Effect of variation in form on the cost of terrestrial locomotion.
The mass-specific minimum cost of terrestrial locomotion (Cmin) decreases with an increase in body mass. This generalization spans nearly eight orders of magnitude in body mass and includes two phyla. The general relationship between metabolic cost and mass is striking. However, a significant amount of unexplained interspecific variation in Cmin exists at any given body mass. To determine how variation in morphology and physiology affects metabolic energy cost, we measured the oxygen consumption of three comparably sized insects running on a miniature treadmill; the American cockroach Periplaneta americana, the caterpillar hunting beetle Calosoma affine and the Australian field cricket Teleogryllus commodus. Steady-state oxygen consumption (VO2ss) increased linearly with speed. Cmin was similar for crickets and cockroaches (8.0 and 8.5 ml O2 g-1km-1, respectively), but was substantially lower for beetles (4.6 ml O2 g-1km-1). The predicted value of Cmin for all three insects was within the 95% confidence intervals of the Cmin versus body mass function. However, the 95% confidence intervals extend approximately 2.5-fold above and 40% below the regression line, making the variation at any given body mass nearly sixfold. Normalizing for the rate of muscle force production by determining the metabolic cost per stride failed to account for the interspecific variation in the cost of locomotion observed in the three insects. Ground contact costs (i.e. VO2ss multiplied by leg contact time during a stride) in insects were similar to those measured in mammals (1.5-3.1 J kg-1) and were independent of speed, but did not explain the interspecific variation in the cost of locomotion. Muscles of the caterpillar hunting beetle may have a greater mechanical advantage than muscles of the Australian field cricket and American cockroach. Variation in musculo-skeletal arrangement, apart from variation in body mass, could translate into significant differences in the minimum cost of terrestrial locomotion.


Angiotensin II promotes development of the renal microcirculation through AT1 receptors.
Pharmacologic or genetic deletion of components of the renin-angiotensin system leads to postnatal kidney injury, but the roles of these components in kidney development are unknown. To test the hypothesis that angiotensin II supports angiogenesis during postnatal kidney development, we quantified CD31(+) postglomerular microvessels, performed quantitative PCR analysis of vascular growth factor expression, and measured renal blood flow by magnetic resonance. Treating rats with the angiotensin II type 1 receptor antagonist candesartan for 2 weeks after birth reduced the total length, volume, and surface area of capillaries in both the cortex and the medulla and inhibited the organization of vasa recta bundles. In addition, angiotensin II type 1 antagonism inhibited the transcription of angiogenic growth factors vascular endothelial growth factor, angiopoietin-1, angiopoietin-2, and the angiopoietin receptor Tie-2 in cortex and medulla. Similarly, Agtr1a(-/-);Agtr1b(-/-) mouse kidneys had decreased angiopoietin-1, angiopoietin-2, and Tie-2 mRNAs at postnatal day 14. To test whether increased urinary flow leads to microvascular injury, we induced postnatal polyuria with either lithium or adrenalectomy, but these did not alter vascular endothelial growth factor expression or vasa recta organization. Compared with vehicle-treated rats, renal blood flow was significantly (approximately 20%) lower in candesartan-treated rats even 14 days after candesartan withdrawal. Taken together, these data demonstrate that angiotensin II promotes postnatal expansion of postglomerular capillaries and organization of vasa recta bundles, which are necessary for development of normal renal blood flow.


Colposcopic assessment in microinvasive carcinoma of the cervix.
Forty of the 87 patients with microinvasive carcinoma (MIC) of the uterine cervix who underwent surgery were diagnosed colposcopically and the results were compared with the cytological and histological diagnoses. The cytology showed preinvasive carcinoma in 20 (50.0%) patients and invasive carcinoma in 19 (47.5%) patients. A correct colposcopic diagnosis was made in nine (22.5%) patients as having microinvasive carcinoma, 21 (52.5%) patients preinvasive carcinoma and eight (20%) patients invasive carcinoma, to sum up accuracy rate as 32.1%. The abnormalities most commonly observed in colposcopy were mosaic, punctuation and white epithelium. In microinvasive carcinoma, the triad co-existed in 43% of the patients. Atypical vessels, characteristic of invasion, were found in only one third of the patients. Microinvasion, therefore, may not be evident on colposcopy alone. It is therefore necessary to apply cone biopsy, prior to definite therapy, to make an accurate assessment of the maximum depth and extent of the invasion prior to definitive therapy.


Toll-like receptor 4 signaling by follicular dendritic cells is pivotal for germinal center onset and affinity maturation.
Germinal centers (GCs) are specialized microenvironments where antigen-activated B cells undergo proliferation, immunoglobulin (Ig) class switch recombination, somatic hypermutation (SHM), and affinity maturation. Within GCs, follicular dendritic cells (FDCs) are key players in driving these events via direct interaction with GC B cells. Here, we provide in vivo evidence that FDCs express and upregulate Toll-like-receptor (TLR) 4 in situ during germinal center reactions, confirm that their maturation is driven by TLR4, and associate the role of FDC-expressed TLR4 with quantitative and qualitative affects of GC biology. In iterative cycles of predictions by in silico modeling subsequently verified by in vivo experiments, we demonstrated that TLR4 signaling modulates FDC activation, strongly impacting SHM and generation of Ig class-switched high-affinity plasma and memory B cells. Thus, our data place TLR4 in the heart of adaptive humoral immunity, providing further insight into mechanisms driving GCs arising in both health and disease.


Polymer microfluidic chips for electrochemical and biochemical analyses.
Our recent developments concerning the fabrication of polymer microchips and their applications for biochemical analyses are reviewed. We first describe two methods of fabrication of polymer microfluidic chips, namely UV-laser photoablation and plasma etching that are well suited for the prototyping and mass fabrication of microchannel networks with integrated microelectrodes. These microanalytical systems can be coupled with various detection means including mass spectrometry, and their applications in capillary electrophoresis are presented here. We also present how UV laser photoablation can be used for the patterning of biomolecules on polymer surfaces for generating two-dimensional arrays of microspots to carry out affinity assays. Finally, the use of the microchips for the development of fast affinity and immunological assays with electrochemical detection is presented, demonstrating the potential of these polymer microchips for medical diagnostics and drug discovery.


Intimate partner violence and severe acute maternal morbidity in the intensive care unit: A case-control study in Peru.
Intimate partner violence is a prevalent public health issue associated with all-cause maternal mortality. This study investigated the relationship between intimate partner violence, severe acute maternal morbidity in the intensive care unit (ICU), and neonatal outcomes. This was a prospective case-control study in a hospital in Lima, Peru, with 109 cases (maternal ICU admissions) and 109 controls (obstetric patients not admitted to the ICU). Data were collected through face-to-face interviews and medical record review. Partner violence was assessed using the World Health Organization instrument. Multivariate logistic regression was used to model the association between intimate partner violence and severe acute maternal morbidity. There was a significantly higher rate of intimate partner violence both before and during pregnancy among cases (58.7%) than controls (27.5%). In multivariate analysis, intimate partner violence both before and during pregnancy (aOR 3.83 (95% CI: 1.99-7.37)), being married (3.86 (1.27-11.73)), having <8 antenatal care visits (2.78 (1.14-6.80)), and having previous abortions (miscarriage, therapeutic, or unsafe) (1.69 (1.13-2.51)) were significantly associated with severe acute maternal morbidity. The ICU admission rate was 18.8 (per 1000 live births), and ICU maternal mortality was 1.7%. The perinatal mortality rate was higher in cases (9.3%) than in controls (1.8%). Intimate partner violence was associated with an increased risk of severe acute maternal morbidity. This suggests a more severe impact of intimate partner violence on pregnancy than has been previously identified. Inquiring about intimate partner violence during prenatal visits may prevent further harm to the mother-baby dyad.


Impact of parental socioeconomic status on excess mortality in a population-based cohort of subjects with childhood-onset type 1 diabetes.
The aim of this study was to analyze the possible impact of parental and individual socioeconomic status (SES) on all-cause mortality in a population-based cohort of patients with childhood-onset type 1 diabetes. Subjects recorded in the Swedish Childhood Diabetes Registry (SCDR) from 1 January 1978 to 31 December 2008 were included (n = 14,647). The SCDR was linked to the Swedish Cause of Death Registry (CDR) and the Longitudinal Integration Database for Health Insurance and Labour Market Studies (LISA). At a mean follow-up of 23.9 years (maximum 46.5 years), 238 deaths occurred in a total of 349,762 person-years at risk. In crude analyses, low maternal education predicted mortality for male patients only (P = 0.046), whereas parental income support predicted mortality in both sexes (P < 0.001 for both). In Cox models stratified by age-at-death group and adjusted for age at onset and sex, parental income support predicted mortality among young adults (≥18 years of age) but not for children. Including the adult patient's own SES in a Cox model showed that individual income support to the patient predicted mortality occurring at ≥24 years of age when adjusting for age at onset, sex, and parental SES. Exposure to low SES, mirrored by the need for income support, increases mortality risk in patients with childhood-onset type 1 diabetes who died after the age of 18 years.


Practice bulletin no. 146: Management of late-term and postterm pregnancies.
Postterm pregnancy refers to a pregnancy that has reached or extended beyond 42 0/7 weeks of gestation from the last menstrual period (LMP), whereas a late-term pregnancy is defined as one that has reached between 41 0/7 weeks and 41 6/7 weeks of gestation (). In 2011, the overall incidence of postterm pregnancy in the United States was 5.5% (). The incidence of postterm pregnancies may vary by population, in part as a result of differences in regional management practices for pregnancies that go beyond the estimated date of delivery. Accurate determination of gestational age is essential to accurate diagnosis and appropriate management of late-term and postterm pregnancies. Antepartum fetal surveillance and induction of labor have been evaluated as strategies to decrease the risks of perinatal morbidity and mortality associated with late-term and postterm pregnancies. The purpose of this document is to review the current understanding of late-term and postterm pregnancies and provide guidelines for management that have been validated by appropriately conducted outcome-based research when available. Additional guidelines on the basis of consensus and expert opinion also are presented.


