in Put catabolism as a result of a reduction in its biosynthesis.


Effect of nitric oxide on spinal evoked potentials and survival rate in rats with decompression sickness.
Nitric oxide (NO) releasing agents have, in experimental settings, been shown to decrease intravascular nitrogen bubble formation and to increase the survival rate during decompression sickness (DCS) from diving. The effect has been ascribed to a possible removal of preexisting micronuclei or an increased nitrogen washout on decompression through augmented blood flow rate. The present experiments were conducted to investigate whether a short- or long-acting NO donor [glycerol trinitrate (GTN) or isosorbide-5-mononitrate (ISMN), respectively] would offer the same protection against spinal cord DCS evaluated by means of spinal evoked potentials (SEPs). Anesthetized rats were decompressed from a 1-h hyperbaric air dive at 506.6 kPa (40 m of seawater) for 3 min and 17 s, and spinal cord conduction was studied by measurements of SEPs. Histological samples of the spinal cord were analyzed for lesions of DCS. In total, 58 rats were divided into 6 different treatment groups. The first three received either saline (group 1), 300 mg/kg iv ISMN (group 2), or 10 mg/kg ip GTN (group 3) before compression. The last three received either 300 mg/kg iv ISMN (group 4), 1 mg/kg iv GTN (group 5), or 75 μg/kg iv GTN (group 6) during the dive, before decompression. In all groups, decompression caused considerable intravascular bubble formation. The ISMN groups showed no difference compared with the control group, whereas the GTN groups showed a tendency toward faster SEP disappearance and shorter survival times. In conclusion, neither a short- nor long-acting NO donor had any protective effect against fatal DCS by intravenous bubble formation. This effect is most likely due to a fast ascent rate overriding the protective effects of NO, rather than the total inert tissue gas load.


Nigella sativa L. for prevention of acute radiation dermatitis in breast cancer: A randomized, double-blind, placebo-controlled, clinical trial.
The present study aimed to evaluate the effectiveness of Nigella sativa L. (N. sativa) extract on preventing the incidence of acute radiation dermatitis (ARD) in breast cancer patients. Sixty-two breast cancer patients undergoing radiotherapy (RT) were randomly assigned to receiveN. sativa 5% gel or placebo. Patients were instructed to apply the medications twice daily during RT period. The severity of ARD, the incidence of moist desquamation, worst experienced pain, and skin-related quality of life (SRQOL) scores were assessed weekly during RT. Patients who were treated with the N. sativa gel developed ARD significantly less frequently compared to those who used the placebo (p < 0.05 for all weeks except week 2, p = 0.36). The incidence time of grade 2 and 3 of Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) toxicity was prolonged significantly with N. sativa gel as compared to placebo (35 vs. 29 days, p = 0.00 and 42 vs. 40 days, p = 0.01, respectively). Furthermore, the occurrence of moist desquamation was delayed in the N. sativa gel group compared with the placebo group (37 vs. 33 days, p = 0.01). The mean score of the worst pain that patients experienced in the placebo group was significantly higher than that of the N. sativa gel group at week 3 (2.5 ± 0.5 vs. 1.2 ± 0.3, p < 0.05). Nonetheless, the application of N. sativa gel had no significant effect on the SRQOL of patients at any week. N. sativa extract significantly decreases the severity of ARD and delays the onset of moist desquamation in breast cancer patients.


Sublethal concentrations of waterborne copper induce cellular stress and cell death in zebrafish embryos and larvae.
Copper is an essential ion that forms part of the active sites of many proteins. At the same time, an excess of this metal produces free radicals that are toxic for cells and organisms. Fish have been used extensively to study the effects of metals, including copper, present in food or the environment. It has been shown that different metals induce different adaptive responses in adult fish. However, until now, scant information has been available about the responses that are induced by waterborne copper during early life stages of fish. Here, acute toxicity tests and LC50 curves have been generated for zebrafish larvae exposed to dissolved copper sulphate at different concentrations and for different treatment times. We determined that the larvae incorporate and accumulate copper present in the medium in a concentration-dependent manner, resulting in changes in gene expression. Using a transgenic fish line that expresses enhanced green fluorescent protein (EGFP) under the hsp70 promoter, we monitored tissue-specific stress responses to waterborne copper by following expression of the reporter. Furthermore, TUNEL assays revealed which tissues are more susceptible to cell death after exposure to copper. Our results establish a framework for the analysis of whole-organism management of excess external copper in developing aquatic animals.


Information about migraine disability influences physicians' perceptions of illness severity and treatment needs.
To assess physician-patient communication about headache-related disability and to evaluate the influence of information about disability on physicians' perceptions of illness severity and the treatment needs of migraineurs. Evidence suggests that migraine is suboptimally treated in clinical practice, partly due to poor communication between physicians and their patients. One hundred five neurologists and primary care physicians with an interest in headache participated in two interactive surveys, one in North America (n=42) and one in Europe (n=63). Each survey focused on the evaluation of four videotaped migraine cases. The first case was evaluated twice, initially after a typical symptom history that centered on diagnosis and then following a fuller history of migraine disability. Additional questions assessed the extent of the collection of migraine disability information in clinical practice. Physicians reported that they recorded symptoms relating to diagnosis (eg, pain location/intensity, associated symptoms) rather than information on headache-related disability. Only about one third of patients volunteered disability information. When made available to them, physicians rated information on disability as one of the most important factors in assessing treatment needs. In particular, when physicians knew the patient's disability history: (1) the proportion of physicians who rated the patient's illness as "severe" increased by 128% in North America, 27% in Europe; (2) the proportion of physicians who recommended immediate treatment increased by 63% in North America, 37% in Europe; and (3) the proportion of patients recommended for a follow-up visit increased by 15% in North America, 18% in Europe. Physicians and patients often fail to discuss headache-related disability during consultation. This information has a powerful influence on physicians' perceptions of illness severity, treatment choice, and the need for follow-up. Tools to improve communication about headache-related disability, such as the Migraine Disability Assessment questionnaire, may favorably improve migraine management.


Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort.
Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is incomplete etiologic understanding of the disease and little progress in identification of early risk biomarkers. To address these aspects, an untargeted nuclear magnetic resonance metabolomic approach was applied to pre-diagnostic serum samples obtained from first incident, primary HCC cases (n = 114) and matched controls (n = 222) identified from amongst the participants of a large European prospective cohort. A metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino acid, lipid, and carbohydrate metabolism was observed. Sixteen metabolites of either endogenous or exogenous origin were found to be significantly associated with HCC risk. The influence of hepatitis infection and potential liver damage was assessed, and further analyses were made to distinguish patterns of early or later diagnosis. Our results show clear metabolic alterations from early stages of HCC development with application for better etiologic understanding, prevention, and early detection of this increasingly common cancer.


β2-Adrenergic receptor signaling in osteoblasts contributes to the catabolic effect of glucocorticoids on bone.
The sympathetic nervous system is a physiological regulator of bone homeostasis. Autonomic nerves are indeed present in bone, bone cells express the β2-adrenergic receptors (β2AR), and pharmacological or genetic disruption of sympathetic outflow to bone induces bone gain in rodents. These recent findings implied that conditions that affect β2AR signaling in osteoblasts and/or sympathetic drive to bone may contribute to bone diseases. In this study, we show that dexamethasone stimulates the expression of the β2AR in differentiated primary calvarial osteoblasts, as measured by an increase in Adrβ2 mRNA and β2AR protein level after short-term dexamethasone treatment. Isoproterenol-induced cAMP accumulation and the expression of the β2AR target gene Rankl were also significantly increased after dexamethasone pretreatment, indicating that dexamethasone promotes the responsiveness of differentiated osteoblasts to adrenergic stimulation. These in vitro results led to the hypothesis that glucocorticoid-induced bone loss, provoked by increased endogenous or high-dose exogenous glucocorticoids given for the treatment of inflammatory diseases, might, at least in part, be mediated by increased sensitivity of bone-forming cells to the tonic inhibitory effect of sympathetic nerves on bone formation or their stimulatory effect on bone resorption. Supporting this hypothesis, both pharmacological and genetic β2AR blockade in mice significantly reduced the bone catabolic effect of high-dose prednisolone in vivo. This study emphasizes the importance of sympathetic nerves in the regulation of bone homeostasis and indicates that this neuroskeletal signaling axis can be modulated by hormones or drugs and contribute to enhance pathological bone loss.


CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose.
The commonly prescribed antiepileptic drug phenytoin has a narrow therapeutic range and wide interindividual variability in clearance explained in part by CYP2C9 and CYP2C19 coding variants. After finding a paradoxically low urinary phenytoin metabolite (S)/(R) ratio in subjects receiving phenytoin maintenance therapy with a CYP2C9*1/*1 and CYP2C19*1/*2 genotype, we hypothesized that CYP2C9 regulatory polymorphisms (rPMs), G-3089A and -2663delTG, in linkage disequilibrium with CYP2C19*2 were responsible. These rPMs explained as much as 10% of the variation in phenytoin maintenance dose in epileptic patients, but were not correlated with other patients' warfarin dose requirements or with phenytoin metabolite ratio in human liver microsomes. We hypothesized the rPMs affected CYP2C9 induction by phenytoin, a pregnane X receptor (PXR), and constitutive androstane receptor (CAR) activator. Transfection studies showed that CYP2C9 reporters with wild-type versus variant alleles had similar basal activity but significantly greater phenytoin induction by cotransfected PXR, CAR, and Nrf2 and less Yin Yang 1 transcription factor repression. Phenytoin induction of CYP2C9 was greater in human hepatocytes with the CYP2C9 wild type versus variant haplotype. Therefore, CYP2C9 rPMs affect phenytoin-dependent induction of CYP2C9 and phenytoin metabolism in humans, with an effect size comparable with that for CYP2C9*2 and 2C9*3. These findings may also be relevant to the clinical use of other PXR, CAR, and Nrf2 activators.


Behavioral interpretations of intrinsic connectivity networks.
An increasingly large number of neuroimaging studies have investigated functionally connected networks during rest, providing insight into human brain architecture. Assessment of the functional qualities of resting state networks has been limited by the task-independent state, which results in an inability to relate these networks to specific mental functions. However, it was recently demonstrated that similar brain networks can be extracted from resting state data and data extracted from thousands of task-based neuroimaging experiments archived in the BrainMap database. Here, we present a full functional explication of these intrinsic connectivity networks at a standard low order decomposition using a neuroinformatics approach based on the BrainMap behavioral taxonomy as well as a stratified, data-driven ordering of cognitive processes. Our results serve as a resource for functional interpretations of brain networks in resting state studies and future investigations into mental operations and the tasks that drive them.


Spatial distribution of hypoxic pulmonary vasoconstriction in the supine pig.
Hypoxic pulmonary vasoconstriction (HPV) serves to maintain optimal gas exchange by decreasing perfusion to hypoxic regions. However, global hypoxia and nonuniform HPV may result in overperfusion of poorly constricted regions leading to local edema seen in high-altitude pulmonary edema. To quantify the spatial distribution of HPV and its response to regional Po2 (Pr(O2)) among small lung regions, five pigs were anesthetized and mechanically ventilated in the supine posture. The animals were ventilated with an inspired O2 fraction (Fi(O2)) of 0.50 and 0.21 and then (in random order) 0.15, 0.12, and 0.09. Regional blood flow (Q) and alveolar ventilation (Va) were measured by using intravenous infusion of 15 microm and inhalation of 1-microm fluorescent microspheres, respectively. Pr(O2) was calculated for each piece at each Fi(O2). Lung pieces differed in their Q response to hypoxia in a manner related to their initial Va/Q with Fi(O2) = 0.21. Reducing Fi(O2) < 0.15 decreased Q to the initially high Va/Q (higher Pr(O2)) regions and forced Q into the low Va/Q (dorsal-caudal) regions. Resistance increased in most lung pieces as Pr(O2) decreased, reaching a maximum resistance when Pr(O2) is between 40 and 50 Torr. Local resistance decreased at PrO2 < 40 Torr. Pieces were statistically clustered with respect to their relative Q response pattern to each Fi(O2). Some clusters were shown to be spatially organized. We conclude that HPV is spatially heterogeneous. The heterogeneity of Q response may be related, in part, to the heterogeneity of baseline Va/Q.


Bioactivity-guided isolation of GABA(A) receptor modulating constituents from the rhizomes of Actaea racemosa.
Black cohosh (Actaea racemosa) is a frequently used herbal remedy for the treatment of mild climacteric symptoms. In the present study, the modulation of γ-aminobutryic acid (GABA)-induced chloride currents (I(GABA)) through GABA type A (GABA(A)) receptors by black cohosh extracts and isolated compounds was investigated. GABA(A) receptors, consisting of α(1), β(2), and γ(2S) subunits, were expressed in Xenopus laevis oocytes, and potentiation of I(GABA) was measured using the two-microelectrode voltage clamp technique. In a bioactivity-guided isolation procedure the positive modulation of I(GABA) could be restricted to the plant terpenoid fractions, resulting in the isolation of 11 cycloartane glycosides, of which four significantly (p < 0.05) enhanced I(GABA). The most efficient effect was observed for 23-O-acetylshengmanol 3-O-β-d-xylopyranoside (4, 100 μM), enhancing I(GABA) by 1692 ± 201%, while actein (1), cimigenol 3-O-β-d-xylopyranoside (6), and 25-O-acetylcimigenol 3-O-α-l-arabinopyranoside (8) were significantly less active. In the absence of GABA, only 4 induced small (not exceeding 1% of I(GABA-max)) chloride inward currents through GABA(A) receptors. It is hypothesized that the established positive allosteric modulation of GABA(A) receptors may contribute to beneficial effects of black cohosh extracts in the treatment of climacteric symptoms.


Ccrn4l as a pre-dose marker for prediction of cisplatin-induced hepatotoxicity susceptibility.
Clinical cisplatin use is often limited by its drug-induced liver injury (DILI). Particularly, individual differences in susceptibility to DILI can cause life-threatening medical conditions. This study aimed to uncover the inherent genetic factors determining individual variations in hepatotoxicity susceptibility. Rats were subjected to liver biopsy and a 3-week postoperative recovery period before cisplatin administration. At 2 days post-treatment with cisplatin, the rats exhibited histopathological and serum biochemical alterations in the liver, and changes in hydrogen peroxide and cytochrome P450-2E1 levels. Based on these results of liver-related biochemical markers, 32 rats were grouped into the susceptible (top five) and resistant (bottom five) groups. Using RNA-sequencing, we compared gene expressions in the liver pre-biopsied from these two groups before cisplatin treatment and found 161 differently expressed genes between the Susceptible and Resistant groups. Among them, the clock-controlled Ccrn4l responsible for 'rhythmic process' was identified as a common gene downregulated inherently prior to drug exposure in both cisplatin- and acetaminophen-sensitive animals. Additionally, low Ccrn4l levels before cisplatin treatment in the Susceptible group were maintained even after treatment, with decreased antioxidants, increased nitration, and apoptosis. The relationship of Ccrn4l with catalase and mitochondrial RNAs in the liver was confirmed by correlation of their hepatic levels among individuals and similar patterns of circadian variation in their mRNA expression. Remarkably, Ccrn4l knockdown promoted cisplatin-induced mitochondrial dysfunction in WB-F344 cells with antioxidant catalase and apoptosis-related Bax changes. Inherent individual hepatic Ccrn4l level might be a novel factor affecting cisplatin-induced hepatotoxicity susceptibility, possibly through regulation of mitochondrial and antioxidant functions.


