Analysis of mortality data from cancer screening studies: looking in the right window.
Appropriate statistical analysis is required to measure the impact of early detection and treatment of cancer. The current practice of using cumulative mortality ignores both (1) the delay between early treatment and the time that any averted deaths would have otherwise occurred, and (2) cessation of these delayed benefits some time after screening is discontinued. We use time-specific mortality density ratios to estimate the mortality ratio in the "window of influence." We then use time-specific incidence density ratios to assess the extent to which the removal of polyps and other possibly precancerous lesions detected by fecal occult blood screening reduces the incidence of colorectal cancer. Applied to a theoretical example, the current practice of using cumulative mortality substantially underestimates the reduction in mortality achievable by early treatment. If there is sufficient time for the full impact to emerge, time-specific mortality patterns provide a more accurate measure. In a previous analysis of the screening study, the reduction in cumulative incidence in the screened groups was just under 20%. In our reanalysis, yearly incidence density ratios indicate that had screening not been interrupted, there might have been a 40% reduction in incidence. Time-specific mortality ratios provide a more sensitive measure of the effects of early detection and treatment. Measures based on cumulative mortality are diluted by inclusion of deaths that occur soon after the initiation of screening as well as deaths that occur too long after the cessation of screening.


Tissue-type plasminogen activator protects the postsynaptic density in the ischemic brain.
Cerebral ischemia causes the presynaptic release of tissue-type plasminogen activator (tPA). The postsynaptic density (PSD) is a postsynaptic structure that provides a matrix where signaling transduction of excitatory synapses takes place. The postsynaptic density protein-95 (PSD-95) is the most abundant scaffolding protein in the postsynaptic density (PSD), where it modulates the postsynaptic response to the presynaptic release of glutamate by regulating the anchoring of glutamate receptors to the PSD. We found that tPA induces the local translation of PSD-95 mRNA and the subsequent recruitment of PSD-95 protein to the PSD, via plasminogen-independent activation of TrkB receptors. Our data show that PSD-95 is removed from the PSD during the early stages of cerebral ischemia, and that this effect is abrogated by either the release of neuronal tPA, or intravenous administration of recombinant tPA (rtPA). We report that the effect of tPA on PSD-95 is associated with inhibition of the phosphorylation and recruitment of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to the PSD, known to amplify the effect of the excitotoxic injury, and that this is followed by TrkB-mediated protection of dendritic spines from the harmful effects of the hypoxic insult. These data reveal that tPA is a synaptic protector in the ischemic brain.


The impact of speech type on listening effort and intelligibility for native and non-native listeners.
Listeners are routinely exposed to many different types of speech, including artificially-enhanced and synthetic speech, styles which deviate to a greater or lesser extent from naturally-spoken exemplars. While the impact of differing speech types on intelligibility is well-studied, it is less clear how such types affect cognitive processing demands, and in particular whether those speech forms with the greatest intelligibility in noise have a commensurately lower listening effort. The current study measured intelligibility, self-reported listening effort, and a pupillometry-based measure of cognitive load for four distinct types of speech: (i) plain i.e. natural unmodified speech; (ii) Lombard speech, a naturally-enhanced form which occurs when speaking in the presence of noise; (iii) artificially-enhanced speech which involves spectral shaping and dynamic range compression; and (iv) speech synthesized from text. In the first experiment a cohort of 26 native listeners responded to the four speech types in three levels of speech-shaped noise. In a second experiment, 31 non-native listeners underwent the same procedure at more favorable signal-to-noise ratios, chosen since second language listening in noise has a more detrimental effect on intelligibility than listening in a first language. For both native and non-native listeners, artificially-enhanced speech was the most intelligible and led to the lowest subjective effort ratings, while the reverse was true for synthetic speech. However, pupil data suggested that Lombard speech elicited the lowest processing demands overall. These outcomes indicate that the relationship between intelligibility and cognitive processing demands is not a simple inverse, but is mediated by speech type. The findings of the current study motivate the search for speech modification algorithms that are optimized for both intelligibility and listening effort.


Assimilation of SMOS Retrievals in the Land Information System.
The Soil Moisture and Ocean Salinity (SMOS) satellite provides retrievals of soil moisture in the upper 5 cm with a 30-50 km resolution and a mission accuracy requirement of 0.04 cm3 cm-3. These observations can be used to improve land surface model soil moisture states through data assimilation. In this paper, SMOS soil moisture retrievals are assimilated into the Noah land surface model via an Ensemble Kalman Filter within the NASA Land Information System. Bias correction is implemented using Cumulative Distribution Function (CDF) matching, with points aggregated by either land cover or soil type to reduce sampling error in generating the CDFs. An experiment was run for the warm season of 2011 to test SMOS data assimilation and to compare assimilation methods. Verification of soil moisture analyses in the 0-10 cm upper layer and root zone (0-1 m) was conducted using in situ measurements from several observing networks in the central and southeastern United States. This experiment showed that SMOS data assimilation significantly increased the anomaly correlation of Noah soil moisture with station measurements from 0.45 to 0.57 in the 0-10 cm layer. Time series at specific stations demonstrate the ability of SMOS DA to increase the dynamic range of soil moisture in a manner consistent with station measurements. Among the bias correction methods, the correction based on soil type performed best at bias reduction but also reduced correlations. The vegetation-based correction did not produce any significant differences compared to using a simple uniform correction curve.


[Intrapopulational heterogeneity of human neutrophils based on chemokinetic and respiratory burst reactions].
The chemokinetic test (ameboid motility) and enhancement of oxygen-dependent metabolism of neutrophils (the NBT test) were considered in human blood stimulated with Staph. aureus allergen. There were three variants of stimulated cells: 1) neutrophils developing ameboid motility (13,5 +/- 1,7% cells), 2) neutrophils with activated oxygen-dependent metabolism (11.5 +/- 0.6%), 3) neutrophils positive in both the tests (2.6 +/- 0.8%). Unstimulated cells accounted for 71.6 +/- 4.1%. Considerable differences were recorded for each variant. The data obtained are regarded as evidence of dissimilar capability of neutrophils of the realization of effector functions.


[Superficial siderosis of the central nervous system: report of two new cases].
Superficial siderosis of the central nervous system (CNS) is a rare disease characterized by deafness, ataxia and pyramidal dysfunction. It is due to hemosiderin deposition in the subpial membranes of the brain, spinal cord and cranial nerves. Most cases are secondary to chronic or recurrent bleeding into the subarachnoid space. Diagnosis is permitted by magnetic resonance imaging (MRI). We report two patients with a chronic, slowly progressive cerebellar ataxia and hearing loss. MRI showed T2 hypointense signals in the brain, cerebellum and spinal cord diagnostic of superficial siderosis of the CNS. Xanthochromia was present in one patient. Evoked potentials showed retrochoclear hearing loss. Extensive vascular studies were negative for bleeding sources. One patient, treated with oral anticoagulants, benefited from reduction of the International Normalized Ratio. Due to its rarity, clinical suspicion is essential for diagnosis of superficial siderosis of the CNS.


Choledocholithiasis-a new clinical pathway.
The incidence of cholecystectomy in children has increased considerably since the early 1990s. Management of gallbladder disease in children must include an awareness of choledocholithiasis treatment strategies. Both endoscopic retrograde cholangiopancreatography (ERCP) and common bile duct exploration (open or laparoscopic) are accepted management techniques for choledocholithiasis. Laparoscopic cholecystectomy with preoperative or postoperative ERCP is at least a two-procedure process while cholecystectomy with laparoscopic common bile duct exploration (LCBDE) can provide definitive treatment in a single procedure under one anesthetic. Despite this, the trend over the last decade continues towards less LCBDE utilization in favor of ERCP. This trend has resulted in decreased familiarity with LCBDE by adult and pediatric surgeons and their trainees. Access to the necessary tools and education on the technical aspects can allow for successful single-stage treatment of choledocholithiasis by surgeons during laparoscopic cholecystectomy. This may include a pre-defined stepwise algorithm and understanding of all the equipment and resources necessary to perform a LCBDE. Ultimately, increased understanding of the equipment and procedural steps necessary for LCBDE will result in widened adoption of the technique and thus confer advantages to the patient such as decreased length of stay and fewer required anesthetics.


Anthropometric and fitness profiles of elite players in two football codes.
The aims were to describe anthropometric and performance characteristics of elite players in two football codes and explore the differences between them. Data were compared by means of "t"-tests. subjects were 19 professional soccer players and 33 inter-county Gaelic football players. measurements were made on members of a Premier League soccer team throughout their regular season, whilst the Gaelic footballers were members of the Mayo squad preparing for the 1999 All-Ireland championship. The variability in stature was significantly greater in the soccer players compared to the Gaelic footballers (p<0.01). Performances in the 10-m and 30-m sprints, and in vertical jump were superior in the soccer group compared to the Gaelic footballers (p<0.01). The intra-group variability on the anthropometric and performance measures of the soccer players is likely to be due to the specificity of positional roles. The combined groups could be described as lean and muscular with a reasonably high level of capacity in all areas of physical performance. Anaerobic characteristics of the professional soccer players were superior to those of Gaelic football players. It is concluded that anthropometric and performance assessment of elite footballers using mean values masks the heterogeneity evident within the football codes.