Bisphosphonates induce apoptosis in mouse macrophage-like cells in vitro by a nitric oxide-independent mechanism.
Bisphosphonates (BPs) are an important class of antiresorptive drugs used in the treatment of bone diseases, including osteoporosis. Although their mechanism of action has not been identified at the molecular level, there is substantial evidence that BPs can have a direct effect on osteoclasts by mechanisms that may lead to osteoclast cell death by apoptosis. BPs can also inhibit proliferation and cause cell death in macrophages in vitro. We have now shown that the toxic effect of BPs on macrophages is also due to the induction of apoptotic, rather than necrotic, cell death. Morphological and biochemical features that are definitive of apoptosis (chromatin condensation, nuclear fragmentation, and endonuclease-mediated internucleosomal cleavage of DNA) could be identified in mouse macrophage-like J774 and RAW264 cells, following treatment with 100 microM pamidronate, alendronate, and ibandronate for 24 h or more. Clodronate was much less potent, even at 2000 microM, while 2000 microM etidronate did not cause apoptosis. Apoptosis was not due to increased synthesis of nitric oxide and could not be prevented by inhibitors of nitric oxide synthases. Since macrophages, like osteoclasts, are particularly susceptible to BPs, these observations support the recent suggestion that the mechanism by which BPs inhibit bone resorption may involve osteoclast apoptosis. Furthermore, the macrophage-like cell lines used in this study may be a convenient model with which to identify the molecular mechanisms by which BPs promote apoptosis in osteoclasts. Induction of macrophage apoptosis by BPs in vivo may also account, at least in part, for the anti-inflammatory properties of BPs as well as the ability of BPs to cause an acute phase response.


The role of magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) in the diagnosis and assessment of resectability of pancreatic tumors.
Carcinoma of the pancreas is one of the most malignant tumors. Symptoms are usually nonspecific and insidious, such that the cancer is advanced by the time of diagnosis. The aim of the study was to assess the usefulness of MRI and MRCP in the diagnosis of patients suspected of pancreatic carcinoma and to define the role of these methods in the evaluation of resectability of pancreatic cancer in comparison with surgical findings. Forty-seven patients (32 men and 15 women) aged 46-81 had undergone MRI and MRCP examination of the upper abdomen on a 1.5 T system with a standard flexible surface coil. The results of those tests were compared with surgical and histopathological findings. The capacity of MR and MRCP to detect pathological mass, assess the nature of the disease process, and accurately assess the resectability of the malignant lesion were evaluated. In the statistical analysis the chi-squared and Fisher's precise tests were performed. Statistical analysis showed 87% sensitivity, 97% specificity, and 95% accuracy of MRI and MRCP in the evaluation of the nature of tumors within the pancreas and 100% sensitivity, 90% specificity, and 93% accuracy in determining the resectability of the lesion. The positive predictive value came to 83%, while the negative predictive value was 100%. The kappa compatibility index in comparison with surgical findings was 0.85714. MR and MRCP is an important diagnostic method in assessing pancreatic tumors. It is very useful in differential diagnosis and determination of tumor resectability.


Parallel adaptation: one or many waves of advance of an advantageous allele?
Models for detecting the effect of adaptation on population genomic diversity are often predicated on a single newly arisen mutation sweeping rapidly to fixation. However, a population can also adapt to a new environment by multiple mutations of similar phenotypic effect that arise in parallel, at the same locus or different loci. These mutations can each quickly reach intermediate frequency, preventing any single one from rapidly sweeping to fixation globally, leading to a "soft" sweep in the population. Here we study various models of parallel mutation in a continuous, geographically spread population adapting to a global selection pressure. The slow geographic spread of a selected allele due to limited dispersal can allow other selected alleles to arise and start to spread elsewhere in the species range. When these different selected alleles meet, their spread can slow dramatically and so initially form a geographic patchwork, a random tessellation, which could be mistaken for a signal of local adaptation. This spatial tessellation will dissipate over time due to mixing by migration, leaving a set of partial sweeps within the global population. We show that the spatial tessellation initially formed by mutational types is closely connected to Poisson process models of crystallization, which we extend. We find that the probability of parallel mutation and the spatial scale on which parallel mutation occurs are captured by a single compound parameter, a characteristic length, which reflects the expected distance a spreading allele travels before it encounters a different spreading allele. This characteristic length depends on the mutation rate, the dispersal parameter, the effective local density of individuals, and to a much lesser extent the strength of selection. While our knowledge of these parameters is poor, we argue that even in widely dispersing species, such parallel geographic sweeps may be surprisingly common. Thus, we predict that as more data become available, many more examples of intraspecies parallel adaptation will be uncovered.


A computationally efficient method for nonparametric modeling of neural spiking activity with point processes.
Point-process models have been shown to be useful in characterizing neural spiking activity as a function of extrinsic and intrinsic factors. Most point-process models of neural activity are parametric, as they are often efficiently computable. However, if the actual point process does not lie in the assumed parametric class of functions, misleading inferences can arise. Nonparametric methods are attractive due to fewer assumptions, but computation in general grows with the size of the data. We propose a computationally efficient method for nonparametric maximum likelihood estimation when the conditional intensity function, which characterizes the point process in its entirety, is assumed to be a Lipschitz continuous function but otherwise arbitrary. We show that by exploiting much structure, the problem becomes efficiently solvable. We next demonstrate a model selection procedure to estimate the Lipshitz parameter from data, akin to the minimum description length principle and demonstrate consistency of our estimator under appropriate assumptions. Finally, we illustrate the effectiveness of our method with simulated neural spiking data, goldfish retinal ganglion neural data, and activity recorded in CA1 hippocampal neurons from an awake behaving rat. For the simulated data set, our method uncovers a more compact representation of the conditional intensity function when it exists. For the goldfish and rat neural data sets, we show that our nonparametric method gives a superior absolute goodness-of-fit measure used for point processes than the most common parametric and splines-based approaches.


Sodium channel heterologous expression in mammalian cells and the role of the endogenous beta1-subunits.
Sodium currents in cell lines transfected with the sole alpha-subunit, or constitutively expressing sodium channels, have an inactivation that is always prevalently mono-exponential. Differently, expression of alpha-subunit in Xenopus oocytes exerts slow inactivating currents with biphasic decay, while simultaneous co-transfection of alpha and beta1 restores a mono-exponential (normal) inactivation. A hypothesis for such differences is that an endogenous presence of beta1 or beta1-alternative splicing, beta1A, in cells could account for the normal inactivation. To test this hypothesis and to evaluate the role for the beta1A, we inhibited the expression of beta1/beta1A by antisense oligonucleotides on Nav1.4-transfected human embryonic cell line 293 (HEK) cells. Reduction of beta1/beta1A produces no significant functional effects in Nav1.4-HEK. This result invalidates the hypothesis that the lack of slow-mode in cell lines is simply due to a constitutive expression of beta1/beta1A.


The distribution and causes of meiotic recombination in the human genome.
Using the statistical analysis of genetic variation, we have developed a high-resolution genetic map of recombination hotspots and recombination rate variation across the human genome. This map, which has a resolution several orders of magnitude greater than previous studies, identifies over 25,000 recombination hotspots and gives new insights into the distribution and determination of recombination. Wavelet-based analysis demonstrates scale-specific influences of base composition, coding context and DNA repeats on recombination rates, though, in contrast with other species, no association with DNase I hypersensitivity. We have also identified specific DNA motifs that are strongly associated with recombination hotspots and whose activity is influenced by local context. Comparative analysis of recombination rates in humans and chimpanzees demonstrates very high rates of evolution of the fine-scale structure of the recombination landscape. In the light of these observations, we suggest possible resolutions of the hotspot paradox.


Cardiometabolic Profile Related to Body Adiposity Identifies Patients Eligible for Bariatric Surgery More Accurately than BMI.
Eligibility criteria for bariatric surgery (BS) are based on BMI and the presence of major comorbidities. Our aim was to analyze the usefulness of body adiposity determination in establishing the indication for BS. In order to analyze the cardiometabolic risk according to eligibility criteria for BS, four groups were studied. Morbidly obese patients with BMI ≥ 40 kg/m(2) (n = 360), and obese subjects with BMI ≥ 35 kg/m(2) and at least one comorbidity (n = 431), represented two groups of patients meeting original NIH criteria for BS. A third group included two cohorts of patients with a high body fat (BF)% that do not meet the original NIH eligibility criteria for BS: patients with either a BMI <35 kg/m(2) or a BMI ≥ 35 kg/m(2) without comorbidities (n = 266, NEHF). Lean subjects by BMI were the reference group (n = 140). BMI, BF% and markers of insulin sensitivity, lipid profile, and cardiovascular risk were measured. Individuals from the NEHF group exhibited increased HbA1c (P < 0.05) and decreased insulin sensitivity evidenced by a significant reduction in QUICKI (P < 0.001). Triglyceride concentrations were similarly increased (P < 0.05) in the three groups of obese patients. Uric acid concentrations were significantly elevated (P < 0.01) to a similar extent in the obese groups. Levels of the inflammatory marker CRP and hepatic enzymes were significantly increased in the three obese groups. The present study provides evidence for the existence of an adverse cardiometabolic profile in subjects currently considered to be outside traditional NIH guidelines but exhibiting a highly increased adiposity. It is concluded that body composition analysis yields valuable information to be incorporated into indication criteria for BS and that adiposity may be an independent indicator for BS.


Establishment of a Developmental Compartment Requires Interactions between Three Synergistic Cis-regulatory Modules.
The subdivision of cell populations in compartments is a key event during animal development. In Drosophila, the gene apterous (ap) divides the wing imaginal disc in dorsal vs ventral cell lineages and is required for wing formation. ap function as a dorsal selector gene has been extensively studied. However, the regulation of its expression during wing development is poorly understood. In this study, we analyzed ap transcriptional regulation at the endogenous locus and identified three cis-regulatory modules (CRMs) essential for wing development. Only when the three CRMs are combined, robust ap expression is obtained. In addition, we genetically and molecularly analyzed the trans-factors that regulate these CRMs. Our results propose a three-step mechanism for the cell lineage compartment expression of ap that includes initial activation, positive autoregulation and Trithorax-mediated maintenance through separable CRMs.