Comparison of the relation between left ventricular anatomy and QRS duration in patients with cardiomyopathy with versus without left bundle branch block.
QRS duration (QRSd) is used to diagnose left bundle branch block (LBBB) and is important to determine cardiac resynchronization therapy eligibility. The same QRSd thresholds established decades ago are used for all patients. However, significant interpatient variability of normal QRSd exists, and individualized QRSd thresholds might improve diagnosis and intervention strategies. Previous work reported left ventricular (LV) mass and papillary muscle location predicted QRSd in healthy subjects, but the relation in diseased ventricles is unknown. The aim of the present study was to determine the association between LV anatomy and QRSd in patients with cardiomyopathy. Patients referred for primary prevention implantable defibrillators (n = 166) received cardiac magnetic resonance imaging, and those with normal conduction (without bundle branch or fascicular block) and LBBB were studied. The LV mass, length, internal diameter, LV end-diastolic volume, septal and lateral wall thicknesses, and papillary muscle location were measured. In patients with normal conduction, LV length (r = 0.35, p <0.001), mass (r = 0.32, p <0.001), diameter (r = 0.20, p = 0.03), and septal wall thickness (r = 0.20, p = 0.03) had positive correlations with QRSd. In patients with LBBB, LV length (r = 0.32, p = 0.03), mass (r = 0.39, p = 0.01), diameter (r = 0.34, p = 0.02), and LV end-diastolic volume (r = 0.32, p = 0.04) had positive correlations with QRSd. Contrary to previous studies in healthy subjects, papillary muscle angle (location) was not associated with QRSd in cardiomyopathy patients with normal conduction or LBBB. In conclusion, increasing LV anatomical measurements were associated with increasing QRSd in patients with cardiomyopathy. Future work should investigate the use of LV anatomical measurements in developing individualized QRSd thresholds for diagnosing conduction abnormalities such as LBBB and identifying candidates for cardiac resynchronization therapy.


Glucose concentration during equine in vitro maturation alters mitochondrial function.
The use of in vitro embryo production in the horse is increasing in clinical and research settings; however, protocols are yet to be optimised. Notably, the two most commonly used base media for in vitro maturation (IVM) supply glucose at markedly different concentrations: physiological (5.6 mM, M199) or supraphysiological (17 mM, DMEM/F-12). Exposure to high glucose has detrimental effects on oocytes and early embryos in many mammalian species, but the impact has not yet been examined in the horse. To address this, we compared the energy metabolism of equine COCs matured in M199-based maturation medium containing either 5.6 or 17 mM glucose, as well as expression of key genes in oocytes and cumulus cells. Oocytes were fertilised by ICSI and cultured. Analysis of spent medium revealed that COC glucose consumption and production of lactate and pyruvate were similar between treatments. However, the glycolytic index was decreased at 17 mM and analysis of mitochondrial function of COCs revealed that IVM in 17 mM glucose was associated with decreased ATP-coupled respiration and increased non-mitochondrial respiration compared to that for 5.6 mM glucose. We also found that the metabolic enzyme lactate dehydrogenase-A (LDHA) was downregulated in cumulus cells of oocytes that completed IVM in 17 mM glucose. There was no difference in maturation or blastocyst rates. These data indicate that COC mitochondrial function and gene expression are altered by high glucose concentration during IVM. Further work is needed to determine if these changes are associated with developmental changes in the resulting offspring.


Mid-fusiform activation during object discrimination reflects the process of differentiating structural descriptions.
The present study explored constraints on mid-fusiform activation during object discrimination. In three experiments, participants performed a matching task on simple line configurations, nameable objects, three dimensional (3-D) shapes, and colors. Significant bilateral mid-fusiform activation emerged when participants matched objects and 3-D shapes, as compared to when they matched two-dimensional (2-D) line configurations and colors, indicating that the mid-fusiform is engaged more strongly for processing structural descriptions (e.g., comparing 3-D volumetric shape) than perceptual descriptions (e.g., comparing 2-D or color information). In two of the experiments, the same mid-fusiform regions were also modulated by the degree of structural similarity between stimuli, implicating a role for the mid-fusiform in fine differentiation of similar visual object representations. Importantly, however, this process of fine differentiation occurred at the level of structural, but not perceptual, descriptions. Moreover, mid-fusiform activity was more robust when participants matched shape compared to color information using the identical stimuli, indicating that activity in the mid-fusiform gyrus is not driven by specific stimulus properties, but rather by the process of distinguishing stimuli based on shape information. Taken together, these findings further clarify the nature of object processing in the mid-fusiform gyrus. This region is engaged specifically in structural differentiation, a critical component process of object recognition and categorization.


Determination of passive moment-angle relationships at the trapeziometacarpal joint.
While modeling the trapeziometacarpal (TMC) joint for determination of tendon forces, the TMC has been considered frictionless and passive moments created by soft tissues neglected. This, however, becomes inaccurate when reaching the joint end range of motion and considering that the TMC is entirely crossed by a complex network of skin, ligaments, soft tissues, and tendons. The objective of this study was to evaluate the passive moments with respect to joint posture in order to further include this relationship in biomechanical modeling. An experimental method was proposed to estimate in vivo a global passive moment including the sum of the actions of each passive anatomical structure. An external force was applied at the level of the metacarpophalangeal joint in various directions ranging from neutral position to full extension and full adduction to full abduction. The passive moment was computed and expressed as a function of the adopted joint angles. An exponential regression was then developed to fit the experimental data and to propose a generic passive moment model. Results showed a good agreement between the proposed exponential regression model and the experimental measures. Moreover, it was shown that joint stiffness could represent more than 60% of the net joint moment during a typical pulp grip task. These results showed the necessity to include the data in biomechanical modeling. The results may help predict more realistic tendons force especially in abduction/adduction muscles.


Phase 1 trial of levonantradol in chemotherapy-induced emesis.
Levonantradol is a synthetic cannabinoid with demonstrated preclinical antiemetic activity. The current phase I trial was undertaken to determine: 1) the maximally tolerated dose; 2) the side effects at the different dosage levels; and 3) to evaluate the antiemetic efficacy of levonantradol in patients receiving emesis-producing chemotherapy. Thirty-four patients received 52 courses of levonantradol. Concurrent chemotherapy most frequently consisted of high dose cisplatin (120 mg/m2), either alone or in combination with other agents. Levonantradol dosage was escalated through seven treatment levels (0.5-4.0 mg per dose) and was given intramuscularly every 4 hours. Toxicity was similar to that observed with other cannabinoids and primarily consisted of dizziness (65%), burning and erythema at the injection site (48%), mild sedation (44%), orthostatic hypotension (37%), dysphoria (29%), and urinary retention (10%). Marked urinary retention occurred in three of seven patients at the 4.0 mg per dose level, and two of 24 patients at either the 2.5 mg and 3.0 mg levels. Major or minor antiemetic responses (0-2 or 3-5 emetic episodes, respectively) occurred in 23% of patients receiving cisplatin and in 53% of patients receiving non-cisplatin containing chemotherapy. Intramuscular levonantradol can be given safely at doses up to 3.0 mg/kg, with toxicity and antiemetic efficacy similar to that observed with other cannabinoids.