Gastrointestinal Stromal Tumours (GISTs) with KRAS Mutation: A Rare but Important Subset of GISTs.
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the GI tract, usually found in the stomach, jejunum, and ileum. Typically, they are KIT or PDGFR-mutated, allowing for targetable treatments with tyrosine kinase inhibitors such as imatinib. Here, we present two KRAS-mutated wild-type gastrointestinal tumours (GISTs). Both cases occurred in the small bowel of females. Immunohistochemical studies on both tumours showed KIT and DOG-1 positivity, with SDHB retained. Molecular analysis revealed a KRAS G12D mutation and a KRAS G13D mutation, respectively. Wild-type GISTs are extremely uncommon. They typically occur in the stomach or the small bowel. KRAS is one of the genes implicated in this subset of GIST, with KRAS G12D being the most frequently encountered mutation. GIST KRAS mutations can arise alone or in conjunction with KIT, PDFRA, or BRAF mutations. Identification of these rare molecular subtypes is clinically important due to their resistance to imatinib therapy.


Medical cause of compartment syndrome: a fatal case of Clostridium septicum.
A 57-year-old woman with non-Hodgkin's lymphoma presented to the emergency department with febrile neutropaenia. She complained of fever and malaise and had a normal physical examination. Ten hours later, she developed worsening right leg pain that required escalating doses of morphine. Her physical examination remained unremarkable. Owing to the increasing pain in her leg, an x-ray was performed which revealed subcutaneous emphysema. She subsequently developed numbness over her right leg and, then, 21 h after admission the leg became cold and ischaemic. Haemorrhagic bullae and bruising began to form and crepitus was palpated. She was taken to the operating room where debridement was attempted, but the surgeons found deep and extensive tissue necrosis. She was transferred to the intensive care unit for a trial of medical therapy and eventual palliation. The pathology revealed severe myonecrosis secondary to Clostridium septicum. She expired 36 h after presentation.


Efficiency of immunocastration with an anti-gonadotropin-releasing hormone vaccine on cryptorchid bulls.
Cryptorchid bulls have low economic value owing to the effects of masculinization. Moreover, surgical removal of an ectopic testis is difficult in certain clinical cases. Recently, immunocastration has garnered popularity as a nonsurgical castration method in pig farming; however, the effects of immunocastration on cryptorchid bulls are yet to be yet. Herein, we investigated endocrine changes due to immunocastration in cryptorchid bulls and studied its effectiveness. This study included 13 Holstein bulls diagnosed with cryptorchidism and classified into two groups based on pubertal period: <8 months of age (pregroup) and ≥8 months of age (postgroup). Antigonadotropin-releasing hormone (GnRH) vaccine was used for immunocastration, and two vaccine doses were administered. Blood testosterone and anti-Müllerian hormone (AMH) levels were measured and analyzed for endocrine evaluation. The testosterone levels significantly decreased following the start of immunocastration in both groups, thereby confirming the efficacy of antiGnRH vaccination in cryptorchid bulls. The AMH levels significantly increased in the pregroup with two antiGnRH vaccination, suggesting a compensatory response via the neutralization of GnRH antibodies. The AMH levels did not significantly change in the postgroup, indicating the partial suppression of AMH secretion in Sertoli cells during sexual maturation and failure of Sertoli cell maturation. Thus, we successfully restrained the serum testosterone levels in cryptorchid bulls using antiGnRH vaccine. The testosterone levels are a useful indicator of the immunocastration effect on cryptorchid bulls. Hereafter, a vaccine program that can sustain the castration effect on cryptorchid bulls is necessary.


From within host dynamics to the epidemiology of infectious disease: Scientific overview and challenges.
Since their earliest days, humans have been struggling with infectious diseases. Caused by viruses, bacteria, protozoa, or even higher organisms like worms, these diseases depend critically on numerous intricate interactions between parasites and hosts, and while we have learned much about these interactions, many details are still obscure. It is evident that the combined host-parasite dynamics constitutes a complex system that involves components and processes at multiple scales of time, space, and biological organization. At one end of this hierarchy we know of individual molecules that play crucial roles for the survival of a parasite or for the response and survival of its host. At the other end, one realizes that the spread of infectious diseases by far exceeds specific locales and, due to today's easy travel of hosts carrying a multitude of organisms, can quickly reach global proportions. The community of mathematical modelers has been addressing specific aspects of infectious diseases for a long time. Most of these efforts have focused on one or two select scales of a multi-level disease and used quite different computational approaches. This restriction to a molecular, physiological, or epidemiological level was prudent, as it has produced solid pillars of a foundation from which it might eventually be possible to launch comprehensive, multi-scale modeling efforts that make full use of the recent advances in biology and, in particular, the various high-throughput methodologies accompanying the emerging -omics revolution. This special issue contains contributions from biologists and modelers, most of whom presented and discussed their work at the workshop From within Host Dynamics to the Epidemiology of Infectious Disease, which was held at the Mathematical Biosciences Institute at Ohio State University in April 2014. These contributions highlight some of the forays into a deeper understanding of the dynamics between parasites and their hosts, and the consequences of this dynamics for the spread and treatment of infectious diseases.


SARS-CoV-2 (Covid-19) vaccines structure, mechanisms and effectiveness: A review.
The world has been suffering from COVID-19 disease for more than a year, and it still has a high mortality rate. In addition to the need to minimize transmission of the virus through non-pharmacological measures such as the use of masks and social distance, many efforts are being made to develop a variety of vaccines to prevent the disease worldwide. So far, several vaccines have reached the final stages of safety and efficacy in various phases of clinical trials, and some, such as Moderna/NIAID and BioNTech/Pfizer, have reported very high safety and protection. The important point is that comparing different vaccines is not easy because there is no set standard for measuring neutralization. In this study, we have reviewed the common platforms of COVID-19 vaccines and tried to present the latest reports on the effectiveness of these vaccines.


[Detection of GABA(A) receptor mRNA in cochlear tissue. An in situ hybridization study].
Gamma-aminobutyric acid (GABA) and the GABAergic system play an important role in the efferent modulation of cochlear function. We examined surface preparations of guinea pig and mouse cochleae by in situ hybridization using radioactive labelled oligonucleotides for several subunits of the GABAA receptor. Frozen sections of rat and guinea pig brain (cortex, hippocampus, cerebellum) served as controls. In the mouse cochlea the mRNA of the alpha-1 and alpha-5, beta-1 and gamma-1 subunit were detected, while in guinea pig cochlea mRNA of the alpha-1, alpha-4, alpha-5, and gamma-1 subunit of the GABAA receptor were found. Positive signals were located in the regions of the outer hair cells and had a weaker intensity in the inner hair cells. In the brain sections the several subunits were detected in a variable distribution in the cerebellum, hippocampus and cortical regions. Rat specimens exhibited stronger signals than guinea pig brain sections. These investigations have extended previous results of immunocytochemical experiments from our laboratory demonstrating mRNA sequences of GABAA receptor subunits in the mammalian inner ear. Detection of these nucleotide sequences using surface preparations of the cochlea on a molecular level by in situ hybridization supports the importance of GABA as a cochlear neurotransmitter. Furthermore, it can be concluded that the mammalian cochlea is able to express a GABA-dependent neurotransmission system.


An in situ assay with the microalga Phaeodactylum tricornutum for sediment-overlying water toxicity evaluations in estuaries.
Given the urgent need for ecologically relevant toxicity tools specific to estuarine systems, the main goal of the present study was to develop and evaluate the potential of an in situ algal assay for estuarine sediment-overlying water toxicity evaluations using the microalga Phaeodactylum tricornutum immobilized in alginate beads. With its simple and cost-effective design, the assay apparatus, coupled with the use of microalgae immobilized in alginate beads, allowed rapid and easy deployment as well as retrieval of assay chambers. The effectiveness of the proposed in situ assay was investigated by deploying it at two reference and six contaminated Portuguese estuaries. By deploying open chambers both with and without an artificial nutrient source and closed chambers with an artificial seawater medium, it was possible to discriminate toxic effects from those caused by differences in temperature, light, and nutrient conditions across sites. A reduction in algal growth was found at contaminated sites relative to reference sites. The strontium alginate beads used for microalgae immobilization were found to be appropriate to perform in situ assays, showing no signs of disruption or dissolution after up to 8 d of exposure in estuarine sediment-overlying waters. The proposed in situ assay was shown to be a useful tool for estuarine sediment-overlying water toxicity testing to provide relevant data concerning primary production to estuarine ecological risk assessment studies.


Serotonin and norepinephrine transporter binding profile of SSRIs.
Even today, pharmacotherapy for mood disorders is based almost entirely on the observation in the 1950s and 1960s that agents that enhance monoamine transmitter activity are effective antidepressants. Preclinical studies have shown that long-term administration of nearly all effective antidepressants increases the efficiency of postsynaptic serotonin transmission; many also modify central noradrenergic activity. For the majority of antidepressants, these changes are the result of their ability to block serotonin and/or norepinephrine activity at their "presynaptic uptake sites" (i.e., at the serotonin transporter [SERT] or the norepinephrine transporter [NET]). Drugs that are highly selective for one transporter over another have been demonstrated to be effective and tolerable, whereas agents that act on multiple transporters may not necessarily achieve better efficacy and may result in additional adverse events. The rationale for the use of drugs that affect multiple transports is based on the suggestion that antidepressants that block both the SERT and the NET may provide better efficacy. This can only be determined through empirical studies.