Silymarin and S-adenosyl-L-methionine (SAMe): two promising pharmacological agents in case of chronic alcoholic hepathopathy. A review and a point of view.
The alcoholic liver disease (ALD) is the leading cause of death from liver failure in Italy and worldwide. Ethanol abstention, a healthy diet, and a significant improvement of life-style are the mainstay of treatment for this disease. Currently, we do not have effective therapeutic options are at our disposal to restore and maintain an improved clinical status. Silymarin is a complementary and alternative medicine often prescribed and self-prescribed; it has anti-oxidant, anti-inflammatory, anti-fibrotic, and metabolic properties. It improves the laboratoristic values and the ultrasonographic grading of liver disease in case of steatosis/steatohepatitis. S-adenosyl-L-methionine (SAMe) is the principal biological methyl donor, and it is also a precursor of glutathione (GSH), essential for the anti-oxidant pathways. SAMe is particularly important for opposing the toxicity of free radicals generated by various toxins, including alcohol. An association between Silymarin and SAMe (labelled as a dietary supplement) has been recently brought to market, and seems to be promising. It could be beneficial in such cases of alcoholic hepathopathies. New therapeutic options are needed by hepatologists to successfully overcome a constantly growing disease.


Nonlinear structured illumination microscopy by surface plasmon enhanced stimulated emission depletion.
Nonlinear structured illumination microscopy (SIM) in theory has unlimited resolution over a full field of view. However under a realistic signal-to-noise ratio and a limited photon budget, the performance of nonlinear SIM strongly depends on the behavior of the nonlinear effect. Saturated SIM (SSIM) is not ideal in biological applications due to its strong photobleaching. Stimulated emission depletion (STED) SIM will have high sensitivity, higher resolution and less photo toxicity than SSIM. However, the laser power necessary to support a strong full-field STED effect is not attainable with current laser technology. We experimentally proved that surface plasmon resonance enhances (SPR) near surface STED effect by a factor of 8, and therefore STED-SIM is feasible in the total internal reflection microscopy mode with SPR enhancement. Simulation analysis predicts that SPR enhanced 2D STED is strong enough for nonlinear SIM to achieve high-speed imaging at 30-nm resolution and single molecule sensitivity. The STED-SIM superresolution microscopy method would provide a solution for observing single molecule processes in vitro or on the basal membrane of live cells.


Higher pregnancy rates using testicular sperm in men with severe oligospermia.
To evaluate assisted reproductive technology (ART) outcomes using testicular sperm in oligospermic men who previously failed to achieve paternity using TUNEL-positive ejaculated sperm. Retrospective cohort. Academic medical center. Twenty-four oligospermic men who failed one or more ART cycles using ejaculated sperm with TUNEL-positive proportion >7%, and subsequently underwent microsurgical testicular sperm extraction (TESE). TESE followed by intracytoplasmic sperm injection (ICSI). TUNEL-positive level in ejaculated and testicular sperm; clinical pregnancy. The mean TUNEL-positive level was 24.5% for ejaculated sperm, and 4.6% for testicular sperm. Clinical pregnancy was achieved in the first ART cycle with testicular sperm in 12 (50%) out of 24 couples. There was no statistically significant difference in maternal and paternal age, maternal gravity and parity, number of previous ART attempts, concentration or motility of retrieved sperm, number of oocytes retrieved, fertilization rate, or number of embryos transferred between couples who did and did not achieve pregnancy. No miscarriages occurred. All 12 pregnancies resulted in the delivery of healthy children. The percentage of TUNEL-positive cells is lower in testicular sperm for oligospermic men who have abnormal ejaculated sperm DNA fragmentation. The use of testicular sperm for ICSI was associated with a 50% pregnancy and live-birth rate for couples who had previously failed one or more IVF-ICSI cycles with ejaculated sperm. No other clinical predictors of successful pregnancies after the use of surgically retrieved sperm could be identified. In men with elevated TUNEL-positive ejaculated sperm and failed ART, TESE may be considered.


Ethics of ambulance diversion.
Ambulance diversion is a common and controversial method used by emergency departments (EDs) to reduce stress on individual departments and providers and relieve mismatches in the supply and demand for ED beds. Under this strategy, ambulances bound for one hospital are redirected to another, usually under policies established by regional emergency medical services systems. Other responses to this mismatch include maladaptive behaviors (such as "boarding" in "hallway beds") and the development of terminology intended to normalize these practices, all of which are reviewed in this article. We examine the history and causes of diversion as well as the ethical foundations and practical consequences of it. We contend that (1) from a moral viewpoint, the most important stakeholder is the individual patient because diversion decisions are usually relative rather than absolute; (2) decisions regarding ambulance diversion should be made with careful consideration of individual patient preferences, local and state emergency medical services laws, and institutional surge capacity; and (3) authorities should consider the potential positive effects of a regional or statewide ban on diversion.


Parental weight perceptions: a cause for concern in the prevention and management of childhood obesity in the United Arab Emirates.
Parental participation is a key factor in the prevention and management of childhood obesity, thus parental recognition of weight problems is essential. We estimated parental perceptions and their determinants in the Emirati population. We invited 1541 students (grade 1-12; 50% boys) and their parents, but only 1440 (6-19 years) and their parents consented. Of these, 945 Emirati nationals provided data for analysis. Anthropometric and demographic variables were measured by standard methods. CDC BMI percentile charts for age and sex were used to classify children's weight. Parental perception of their children's weight status (underweight, normal, and overweight/obese) was recorded. Logistic regression analyses were used to identify independent predictors of parental perceptions of children's weight status. Of all parents, 33.8% misclassified their children's' weight status; underestimating (27.4%) or overestimating (6.3%). Misclassification was highest among parents of overweight/obese children (63.5%) and underweight (55.1%) children. More importantly, parental perceptions of their children being overweight or obese, among truly overweight/obese children, i.e. correct identification of an overweight/obese child as such, were associated with the true child's BMI percentile (CDC) with an OR of 1.313 (95% CI: 1.209-1.425; p<0.001) per percentile point, but not age, parental education, household income, and child's sex. We conclude that the majority of parents of overweight/obese children either overestimated or, more commonly, underestimated children's weight status. Predictors of accurate parental perception, in this population, include the true children's BMI, but not age, household income, and sex. Thus, parents having an incorrect perception of their child's weight status may ignore otherwise appropriate health messages.


Effect of zinc supplementation on superoxide dismutase activity in patients with ulcerative rectocolitis.
Ulcerative rectocolitis is characterized by diffuse mucosal inflammation and oxidative stress. Thus, the organism activates the antioxidant defence system in an attempt to reduce the excessive production of reactive oxygen species or neutralize them. This study evaluated the effect of zinc supplementation on the activity of the enzyme superoxide dismutase (SOD) in patients with ulcerative rectocolitis. The study included 24 patients, aged between 20 and 59 years and diagnosed with ulcerative rectocolitis, in the remission stage of the disease, who were divided into two groups: experimental - deficient in zinc (n=12) and control - normal or high zinc (n=12). Only the first group underwent supplement intervention, in the form of zinc gluconate (30 mg Zn/day), taken daily in the morning, fasted for 60 days. Plasma and erythrocyte zinc concentrations were determined by flame atomic absorption spectrophotometer. The erythrocyte SOD activity was determined in vitro according to the methodology recommended by the manufacturer Randox. Zinc supplementation caused a significant increase in the plasma concentrations of the mineral, and showed a significant reduction in erythrocyte zinc, remaining within normal limits. The SOD activity was high in patients of both the experimental and control groups, with no difference after supplementation. This study demonstrates that zinc supplementation improves the homeostatic condition of the mineral, with no change in SOD activity, as a marker of oxidative stress in patients with ulcerative rectocolitis.


Examining the factor structure of the Motives for Playing Drinking Games measure among Australian university students.
Given the prevalence of drinking games among university students and the health risks associated with playing drinking games, it is important to consider motivations for participation. The psychometric properties of the Motives for Playing Drinking Games (MPDG) measure have been examined among US college student samples, but mixed findings have been reported regarding the number of factors in the measure. This is the first study to examine the factor structure and applicability of the MPDG measure among a sample of Australian university students. University students (N = 254; aged 18-46 years; 62% female) with prior drinking experience completed an online survey which included questions pertaining to demographics, drinking game frequency and consumption, drinking game consequences and the MPDG measure. Confirmatory factor analyses demonstrated that the originally proposed 8-factors within the MPDG measure were problematic in the current sample and a revised 7-factor solution was preferred. Analyses examining the relations of the revised 7 MPDG factors with drinking game behaviours (e.g. gaming-specific consequences and amount consumed during play) highlighted the importance of some MPDG (enhancement/thrills, conformity and sexual pursuit motives). While the MPDG measure shows promise for assessing drinking game-specific motives, the need to consider the applicability of MPDG subscales across different samples was apparent.


Multimodal neuroimaging feature learning for multiclass diagnosis of Alzheimer's disease.
The accurate diagnosis of Alzheimer's disease (AD) is essential for patient care and will be increasingly important as disease modifying agents become available, early in the course of the disease. Although studies have applied machine learning methods for the computer-aided diagnosis of AD, a bottleneck in the diagnostic performance was shown in previous methods, due to the lacking of efficient strategies for representing neuroimaging biomarkers. In this study, we designed a novel diagnostic framework with deep learning architecture to aid the diagnosis of AD. This framework uses a zero-masking strategy for data fusion to extract complementary information from multiple data modalities. Compared to the previous state-of-the-art workflows, our method is capable of fusing multimodal neuroimaging features in one setting and has the potential to require less labeled data. A performance gain was achieved in both binary classification and multiclass classification of AD. The advantages and limitations of the proposed framework are discussed.


Structural and functional studies on the interaction of GspC and GspD in the type II secretion system.
Type II secretion systems (T2SSs) are critical for secretion of many proteins from Gram-negative bacteria. In the T2SS, the outer membrane secretin GspD forms a multimeric pore for translocation of secreted proteins. GspD and the inner membrane protein GspC interact with each other via periplasmic domains. Three different crystal structures of the homology region domain of GspC (GspC(HR)) in complex with either two or three domains of the N-terminal region of GspD from enterotoxigenic Escherichia coli show that GspC(HR) adopts an all-β topology. N-terminal β-strands of GspC and the N0 domain of GspD are major components of the interface between these inner and outer membrane proteins from the T2SS. The biological relevance of the observed GspC-GspD interface is shown by analysis of variant proteins in two-hybrid studies and by the effect of mutations in homologous genes on extracellular secretion and subcellular distribution of GspC in Vibrio cholerae. Substitutions of interface residues of GspD have a dramatic effect on the focal distribution of GspC in V. cholerae. These studies indicate that the GspC(HR)-GspD(N0) interactions observed in the crystal structure are essential for T2SS function. Possible implications of our structures for the stoichiometry of the T2SS and exoprotein secretion are discussed.