Factors associated with outcomes in allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning after failed myeloablative hematopoietic cell transplantation.
Several studies have investigated the feasibility of allogeneic hematopoietic cell transplantations (HCTs) after reduced-intensity conditioning in patients who experienced relapse after myeloablative HCT. Although most studies showed relatively low nonrelapse mortality (NRM) rates and encouraging short-term results, it has yet to be defined which patients would benefit most from these approaches. We analyzed data from 147 patients with hematologic malignancies who experienced treatment failure with conventional autologous (n = 135), allogeneic (n = 10), or syngeneic (n = 2) HCT and were treated with HLA-matched related (n = 62) or unrelated (n = 85) grafts after conditioning with 2 Gy of total-body irradiation with or without fludarabine. Three-year probabilities of NRM, relapse, and overall survival were 32%, 48%, and 27%, respectively, for related recipients, and 28%, 44%, and 44%, respectively, for unrelated recipients. The best outcomes were observed in patients with non-Hodgkin's lymphoma, whereas patients with multiple myeloma and Hodgkin's disease had worse outcomes as a result of high incidences of relapse and progression. Being in partial remission (PR) or complete remission (CR) at HCT (P = .002) and developing chronic graft-versus-host disease (GVHD; P = .03) resulted in lower risks of relapse and progression. Factors associated with better overall survival were PR or CR (P = .01) and lack of comorbidity (P = .03) at HCT and absence of acute GVHD after HCT (P = .06). Encouraging outcomes were seen with allogeneic HCT after nonmyeloablative conditioning in selected patients who had experienced relapse after a high-dose HCT, particularly in patients with non-Hodgkin's lymphoma. Results with unrelated grafts were comparable with results with related grafts.


Effect of O6-(4-bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model.
The DNA repair protein O(6)-alkylguanine DNA alkyltransferase (ATase) is a major component of resistance to treatment with methylating agents and nitrosoureas. Inactivation of the protein, via the administration of pseudosubstrates, prior to chemotherapy has been shown to improve the latter's therapeutic index in animal models of human tumours. We have also shown that rational scheduling of temozolomide, so that drug is administered at the ATase nadir after the preceding dose, increases tumour growth delay in these models. We now report the results of combining these two approaches. Nude mice bearing A375M human melanoma xenografts were treated with vehicle or 100 mg/kg temozolomide ip for 5 doses spaced 4, 12 or 24 hr apart. Each dose was preceded by the injection of vehicle or 20 mg/kg 4BTG. All treatments resulted in significant delays in tumour quintupling time compared with controls: by 6.2, 5.9 and 16.8 days, respectively, for 24-, 12- and 4-hourly temozolomide alone and by 22.3, 21.3 and 22.1 days, respectively, in combination with 4BTG. Weight loss due to TMZ was unaffected by the presence of 4BTG. This was of the order of 6.2-10.6% with 24- and 12-hourly administration and 17.4-20.1% (p < 0.0001) with 4-hourly treatment. In our model, combining daily temozolomide with 4-BTG confers increased antitumour activity equivalent to that achieved by compressing the temozolomide schedule but with less toxicity. Using temozolomide schedule compression with 4-BTG does not improve on this result, suggesting that ATase inactivation with pseudosubstrates is a more promising means of enhancing the activity of temozolomide than compressed scheduling.


Aging effects in sequential modulations of poorer-strategy effects during execution of memory strategies.
In this study, we asked young adults and older adults to encode pairs of words. For each item, they were told which strategy to use, interactive imagery or rote repetition. Data revealed poorer-strategy effects in both young adults and older adults: Participants obtained better performance when executing better strategies (i.e., interactive-imagery strategy to encode pairs of concrete words; rote-repetition strategy on pairs of abstract words) than with poorer strategies (i.e., interactive-imagery strategy on pairs of abstract words; rote-repetition strategy on pairs of concrete words). Crucially, we showed that sequential modulations of poorer-strategy effects (i.e., poorer-strategy effects being larger when previous items were encoded with better relative to poorer strategies), previously demonstrated in arithmetic, generalise to memory strategies. We also found reduced sequential modulations of poorer-strategy effects in older adults relative to young adults. Finally, sequential modulations of poorer-strategy effects correlated with measures of cognitive control processes, suggesting that these processes underlie efficient trial-to-trial modulations during strategy execution. Differences in correlations with cognitive control processes were also found between older adults and young adults. These findings have important implications regarding mechanisms underlying memory strategy execution and age differences in memory performance.


Caffeine and exercise: metabolism, endurance and performance.
Caffeine is a common substance in the diets of most athletes and it is now appearing in many new products, including energy drinks, sport gels, alcoholic beverages and diet aids. It can be a powerful ergogenic aid at levels that are considerably lower than the acceptable limit of the International Olympic Committee and could be beneficial in training and in competition. Caffeine does not improve maximal oxygen capacity directly, but could permit the athlete to train at a greater power output and/or to train longer. It has also been shown to increase speed and/or power output in simulated race conditions. These effects have been found in activities that last as little as 60 seconds or as long as 2 hours. There is less information about the effects of caffeine on strength; however, recent work suggests no effect on maximal ability, but enhanced endurance or resistance to fatigue. There is no evidence that caffeine ingestion before exercise leads to dehydration, ion imbalance, or any other adverse effects. The ingestion of caffeine as coffee appears to be ineffective compared to doping with pure caffeine. Related compounds such as theophylline are also potent ergogenic aids. Caffeine may act synergistically with other drugs including ephedrine and anti-inflammatory agents. It appears that male and female athletes have similar caffeine pharmacokinetics, i.e., for a given dose of caffeine, the time course and absolute plasma concentrations of caffeine and its metabolites are the same. In addition, exercise or dehydration does not affect caffeine pharmacokinetics. The limited information available suggests that caffeine non-users and users respond similarly and that withdrawal from caffeine may not be important. The mechanism(s) by which caffeine elicits its ergogenic effects are unknown, but the popular theory that it enhances fat oxidation and spares muscle glycogen has very little support and is an incomplete explanation at best. Caffeine may work, in part, by creating a more favourable intracellular ionic environment in active muscle. This could facilitate force production by each motor unit.


Systems Toxicology: Real World Applications and Opportunities.
Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized from empirical end points to describing modes of action as adverse outcome pathways and perturbed networks. Toward this aim, Systems Toxicology entails the integration of in vitro and in vivo toxicity data with computational modeling. This evolving approach depends critically on data reliability and relevance, which in turn depends on the quality of experimental models and bioanalysis techniques used to generate toxicological data. Systems Toxicology involves the use of large-scale data streams ("big data"), such as those derived from omics measurements that require computational means for obtaining informative results. Thus, integrative analysis of multiple molecular measurements, particularly acquired by omics strategies, is a key approach in Systems Toxicology. In recent years, there have been significant advances centered on in vitro test systems and bioanalytical strategies, yet a frontier challenge concerns linking observed network perturbations to phenotypes, which will require understanding pathways and networks that give rise to adverse responses. This summary perspective from a 2016 Systems Toxicology meeting, an international conference held in the Alps of Switzerland, describes the limitations and opportunities of selected emerging applications in this rapidly advancing field. Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized, from empirical end points to pathways of toxicity. This requires the integration of in vitro and in vivo data with computational modeling. Test systems and bioanalytical technologies have made significant advances, but ensuring data reliability and relevance is an ongoing concern. The major challenge facing the new pathway approach is determining how to link observed network perturbations to phenotypic toxicity.