Chemotaxis, phagocytosis, and oxidative metabolism in bovine macrophages exposed to a novel interdigital phlegmon (foot rot) lesion isolate, Porphyromonas levii.
To examine the host response toward Porphyromonas levii, by evaluating chemotaxis, phagocytosis, and oxidative burst of bovine macrophages in vitro. Cultured bovine macrophages obtained from monocytes harvested from blood samples of 15 Holstein steers. Porphyromonas levii was isolated from the foot rot lesion of an acutely affected feedlot steer. Monocytes were cultured for macrophage differentiation over 7 days. Porphyromonas levii was cultured in strict anaerobic conditions for experimentation. Chemotaxis was evaluated by quantifying macrophage migration toward P. levii in Boyden chambers. Phagocytosis was assessed by quantification of macrophages engulfing P. levii following incubation with or without anti-P. levii serum or purified IgG. Oxidative burst was measured by use of the nitroblue tetrazolium reduction assay. Chemotaxis toward P. levii was not significantly different from control values at any of the tested bacterial concentrations. Phagocytosis of P. levii was approximately 10% at a 10:1 bacterium to macrophage ratio and did not change significantly over time. When higher proportions of P. levii were tested for phagocytosis, the 1,000:1 bacterium to macrophage ratio had a significant increase, compared with the 10:1 test group. Opsonization of P. levii with high-titeranti-P. levii serum or anti-P. levii IgG produced a significant increase in macrophage phagocytosis. Oxidative production significantly increased compared with control in the 1,000:1 test group only. Porphyromonas levii may evade host detection by decreased chemotaxis, phagocytosis, and oxidative burst by macrophages. Acquired immunity may be beneficial for clearance of P. levii in foot rot lesions in cattle.


Early-life determinants of hypoxia-inducible factor 3A gene (HIF3A) methylation: a birth cohort study.
Methylation of the hypoxia-inducible factor 3α gene (HIF3A) has been linked to pregnancy exposures, infant adiposity and later BMI. Genetic variation influences HIF3A methylation levels and may modify these relationships. However, data in very early life are limited, particularly in association with adverse pregnancy outcomes. We investigated the relationship between maternal and gestational factors, infant anthropometry, genetic variation and HIF3A DNA methylation in the Barwon Infant Study, a population-based birth cohort. Methylation of two previously studied regions of HIF3A were tested in the cord blood mononuclear cells of 938 infants. No compelling evidence was found of an association between birth weight, adiposity or maternal gestational diabetes with methylation at the most widely studied HIF3A region. Male sex (- 4.3%, p < 0.001) and pre-eclampsia (- 5.4%, p = 0.02) negatively associated with methylation at a second region of HIF3A; while positive associations were identified for gestational diabetes (4.8%, p = 0.01) and gestational age (1.2% increase per week, p < 0.001). HIF3A genetic variation also associated strongly with methylation at this region (p < 0.001). Pre- and perinatal factors impact HIF3A methylation, including pre-eclampsia. This provides evidence that specific pregnancy complications, previously linked to adverse outcomes for both mother and child, impact the infant epigenome in a molecular pathway critical to several vascular and metabolic conditions. Further work is required to understand the mechanisms and clinical relevance, particularly the differing effects of in utero exposure to gestational diabetes or pre-eclampsia.


The effect of mass vaccination campaigns against polio on the utilization of routine immunization services: A regression discontinuity design.
In most low and middle-income countries (LMIC), vaccines are primarily distributed by routine immunization services (RI) at health facilities. Additional opportunities for vaccination are also provided through mass vaccination campaigns, conducted periodically as part of disease-specific initiatives. It is unclear whether these campaigns are detrimental to RI services, or wether they may stimulate the utilization of RI. Unobserved confounders and reverse causality have limited existing evaluations of the effects of mass vaccination campaigns on RI services. We explored the use of a regression discontinuity design (RDD) to measure these effects more precisely. This is a quasi-experimental method, which exploits random variations in birth dates to identify the causal effects of vaccination campaigns. We applied RDD to survey data on a nationwide vaccination campaign against Polio conducted in Bangladesh. We compared systematically the children born immediately before vs. after the vaccination campaign. These two groups had similar background characteristics, but differed by their exposure to the vaccination campaign. Contrary to previous studies, exposure to the campaign had positive effects on RI utilization. Children exposed to the campaign received between 0.296 and 0.469 additional doses of DPT vaccine by age 4months than unexposed children. RDD constitutes a promising tool to assess the effects of mass vaccination campaigns on RI services. It could be tested in additional settings, using larger and more precise datasets. It could also be extended to measure the effects of other disease-specific interventions on the functioning of health systems, in particular those that occur at a discrete point in time and/or include age-related eligibility criteria.


Retinal Ganglion Cell Axon Regeneration Requires Complement and Myeloid Cell Activity within the Optic Nerve.
Axon regenerative failure in the mature CNS contributes to functional deficits following many traumatic injuries, ischemic injuries, and neurodegenerative diseases. The complement cascade of the innate immune system responds to pathogen threat through inflammatory cell activation, pathogen opsonization, and pathogen lysis, and complement is also involved in CNS development, neuroplasticity, injury, and disease. Here, we investigated the involvement of the classical complement cascade and microglia/monocytes in CNS repair using the mouse optic nerve injury (ONI) model, in which axons arising from retinal ganglion cells (RGCs) are disrupted. We report that central complement C3 protein and mRNA, classical complement C1q protein and mRNA, and microglia/monocyte phagocytic complement receptor CR3 all increase in response to ONI, especially within the optic nerve itself. Importantly, genetic deletion of C1q, C3, or CR3 attenuates RGC axon regeneration induced by several distinct methods, with minimal effects on RGC survival. Local injections of C1q function-blocking antibody revealed that complement acts primarily within the optic nerve, not retina, to support regeneration. Moreover, C1q opsonizes and CR3+ microglia/monocytes phagocytose growth-inhibitory myelin debris after ONI, a likely mechanism through which complement and myeloid cells support axon regeneration. Collectively, these results indicate that local optic nerve complement-myeloid phagocytic signaling is required for CNS axon regrowth, emphasizing the axonal compartment and highlighting a beneficial neuroimmune role for complement and microglia/monocytes in CNS repair.SIGNIFICANCE STATEMENT Despite the importance of achieving axon regeneration after CNS injury and the inevitability of inflammation after such injury, the contributions of complement and microglia to CNS axon regeneration are largely unknown. Whereas inflammation is commonly thought to exacerbate the effects of CNS injury, we find that complement proteins C1q and C3 and microglia/monocyte phagocytic complement receptor CR3 are each required for retinal ganglion cell axon regeneration through the injured mouse optic nerve. Also, whereas studies of optic nerve regeneration generally focus on the retina, we show that the regeneration-relevant role of complement and microglia/monocytes likely involves myelin phagocytosis within the optic nerve. Thus, our results point to the importance of the innate immune response for CNS repair.


Impact of Trap Design and Density on Effectiveness of a Commercial Pheromone Lure for Monitoring Navel Orangeworm (Lepidoptera: Pyralidae).
The navel orangeworm is an important pest of almonds, pistachios, and walnuts. A commercial pheromone lure for this pest became publicly available in 2013. We compared effectiveness of this synthetic lure (NOW Biolure) between common commercial trap designs, and with unmated females in wing traps. Orange wing traps and delta traps captured similar numbers of males when each was baited with females, although there was a significantly greater density of captured males on the smaller glue area of the delta traps. In contrast, lure-baited wing traps captured about half the males captured in female-baited wing traps in single-night tests. In these single-night tests, wing traps baited with NOW Biolure captured significantly more males than delta traps baited with NOW Biolure, and bucket traps and delta traps baited with NOW Biolure captured similar numbers of males. When the sampling interval was extended to a week, the performance of lure-baited and female-baited wing traps was more similar. Delta and bucket traps baited with NOW Biolure generally performed more poorly than wing traps baited with NOW Biolure in these weekly monitoring tests. However, the bucket traps occasionally outperformed the other trap types during periods of peak abundance. Navel orangeworm traps at a density of one per 4 ha detected differences in abundance between adjacent walnut varieties, whereas such differences were not detected with one trap per 20 ha. The implications of these findings for monitoring for navel orangeworm in these different host crops are discussed.


Allogeneic bone marrow transplantation for acute leukaemia: comparative outcomes for adults and children.
Advances in both allogeneic marrow transplantation and conventional therapy for acute leukaemia have complicated the choice between bone marrow transplantation (BMT) and other remission treatment options. Because older patients may be more susceptible to BMT-related complications, this study analysed the effect of age on clinical outcome for 149 patients with acute leukaemia in remission receiving allogeneic BMT. Overall projected relapse-free survival at 3 years post-transplant is equivalent for 48 adults (18 years or older) and 101 children (less than 18) at 45.4% (31.1-59.6; 95% confidence interval) and 39.9% (30.1-49.7; 95% C.I.), respectively. Among 73 patients with acute lymphocytic leukaemia (ALL) 35.3% of adults and 30.1% of children survive relapse-free at 3 years. Cox multiple regression analysis demonstrated that higher diagnostic white count, but not pre-transplant extramedullary leukaemia, remission number, or age, was important as an independent adverse clinical prognostic factor for patients with ALL. Overall outcome was better for 76 patients with acute myeloid leukaemia (AML) with 51.6% of adults and 52.9% of children surviving relapse-free at 3 years post-transplant. Cox multivariate regression analysis identified first remission status and lower white cell count, but not patient age, as independent predictors of improved relapse-free survival for AML patients. Adults had greater transplant morbidity, predominantly related to a higher incidence of acute graft-versus-host disease (GVHD), resulting in longer hospital stay. Survival at 100 d, long-term survival and clinical performance status were similar in both age groups. These data suggest that results of allogeneic BMT for adults with acute leukaemia compare favourably with those found in children and are superior to most reports of conventional chemotherapy. Allogeneic BMT remains a reasonable option for remission acute leukaemia patients up to the age of 45.