Differences in clearance of mycophenolic acid among renal transplant recipients, hematopoietic stem cell transplant recipients, and patients with autoimmune disease.
For more than a decade, mycophenolate mofetil (MMF) has been used as an immunosuppressive drug in solid organ transplant recipients to prevent graft rejection. After oral administration, the prodrug MMF is rapidly hydrolyzed to the active metabolite mycophenolic acid (MPA). MMF is being used increasingly in hematopoietic stem cell transplantation (HSCTx) and autoimmune diseases (AID). The pharmacokinetics of MPA are markedly different in these patients. In comparison with renal transplant recipients (RTx), MPA clearance is increased in HSCTx patients and decreased in AIDS. The aim of this study was to characterize MPA clearance in RTx, HSCTx, and AID patients and to test whether the differences in clearance can be described by clinical chemical parameters. MPA concentration-time profiles from 19 RTx patients coprescribed cyclosporine, 17 RTx patients coprescribed tacrolimus, 38 HSCTx patients coprescribed cyclosporine, and 36 patients with AID were analyzed retrospectively with nonlinear mixed effects modeling (first-order conditional estimate). The following covariates were tested: indication for MMF treatment, sex, age, weight, plasma albumin, cyclosporine cotreatment, dose and predose blood concentration, creatinine clearance, and hemoglobin. Pharmacokinetics of MPA were described by a two-compartment model with time-lagged first-order absorption. MPA clearance was correlated in univariate analysis with plasma albumin, cyclosporine dose and predose blood concentration, creatinine clearance, hemoglobin, and indication for MMF treatment (RTx, HSCTx, or AID) (P < 0.001). All significant covariates were combined in an intermediate multivariate model followed by backward elimination. The indication for MMF treatment could be removed from the intermediate model without compromising the fit. The correlation between clearance and cyclosporine predose concentrations and plasma albumin remained significant in the final model and could describe the difference in clearance between the different indications for MMF treatment. Median clearance was 30.2, 45.6, and 10.7 L/h in RTx, HSCTx, and AID patients, respectively. In conclusion, plasma albumin concentrations and cyclosporine predose concentrations are able to describe the difference in MPA clearance among RTx, HSCTx, and AID patients.


TALEN-based gene correction for epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is characterized by a functional deficit of type VII collagen protein due to gene defects in the type VII collagen gene (COL7A1). Gene augmentation therapies are promising, but run the risk of insertional mutagenesis. To abrogate this risk, we explored the possibility of using engineered transcription activator-like effector nucleases (TALEN) for precise genome editing. We report the ability of TALEN to induce site-specific double-stranded DNA breaks (DSBs) leading to homology-directed repair (HDR) from an exogenous donor template. This process resulted in COL7A1 gene mutation correction in primary fibroblasts that were subsequently reprogrammed into inducible pluripotent stem cells and showed normal protein expression and deposition in a teratoma-based skin model in vivo. Deep sequencing-based genome-wide screening established a safety profile showing on-target activity and three off-target (OT) loci that, importantly, were at least 10 kb from a coding sequence. This study provides proof-of-concept for TALEN-mediated in situ correction of an endogenous patient-specific gene mutation and used an unbiased screen for comprehensive TALEN target mapping that will cooperatively facilitate translational application.


Magnetic protein imprinted polymers: a review.
Protein imprinted polymers have received a lot of interest in the past few years because of their applications as tailor-made receptors for biomacromolecules. Generally, the preparation of these polymers requires numerous and time-consuming steps. But their coupling with magnetic nanoparticles simplifies and speeds up the synthesis of these materials. Some recent papers describe the use of protein imprinted polymer (PIP) coupled to magnetic iron oxide nanoparticles (MION) for the design of MION@PIP biosensors. With such systems, a target protein can be specifically and selectively captured from complex media due to exceptional chemical properties of the polymer. Despite such performances, only a limited number of studies address these hybrid nanosystems. This review focuses on the chemistry and preparation of MION@PIP nanocomposites as well as on the metrics used to characterize their performances.


Effectiveness of adjuvant chemotherapy for node-positive operable breast cancer in older women.
Randomized clinical trials have shown the efficacy of adjuvant chemotherapy in treating node-positive operable breast cancer in women aged < or = 69 years, but the benefit of chemotherapy in women aged > or = 70 is questionable. This study was to examine if adjuvant chemotherapy is effective for these women with breast cancer. We studied a cohort of 5464 women diagnosed with node-positive operable breast cancer at age > or = 65 in 1992 through 1996 with last follow-up of December 31, 1999 in five states and six metropolitan areas. Hazard ratio (HR) for all-cause mortality was used for survival analysis with adjustment for patient and tumor characteristics; propensity analysis was used to control for observed factors; and sensitivity analysis was used to estimate potential effects of unmeasured confounders. After adjusting for propensity to receive chemotherapy, the chemotherapy-treated and untreated groups were not statistically significantly different for covariates except for age and hormone receptor status. Mortality was significantly reduced in women aged 65-69 who received adjuvant chemotherapy compared to those who did not, after adjusting for patient and tumor characteristics (HR = 0.70, 95% confidence interval [CI], 0.57-0.88) or after adjusting for propensity scores (HR = 0.76, 95% CI, 0.62-0.94). HR did not significantly differ between the treated and untreated women aged > or = 70 (HR = 0.96, 95% CI = 0.83-1.09, and HR = 0.99, 95% CI, 0.87-1.14). These results were relatively insensitive to changes in unmeasured confounders. Adjuvant chemotherapy is associated with improved survival in women with node-positive operable breast cancer aged 65-69 living in the community, but not in women aged > or = 70. These findings are consistent with those found in randomized controlled trials.


View-synchronized robotic image-guided therapy for atrial fibrillation ablation: experimental validation and clinical feasibility.
A robotic catheter navigation system has been developed that provides a significant degree of freedom of catheter movement. This study examines the feasibility of synchronizing this robotic navigation system with electroanatomic mapping and 3-dimensional computed tomography imaging to perform view-synchronized left atrial (LA) ablation. This study consisted of a porcine experimental validation phase (9 animals) and a clinical feasibility phase (9 atrial fibrillation patients). Preprocedural computed tomography images were reconstructed to provide 3-dimensional surface models of the LA pulmonary veins and aorta. Aortic electroanatomic mapping was performed manually, followed by registration with the corresponding computed tomography aorta image using custom software. The mapping catheter was remotely manipulated with the robotic navigation system within the registered computed tomography image of the LA pulmonary veins. The point-to-surface error between the LA electroanatomic mapping data and the computed tomography image was 2.1+/-0.7 and 1.6+/-0.1 mm in the preclinical and clinical studies, respectively. The catheter was remotely navigated into all pulmonary veins, the LA appendage, and circumferentially along the mitral valve annulus. In 7 of 9 animals, circumferential radiofrequency ablation lesions were applied periostially to ablate 11 pulmonary veins. In patients, all of the pulmonary veins were remotely electrically isolated in an extraostial fashion. Adjunctive ablation included superior vena cava isolation in 6 patients, cavotricuspid isthmus ablation in 5 patients, and ablation of sites of complex fractionated activity and atypical LA flutters in 3 patients. This study demonstrates the safety and feasibility of an emerging paradigm for atrial fibrillation ablation involving the confluence of 3 technologies: 3-dimensional imaging, electroanatomic mapping, and remote robotic navigation.


The cost of schizophrenia in Japan.
Schizophrenia is a disorder that produces considerable burdens due to its often relapsing/remitting or chronic longitudinal course. This burden is felt not only by patients themselves, but also by their families and health care systems. Although the societal burden caused by this disorder has been evaluated in several countries, the magnitude of the societal cost of schizophrenia in Japan has never been estimated. The aim of this study is to clarify the societal burden of schizophrenia by estimating the cost of schizophrenia in Japan in 2008. A human capital approach was adopted to estimate the cost of schizophrenia. The total cost of schizophrenia was calculated as the sum of the direct, morbidity, and mortality costs. Schizophrenia was defined as disorders coded as F20.0-F20.9 according to the International Classification of Diseases-10. The data required to estimate the total cost was collected from publicly available statistics or previously reported studies. The total cost of schizophrenia in Japan in 2008 was JPY 2.77 trillion (USD 23.8 billion). While the direct cost was JPY 0.770 trillion (USD 6.59 billion), the morbidity and mortality costs were JPY 1.85 trillion (USD 15.8 billion) and JPY 0.155 trillion (USD 1.33 billion), respectively. The societal burden caused by schizophrenia is tremendous in Japan, similar to that in other developed countries where published data exist. Compared with other disorders, such as depression or anxiety disorders, the direct cost accounted for a relatively high proportion of the total cost. Furthermore, absolute costs arising from unemployment were larger, while the prevalence rate was smaller, than the corresponding results for depression or anxiety in Japan.


Adapting Document Similarity Measures for Ligand-Based Virtual Screening.
Quantifying the similarity of molecules is considered one of the major tasks in virtual screening. There are many similarity measures that have been proposed for this purpose, some of which have been derived from document and text retrieving areas as most often these similarity methods give good results in document retrieval and can achieve good results in virtual screening. In this work, we propose a similarity measure for ligand-based virtual screening, which has been derived from a text processing similarity measure. It has been adopted to be suitable for virtual screening; we called this proposed measure the Adapted Similarity Measure of Text Processing (ASMTP). For evaluating and testing the proposed ASMTP we conducted several experiments on two different benchmark datasets: the Maximum Unbiased Validation (MUV) and the MDL Drug Data Report (MDDR). The experiments have been conducted by choosing 10 reference structures from each class randomly as queries and evaluate them in the recall of cut-offs at 1% and 5%. The overall obtained results are compared with some similarity methods including the Tanimoto coefficient, which are considered to be the conventional and standard similarity coefficients for fingerprint-based similarity calculations. The achieved results show that the performance of ligand-based virtual screening is better and outperforms the Tanimoto coefficients and other methods.