Mismatch-induced growth reductions in a clade of Arctic-breeding shorebirds are rarely mitigated by increasing temperatures.
In seasonal environments subject to climate change, organisms typically show phenological changes. As these changes are usually stronger in organisms at lower trophic levels than those at higher trophic levels, mismatches between consumers and their prey may occur during the consumers' reproduction period. While in some species a trophic mismatch induces reductions in offspring growth, this is not always the case. This variation may be caused by the relative strength of the mismatch, or by mitigating factors like increased temperature-reducing energetic costs. We investigated the response of chick growth rate to arthropod abundance and temperature for six populations of ecologically similar shorebirds breeding in the Arctic and sub-Arctic (four subspecies of Red Knot Calidris canutus, Great Knot C. tenuirostris and Surfbird C. virgata). In general, chicks experienced growth benefits (measured as a condition index) when hatching before the seasonal peak in arthropod abundance, and growth reductions when hatching after the peak. The moment in the season at which growth reductions occurred varied between populations, likely depending on whether food was limiting growth before or after the peak. Higher temperatures led to faster growth on average, but could only compensate for increasing trophic mismatch for the population experiencing the coldest conditions. We did not find changes in the timing of peaks in arthropod availability across the study years, possibly because our series of observations was relatively short; timing of hatching displayed no change over the years either. Our results suggest that a trend in trophic mismatches may not yet be evident; however, we show Arctic-breeding shorebirds to be vulnerable to this phenomenon and vulnerability to depend on seasonal prey dynamics.


Malaria case-management following change of policy to universal parasitological diagnosis and targeted artemisinin-based combination therapy in Kenya.
The change of malaria case-management policy in Kenya to recommend universal parasitological diagnosis and targeted treatment with artemether-lumefantrine (AL) is supported with activities aiming by 2013 at universal coverage and adherence to the recommendations. We evaluated changes in health systems and case-management indicators between the baseline survey undertaken before implementation of the policy and the follow-up survey following the first year of the implementation activities. National, cross-sectional surveys using quality-of-care methods were undertaken at public facilities. Baseline and follow-up surveys respectively included 174 and 176 facilities, 224 and 237 health workers, and 2,405 and 1,456 febrile patients. Health systems indicators showed variable changes between surveys: AL stock-out (27% to 21%; p = 0.152); availability of diagnostics (55% to 58%; p = 0.600); training on the new policy (0 to 22%; p = 0.001); exposure to supervision (18% to 13%; p = 0.156) and access to guidelines (0 to 6%; p = 0.001). At all facilities, there was an increase among patients tested for malaria (24% vs 31%; p = 0.090) and those who were both tested and treated according to test result (16% to 22%; p = 0.048). At facilities with AL and malaria diagnostics, testing increased from 43% to 50% (p = 0.196) while patients who were both, tested and treated according to test result, increased from 28% to 36% (p = 0.114). Treatment adherence improved for test positive patients from 83% to 90% (p = 0.150) and for test negative patients from 47% to 56% (p = 0.227). No association was found between testing and exposure to training, supervision and guidelines, however, testing was significantly associated with facility ownership, type of testing, and patients' caseload, age and clinical presentation. Most of the case-management indicators have shown some improvement trends; however differences were smaller than expected, rarely statistically significant and still leaving a substantial gap towards optimistic targets. The quantitative and qualitative improvement of interventions will ultimately determine the success of the new policy.


The Use of Electrical Impedance to Identify Intraneural Needle Placement in Human Peripheral Nerves: A Study on Amputated Human Limbs.
Even as the use of peripheral nerve blockade in the perioperative setting is increasing, neural injury secondary to accidental intraneural injection remains a significant patient safety concern. Current modalities, including electrical stimulation and ultrasound imaging, still lack consistency and absolute reliability in both the detection and prevention of this complication. The measurement of electrical impedance (EI) could be an easy and valuable additional tool to detect intraneural needle placement. Our objectives in this study were to measure the change in EI with intraneural needle advancement in recently amputated human limbs. The study was conducted within 45 minutes of amputation. The nerves that were studied were the sciatic nerve in the popliteal fossa in above-knee amputations or the tibial nerve below the calf in below-knee amputations. The amputated limb was placed on a tray and under ultrasound imaging guidance, an insulated peripheral block needle connected to a nerve stimulator was placed extraneurally and subsequently advanced intraneurally. The experiment was repeated on the same nerve after exposure by surgical dissection. The differences in impedance measurements between intraneural and extraneural needle placement were compared. In the below-knee amputated extremity (tibial nerve, n = 6) specimens based on the ultrasound methods, mean ± SD for ultrasound-guided intraneural impedance was 10 ± 2 kΩ compared with an extraneural impedance of 6 ± 1.6 kΩ (P = 0.005). The difference between intraneural and extraneural impedance after open dissection was also significant when we repeated the analysis based on the same specimens (P = 0.005). Similarly, in the above-the-knee amputated extremity (sciatic nerve, n = 5) specimens, mean intraneural impedance was 35.2 ± 7.9 kΩ compared with an extraneural impedance of 25.2 ± 5.3 kΩ (P = 0.037). The difference between intraneural and extraneural impedance obtained after open dissection was also significant when we repeated the analysis based on the same specimens (P = 0.0002). The impedance values were consistent and similar to those obtained after open dissection. There is no reliable "gold standard" to predict or prevent intraneural needle placement during peripheral nerve blockade. This small sample-sized study demonstrated that there is a change in EI with intraneural needle advancement. In clinical practice, measurement of the EI in conjunction with nerve stimulation may serve as another tool to use for identifying intraneural needle placement during peripheral nerve blockade.


Effects of vitamin D on patients with fibromyalgia syndrome: a randomized placebo-controlled trial.
The role of calcifediol in the perception of chronic pain is a widely discussed subject. Low serum levels of calcifediol are especially common in patients with severe pain and fibromyalgia syndrome (FMS). We lack evidence of the role of vitamin D supplementation in these patients. To our knowledge, no randomized controlled trial has been published on the subject. Thirty women with FMS according to the 1990 and 2010 American College of Rheumatology criteria, with serum calcifediol levels <32ng/mL (80nmol/L), were randomized to treatment group (TG) or control group (CG). The goal was to achieve serum calcifediol levels between 32 and 48ng/mL for 20weeks via oral supplementation with cholecalciferol. The CG received placebo medication. Re-evaluation was performed in both groups after a further 24weeks without cholecalciferol supplementation. The main hypothesis was that high levels of serum calcifediol should result in a reduction of pain (visual analog scale score). Additional variables were evaluated using the Short Form Health Survey 36, the Hospital Anxiety and Depression Scale, the Fibromyalgia Impact Questionnaire, and the Somatization subscale of Symptom Checklist-90-Revised. A marked reduction in pain was noted over the treatment period in TG: a 2 (groups)×4 (time points) variance analysis showed a significant group effect in visual analog scale scores. This also was correlated with scores on the physical role functioning scale of the Short Form Health Survey 36. Optimization of calcifediol levels in FMS had a positive effect on the perception of pain. This economical therapy with a low side effect profile may well be considered in patients with FMS. However, further studies with larger patient numbers are needed to prove the hypothesis.