Serum free fatty acid levels in PCOS patients treated with glucophage, magnesium oxide and spironolactone.
To assess the effect of glucophage, magnesium oxide and spironolactone in altering free fatty acids (FFAs), 36 PCOS women were randomly divided into three groups. Group 1 (n = 14) was treated with 500 mg glucophage po bid, group 2 (n = 10) was treated with 400 mg magnesium oxide po bid and group 3 (n = 12) was treated with 50 mg spironolactone po bid for 12 weeks. A glucose tolerance test with 75 g glucose load was performed before and after treatment, collecting blood at 0, 1 and 2 h for insulin, glucose, FFA and aldosterone. Amount of FFA before and after treatment were compared by repeated measure ANOVA and represented as area under the curve. FFA levels before treatment were 0.83 ± 0.23, 0.77 ± 0.15 and 0.85 ± 0.28 and after treatment were 0.77 ± 0.48, 0.71 ± 0.18 and 0.66 ± 0.25 for glucophage, magnesium oxide and spironolactone-treated patients, respectively. The FFA levels were unchanged in the groups treated with glucophage and magnesium oxide but were significantly (p < 0.03) decreased in the group treated with spironolactone. Since FFAs are known to be involved in the development of insulin resistance, these results suggest that spironolactone may be useful for lowering insulin resistance in PCOS patients.


Detection of glycemic abnormalities in adolescents with beta thalassemia using continuous glucose monitoring and oral glucose tolerance in adolescents and young adults with β-thalassemia major: Pilot study.
Both insulin deficiency and resistance are reported in patients with β-thalassemia major (BTM). The use of continuous blood glucose monitoring (CGM), among the different methods for early detection of glycemic abnormalities, has not been studied thoroughly in these adolescents. To assess the oralglucose tolerance (OGT) and 72-h continuous glucose concentration by the continuous glucose monitoring system (CGMS) and calculate homeostatic model assessment (HOMA), and the quantitative insulin sensitivity check index (QUICKI) was conducted in 16 adolescents with BTM who were receiving regular blood transfusions every 2-4 weeks and iron-chelation therapy since early childhood. SIXTEEN ADOLESCENTS WITH BTM (AGE: 19.75 ± 3 years) were investigated. Using OGTT, (25%) had impaired fasting blood (plasma) glucose concentration (BG) (>5.6 mmol/L). 2-h after the glucose load, one of them had BG = 16.2 mmol/L (diabetic) and two had impaired glucose tolerance (IGT) (BG > 7.8 and <11.1 mmol/L). Monitoring the maximum (postprandial) BG using CGMS,4 adolescents were diagnosed with diabetes (25%) (BG >11.1 mmol/L) and 9 with IGT (56%). HOMA and QUICKI revealed levels <2.6 (1.6 ± 0.8) and >0.33 (0.36 ± 0.03), respectively, ruling out significant insulin resistance in these adolescents. There was a significant negative correlation between the β-cell function (B%) on one hand and the fasting and the 2-h BG (r=-0.6, and - 0.48, P < 0.01, respectively) on the other hand. Neither fasting serum insulin nor c-peptide concentrations were correlated with fasting BG or ferritin levels. The average and maximum blood glucose levels during CGM were significantly correlated with the fasting BG (r = 0.68 and 0.39, respectively, with P < 0.01) and with the BG at 2-hour after oral glucose intake (r = 0.87 and 0.86 respectively, with P < 0.001). Ferritin concentrations were correlated with the fasting BG and the 2-h blood glucose levels in the OGTT (r = 0.52, and r = 0.43, respectively, P < 0.01) as well as with the average BG recorded by CGM (r = 0.75, P < 0.01). CGM has proven to be superior to OGTT for the diagnosis of glycemic abnormalities in adolescents with BTM. Defective β-cell function rather than insulin resistance appeared to be the cause for these abnormalities.


Characterization of cysteinyl leukotriene-related receptors and their interactions in a mouse model of asthma.
Identification of the characterization of cysteinyl leukotrienes receptor (CysLTRs) could facilitate our understanding of these receptors' role in asthma. We aimed to investigate the localization and interactions of CysLTRs using a mouse model of asthma. BALB/c mice were administered ovalbumin (OVA) to induce allergic asthma. Some mice were administered the antagonists of CysLTR1, CysLTR2, and purinergic receptor P2Y12 (P2Y12R) (montelukast, HAMI 3379 and clopidogrel, respectively). The expression levels of CysLTR1, CysLTR2, and P2Y12R on lung tissues and inflammatory cells were evaluated by western blot, flow cytometry, and immunochemistry. CysLTR1 and P2Y12R were significantly up-regulated in lung tissues (P < 0.05 for each) from mouse after being sensitized and challenged with OVA (OVA/OVA). The ratio of CysLTR1: CysLTR2: P2Y12R in lungs of negative control (NC) mice was shifted from 1:0.43:0.35 to 1:0.65:1.34 in OVA/OVA mice. Montelukast significantly diminished the up-regulation of CysLTR1, CysLTR2, and P2Y12R (P < 0.05 for each), while the effects of HAMI 3379 and clopidogrel were predominant on the expression of CysLTR2 and P2Y12R, respectively. Montelukast predominantly diminished the cell count, while clopidogrel potently inhibited the release of interleukin (IL)-4, IL-5, and IL-13. Our study demonstrated the interactions between CysLTRs, thereby highlighting the potential synergistic effects of CysLTR antagonists in asthma treatment.


[Determination of medullasin levels for the diagnosis of multiple sclerosis].
Medullasin levels in granulocytes of patients with neurological diseases and healthy volunteers were determined by the enzyme immunoassay using mouse monoclonal antibodies against human medullasin and o-phenylenediamine-H2O2 as the detection system of the enzyme activity. One hundred twenty-one out of 159 patients with multiple sclerosis (76.1%) showed positive results (above means of normals + 2SD) in this test, while only 16.9% (24/142) of patients with non-inflammatory neurological diseases had positive results. This enzyme immunoassay method for medullasin is considered to be an useful paraclinical test for the diagnosis of multiple sclerosis.


Sensorimotor gating characteristics of violent men with comorbid psychosis and dissocial personality disorder: Relationship with antisocial traits and psychosocial deprivation.
Evidence suggests violence amongst those with psychosis is not aetiologically homogeneous, and that a large proportion of those who engage in violent behaviour have a comorbid antisocial personality disorder. Initial investigations indicate that this subgroup has distinct historical and neuropsychological characteristics, which may indicate diverse treatment needs. This study investigated sensorimotor gating characteristics of violent men with diagnoses of both psychosis and dissocial personality disorder (DPD) (n=21) relative to violent men with psychosis alone (n=12), DPD alone (n=14) and healthy, non-violent male controls (n=27), using the prepulse inhibition (PPI) paradigm. The results indicated that, relative to the psychosis alone and healthy control groups, the comorbid group had lower PPI, especially at 60-ms prepulse-to-pulse interval. The DPD group took an intermediary position and did not differ from any group. Antisocial personality traits (factor two scores of the Psychopathy Checklist - Revised), and greater severity of childhood psychosocial deprivation (including physical and sexual abuse), were significantly correlated with poor PPI across the clinical sample. The findings suggest diverse sensorimotor gating profiles amongst subgroups of violent offenders, with comorbid psychosis and DPD showing most impairment. This is consistent with a 'double dose' of deficit explanation amongst those with both diagnoses, explained at least in part by presence of antisocial personality traits and childhood psychosocial deprivation.


Hypoxia inhibits Cavin-1 and Cavin-2 expression and down-regulates caveolae in adipocytes.
During obesity, a hypoxic state develops within the adipose tissue, resulting in insulin resistance. To understand the underlying mechanism, we analyzed the involvement of caveolae because they play a crucial role in the activation of insulin receptors. In the present study, we demonstrate that in 3T3-L1 adipocytes, hypoxia induces the disappearance of caveolae and inhibits the expression of Cavin-1 and Cavin-2, two proteins necessary for the formation of caveolae. In mice, hypoxia induced by the ligature of the spermatic artery results in the decrease of cavin-1 and cavin-2 expression in the epididymal adipose tissue. Down-regulation of the expression of cavins in response to hypoxia is dependent on hypoxia-inducible factor-1. Indeed, the inhibition of hypoxia-inducible factor-1 restores the expression of cavins and caveolae formation. Expression of cavins regulates insulin signaling because the silencing of cavin-1 and cavin-2 impairs insulin signaling pathway. In human, cavin-1 and cavin-2 are decreased in the sc adipose tissue of obese diabetic patients compared with lean subjects. Moreover, the expression of cavin-2 correlates negatively with the homeostatic model assessment index of insulin resistance and glycated hemoglobin level. In conclusion, we propose a new mechanism in which hypoxia inhibits cavin-1 and cavin-2 expression, resulting in the disappearance of caveolae. This leads to the inhibition of insulin signaling and the establishment of insulin resistance.