Fröhlich effect and delays of visual attention.
In the Fröhlich effect, the initial position of an object that suddenly appears in motion is perceived as being shifted in the direction of its motion. Here we establish that this shift is not an obligatory consequence of motion, but it is driven by focused attention. In Experiment 1 using different cueing conditions, we found that invalid cues produced larger perceptual shifts, although the Fröhlich effect was still present for valid and neutral cues. These results support Müsseler and Aschersleben's (1998) proposal that the Fröhlich effect is the result of the time it takes to shift focal attention to the moving stimulus. In Experiment 2 we found that the Fröhlich effect increased when the valid cue arrived more than 100 ms after the start of motion, suggesting again that a delay in attention's arrival shifted the location of the perceived motion onset. In Experiment 3 we compare the motion-induced shifts when the subjects attended to a set of moving stimuli as a group and when they attended to an orientation singleton. We showed that Fröhlich effect was only present when the target was individuated and disappeared when the stimulus was perceived globally. We conclude that the Fröhlich effect is a predictive spatial shift produced and modulated by focal attention.


Occupational exposure to extremely low frequency magnetic fields and risk of Alzheimer disease: A systematic review and meta-analysis.
Occupational exposure to extremely low frequency magnetic fields (ELF-MF) occurs in many occupations such as welders, electric utility workers, train drivers and sewing machine operators. There is some evidence suggesting ELF-MF exposure to be a risk factor for Alzheimer's disease (AD). The current study aims at systematically reviewing the literature and conducting a meta-analysis to evaluate the risk of AD amongst workers exposed to ELF-MF. Bibliographic databases were searched including PubMed, EMBASE, Cochrane Library, and Web of Science in November 2017. Risk of bias was assessed in the all included studies. Pooled estimates were obtained using random-effects meta-analysis. In addition, sources of heterogeneity between studies and publication bias were explored. In total, 20 articles met the inclusion criteria. The pooled results suggest an increased risk of AD (RR: 1.63; 95% CI: 1.35, 1.96). Higher risk estimates were obtained from case-control studies (OR: 1.80; 95% CI: 1.40, 2.32) than from cohort studies (RR: 1.42; 95% CI: 1.08, 1.87). A moderate to high heterogeneity (I2 = 61.0%) and indication for publication bias (Egger test: p < 0.001) were found. The results suggested that occupational exposure to ELF-MF might increase the risk of AD. However, this suggestion should be interpreted with caution given the moderate to high heterogeneity and indication for publication bias.


Genomic basis of the differences between cider and dessert apple varieties.
Unraveling the genomic processes at play during variety diversification is of fundamental interest for understanding evolution, but also of applied interest in crop science. It can indeed provide knowledge on the genetic bases of traits for crop improvement and germplasm diversity management. Apple is one of the most important fruit crops in temperate regions, having both great economic and cultural values. Sweet dessert apples are used for direct consumption, while bitter cider apples are used to produce cider. Several important traits are known to differentiate the two variety types, in particular fruit size, biennial versus annual fruit bearing, and bitterness, caused by a higher content in polyphenols. Here, we used an Illumina 8k SNP chip on two core collections, of 48 dessert and 48 cider apples, respectively, for identifying genomic regions responsible for the differences between cider and dessert apples. The genome-wide level of genetic differentiation between cider and dessert apples was low, although 17 candidate regions showed signatures of divergent selection, displaying either outlier F ST values or significant association with phenotypic traits (bitter versus sweet fruits). These candidate regions encompassed 420 genes involved in a variety of functions and metabolic pathways, including several colocalizations with QTLs for polyphenol compounds.


The pea GIGAS gene is a FLOWERING LOCUS T homolog necessary for graft-transmissible specification of flowering but not for responsiveness to photoperiod.
Garden pea (Pisum sativum) was prominent in early studies investigating the genetic control of flowering and the role of mobile flowering signals. In view of recent evidence that genes in the FLOWERING LOCUS T (FT) family play an important role in generating mobile flowering signals, we isolated the FT gene family in pea and examined the regulation and function of its members. Comparison with Medicago truncatula and soybean (Glycine max) provides evidence of three ancient subclades (FTa, FTb, and FTc) likely to be common to most crop and model legumes. Pea FT genes show distinctly different expression patterns with respect to developmental timing, tissue specificity, and response to photoperiod and differ in their activity in transgenic Arabidopsis thaliana, suggesting they may have different functions. We show that the pea FTa1 gene corresponds to the GIGAS locus, which is essential for flowering under long-day conditions and promotes flowering under short-day conditions but is not required for photoperiod responsiveness. Grafting, expression, and double mutant analyses show that GIGAS/FTa1 regulates a mobile flowering stimulus but also provide clear evidence for a second mobile flowering stimulus that is correlated with expression of FTb2 in leaf tissue. These results suggest that induction of flowering by photoperiod in pea results from interactions among several members of a diversified FT family.


Serum level of substance P in patients with lung injuries due to sulfur mustard.
Chronic bronchiolitis is the most important problems of chemical victims of mustard gas. Diverse studies suggest that substance P (SP) as a member of tachykinin neuropeptides, has a significant role in the neurogenic inflammation processes of the airways and lungs. We aimed to determine the serum level of SP in chemical victims of mustard gas and compare it with normal subjects. The chemical victims were divided into the 2 groups of 30:A group with mild to moderate pulmonary symptoms and other group with moderate to severe symptoms and compared with 3(rd) group as healthy controls. After preparing our samples and using the SP kit, final analysis was performed with enzyme-linked immunosorbent assay reader. The Concentration of circulatory SP levels in the chemical patients was 2.86 ± 1.47 ng/ml and had not a significant difference with the control group (3.15 ± 1.03 ng/ml) (P > 0.05). The circulatory SP levels were 2.48 ± 0.92 ng/ml and 3.28 ± 1.73 ng/ml in patients with moderate to severe symptoms and mild to moderates (P < 0.05) respectively. The SP may have a role in pulmonary complications of mustard gas. The lower level of SP in the moderate to severe patients may be due to corticosteroid consumption in such severe cases. However, further studies are needed to clarify the roles and mechanism of SP in this setting.


Immediate inferences from quantified assertions.
We propose a theory of immediate inferences from assertions containing a single quantifier, such as: All of the artists are bakers; therefore, some of the bakers are artists. The theory is based on mental models and is implemented in a computer program, mReasoner. It predicts three main levels of increasing difficulty: (a) immediate inferences in which the premise and conclusion have identical meanings; (b) those in which the initial mental model of the premise yields the correct conclusion; and (c) those in which only an alternative to the initial model establishes the correct conclusion. These levels of difficulty were corroborated for inferences to necessary conclusions (in a reanalysis of data from Newstead, S. E., & Griggs, R. A. (1983). Drawing inferences from quantified statements: A study of the square of opposition. Journal of Verbal Learning and Verbal Behavior, 22, 535-546), for inferences to modal conclusions, such as, it is possible that all of the bakers are artists (Experiment 1), for inferences with unorthodox quantifiers, such as, most of the artists (Experiment 2), and for inferences about the consistency of pairs of quantified assertions (Experiment 3). The theory also includes three parameters in a stochastic system that predicted quantitative differences in accuracy within the three main sorts of inference.


Studies using macaque monkeys to address excessive alcohol drinking and stress interactions.
The use of non-human primates (NHPs) in studies of volitional, oral self-administration of alcohol can help address the complex interplay between stress and excessive alcohol consumption. There are aspects to brain, endocrine and behavior of NHPs, particularly macaques, that provide a critical translational link towards understanding the risks and consequences of alcohol use disorders (AUDs) in humans. These include wide individual differences in escalating daily alcohol intake, accurate measures of hypothalamic-pituitary-adrenal (HPA) axis hormonal interactions, neuroanatomical specificity of synaptic adaptations to chronic alcohol, genetic similarities to humans, and the ability to conduct in vivo brain imaging. When placed in a framework that alcohol addiction is a sequence of dysregulations in motivational circuitry associated with severity of AUD, the NHP can provide within-subject information on both risks for and consequences of repeatedly drinking to intoxication. Notably, long-term adaptations in neurocircuitry that mediate behavioral reinforcement, stress responses and executive functions are possible with NHPs. We review here the substantial progress made using NHPs to address the complex relationship between alcohol and stress as risk factors and consequences of daily drinking to intoxication. This review also highlights areas where future studies of brain and HPA axis adaptations are needed to better understand the mechanisms involved in stress leading to excessive alcohol consumption. This article is part of the Special Issue entitled "Alcoholism".


Kinome RNAi Screens Reveal Synergistic Targeting of MTOR and FGFR1 Pathways for Treatment of Lung Cancer and HNSCC.
The FGFR1 is a therapeutic target under investigation in multiple solid tumors and clinical trials of selective tyrosine kinase inhibitors (TKI) are underway. Treatment with a single TKI represents a logical step toward personalized cancer therapy, but intrinsic and acquired resistance mechanisms limit their long-term benefit. In this study, we deployed RNAi-based functional genomic screens to identify protein kinases controlling the intrinsic sensitivity of FGFR1-dependent lung cancer and head and neck squamous cell cancer (HNSCC) cells to ponatinib, a multikinase FGFR-active inhibitor. We identified and validated a synthetic lethal interaction between MTOR and ponatinib in non-small cell lung carcinoma cells. In addition, treatment with MTOR-targeting shRNAs and pharmacologic inhibitors revealed that MTOR is an essential protein kinase in other FGFR1-expressing cancer cells. The combination of FGFR inhibitors and MTOR or AKT inhibitors resulted in synergistic growth suppression in vitro. Notably, tumor xenografts generated from FGFR1-dependent lung cancer cells exhibited only modest sensitivity to monotherapy with the FGFR-specific TKI, AZD4547, but when combined with the MTOR inhibitor, AZD2014, significantly attenuated tumor growth and prolonged survival. Our findings support the existence of a signaling network wherein FGFR1-driven ERK and activated MTOR/AKT represent distinct arms required to induce full transformation. Furthermore, they suggest that clinical efficacy of treatments for FGFR1-driven lung cancers and HNSCC may be achieved by combining MTOR inhibitors and FGFR-specific TKIs.