A proteomic perspective of inbuilt viral protein regulation: pUL46 tegument protein is targeted for degradation by ICP0 during herpes simplex virus type 1 infection.
Much like the host cells they infect, viruses must also regulate their life cycles. Herpes simples virus type 1 (HSV-1), a prominent human pathogen, uses a promoter-rich genome in conjunction with multiple viral trans-activating factors. Following entry into host cells, the virion-associated outer tegument proteins pUL46 and pUL47 act to increase expression of viral immediate-early (α) genes, thereby helping initiate the infection life cycle. Because pUL46 has gone largely unstudied, we employed a hybrid mass spectrometry-based approach to determine how pUL46 exerts its functions during early stages of infection. For a spatio-temporal characterization of pUL46, time-lapse microscopy was performed in live cells to define its dynamic localization from 2 to 24 h postinfection. Next, pUL46-containing protein complexes were immunoaffinity purified during infection of human fibroblasts and analyzed by mass spectrometry to investigate virus-virus and virus-host interactions, as well as post-translational modifications. We demonstrated that pUL46 is heavily phosphorylated in at least 23 sites. One phosphorylation site matched the consensus 14-3-3 phospho-binding motif, consistent with our identification of 14-3-3 proteins and host and viral kinases as specific pUL46 interactions. Moreover, we determined that pUL46 specifically interacts with the viral E3 ubiquitin ligase ICP0. We demonstrated that pUL46 is partially degraded in a proteasome-mediated manner during infection, and that the catalytic activity of ICP0 is responsible for this degradation. This is the first evidence of a viral protein being targeted for degradation by another viral protein during HSV-1 infection. Together, these data indicate that pUL46 levels are tightly controlled and important for the temporal regulation of viral gene expression throughout the virus life cycle. The concept of a structural virion protein, pUL46, performing nonstructural roles is likely to reflect a theme common to many viruses, and a better understanding of these functions will be important for developing therapeutics.


Optimization of combination therapy of arsenic trioxide and fractionated radiotherapy for malignant glioma.
The primary objective was to optimize the combined treatment regimen using arsenic trioxide (ATO) and fractionated radiotherapy for the treatment of malignant glioma. Nude mice with human glioma xenograft tumors were treated with fractionated local tumor radiation of 250 cGy/fraction/day and 5 mg/kg ATO for 5-10 days. Time course experiments demonstrated that maximal tumor growth delay occurred when ATO was administered between 0 and 4 h after radiation. The combination treatment of ATO and radiation synergistically inhibited tumor growth and produced a tumor growth delay time of 13.2 days, compared with 1.4 days and 6.5 days for ATO and radiation alone (p < 0.01), respectively. The use of concurrent therapy of radiation and ATO initially, followed by ATO as maintenance therapy, was superior to the use of preloading with ATO before combined therapy and produced a tumor growth delay time of 22.7 days as compared with 11.7 days for the ATO preloading regimen (p < 0.01). The maintenance dose of ATO after concurrent therapy was effective and important for continued inhibition of tumor growth. The combined use of fractionated radiation and ATO is effective for the treatment of glioma xenograft tumors. ATO was most effective when administered 0-4 h after radiation without pretreatment with ATO. These results have important implications for the optimization of treatment regimen using ATO and fractionated radiotherapy for the treatment of brain tumors.


Can sesame consumption improve blood pressure? A systematic review and meta-analysis of controlled trials.
Hypertension is a major risk factor for cardiovascular disease, myocardial infarction, stroke and renal failure. Sesame consumption may benefit blood pressure (BP) owing to its high polyunsaturated fatty acid, fibre, phytosterol and lignan contents. To clarify this, a systematic review and meta-analysis of controlled trials was conducted. The PubMed (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Library (Central) databases were systematically searched until August 2016. Eight controlled trials with a total of 843 participants met the eligibility criteria. A random effect meta-analysis showed that sesame consumption can reduce systolic BP (-7.83 mmHg, 95% CI: -14.12, -1.54; P < 0.05, I2 = 99%) and diastolic BP (-5.83 mmHg, 95% CI: -9.58, -2.08; P < 0.01, I2 = 98%). To reduce the heterogeneity, the meta-analysis was limited to high methodology quality trials (n = 4), which resulted in a significant reduction in systolic BP (-3.23 mmHg, 95% CI: -5.67, -0.79; I2 = 33%) and a non-significant reduction in diastolic BP (-2.08 mmHg, 95% CI: -4.85, 0.69; I2 = 62%). This study concluded that sesame consumption can reduce systolic and diastolic BP. However, further investigations with larger sample sizes and better methodology quality are required to confirm the BP-lowering effect of sesame consumption. © 2017 Society of Chemical Industry.


Common origins of diverse misconceptions: cognitive principles and the development of biology thinking.
Many ideas in the biological sciences seem especially difficult to understand, learn, and teach successfully. Our goal in this feature is to explore how these difficulties may stem not from the complexity or opacity of the concepts themselves, but from the fact that they may clash with informal, intuitive, and deeply held ways of understanding the world that have been studied for decades by psychologists. We give a brief overview of the field of developmental cognitive psychology. Then, in each of the following sections, we present a number of common challenges faced by students in the biological sciences. These may be in the form of misconceptions, biases, or simply concepts that are difficult to learn and teach, and they occur at all levels of biological analysis (molecular, cellular, organismal, population, and ecosystem). We then introduce the notion of a cognitive construal and discuss specific examples of how these cognitive principles may explain what makes some misconceptions so alluring and some biological concepts so challenging for undergraduates. We will argue that seemingly unrelated misconceptions may have common origins in a single underlying cognitive construal. These ideas emerge from our own ongoing cross-disciplinary conversation, and we think that expanding this conversation to include other biological scientists and educators, as well as other cognitive scientists, could have significant utility in improving biology teaching and learning.


Comparative gene expression analysis in mouse models for identifying critical pathways in mammary gland development.
Functional development of the mammary gland is an important physiological process. Several studies have used gene expression profiling of mammary gland development to identify the key genes in the process, but few focused on the involved pathways. And there is a lack of concordance between those observed pathways. In this article, we applied a standardized microarray preprocessing to four independent studies, and then used gene set enrichment analysis (GSEA) to identify the key pathways. The result demonstrated an increased concordance between these expression profiling data sets. From the stage of puberty to pregnancy, we found 7 up-regulated and 6 down-regulated pathways in common. From the period of pregnancy to lactation, we found 7 up-regulated and 58 down-regulated pathways in common. And 10 up-regulated and 3 down-regulated pathways were found in common from lactation to the involution period. The main canonical pathways identified belong to immune system, cell communication, metabolism, and disease-related pathways. Pathway analysis is a more effective method than single gene analysis because the former one can able to detect genes weakly connected to the phenotype. As we applied GSEA to the study, our findings suggested a greater concordance in this physiological process. The critical pathways we find can provide some insight of functional development of the mammary gland and motivate other relative studies.


The influence of pyridoxine in diabetic peripheral neuropathy.
To determine the role of pyridoxine in the treatment of diabetic peripheral neuropathy, 18 symptomatic diabetic patients were treated with vitamin B6 or placebo in a double-blind controlled study. Only one patient had a low plasma pyridoxal phosphate level at the start of the study. After 4 mo of treatment with pyridoxine hydrochloride (50 mg three times daily) 6 of 9 pyridoxine-treated and 4 of 9 placebo-treated patients noted significant relief from their neuropathic symptoms. There was no difference between the two groups with regard to fasting plasma glucose, motor nerve conduction velocity, or ophthalmologic examination at the beginning or at the conclusion of the study. Our results suggest that vitamin B6 deficiency is not a factor in the etiology of diabetic peripheral neuropathy. Furthermore, treating diabetic peripheral neuropathy with high dose vitamin B6 or placebo results in a similar frequency of symptomatic improvement.