Inhibition of Caenorhabditis elegans social feeding by FMRFamide-related peptide activation of NPR-1.
Social and solitary feeding in natural Caenorhabditis elegans isolates are associated with two alleles of the orphan G-protein-coupled receptor (GPCR) NPR-1: social feeders contain NPR-1 215F, whereas solitary feeders contain NPR-1 215V. Here we identify FMRFamide-related neuropeptides (FaRPs) encoded by the flp-18 and flp-21 genes as NPR-1 ligands and show that these peptides can differentially activate the NPR-1 215F and NPR-1 215V receptors. Multicopy overexpression of flp-21 transformed wild social animals into solitary feeders. Conversely, a flp-21 deletion partially phenocopied the npr-1(null) phenotype, which is consistent with NPR-1 activation by FLP-21 in vivo but also implicates other ligands for NPR-1. Phylogenetic studies indicate that the dominant npr-1 215V allele likely arose from an ancestral npr-1 215F gene in C. elegans. Our data suggest a model in which solitary feeding evolved in an ancestral social strain of C. elegans by a gain-of-function mutation that modified the response of NPR-1 to FLP-18 and FLP-21 ligands.


Identification of a novel matrix protein that promotes biofilm maturation in Vibrio fischeri.
Bacteria form communities, termed biofilms, in which cells adhere to each other within a matrix, typically comprised of polysaccharides, proteins, and extracellular DNA. Biofilm formation by the marine bacterium Vibrio fischeri requires the Syp polysaccharide, but the involvement of matrix proteins is as yet unknown. Here we identified three genes, termed bmpA, -B, and -C (biofilm maturation protein), with overlapping functions in biofilm maturation. A triple bmpABC mutant, but not single or double mutants, was defective in producing wrinkled colonies, a form of biofilm. Surprisingly, the triple mutant was competent to form pellicles, another biofilm phenotype, but they generally lacked a three-dimensional architecture. Transmission electron microscopy revealed that the extracellular matrix of the bmp mutant contained electron-dense, thread-like structures that were also present in the wild type but lacking in syp mutant strains. We hypothesized that the bmp mutant produces the Syp polysaccharide but fails to produce/export a distinct matrix component. Indeed, a mixture of the bmp and syp mutants produced a wrinkled colony. Finally, BmpA could be detected in cell-free supernatants from disrupted pellicles. Thus, this work identifies a new matrix protein necessary for biofilm maturation by V. fischeri and, based on the conservation of bmp, potentially other microbes.


MicroRNAs in cancer metastasis and angiogenesis.
Cancer metastasis is a malignant process by which tumor cells migrate from their primary site of origin to other organs. It is the main cause of poor prognosis in cancer patients. Angiogenesis is the process of generating new blood capillaries from pre-existing vasculature. It plays a vital role in primary tumor growth and distant metastasis. MicroRNAs are small non-coding RNAs involved in regulating normal physiological processes as well as cancer pathogenesis. They suppress gene expression by specifically binding to the 3'-untranslated region (3'-UTR) of their target genes. They can thus act as oncogenes or tumor suppressors depending on the function of their target genes. MicroRNAs have shown great promise for use in anti-metastatic cancer therapy. In this article, we review the roles of various miRNAs in cancer angiogenesis and metastasis and highlight their potential for use in future therapies against metastatic cancer.


Reticulo-tubular structures in endothelium of vascular ansa of kidney glomeruli in children.
In the presented cases, paramyxoviral-like reticulotubular structures were found in morphologically different forms of primary glomerular diseases in children. On the basis of the data obtained it seems likely that the diagnostic significance of these structures during the course of systemic lupus erythematosus and other collagen-related diseases must be carefully evaluated.


'I have no love for such people, because they leave us to suffer': a qualitative study of health workers' responses and institutional adaptations to absenteeism in rural Uganda.
Achieving positive treatment outcomes and patient safety are critical goals of the healthcare system. However, this is greatly undermined by near universal health workforce absenteeism, especially in public health facilities of rural Uganda. We investigated the coping adaptations and related consequences of health workforce absenteeism in public and private not-for-profit (PNFP) health facilities of rural Uganda. An empirical qualitative study involving case study methodology for sampling and principles of grounded theory for data collection and analysis. Focus groups and in-depth interviews were used to interview a total of 95 healthcare workers (11 supervisors and 84 frontline workers). The NVivo V.10 QSR software package was used for data management. There was tolerance of absenteeism in both the public and PNFP sectors, more so for clinicians and managers. Coping strategies varied according to the type of health facility. A majority of the PNFP participants reported emotion-focused reactions. These included unplanned work overload, stress, resulting anger directed towards coworkers and patients, shortening of consultation times and retaliatory absence. On the other hand, various cadres of public health facility participants reported ineffective problem-solving adaptations. These included altering weekly schedules, differing patient appointments, impeding absence monitoring registers, offering unnecessary patient referrals and rampant unsupervised informal task shifting from clinicians to nurses. High levels of absenteeism attributed to clinicians and health service managers result in work overload and stress for frontline health workers, and unsupervised informal task shifting of clinical workload to nurses, who are the less clinically skilled. In resource-limited settings, the underlying causes of absenteeism and low staff morale require attention, because when left unattended, the coping responses to absenteeism can be seen to compromise the well-being of the workforce, the quality of healthcare and patients' access to care.


Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions.
There are more and more data concerning the role of cellular metabolism in innate immune cells, such as macrophages or conventional dendritic cells. However, few data are available currently concerning plasmacytoid dendritic cells (PDC), another type of innate immune cells. These cells are the main type I interferon (IFN) producing cells, but they also secrete other pro-inflammatory cytokines (e.g., tumor necrosis factor or interleukin [IL]-6) or immunomodulatory factors (e.g., IL-10 or transforming growth factor-β). Through these functions, PDC participate in antimicrobial responses or maintenance of immune tolerance, and have been implicated in the pathophysiology of several autoimmune diseases, as well as in tumor immune escape mechanisms. Recent data support the idea that the glycolytic pathway (or glycolysis), as well as lipid metabolism (including both cholesterol and fatty acid metabolism) may impact some innate immune functions of PDC or may be involved in these functions after Toll-like receptor (TLR) 7/9 triggering. The kinetics of glycolysis after TLR7/9 triggering may differ between human and murine PDC. In mouse PDC, metabolism changes promoted by TLR7/9 activation may depend on an autocrine/paracrine loop, implicating type I IFN and its receptor IFNAR. This could explain a delayed glycolysis in mouse PDC. Moreover, PDC functions can be modulated by the metabolism of cholesterol and fatty acids. This may occur via the production of lipid ligands that activate nuclear receptors (e.g., liver X receptor [LXR]) in PDC or through limiting intracellular cholesterol pool size (by statin or LXR agonist treatment) in these cells. Finally, lipid-activated nuclear receptors (i.e., LXR or peroxisome proliferator activated receptor) may also directly interact with pro-inflammatory transcription factors, such as NF-κB. Here, we discuss how glycolysis and lipid metabolism may modulate PDC functions and how this may be harnessed in pathological situations where PDC play a detrimental role.


[Is sentinel lymph node mapping relevant for colon cancer?: a feasibility study].
Sentinel lymph node (sln) technique using blue injection is controversial for colon cancer. The aim of this study was to evaluate the feasibility and interest of sentinel node detection to identify the ultrastaging rate detecting occult nodal micrometastases missed on routine H&E examination. During surgery blue dye was injected subserously around the tumor in 30 patients operated for a colon cancer. The first lymph nodes to turn blue were noted as sln. For each sln three examination levels were performed; if no tumor was detected by H&E examination, a cytokeratine immunohistochemistry study was performed. For each case, one or more sln were found (100%). The median number of lymph nodes examined and of sln found was, respectively, 23 (range 10-55) and 2 (1-4). There were 21 pN0 tumors, among which we found two cases (9%) with a micrometastasis and one case of isolated tumor cells detected, resulting in a 14% (3/21) ultrastaging for pTxN0. The sln was positive in five patients out of nine with a N+ disease. Sln detection was a successful technique when there was no evident lymph node involvement, no primary large lesion or no associated liver metastasis. Focused examination of the sln identified 10-20% of additional ultrastaging disease for staged pT1, 2, 3N0M0 tumor. This may have an important implication for follow-up and adjuvant treatment in future protocols.