Physiological genomics of antidepressant targets: keeping the periphery in mind.
The plasma membrane transporters that clear extracellular serotonin (5-HT) and norepinephrine (NE), serotonin transporters (SERTs) and NE transporters (NETs), have received considerable attention over the past four decades because of their roles in amine neurotransmitter inactivation. In addition, they interact with many centrally active drugs, including multiple classes of antidepressants such as the serotonin-selective reuptake inhibitors, typified by fluoxetine (Prozac), and the more recently developed norepinephrine-selective transporter antagonists, such as reboxetine. The therapeutic utility of these agents supports biogenic amine theories of affective disorders and raises the question as to whether SERT and NET exhibit a functional genetic variation that could influence risk for behavioral disorders. Although evidence exists that a promoter polymorphism in SERT may influence behavioral states, this contention is not without complexity and its mechanism of action remains poorly understood. The identification of coding variants of NETs and SERTs would offer important opportunities to connect genotype to phenotype. However, given the limited frequency of transporter coding variations evident to date in general population surveys or in psychiatric genetic studies, the identification of informative functional variants of transporters will likely require refined phenotypes. In this regard, NET and SERT play critical roles in cardiovascular and gastrointestinal physiology, respectively. This perspective reviews recent human and mouse studies that suggest how peripheral autonomic phenotypes, linked to genetic disruption of NET and SERT function, can aid in the phenotypic segregation needed for advanced theories of biogenic amine dysfunction and pharmacogenetics.


Inflammatory and immune markers associated with physical frailty syndrome: findings from Singapore longitudinal aging studies.
Chronic systematic inflammation and reduced immune system fitness are considered potential contributing factors to the development of age-related frailty, but the underlying mechanisms are poorly defined. This exploratory study aimed to identify frailty-related inflammatory markers and immunological phenotypes in a cohort of community-dwelling adults aged ≥ 55 years. Frailty was assessed using two models, a Frailty Index and a categorical phenotype, and correlated with levels of circulating immune biomarkers and markers of senescence in immune cell subsets. We identified eight serological biomarkers that were associated with frailty, including sgp130, IL-2Rα, I-309, MCP-1, BCA-1, RANTES, leptin, and IL-6R. Frailty Index was inversely predicted by the frequency of CD3+, CD45RA+, and central memory CD4 cells, and positively predicted by the loss of CD28 expression, especially in CD8+ T cells, while frailty status was predicted by the frequency of terminal effector CD8+ T cells. In γ/δ T cells, frailty was negatively associated with CD27, and positively associated with IFNγ+TNFα- secretion by γ/δ2+ cells and IFNγ-TNFα+ secretion by γ/δ2- cells. Increased numbers of exhausted and CD38+ B cells, as well as CD14+CD16+ inflammatory monocytes, were also identified as frailty-associated phenotypes. This pilot study supports an association between inflammation, cellular immunity, and the process of frailty. These findings have significance for the early identification of frailty using circulating biomarkers prior to clinical manifestations of severe functional decline in the elderly.


Transnational dental care among Canadian immigrants.
This study examines predictors of transnational dental care utilization, or the use of dental care across national borders, over a 4-year period among immigrants to Canada. Data from the Longitudinal Survey of Immigrants to Canada (LSIC, 2001-2005) were used. Sampling and bootstrap weights were applied to make the data nationally representative. Bivariate and multiple logistic regression analyses were applied to identify factors associated with immigrants' transnational dental care utilization. Approximately 13% of immigrants received dental care outside Canada over a period of 4 years. Immigrants lacking dental insurance (OR = 2.05; 95% CI: 1.55-2.70), those reporting dental problems (OR = 1.45; 95% CI: 1.12-1.88), who were female (OR = 1.59; 95% CI: 1.22-2.08), aged ≥ 50 years (OR = 2.30; 95% CI: 1.45-3.64), and who were always unemployed (OR = 1.70; 95% CI: 1.20-2.39) were more likely to report transnational dental care utilization. History of social assistance was inversely correlated with the use of dental services outside Canada (OR = 0.48; 95% CI: 0.30-0.83). It is estimated that roughly 11 500 immigrants have used dental care outside Canada over a 4-year period. Although transnational dental care utilization may serve as an individual solution for immigrants' initial barriers to accessing dental care, it demonstrates weaknesses to in-country efforts at providing publicly funded dental care to socially marginalized groups. Policy reforms should be enacted to expand dental care coverage among adult immigrants.


The current and future therapies of bone regeneration to repair bone defects.
Bone defects often result from tumor resection, congenital malformation, trauma, fractures, surgery, or periodontitis in dentistry. Although dental implants serve as an effective treatment to recover mouth function from tooth defects, many patients do not have the adequate bone volume to build an implant. The gold standard for the reconstruction of large bone defects is the use of autogenous bone grafts. While autogenous bone graft is the most effective clinical method, surgical stress to the part of the bone being extracted and the quantity of extractable bone limit this method. Recently mesenchymal stem cell-based therapies have the potential to provide an effective treatment of osseous defects. In this paper, we discuss both the current therapy for bone regeneration and the perspectives in the field of stem cell-based regenerative medicine, addressing the sources of stem cells and growth factors used to induce bone regeneration effectively and reproducibly.


A 4-week Repeated Dose Toxicity Study of Glycine in Rats by Gavage Administration.
In order to examine the toxicity profile of glycine, an authorized food additive, a solution of glycine in water for injection was administered orally (via gavage) to male SD rats (Crl:CD(SD)) once daily for 4 weeks at doses of 500, 1000 and 2000 mg/kg/day in a volume of 10 mL/kg. Control animals received vehicle only. No animals died, and no glycine-related changes were observed in body weight, food consumption, water consumption, hematology, organ weight, gross pathological examination or histopathological examination. In urinalysis, daily urinary volume and urinary Cl excretion were significantly higher in the 2000 mg/kg/day dose group, and urine pH and urinary protein showed lower trends in the glycine-treated groups. However, these changes were considered to be of little toxicological significance, because there were no histopathological changes in the kidneys or urinary bladder and no changes in other urinary parameters. As regards blood chemistry, phospholipids were significantly higher in the 2000 mg/kg/day dose group. However, the increase was small and was not considered to be toxicologically significant. In conclusion, none of the animals in any of the glycine-treated groups showed changes that were considered toxicologically significant. Therefore, the no-observed-adverse-effect level of glycine was estimated to be at least 2000 mg/kg/day under the conditions of this study.


Association between childhood trauma and physical disorders among adults in the United States.
The goal of this investigation was to determine the association between self-reported childhood trauma and physical disorders among adults in the United States. Data were drawn from the National Comorbidity Survey (N=5877). Multiple logistic regression analyses were used to determine the associations between childhood physical abuse, sexual abuse, and childhood neglect and the likelihood of specific physical disorders among adults. Childhood physical abuse, sexual abuse and neglect were associated with a statistically significantly increased risk of a wide range of physical illnesses during adulthood. After adjusting for demographic characteristics, lifetime anxiety and depressive disorders, alcohol and substance dependence, and all types of trauma: results showed that childhood physical abuse was associated with increased risk of lung disease (OR= 1.5 (1.1, 2.2)), peptic ulcer (OR= 1.5 (1.03, 2.2)) and arthritic disorders (OR= 1.5 (1.1, 2.2)); childhood sexual abuse was associated with increased risk of cardiac disease (OR = 3.7 (1.5, 9.4)); and childhood neglect was associated with increased risk of diabetes (OR=2 2 (1.1, 4.4)) and autoimmune disorders (OR =4.4 (1.7, 11.6)). Consistent with previous work, these results suggest that self-reported childhood trauma is associated with increased risk of a range of physical illnesses during adulthood. Future research that includes replication of these findings using prospectively assessed physical and mental disorders with objectively measured biological data using a longitudinal design, including other known risk factors for these diseases and more detailed information on specific forms of abuse, is needed to understand the potential mechanisms of these links.


Recent advances in layered double hydroxides applied to photoprotection.
Layered double hydroxides have received more attention from researchers due to their range of applications, ease of synthesis and low cost of production. With broader knowledge about solar radiation effects on the body, the use of sunscreens has become even more important. The ability of some nanostructures, such as layered double hydroxides, to act as matrices has made it possible to obtain improvements in photoprotective formulations, with solutions to problems caused by radiation and sunscreens. This review article brings together the most recent advances of these clays, the layered double hydroxides, applied to photoprotection.


Comparative efficacy versus effectiveness of initial antiretroviral therapy in clinical trials versus routine care.
The applicability of clinical trial findings (efficacy) to the routine care setting (effectiveness) may be limited because of study eligibility criteria and volunteer bias. Although well-chronicled in many conditions, the efficacy versus effectiveness of antiretroviral therapy (ART) remains understudied. A retrospective study of the University of Alabama at Birmingham 1917 Clinic Cohort evaluated ART-naive patients who started ART from 1 January 2000 through 31 December 2006. Patients received ART through clinical trials or routine care. Multivariable logistic and linear regression models were fit to evaluate factors associated with virological failure (virological failure was defined as a viral load >50 copies/mL) and change from baseline CD4+ cell count 6 and 12 months after ART initiation. Sensitivity analyses evaluated the impact of missing data on outcomes. Among 570 patients starting ART during the study period, 121 (21%) enrolled in clinical trials, and 449 (79%) received ART via routine care. ART receipt through routine care was not associated with viral failure at either 6 months (odds ratio [OR], 1.00; 95% confidence interval [CI], 0.54-1.86) or 12 months (OR, 1.56; 95% CI, 0.80-3.05) in primary analyses. No statistically significant differences in CD4+ cell count responses at 6 and 12 months were observed. Although marked differences in efficacy versus effectiveness have been observed in the therapeutic outcomes of other conditions, our analyses found no evidence of such divergence among our patients who initiated antiretroviral therapy for human immunodeficiency virus infection.


Human rhinovirus infection causes different DNA methylation changes in nasal epithelial cells from healthy and asthmatic subjects.
Mechanisms underlying the development of virus-induced asthma exacerbations remain unclear. To investigate if epigenetic mechanisms could be involved in virus-induced asthma exacerbations, we undertook DNA methylation profiling in asthmatic and healthy nasal epithelial cells (NECs) during Human Rhinovirus (HRV) infection in vitro. Global and loci-specific methylation profiles were determined via Alu element and Infinium Human Methylation 450 K microarray, respectively. Principal components analysis identified the genomic loci influenced the most by disease-status and infection. Real-time PCR and pyrosequencing were used to confirm gene expression and DNA methylation, respectively. HRV infection significantly increased global DNA methylation in cells from asthmatic subjects only (43.6% to 44.1%, p = 0.04). Microarray analysis revealed 389 differentially methylated loci either based on disease status, or caused by virus infection. There were disease-associated DNA methylation patterns that were not affected by HRV infection as well as HRV-induced DNA methylation changes that were unique to each group. A common methylation locus stood out in response to HRV infection in both groups, where the small nucleolar RNA, H/ACA box 12 (SNORA12) is located. Further analysis indicated that a relationship existed between SNORA12 DNA methylation and gene expression in response to HRV infection. We describe for the first time that Human rhinovirus infection causes DNA methylation changes in airway epithelial cells that differ between asthmatic and healthy subjects. These epigenetic differences may possibly explain the mechanism by which respiratory viruses cause asthma exacerbations.