Developmental Shifts in Detection and Attention for Auditory, Visual, and Audiovisual Speech.
Successful speech processing depends on our ability to detect and integrate multisensory cues, yet there is minimal research on multisensory speech detection and integration by children. To address this need, we studied the development of speech detection for auditory (A), visual (V), and audiovisual (AV) input. Participants were 115 typically developing children clustered into age groups between 4 and 14 years. Speech detection (quantified by response times [RTs]) was determined for 1 stimulus, /buh/, presented in A, V, and AV modes (articulating vs. static facial conditions). Performance was analyzed not only in terms of traditional mean RTs but also in terms of the faster versus slower RTs (defined by the 1st vs. 3rd quartiles of RT distributions). These time regions were conceptualized respectively as reflecting optimal detection with efficient focused attention versus less optimal detection with inefficient focused attention due to attentional lapses. Mean RTs indicated better detection (a) of multisensory AV speech than A speech only in 4- to 5-year-olds and (b) of A and AV inputs than V input in all age groups. The faster RTs revealed that AV input did not improve detection in any group. The slower RTs indicated that (a) the processing of silent V input was significantly faster for the articulating than static face and (b) AV speech or facial input significantly minimized attentional lapses in all groups except 6- to 7-year-olds (a peaked U-shaped curve). Apparently, the AV benefit observed for mean performance in 4- to 5-year-olds arose from effects of attention. The faster RTs indicated that AV input did not enhance detection in any group, but the slower RTs indicated that AV speech and dynamic V speech (mouthing) significantly minimized attentional lapses and thus did influence performance. Overall, A and AV inputs were detected consistently faster than V input; this result endorsed stimulus-bound auditory processing by these children.


A genomewide survey argues that every zygotic gene product is dispensable for the initiation of somatic homolog pairing in Drosophila.
Studies from diverse organisms show that distinct interchromosomal interactions are associated with many developmental events. Despite recent advances in uncovering such phenomena, our understanding of how interchromosomal interactions are initiated and regulated is incomplete. During the maternal-to-zygotic transition (MZT) of Drosophila embryogenesis, stable interchromosomal contacts form between maternal and paternal homologous chromosomes, a phenomenon known as somatic homolog pairing. To better understand the events that initiate pairing, we performed a genomewide assessment of the zygotic contribution to this process. Specifically, we took advantage of the segregational properties of compound chromosomes to generate embryos lacking entire chromosome arms and, thus, all zygotic gene products derived from those arms. Using DNA fluorescence in situ hybridization (FISH) to assess the initiation of pairing at five separate loci, this approach allowed us to survey the entire zygotic genome using just a handful of crosses. Remarkably, we found no defect in pairing in embryos lacking any chromosome arm, indicating that no zygotic gene product is essential for pairing to initiate. From these data, we conclude that the initiation of pairing can occur independently of zygotic control and may therefore be part of the developmental program encoded by the maternal genome.


Ejaculate characteristics of sheep infected with Trypanosoma brucei and T vivax: changes caused by treatment with diminazene aceturate.
The effect of Trypanosoma brucei and T vivax on the ejaculate of sheep and the rate of recovery with diminazene aceturate treatment was investigated. Animals were made to ejaculate once a week before infection, during infection and after treatment. Parameters studied were semen volume, semen colour, sperm motility and concentration, percentage dead spermatozoa and sperm morphology. Both infections severely affected the quality of the ejaculate although in T vivax infection there was no appreciable change in semen volume and sperm concentration. There was a reduction in sperm motility and concentration, an increase in the percentage of dead spermatozoa and in abnormal sperm morphology. Treatment led to improvement in all parameters but recovery was faster in T vivax than in T brucei infection. Ejaculate with few primary abnormalities was not obtained until 19 weeks after treatment.


Parenteral immunonutrition in patients with acute pancreatitis: a systematic review and meta-analysis.
Acute pancreatitis is a systemic immunoinflammatory response to auto-digestion of the pancrease and peri-pancreatic organs. Patients with acute pancreatitis can rapidly develop nutritional deficiency; hence nutritional support is important and critical. Sometimes parenteral nutrition (PN) is inevitable in acute pancreatitis. Due to immunosuppressive and inflammatory nature of the disease, it seems that immunonutrients like glutamine and omega-3 fatty acids (ω-3 FAs) added to parenteral formulas may improve the conditions. We conducted a meta-analysis to evaluate the effects of parenteral immunonutrition on clinical outcomes (infectious complications, length of hospital stay (LOS) and mortality) in patients with acute pancreatitis. A computerized literature search on four databases (PubMed, Cochrane, ISI Web of Science, and Iran Medex) was performed to find all the randomized controlled trials (RCTs) assessed the effects of parenteral immunonutrition in acute pancreatitis. Necessary data were extracted and quality assessment of RCTs was performed with consensus in the study team. Fixed effects model was used to conduct the meta-analysis. One hundred and ninety four references were found via our search in which 7 articles matched our criteria for enrolling the meta-analysis. Parenteral immunonutrition significantly reduced the risk of infectious complications (RR = 0.59; 95% CI, 0.39-0.88; p ≤ 0.05) and mortality (RR = 0.26; 95% CI, 0.11-0.59; p ≤ 0.001). LOS was also shorter in patients who received immunonutrition (MD = -2.93 days; 95% CI, -4.70 to -1.15; p ≤ 0.001). Immunonutrients like glutamine and ω-3 FAs added to parenteral formulas can improve prognoses in patients with acute pancreatitis.


[Primary intestinal lymphangiectasia: first case report in Peru].
Primary intestinal lymphangiectasia is a rare clinical condition of unknown etiology. The common age of presentation is during the first 3 years of life, but cases in adults have also been reported. It has a variable symptomatology, but the main clinical manifestation is edema, also diarrhea and weight loss can occur. The loss of lymph fluid into the gastrointestinal tract also leads to hypoproteinemia and lymphopenia. Diagnosis is based on clinical manifestations, laboratory and endoscopic findings, and is confirmed on histopathological examination of biopsy. The main treatment is a protein rich, low in fat and medium chain triglyceride diet. We present the case of a 1-year-old male patient who presents with generalized edema, predominantly in lower limbs, and diarrhea. Laboratory findings show the presence of marked hypoproteinemia. Then an endoscopy and a duodenal biopsy are performed, and the histopathological study confirms the diagnosis of primary intestinal lymphangiectasia. The patient is treated and after a satisfactory evolution, is discharged.


Time-lapse live cell imaging to monitor doxorubicin release from DNA origami nanostructures.
Self-assembled DNA nanostructures have attracted significant research interest in biomedical applications because of their excellent programmability and biocompatibility. To develop multifunctional drug delivery from DNA nanostructures, considerable key information is still needed for clinical application. Traditional fixed endpoint assays do not reflect the dynamic and heterogeneous responses of cells with regard to drugs, and may lead to the misinterpretation of experimental results. For the first time, an integrated time-lapse live cell imaging system was used to study the cellular internalization and controlled drug release profile of three different shaped DNA origami/doxorubicin (DOX) complexes for three days. Our results demonstrated the dependence of DNA nanostructures on shape for drug delivery efficiency, while the rigid 3D DNA origami triangle frame exhibited enhanced cellular uptake capability, as compared with flexible 2D DNA structures. In addition, the translocation of released DOX into the nucleus was proved by fluorescence microscopy, in which a DOX-loaded 3D DNA triangle frame displayed a stronger accumulation of DOX in nuclei. Moreover, given the facile drug loading and auto fluorescence of the anti-cancer drug, DOX, our results suggest that the DNA nanostructure is a promising candidate, as a label-free nanocarrier, for DOX delivery, with great potential for anticancer therapy as well.