Assessment of an enhanced program for depression management in primary care: a cluster randomized controlled trial. The INDI project (Interventions for Depression Improvement).
Most depressed patients are attended at primary care. However, there are significant shortcomings in the diagnosis, management and outcomes of these patients. The aim of this study is to determine whether the implementation of a structured programme for managing depression will provide better health outcomes than usual management. A cluster-randomized controlled trial involving two groups, one of which is the control group consisting of patients who are treated for depression in the usual way and the other is the intervention group consisting of patients on a structured programme for treating depression. 20 primary care centres in the province of Tarragona (Spain) 400 patients over 18 years of age who have experienced an episode of major depression (DSM-IV) and who need to initiate antidepressant treatment A multi-component programme with clinical, educational and organisational procedures that includes training for the health care provider and evidence-based clinical guidelines. It also includes primary care nurses working as care-managers who provide educational and emotional support for the patients and who are responsible for active and systematic clinical monitoring. The programme aims to improve the primary care/specialized level interface. The patients will be monitored by telephone interviews. The interviewer will not know which group the patient belongs to (blind trial). These interviews will be given at 0, 3, 6 and 12 months. Severity of the depressive symptoms, response rate and remission rate. Outcomes will be analyzed on an intent-to-treat basis and the unit of analysis will be the individual patient. This analysis will take into account the effect of study design on potential lack of independence between observations within the same cluster. The effectiveness of caring for depression in primary care can be improved by various strategies. The most effective models involve organisational changes and a greater role of nurses. However, these models are almost exclusively from the USA, and this randomized clinical trial will determine if this approach could be effective to improve the outcomes of depression in primary care in the Spanish health care system. ISRCTN16384353.


Barriers to Office-Based Mental Health Care and Interest in E-Communication With Providers: A Survey Study.
With rising availability and use of Internet and mobile technology in society, the demand and need for its integration into health care is growing. Despite great potential within mental health care and growing uptake, there is still little evidence to guide how these tools should be integrated into traditional care, and for whom. To examine factors that might inform how e-communication should be implemented in our local outpatient mental health program, including barriers to traditional office-based care, patient preferences, and patient concerns. We conducted a survey in the waiting room of our outpatient mental health program located in an urban, academic ambulatory hospital. The survey assessed (1) age, mobile phone ownership, and general e-communication usage, (2) barriers to attending office-based appointments, (3) preferences for, and interest in, e-communication for mental health care, and (4) concerns about e-communication use for mental health care. We analyzed the data descriptively and examined associations between the presence of barriers, identifying as a social media user, and interest level in e-communication. Respondents (N=68) were predominantly in the age range of 25-54 years. The rate of mobile phone ownership was 91% (62/68), and 59% (40/68) of respondents identified as social media users. There was very low existing use of e-communication between providers and patients, with high levels of interest endorsed by survey respondents. Respondents expressed an interest in using e-communication with their provider to share updates and get feedback, coordinate care, and get general information. In regression analysis, both a barrier to care and identifying as a social media user were significantly associated with e-communication interest (P=.03 and P=.003, respectively). E-communication interest was highest among people who both had a barrier to office-based care and were a social media user. Despite high interest, there were also many concerns including privacy and loss of in-person contact. A high burden of barriers to attending office-based care paired with a high interest in e-communication supports the integration of e-communication within our outpatient services. There may be early adopters to target: those with identified barriers to office-based care and who are active on social media. There is also a need for caution and preservation of existing services for those who choose not to, or cannot, access e-services.


Serum aluminum levels and peritoneal dialysis.
Serum aluminum levels, significantly higher in dialysis patients than in normal subjects, were also found to be significantly higher in patients on PD than in those on HD. This could be related to a higher AI transport rate across membrane during PD than during HD. The easier contamination of PD dialysates and their acidic pH could account for this trend to a positive AI balance in PD. On the basis of our observations, however, the significance of the serum aluminum level could be very low, since aluminemia does not seem to reflect the cumulative amount of AI ingested and might not readily help predict the risk of AI intoxication.


Prenatal Environment and Neurodevelopmental Disorders.
The internal and external environment of the mother during the developmental stages of the fetus affects the offspring's health. According to the developmental origins of health and disease (DOHaD) theory, environmental factors influence the offspring and also affect health in adulthood. Recently, studies based on this theory have gained attracted attention because of their clinical utility in identifying the risk groups for various diseases. Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) can be caused by exposure to certain prenatal environments during pregnancy. This review describes the latest findings on the effect of prenatal environment on the onset mechanism of NDDs based on the DOHaD theory. Unravelling the molecular mechanisms underlying the pathogenesis of NDDs is important, because there are no therapeutic drugs for these disorders. Furthermore, elucidating the relationship between the DOHaD theory and NDDs will contribute to the popularization of preventive medicine.


The relationship between the plant-encoded RNA-dependent RNA polymerase 1 and alternative oxidase in tomato basal defense against Tobacco mosaic virus.
Salicylic acid (SA) plays a critical role in plant defense against pathogen attack. The SA-induced viral defense in plants is distinct from the pathways mediating bacterial and fungal defense, which is pathogenesis-related protein-independent but involves an RNA-dependent RNA polymerase 1 (RDR1)-mediated RNA silencing mechanism and/or an alternative oxidase (AOX)-associated defense pathway. However, the relationship between these two viral defense-related pathways remains unclear. In this study, Tobacco mosaic virus (TMV) inoculation onto Solanum lycopersicum (tomato) leaves induced a rapid induction of the SlAOX1a transcript level as well as the total and CN-resistant respiration at 0.5 dpi, followed by an increase in SlRDR1 gene expression at 1 dpi in the upper uninoculated leaves. Silencing SlRDR1 using virus-induced gene silencing system significantly reduced SlRDR1 expression and tomato defense against TMV but had no evident effect on SlAOX1a transcription. Conversely, silencing SlAOX1a not only effectively reduced the AOX1a transcript level, but also blocked the TMV-induced SlRDR1 expression and decreased the basal defense against TMV. Furthermore, the application of an exogenous AOX activator on empty vector-silenced control plants greatly induced the accumulation of SlRDR1 and SlAOX1a transcript and reduced TMV viral RNA accumulation, but failed to have such effects on SlRDR1-silenced plants. Moreover, RDR1-overexpressed transgenic Nicotiana benthamiana plants enhanced defense against TMV than the empty vector-transformed plants, but these effects were not affected by the exogenous AOX activator or inhibitor. These results indicate that RDR1 is involved in the AOX-mediated defense pathway against TMV infection and plays a crucial role in enhancing RNA silencing to limit virus systemic spread.


Increased pharmacy purchases of cardiovascular drugs from wholesalers prior to the first and second COVID-19 lockdowns.
The aim of this study was to examine the development of drug purchases over the course of the coronavirus crisis in Germany in 2020. The evaluations in this retrospective cross-sectional study are based on the IMS RPM (Regional Pharmaceutical Market) weekly database, which shows weekly purchases by public pharmacies from full-service wholesalers at the time the pharmacy purchase is made in Germany. The outcome of this investigation was the development of cardiovascular drug sales by packing unit over all 52 weeks of 2020. We found an increase of 68% in week 12 compared to the average sales for weeks 2 - 11, 2020 (vs. -2% in week 12, 2019), while the increase in week 51 was 61%, compared to the average sales for weeks 13 - 50, 2020 (vs. 35% in week 51, 2019). The largest increases in week 12 were for calcium channel blockers (64%), and the largest increases in week 51 were for lipid-lowering drugs (67%). The results of this retrospective cross-sectional study suggest that the COVID-19 lockdown in Germany was associated with a significant surge in pharmacy purchases of cardiovascular drugs, indicating panic buying. Although there were no drug shortages during the first lockdown, this panic buying recurred shortly before the second lockdown, albeit to a lesser extent.


Association of childhood socioeconomic position with cause-specific mortality in a prospective record linkage study of 1,839,384 individuals.
Previous studies have lacked sufficient power to assess associations between early-life socioeconomic position and adult cause-specific mortality. The authors examined associations of parental social class at age 0-16 years with mortality among 1,824,064 Swedes born in 1944-1960. Females and males from manual compared with nonmanual childhood social classes were more likely to die from smoking-related cancers, stomach cancer, respiratory disease, cardiovascular disease, and diabetes. Males from manual compared with nonmanual social classes were more likely to die from unintentional injury, homicide, and alcoholic cirrhosis. The association with stomach cancer was little affected by adjustment for parental later-life and own adult social class or education. For other outcomes, educational attainment resulted in greater attenuation of associations than did adjustment for adult social class. Early-life social class was not related to suicide or to melanoma, colon, breast, brain, or lymphatic cancers or to leukemia. With the exception of stomach cancer, caused by Helicobacter pylori infection acquired in childhood, poorer social class in early life was associated with diseases largely caused by behavioral risk factors such as smoking, physical inactivity, and an unhealthy diet. Educational attainment may be important in reducing the health inequalities associated with early-life disadvantage.


Polyol Structure Influences Enzymatic Hydrolysis of Bio-Based 2,5-Furandicarboxylic Acid (FDCA) Polyesters.
Polyesters of 2,5-furandicarboxylic acid (FDCA) have gained attention as they can be regarded as the bio-based alternatives to the petroleum-based polyesters of terephthalic acid. However, only little is known about the biodegradation and enzymatic hydrolysis of FDCA-based polyesters. This work aims to investigate the influence of different polyols on enzymatic hydrolysis of FDCA-based polyesters. A series of polyesters containing various polyols are synthesized and analyzed regarding susceptibility to enzymatic hydrolysis by cutinase 1 from Thermobifida cellulosilytica (Thc_Cut1). FDCA-based polyesters' number average molecular weight (Mn ) ranged from 9360-35 800 g mol-1 according to gel permeation chromatography (GPC) analysis. Differential scanning calorimetry (DSC) analyses show decreasing glass transition temperature (Tg ) with increasing diol chain length. Crystallinity of all polyesters is below 1% except for polyesters containing 1,6-hexanediol, 1,8-octanediol, and 1,12-dodecanediol for which calculated crystallinities are 27, 37, and 30%, respectively. Thc_Cut1 hydrolyzes all tested polyesters with preference for polyesters containing 1,5-pentanediol and 1,9-nonanediol (57.7 ± 7.5 and 52.8 ± 4.0% released FDCA). Enzyme activity increases when the linear diol 1,3-propanediol is replaced by the branched analog 1,2-propanediol or ethoxy units are introduced into the polyester chain. The results will contribute to expand the knowledge of microbial biodegradation of FDCA-based polyesters.