Stopping of light by the dynamic tuning of photonic crystal slow light device.
We propose a simple technique of stopping light pulses using a slow-light device based on photonic crystal coupled waveguide (PCCW). Dynamically tuning the material index chirp in the PCCW adiabatically transforms slow-light pulses into stopped ones. We demonstrate this in finite-difference time-domain simulation assuming ideal and actual tuning of the index chirp. In the ideal case, the group velocity of the almost stopped pulse is reduced to 190 times smaller than that of simple slow light pulse. The smallest limit is affected by the timing error of the tuning between wavelengths. Re-ordering and stopping of a pulse train are possible by optimizing the device length and timing. As a practical tuning method, we discuss carrier effects induced by photo-excitation. Taking into account carrier distribution and free carrier absorption, the actual behaviors of stopped light are estimated. We define and evaluate an effective delay-bandwidth product, which is affected by free carrier absorption.


Requirement for a uroplakin 3a-like protein in the development of zebrafish pronephric tubule epithelial cell function, morphogenesis, and polarity.
Uroplakin (UP)3a is critical for urinary tract development and function; however, its role in these processes is unknown. We examined the function of the UP3a-like protein Upk3l, which was expressed at the apical surfaces of the epithelial cells that line the pronephric tubules (PTs) of the zebrafish pronephros. Embryos treated with upk3l-targeted morpholinos showed decreased pronephros function, which was attributed to defects in PT epithelial cell morphogenesis and polarization including: loss of an apical brush border and associated phospho-ERM proteins, apical redistribution of the basolateral Na(+)/K(+)-ATPase, and altered or diminished expression of the apical polarity complex proteins Prkcz (atypical protein kinase C zeta) and Pard3 (Par3). Upk3l missing its C-terminal cytoplasmic domain or containing mutations in conserved tyrosine or proline residues did not rescue, or only partially rescued the effects of Upk3l depletion. Our studies indicate that Upk3l promotes epithelial polarization and morphogenesis, likely by forming or stimulating interactions with cytoplasmic signaling or polarity proteins, and that defects in this process may underlie the pathology observed in UP3a knockout mice or patients with renal abnormalities that result from altered UP3a expression.


Palliative care education in neonatal units: impact on knowledge and attitudes.
To facilitate improved and earlier access to palliative care for babies, a 4-h workshop on the principles, practice and resources in palliative care was delivered in 21 neonatal units across London. This paper assesses the impact of these workshops. As part of mixed methods, processual evaluation of a series of education workshops, a pre and post survey instrument was developed, consisting of open and closed questions assessing knowledge of services and attitudes towards palliative care. Before and after each workshop attendees were invited to complete the survey. Neonatal units in hospitals across London, including examples of intensive care, high dependency and special care units. 331 healthcare professionals attended the sessions, and 264 (80%) completed questionnaires. The majority of attendees were experienced neonatal nurses working in neonatal intensive care (61% more than 7 years) but with limited experience of palliative care services. Over 79% of respondents reported that the workshop completely met their learning needs. Post-session 80% of respondents felt confident referring to palliative care services, compared with 46% before (p<0.001). Analysis of open and closed text responses revealed a shift in attitude after the sessions from a focus on dying/end-of-life, towards integrating palliative care as part of a holistic treatment plan. A short (half day), locally delivered workshop can change attitudes and increase knowledge in neonatal staff. Such a workshop can serve as a first step in facilitating access to and utilisation of a variety of palliative care services.


Cellular immunohistopathology of acute, subacute, and chronic synovitis in rheumatoid arthritis.
Cellular inflammation in rheumatoid arthritis (RA) synovial membrane was studied in biopsy specimens taken at different stages of synovitis and disease. Patients were classified into three subgroups: acute RA, subacute RA, and chronic RA. Inflammatory cells were characterised by a histochemical esterase method and immunohistochemical peroxidase-antiperoxidase (PAP) and avidin-biotin-peroxidase (ABC) staining. The amounts and distribution of inflammatory cells were different in various stages of the synovitis. In acute onset RA monocytes and granulocytes predominated, suggesting that the beginning of rheumatoid inflammation is similar to inflammatory reaction in general. The presence of T cells and also of plasma cells in subacute RA suggests underlying subclinical changes also in apparently healthy joints in RA. The most typical feature of prolonged synovitis in chronic RA was its intensity, characterised by the presence of large T cell and plasma cell infiltrates. Our findings suggest that the immunological mechanisms are secondary to the tissue damage caused by the initial inflammatory events of unknown cause. However, the immunological mechanisms may still play a central role in the aetiopathogenesis, because findings in chronic RA suggest a defective down-regulation of the immune response.


A cost effective 5΄ selective single cell transcriptome profiling approach with improved UMI design.
Single cell RNA sequencing approaches are instrumental in studies of cell-to-cell variability. 5΄ selective transcriptome profiling approaches allow simultaneous definition of the transcription start size and have advantages over 3΄ selective approaches which just provide internal sequences close to the 3΄ end. The only currently existing 5΄ selective approach requires costly and labor intensive fragmentation and cell barcoding after cDNA amplification. We developed an optimized 5΄ selective workflow where all the cell indexing is done prior to fragmentation. With our protocol, cell indexing can be performed in the Fluidigm C1 microfluidic device, resulting in a significant reduction of cost and labor. We also designed optimized unique molecular identifiers that show less sequence bias and vulnerability towards sequencing errors resulting in an improved accuracy of molecule counting. We provide comprehensive experimental workflows for Illumina and Ion Proton sequencers that allow single cell sequencing in a cost range comparable to qPCR assays.


Measurement of local capillary permeability in skeletal muscle by microscopic clearance method.
To measure local capillary permeability to lipid-insoluble substances, we developed a microscopic tissue clearance method. It has been theoretically predicted that, when a tissue is stained with a dye by suffusing its solution around the tissue, subsequent concentration changes of the dye in the tissue due to adequate capillary flow washout takes a monoexponential time course of which decay constant is equal to the local capillary permeability surface area product (PS) per unit tissue volume. Therefore, when the capillary surface area (S) is calculated from the open capillary density in the adjacent tissue, it is possible to estimate the local permeability (P). This method was applied to the rabbit tenuissimus muscle under maximum vasodilatation, using Cr-EDTA (M.W. = 341) as a tracer. The correlation coefficient of the obtained clearance curves to the monoexponential decay was averaged to be 0.958 +/- 0.029 in 12 curves. The calculated values of Cr-EDTA permeability, 6.0 +/- 0.7 x 10(-6) cm/s, fairly well agreed with those reported for sucrose (M.W. = 342). It was concluded that this method is useful to measure local capillary permeability of small lipid-insoluble tracers.


Complete Genome Sequence of Actinomadura Parvosata Subsp. Kistnae, A Rich Source of Novel Natural Product (Bio-)Chemistry.
The soil dwelling actinomycete strain Actinomadura parvosata subsp. kistnae is the producer of the antiviral antibiotics kistamicin A and B. Genome sequencing and bioinformatic analysis revealed the presence of the kistamycin biosynthetic gene cluster responsible for the formation of these non-ribosomal peptides as well as an impressive number of yet uncharacterized biosynthetic pathways. This includes polyketide, ribosomal and non-ribosomal peptide and a large number of terpenoid biosynthetic loci encoding yet unknown natural products. The genomic data of this strain is thus a treasure trove for genome mining for novel functional metabolites and new biocatalysts.


Non-invasive and real-time passive acoustic mapping of ultrasound-mediated drug delivery.
New classes of biologically active materials, such as viruses, siRNA, antibodies and a wide range of engineered nanoparticles have emerged as potent agents for diagnosing and treating diseases, yet many of these agents fail because there is no effective route of delivery to their intended targets. Focused ultrasound and its ability to drive microbubble-seeded cavitation have been shown to facilitate drug delivery. However, cavitation is difficult to control temporally and spatially, making prediction of therapeutic outcomes deep in the body difficult. Here, we utilized passive acoustic mapping in vivo to understand how ultrasound parameters influence cavitation dynamics and to correlate spatial maps of cavitation to drug delivery. Focused ultrasound (center frequency: 0.5 MHz, peak-rarefactional pressure: 1.2 MPa, pulse length: 25 cycles or 50,000 cycles, pulse repetition interval: 0.02, 0.2, 1 or 3 s, number of pulses: 80 pulses) was applied to murine xenograft-model tumors in vivo during systemic injection of microbubbles with and without cavitation-sensitive liposomes or type 5 adenoviruses. Analysis of in vivo cavitation dynamics through several pulses revealed that cavitation was more efficiently produced at a lower pulse repetition frequency of 1 Hz than at 50 Hz. Within a pulse, inertial cavitation activity was shown to persist but reduced to 50% and 25% of its initial magnitude in 4.3 and 29.3 ms, respectively. Both through several pulses and within a pulse, the spatial distribution of cavitation was shown to change in time due to variations in microbubble distribution present in tumors. Finally, we demonstrated that the centroid of the mapped cavitation activity was within 1.33 ± 0.6 mm and 0.36 mm from the centroid location of drug release from liposomes and expression of the reporter gene encoded by the adenovirus, respectively. Thus passive acoustic mapping not only unraveled key mechanisms whereby a successful outcome is achieved, but also a predicted drug delivery outcome.