Racial and Ethnic Disparities in Birth Outcomes and Labor and Delivery Charges Among Massachusetts Women With Intellectual and Developmental Disabilities.
Understanding the pregnancy experiences of racial and ethnic minority women with intellectual and developmental disabilities (IDD) is critical to ensuring that policies can effectively support these women. This research analyzed data from the 1998-2013 Massachusetts Pregnancy to Early Life Longitudinal (PELL) data system to examine the racial and ethnic disparities in birth outcomes and labor and delivery charges of U.S. women with IDD. There was significant preterm birth disparity among non-Hispanic Black women with IDD compared to their non-Hispanic White peers. There were also significant racial and ethnic differences in associated labor and delivery-related charges. Further research, examining potential mechanisms behind the observed racial and ethnic differences in labor and delivery-related charges in Massachusetts' women with IDD is needed.


Integrity of a HPV11 infection cell model and identification of (-)-Epigallocatechin-3-gallate as a potential HPV11 inhibitor.
Condyloma acuminatum (CA) is one of the most common sexually transmitted diseases and induced by low-risk human papillomaviruses (HPVs), mainly HPV type 6 and 11. Here, we report the identification of (-)-Epigallocatechin-3-gallate (EGCG) by an HPV11 infection cell model. The recombined HPV11.HaCaT cells had stable HPV 11 early genes expression. The introducing of HPV11 genome significantly increased the proliferation of HPV11.HaCaT cells, as well as the proportion of cells in S and G2/M phases. After treated with rhIFN-α 2a, IFN signaling pathway was activated in both HaCaT and HPV11.HaCaT cells, while HPV11 decreased the activation level. In addition, rhIFN-α 2a, could inhibit expression of HPV 11 E6 and E7 mRNA significantly (P<0.05). However, cell growth and cell cycle did not show statistical difference (P>0.05). Nevertheless, EGCG, a major active constituent in tea polyphenol, showed strong anti-HPV11 effect, which inhibited HPV11 E6 and E7 mRNA. Gene transfection technique was used to introduce HPV11 genome into HaCaT cells, named HPV11.HaCaT cells. With the established cell model, we explore the anti-HPV11 effect of (-)-Epigallocatechin-3-gallate (EGCG) on cell growth, viability and affection on expression HPV11 E6 and E7 mRNA. Our data collectively demonstrated that the recombinant HPV11.HaCaT cells were integral and practical to be a cell model to test anti-HPV11 agents and explore the interaction between HPV11 genes and host cells. And EGCG inhibits expression of HPV11 E6 and E7 mRNA in the recombinant HPV11.HaCaT cells.


Technology and diabetes self-management: An integrative review.
Technology can be used to supplement healthcare provider diabetes care by providing both educational and motivational support. Education can be provided using technology allowing patients to learn new practices and routines related to diabetes management. Technology can support daily diabetes self-management activities including blood glucose monitoring, exercising, healthy eating, taking medication, monitoring for complications, and problem-solving. This article describes an integrative review conducted to evaluate the types of technology being used to facilitate diabetes self-management and the effect of that technology on self-management and diabetes outcomes for adults living with type 2 diabetes mellitus. A literature review was conducted by searching Medline, PubMed, and Psych INFO databases using the search terms: diabetes self-management, technology, type 2 diabetes, smartphones, cell phones, and diabetes mellitus covering the years from 2008-2013. Articles relying on secondary data (editorials, systematic reviews) and articles describing study protocol only were excluded. Fourteen studies including qualitative, quasi-experimental, and randomized controlled trial designs were identified and included in the review. The review found that technological interventions had positive impacts on diabetes outcomes including improvements in hemoglobin A1C levels, diabetes self-management behaviors, and diabetes self-efficacy. Results indicate that technological interventions can benefit people living with diabetes when used in conjunction with diabetes care delivered by healthcare providers.


Plant pathogen population dynamics in potato fields.
Modern technologies incorporating Geographic Information Systems (GIS), Global Positioning Systems (GPS), remote sensing, and geostatistics provide unique opportunities to advance ecological understanding of pests across a landscape. Increased knowledge of the population dynamics of plant pathogens will promote management strategies, such as site-specific management, and cultural practices minimizing the introduction and impact of plant pathogens. The population dynamics of Alternaria solani, Verticillium dahliae, and Pratylenchus penetrans were investigated in commercial potato fields. A 0.5-ha diamond grid-sampling scheme was georeferenced, and all disease ratings and nematode samples were taken at these grid points. Percent disease severity was rated weekly, and P. penetrans densities were quantified 4 weeks after potato emergence. Spatial statistics and interpolation methods were used to identify the spatial distribution and population dynamics of each pathogen. Interpolated maps and aerial imagery identified A. solani intra-season progression across the fields as the potato crop matured. Late-season nitrogen application reduced A. solani severity. The spatial distributions of V. dahliae and P. penetrans were spatially correlated.


Embryonal carcinoma cells express Qa and Tla class I genes of the major histocompatibility complex.
The murine major histocompatibility complex encodes H-2K and H-2D transplantation antigens and other class I-like proteins called Qa and Tla molecules; the functions of the Qa/Tla molecules are not known. That they may participate in embryonic cell-cell interactions and/or play a role in immune responses against tumors has been speculated. We have studied two murine embryonal carcinoma tumors, 402AX and PCC4, that are rejected in vivo immunologically, although they do not express H-2K or H-2D antigens. Transplantation studies with these cells suggest that rejection is mediated by class-I-like major histocompatibility complex antigens. As a first step in evaluating Qa/Tla function(s), we have characterized expression of class I-like genes and proteins in 402AX and PCC4 cells. Northern (RNA) blot hybridizations, polymerase chain reaction studies, and cDNA cloning experiments demonstrate that EC lines transcribe genes allelic to the Tla region gene "37", Qa-2 region gene "Q7", and another, previously uncharacterized, class I-like gene. Immunoprecipitation studies show that the embryonal carcinoma tumor cells contain low levels of beta 2-microglobulin expressed in association with non-H-2K, non-H-2D class I-like proteins.


[Fatigue and sleepiness in interprovincial road bus drivers: comparative study between formality and informality].
To compare the levels of fatigue, sleepiness and their consequences between formal and informal drivers of interprovincial buses. To evaluate labor conditions between both study groups. A comparative cross-sectional study was performed with non-probabilistic sampling. 100 companies of land transport were included, out of which 17 were formal according to the official registries of the Ministry of Transport and Communications (MTC), the drivers were also classified as formal or informal. The survey included one questionnaire and a Peruvian validated version of the Epworth sleepiness scale. 71 formal drivers and 274 informal drivers participated, all were males. Out of the 134 drivers that worked for the formal companies according to the MTC, only 43 (32%) belong to the formal group based on the proposed criteria. 48% (34) of the formal drivers and 43% (118) of the informal sleep less than 7 hours a day. 48% (34) of the formal and 49% (135) of the informal admitted having had an accident or "almost" having had it, the most frequent time of the day was between 01.00 and 04.00 in the morning. The dawn is the period in which both groups feel most tired. 44% (30) of the formal drivers and 54% (144) of the informal ones perform 5 or more night shifts per week. Out of the total of interviewed, 16% (56) had sleepiness. The association with road traffic accidents was similar. The fatigue and sleepiness levels were similar between formal and informal drivers. Companies classified as formal, have a high percentage of informality amongst their drivers.


The prevalence and pattern of distribution of root caries in a Scottish medieval population.
The prevalence and pattern of distribution of root caries were determined in a Scottish Medieval population. The principal finding was a lower root caries prevalence, compared with that of modern times, with respect to surfaces at risk; this was particularly marked with respect to buccal root caries. A lower intake of refined sugars and the presence of heavy deposits of supragingival calculus are suggested as factors that may be responsible for the observed differences. The common site for the early root caries lesion was just apical to the enamel-cementum junction. Initially, it extended laterally in the form of an elliptical erosion; however, the greater the depth of the lesion, the more circular the outline became.