[Use of foaming and nonfoaming gentamycin tablets in treating cows with chronic endometritis].
Biopharmaceutic and therapeutic investigations were carried out with foaming and nonfoaming gentamycin sulfate tablets. The experiments were conducted with a total of 100 cows affected with chronic inflammation of the uterus. Both types of tablets, containing 30,000 IU of gentamycin sulfate each were introduced into the uterus via Andreev's catheter, bimanually or by means of a vaginal speculum and Albrechtzen's clamp, at the rate of 10. Followed up were the serum levels, the excretion with the milk, and the content in the uterine secretion of gentamycin after using the tablets. There was no statistically significant difference in the serum levels of gentamycin as initiated by the two types of tablets. In milk the peak values reached 0.02 micrograms/cm3, and in uterine washings (with 15 cm3 isotonic solution of sodium chloride) the proper levels were established up to 74nd hour. Demonstrated was the therapeutic effect in the treatment of cows with chronic endometritis - 77.4 per cent with the use of foaming and 71.4 per cent with the use of nonfoaming tablets. There was also a rising trend with the conception rate in the treatment of sterile cows (otherwise having no signs of uterine inflammation) with the use of nonfoaming tablets of gentamycin sulfate at the rate of 5, introduced 24 hours after insemination.


Efficient iodine catalyzed three components domino reaction for the synthesis of 1-((phenylthio)(phenyl)methyl)pyrrolidin-2-one derivatives possessing anticancer activities.
A simple and efficient three components domino reaction of γ-butyrolactam (2-pyrrolidinone), aromatic aldehyde and substituted thiophenol catalyzed by elemental iodine resulted in the formation of 1-((phenylthio)(phenyl)methyl)pyrrolidin-2-one derivatives. The stability of the synthesized analogues was evaluated in stimulated gastric fluid (SGF) and bovine serum albumin (BSA). In vitro anticancer activity was investigated in the low micromolar range and a few analogues were found to possess good activity. This current protocol provides several advantages like shorter reaction time, excellent yield and convenient work-up.


Prevalence of Cigarette Smoking among Patients with Different Histologic Types of Kidney Cancer.
Cigarette smoking is causally linked to renal cell carcinoma (RCC). However, associations for individual RCC histologies are not well described. Newly available data on tobacco use from population-based cancer registries allow characterization of associations with individual RCC types. We analyzed data for 30,282 RCC cases from 8 states that collected tobacco use information for a National Program of Cancer Registry project. We compared the prevalence and adjusted prevalence ratios (aPR) of cigarette smoking (current vs. never, former vs. never) among individuals diagnosed between 2011 and 2016 with clear cell RCC, papillary RCC, chromophobe RCC, renal collecting duct/medullary carcinoma, cyst-associated RCC, and unclassified RCC. Of 30,282 patients with RCC, 50.2% were current or former cigarette smokers. By histology, proportions of current or formers smokers ranged from 38% in patients with chromophobe carcinoma to 61.9% in those with collecting duct/medullary carcinoma. The aPRs (with the most common histology, clear cell RCC, as referent group) for current and former cigarette smoking among chromophobe RCC cases (4.9% of our analytic sample) were 0.58 [95% confidence interval (CI), 0.50-0.67] and 0.88 (95% CI, 0.81-0.95), respectively. Other aPRs were slightly increased (papillary RCC and unclassified RCC, current smoking only), slightly decreased (unclassified RCC, former smoking only), or not significantly different from 1.0 (collecting duct/medullary carcinoma and cyst-associated RCC). Compared with other RCC histologic types, chromophobe RCC has a weaker (if any) association with smoking. This study shows the value of population-based cancer registries' collection of smoking data, especially for epidemiologic investigation of rare cancers.


Improved intraocular bioavailability of ganciclovir by mucoadhesive polymer based ocular microspheres: development and simulation process in Wistar rats.
The poor ocular bioavailability of the conventional eye drops is due to lack of corneal permeability, nasolacrimal drainage and metabolic degradation. To overcome this issue, drug encapsulated in mucoadhesive polymer based ocular microspheres have the advantages of improved drug stability, easy administration in liquid form, diffuse rapidly and better ocular tissue internalization. The ganciclovir chitosan microspheres (GCM) were prepared by modified water-in-oil emulsification method. The formulation was optimized and characterized by investigating in vitro release study, release kinetics, XRD and microspheres stability. Ocular irritancy, in vivo ocular pharmacokinetic parameters and histopathology study was evaluated in Wistar rats. The use of pharmacokinetic/pharmacodynamic indices and simulation process was carried out to further ensure clinical applicability of the formulation. The in vitro release study showed initial burst (nearly 50 %) in first few minutes and followed Fickian (R(2) = 0.9234, n-value = 0.2329) type of diffusion release mechanism. The XRD and stability studies showed favorable results. The Wistar rat eyes treated with GCM showed significant increase in ganciclovir AUC (~4.99-fold) and Cmax (2.69-fold) in aqueous humor compared to ganciclovir solution and delay in Tmax. The Cmax/MIC90, AUC0-24/MIC90, AUC above MIC90 and T above MIC90 were significantly higher in GCM group. The aqueous humor concentration-time profile of ganciclovir in GCM and ganciclovir solution was simulated with every 28.1 and 12.8 h, respectively. The simulated concentration-time profile shows that in duration of 75 h, the ganciclovir solution require six ocular instillations compared to three ocular instillations of the GCM formulation. The photomicrograph of GCM and ganciclovir solution treated rat retina showed normal organization and cytoarchitecture. Correlating with in vitro data, the formulation showed sustained drug release along with improved intraocular bioavailability of ganciclovir in Wistar rats.


Gastric GIST with synchronous neuroendocrine tumour of the pancreas in a patient without neurofibromatosis type 1.
The gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. These are rare tumours with an incidence of 15 new cases per million per year. The occurrence of neuroendocrine tumours of the pancreas is rare, representing 1-5% of pancreatic cancers, and it is estimated that its incidence does not exceed five to one million. GISTs are common in patients with neurofibromatosis type 1 (NF1); there are few reported cases of synchronous neuroendocrine tumours in these patients and most are pheochromocytomas. The case reports a 64-year-old woman referred to the General Surgery Outpatient for incidental finding of gastric and pancreatic tumours. She underwent a radical subtotal pancreatectomy + partial gastrectomy with jejunal transposition. The pathological examination revealed: gastric GISTs and a well-differentiated neuroendocrine carcinoma of the pancreas. This is the second case published so far of a patient with both tumours and without NF1. Posterior studies must be performed to evaluate if some other genetic disorder is involved in these patients without NF1.


"Choose-a-size" approach in dynamic combinatorial chemistry: a single substrate dynamic combinatorial library of oligomacrocycles that adapts to the size and shape of carboxylates.
A neutral anion binding receptor based on dipicolinic acid diamide was equipped with thiol groups in the amidic side arms. After the thiol was oxidized to disulfide groups with I2, a mixture of cyclic oligomers (a library) was obtained. The distribution of macrocycles can be controlled kinetically during the oxidation process or thermodynamically at basic conditions via disulfide bond exchange. The library proved to be very sensitive to templation with various carboxylates in DMSO. The amplification pattern reflects the structural features of the anionic template and is sensitive to changes in the template's geometry. The application of carboxylates with multiple functional groups resulted in very strong amplification of the large penta- and hexameric macrocycles. The thermodynamic parameters of some templation effects were rationalized using a simple model and confirmed using competitive NMR titration.


Current management of Helicobacter pylori infections in the elderly.
Helicobacter pylori infection is a chronic gastric gram-negative infection that increases with age worldwide. However, the percentage age of H. pylori-positive elderly patients who are tested and treated for their infection remains very low. It is now demonstrated that H. pylori infection induces a whole cascade of events leading to gastric pathologies, such as peptic ulcer diseases, gastric precancerous lesions and gastric cancer. Recent data also demonstrated that H. pylori chronic infection can play a role in gastric aging, appetite regulation and extradigestive diseases, such as Alzheimer's disease, in the elderly. The diagnosis of H. pylori infection remains difficult to realize in the very old population, and the urea breath test obtains the best performance in this population. 1-week proton pump inhibitor-based triple therapy regimens are highly effective and well tolerated in elderly patients, and antibiotic resistance remains very low. Low compliance is the main factor related to treatment failure in this population.


Emergency medicine and the development of the Food and Drug Administration's final rule on informed consent and waiver of informed consent in emergency research circumstances.
This article reviews the federal regulations for emergency and acute resuscitation research in effect prior to October 1996, the historical issues that contributed to the development of these regulations, the controversies that arose surrounding the application of these regulations to emergency research circumstances, and the methods by which the regulations were changed. The new regulations introduced by the U.S. Food and Drug Administration (FDA) also are reviewed.