Cervical Adenocarcinoma: Histopathologic Features From Biopsies to Predict Tumor Behavior.
The pattern-based classification system of endocervical adenocarcinoma correlates with nodal metastasis and clinical outcomes, but its application in biopsies is challenging. The aim of this study was the correlation of additional histologic features with patterns of invasion as well as prognosis. A total of 103 specimens from 71 cervical adenocarcinoma cases were studied. Among the 71 cases, all had resection specimens including hysterectomy, cold knife cone excision or loop electrosurgical excision procedure excision, and 32 of these had prior cervical biopsies. We applied the pattern-based classification system to all the specimens and evaluated histopathologic features microscopically. Findings in biopsies were compared with their corresponding resections and correlated with nodal status and disease stage. In 71 resection specimens, pattern A was present in 10 (14.1%), pattern B in 12 (16.9%), and pattern C in 49 (69%) cases. Of the 32 cervical biopsies, pattern of invasion could be classified in only 16 (50%) cases, including 1 (6%) with pattern A, 4 (25%) with pattern B, and 11 (69%) with pattern C. Of the 32 cervical biopsies, 30 could be evaluated for intraluminal necrotic/tumor debris and/or grade 3 nuclei, which correlated with pattern C as well as with lymph node metastasis in the subsequent staging specimens. No tumor with patterns A or B had intraluminal necrotic/tumor debris or grade 3 nuclei in either biopsy or resection specimens. Therefore, intraluminal necrotic/tumor debris and grade 3 nuclei are highly predictive histologic features for cervical adenocarcinomas with pattern C invasion and nodal metastasis.


The impact of age on complications, survival, and cause of death following colon cancer surgery.
Given scarce data regarding the relationship among age, complications, and survival beyond the 30-day postoperative period for oncology patients in the United States, this study identified age-related differences in complications and the rate and cause of 1-year mortality following colon cancer surgery. The NY State Cancer Registry and Statewide Planning and Research Cooperative System identified stage I-III colon cancer resections (2004-2011). Multivariable logistic regression and survival analyses assessed the relationship among age (<65, 65-74, ⩾75), complications, 1-year survival, and cause of death. Among 24 426 patients surviving >30 days, 1-year mortality was 8.5%. Older age groups had higher complication rates, and older age and complications were independently associated with 1-year mortality (P<0.0001). Increasing age was associated with a decrease in the proportion of deaths from colon cancer with a concomitant increase in the proportion of deaths from cardiovascular disease. Older age and sepsis were independently associated with higher risk of colon cancer-specific death (65-74: HR=1.59, 95% CI=1.26-2.00; ⩾75: HR=2.57, 95% CI=2.09-3.16; sepsis: HR=2.58, 95% CI=2.13-3.11) and cardiovascular disease-specific death (65-74: HR=3.72, 95% CI=2.29-6.05; ⩾75: HR=7.02, 95% CI=4.44-11.10; sepsis: HR=2.33, 95% CI=1.81-2.99). Older age and sepsis are associated with higher 1-year overall, cancer-specific, and cardiovascular-specific mortality, highlighting the importance of geriatric assessment, multidisciplinary care, and cardiovascular optimisation for older patients and those with infectious complications.


The Tat protein of human immunodeficiency virus type 1 is a substrate and inhibitor of the interferon-induced, virally activated protein kinase, PKR.
We demonstrate that the interferon-induced, double-stranded (ds) RNA-activated kinase, PKR, is able to bind to and phosphorylate the human immunodeficiency virus type 1 (HIV-1) trans-activating protein, Tat. Furthermore, Tat can inhibit the activation and activity of the kinase. Phosphorylation of Tat by PKR is dependent on the prior activation of PKR by dsRNA and occurs on serine and threonine residues adjacent to the basic region important for TAR RNA binding and Tat function. Activated PKR efficiently phosphorylates both the two-exon form of Tat (Tat-86) and the single exon form (Tat-72). Mutagenesis indicates that the interaction between PKR and Tat requires the RNA-binding region of Tat. Tat competes with eukaryotic initiation factor 2, a well-characterized substrate of PKR, for phosphorylation by activated PKR. Tat also inhibits the autophosphorylation of PKR by dsRNA. This biochemical evidence of an intimate relationship between Tat, an important regulator of HIV transcription, and PKR, a pleiotropic cellular regulator, may provide insights into HIV-1 pathogenesis and, more generally, virus/host interactions.


Acromegaly in the elderly patients.
Acromegaly is a rare disease characterized by a chronic exposition to growth hormone (GH) and insulin-like growth factor-1 (IGF-1), caused in most cases by a pituitary GH-secreting adenoma. Chronic GH excess induces systemic complications (metabolic, cardiovascular, respiratory, neoplastic, and musculoskeletal) and increased mortality if not appropriately treated. Recent epidemiological data report an improved life span of patients with acromegaly probably due to better acromegaly management; additionally, the number of pituitary incidentaloma in general population also increased over time due to more frequent imaging. Therefore, the number of elderly patients, newly diagnosed with acromegaly or in follow-up, is expected to grow in the coming years and clinicians will need to be aware of particularities in managing these patients. This review aims to explore different aspects of acromegaly of the elderly patients, focusing on epidemiology, diagnosis, clinical presentation, complications, and management options. Available literature has been assessed through PubMed (data until August 2019) by specific keywords. Available data on acromegaly in the elderly patient are sparse, but point to important differences. Further studies are needed comparing elderly with younger patients with acromegaly to better define a tailored diagnostic and therapeutic management.


FR167653 inhibits fibronectin expression and apoptosis in diabetic glomeruli and in high-glucose-stimulated mesangial cells.
Previous in vitro studies suggest that the p38 MAPK pathway may be involved in the pathogenesis of diabetic nephropathy, but the consequences of the inhibition of the p38 MAPK pathway have not been well elucidated in diabetic (DM) glomeruli. This study was undertaken to investigate the effect of p38 MAPK inhibitor, FR167653, on fibronectin expression and apoptosis in DM glomeruli and in high-glucose-stimulated mesangial cells (MC). In vivo, 32 Sprague-Dawley rats were injected with diluent (control, N = 16) or streptozotocin intraperitoneally (DM, N = 16). Eight rats from each group were treated with FR167653 for 3 mo. In vitro, rat MC were exposed to medium containing 5.6 mM glucose or 30 mM glucose [high glucose (HG)] with or without 10(-6) M FR167653 for 24 h. Fibronectin mRNA and protein expression were determined by real-time PCR and Western blot, respectively. Western blot for apoptosis-related molecules, terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, and Hoechst 33342 staining were performed to determine apoptosis. FR167653 ameliorated the increases in fibronectin-to-GAPDH mRNA ratio and protein expression in DM glomeruli by 89 and 79% and in HG-stimulated MC by 70 and 91%, respectively (P < 0.05). Under diabetic conditions, Bcl-2 protein expression was decreased, whereas cleaved caspase-3 protein expression was increased (P < 0.05), and these changes were inhibited by FR167653 treatment. Apoptotic cells were also significantly increased in DM glomeruli and in HG-stimulated MC (P < 0.05), and FR167653 ameliorated these increases in apoptotic cells, both in vivo and in vitro. In conclusion, these findings suggest that the inhibition of the p38 MAPK pathway has a beneficial effect on the development of diabetic nephropathy by inhibiting the increase in fibronectin expression and apoptosis.


Pneumocystis jirovecii pneumonia: still a concern in patients with haematological malignancies and stem cell transplant recipients.
Pneumocystis jirovecii can cause life-threatening pneumonia following treatment for haematological malignancies or after HSCT. The mortality rate of P. jirovecii pneumonia (PCP) in these patients is 30%-60%, especially after HSCT. The clinical presentation of PCP in haematology differs from that associated with HIV infection, with the disease being acute and more often severe, having a lower fungal burden and being more frequently linked to treatment with corticosteroids. Most cases occur in patients not receiving adequate prophylaxis. The development of new therapies, including targeted treatments and monoclonal antibodies in various haematological diseases, justifies constant vigilance in order to identify new at-risk populations and give prophylaxis accordingly. The fifth and sixth European Conferences on Infections in Leukaemia (ECIL-5 and ECIL-6) aimed to review risk factors for PCP in haematology patients and to establish evidence-based recommendations for PCP diagnosis, prophylaxis and treatment. This article focuses on the magnitude of the problem, the main differences in clinical presentation between haematology patients and other immunocompromised populations, especially HIV-infected patients, and the main risk factors.


Chronic pain with neuropathic characteristics after surgery for major trauma to the lower limb: prevalence, predictors, and association with pain severity, disability, and quality of life in the UK WHiST trial.
To identify the prevalence of neuropathic pain after lower limb fracture surgery, assess associations with pain severity, quality of life and disability, and determine baseline predictors of chronic neuropathic pain at three and at six months post-injury. Secondary analysis of a UK multicentre randomized controlled trial (Wound Healing in Surgery for Trauma; WHiST) dataset including adults aged 16 years or over following surgery for lower limb major trauma. The trial recruited 1,547 participants from 24 trauma centres. Neuropathic pain was measured at three and six months using the Doleur Neuropathique Questionnaire (DN4); 701 participants provided a DN4 score at three months and 781 at six months. Overall, 933 participants provided DN4 for at least one time point. Physical disability (Disability Rating Index (DRI) 0 to 100) and health-related quality-of-life (EuroQol five-dimension five-level; EQ-5D-5L) were measured. Candidate predictors of neuropathic pain included sex, age, BMI, injury mechanism, concurrent injury, diabetes, smoking, alcohol, analgaesia use pre-injury, index surgery location, fixation type, Injury Severity Score, open injury, and wound care. The median age of the participants was 51 years (interquartile range 35 to 64). At three and six months post-injury respectively, 32% (222/702) and 30% (234/787) had neuropathic pain, 56% (396/702) and 53% (413/787) had chronic pain without neuropathic characteristics, and the remainder were pain-free. Pain severity was higher among those with neuropathic pain. Linear regression analyses found that those with neuropathic pain at six months post-injury had more physical disability (DRI adjusted mean difference 11.49 (95% confidence interval (CI) 7.84 to 15.14; p < 0.001) and poorer quality of life (EQ-5D utility -0.15 (95% CI -0.19 to -0.11); p < 0.001) compared to those without neuropathic characteristics. Logistic regression identified that prognostic factors of younger age, current smoker, below knee fracture, concurrent injuries, and regular analgaesia pre-injury were associated with higher odds of post-injury neuropathic pain. Pain with neuropathic characteristics is common after lower limb fracture surgery and persists to six months post-injury. Persistent neuropathic pain is associated with substantially poorer recovery. Further attention to identify neuropathic pain post-lower limb injury, predicting patients at risk, and targeting interventions, is indicated. Cite this article: Bone Joint J 2021;103-B(6):1047-1054.