Consumption of sugar-sweetened beverages in relation to stroke: a case-control study.
Sugar-sweetened beverages (SSBs) have recently received great attention in the field of diet-disease relations. Limited data are available linking SSBs intake to the risk of stroke. This study was conducted to examine the association between habitual intake of SSBs and risk of stroke among Iranian population. This hospital-based case-control study was conducted in Alzahra University Hospital, Iran. Cases were stroke patients and controls were selected among hospitalized patients without prior history of stroke. A semi-quantitative food frequency questionnaire was used to assess the usual intakes of SSBs. Total intake of SSBs was not significantly different between cases and controls (48.2 ± 6.2 vs. 47.2 ± 6.2 g/day, p = 0.90). After adjustment for potential confounders, the odds ratios for stroke across increasing tertiles of SSB consumption were 1.00, 0.84 (95% CI: 0.46-1.54) and 0.85 (0.43-1.66) (p(trend) = 0.12). No statistically significant association was found between habitual intakes of SSBs and stroke.


Water-salt balance, plasma renin activity and catecholamine excretion in renovascular hypertension in the rat.
Water-electrolyte balance, plasma renin activity and urinary catecholamine excretion were studied for a period of 10 weeks after clipping the renal artery in the rat. Two groups of rats were examined; in Group I, a silver clip was applied on the left renal artery leaving the contralateral kidney untouched; in Group II, both renal arteries were clipped. Neither water-salt retention nor the increase inthe activity of the renin-angiotensin system or in the neural tone seem to be essential in the development of high arterial pressure after renal ischemia. All these factors would seem to be secondary mechanisms the contribution of which would depend on the experimental model or the hypertensive period under consideration.


Fatty acid omega-oxidation as a rescue pathway for fatty acid oxidation disorders in humans.
Fatty acids (FAs) can be degraded via different mechanisms including α-, β- and ω-oxidation. In humans, a range of different genetic diseases has been identified in which either mitochondrial FA β-oxidation, peroxisomal FA β-oxidation or FA α-oxidation is impaired. Treatment options for most of these disorders are limited. This has prompted us to study FA ω-oxidation as a rescue pathway for these disorders, based on the notion that if the ω-oxidation of specific FAs could be upregulated one could reduce the accumulation of these FAs and the subsequent detrimental effects in the different groups of disorders. In this minireview, we describe our current state of knowledge in this area with special emphasis on Refsum disease and X-linked adrenoleukodystrophy.


Baseline Dysgeusia in Chemotherapy-Naïve Non-Small Cell Lung Cancer Patients: Association with Nutrition and Quality of Life.
Purpose: Dysgeusia can be found in 50% of cancer patients undergoing chemotherapy. Nonetheless, dysgeusia can be present in treatment-naïve patients, and may negatively impact nutrition and quality of life.Methods: Treatment-naïve non-small cell lung cancer (NSCLC) was assessed for dysgeusia using a self-reporting questionnaire and a rinse stimuli technique. Patients were evaluated in terms of health-related quality of life (HRQL) using the EORTC-QLQ-C30 questionnaire and in terms of nutrition using the subjective global assessment (SGA), energy consumption and body composition.Results: Among 65 treatment-naïve patients, dysgeusia was self-reported in 35%. Using the rinse stimuli technique, most of the patients perceived taste stimuli with a minimal concentration, but could not recognize the taste. Patients with dysgeusia presented significantly less lean-body mass (P = 0.027), and higher fat mass (P = 0.027). Additionally, these patients had significantly more gastrointestinal symptoms including nausea (P = 0.042), anorexia (P = 0.004), and early satiety (P < 0.0001). Dysgeusia was also associated with less food consumption (P = 0.010). Last, patients with dysgeusia had clinically-significant alterations in HRQL scales.Conclusion: Presence of dysgeusia in NSCLC patients before undergoing chemotherapy is associated with worse nutritional outcomes. The routine assessment of dysgeusia in treatment-naïve patients should be encouraged to timely assess and follow nutritional parameters.


Vulvar vestibular papillomatosis: A diagnostic conundrum.
Vulvar vestibular papillomatosis (VP) is considered a normal anatomical variant of the vulva. We present a 19-year-old girl with a history of "small itchy growths" on the vulva for 2 months without any associated discharge. These lesions were causing significant anxiety to the patient. Cutaneous examination revealed multiple, uniformly arranged, skin-colored, monomorphic micropapillae on the inner aspect of the labia minora. Biopsy showed mucosal hyperplasia with papillomatosis and loosely arranged subdermal tissue, no koilocytes were spotted. The diagnosis of vulvar VP was made. We want to highlight this clinical entity as most dermatologists are not familiar with this benign condition and easily confuse it with genital warts. This inexperience may result in unnecessary investigations causing psychological discomfort to the patient. We herein present such a case which brings out the diagnostic dilemma.


Cellular-mediated immune responses in the liver tissue of patients with severe Plasmodium falciparum malaria.
The immune responses against Plasmodiumfalciparum malaria infections are complex and poorly understood. No published studies have yet reported the lymphocyte subsets involved in the human liver tissue of P. falciparum malaria patients. To understand the cellular-mediated immune responses in the liver during malaria infection, we determined the numbers of the various lymphocyte subsets in tissue samples obtained at autopsy from patients who died with P. falciparum malaria infection. All the liver tissue specimens had been stored at the Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Thailand. On the basis of total bilirubin (TB) levels prior to death, patients were divided into 2 groups: those with hyperbilirubinemia [total bilirubin (TB) > or =51.3 micromol/l) (n = 9)] and those without hyperbilirubinemia (TB < 51.3 micromol/l) (n = 12). Normal liver specimens (n = 10) were used as controls. An immunohistochemistry method was used to analyze the types and numbers of lymphocytes (T and B lymphocytes), and Kupffer cells, using specific antibodies against CD3+, CD4+, CD8+, CD20+, and CD68+. Our findings reveal the numbers of T lymphocytes (CD3+ T-cells) and their subsets (CD4+ and CD8+ T-cells) were significantly greater in the portal tracts and sinusoids of liver tissue obtained from P. falciparum malaria cases with hyperbilirubinemia than those without hyperbilirubinemia or controls. CD8+ T-cells were the major lymphocyte subset in the liver tissue of patients with severe falciparum malaria. A significant positive correlation was seen between the numbers of CD4+ and CD8+ T-cells and the liver enzyme levels among P. falciparum malaria patients. The number of CD68+ cells (Kupffer cells) was significantly greater in the liver sinusoids of P. falciparum malaria cases with hyperbilirubinemia than those without hyperbilirubinemia. These findings suggest T-cells, especially CD8+ T-cells and Kupffer cells are an important part of the cellular immune response in the liver tissue of P. falciparum infected patients.


Small GTPase Immunity-Associated Proteins Mediate Resistance to Toxoplasma gondii Infection in Lewis Rat.
Rats vary in their susceptibilities to Toxoplasma gondii infection depending on the rat strain. Compared to the T. gondii-susceptible Brown Norway (BN) rat, the Lewis (LEW) rat is extremely resistant to T. gondii Thus, these two rat strains are ideal models for elucidating host mechanisms that are important for host resistance to T. gondii infection. Therefore, in our efforts to unravel molecular factors directing the protective early innate immune response in the LEW rat, we performed RNA sequencing analysis of the LEW versus BN rat with or without T. gondii infection. We identified three candidate small GTPase immunity-associated proteins (GIMAPs) that were upregulated (false discovery rate, 0.05) in the LEW rat in response to T. gondii infection. Subsequently, we engineered T. gondii-susceptible NR8383 rat macrophage cells for overexpression of LEW rat-derived candidate GIMAP 4, 5, and 6. By immunofluorescence analysis we observed that GIMAP 4, 5, and 6 in T. gondii-infected NR8383 cells each colocalized with GRA5, a parasite parasitophorous vacuole membrane (PVM) marker protein, suggesting their translocation to the PVM. Interestingly, overexpression of each candidate GIMAP in T. gondii-infected NR8383 cells induced translocation of LAMP1, a lysosome marker protein, to the T. gondii surface membrane. Importantly, overexpression of GIMAP 4, 5, or 6 individually inhibited intracellular T. gondii growth, with GIMAP 4 having the highest inhibitory effect. Together, our findings indicate that upregulation of GIMAP 4, 5, and 6 contributes to the robust refractoriness of the LEW rat to T. gondii through induction of lysosomal fusion to the otherwise nonfusogenic PVM.


Aerobic endurance training program improves exercise performance in lung transplant recipients.
To determine whether an aerobic endurance training program (AET) in comparison to normal daily activities improves exercise capacity in lung transplant recipients. Nine lung transplant recipients (12+/-6 months after transplant) were examined. All patients underwent incremental bicycle ergometry with the work rate increased in increments of 20 W every 3 min. Identical exercise tests were performed after 11+/-5 weeks of normal daily activities and then after a 6-week AET. The weekly aerobic training time increased from 60 min at the beginning to 120 min during the last week. Training intensity ranged from 30 to 60% of the maximum heart rate reserve. Normal daily activities had no effect on exercise performance. The AET induced a significant decrease in resting minute ventilation from 14+/-5 to 11+/-3 L/min. At an identical, submaximal level of exercise, a significant decrease in minute ventilation from 47+/-14 L/min to 39+/-13 L/min and heart rate from 144+/-12 to 133+/-17 beats/min, before and after the AET, was noted. The increase in peak oxygen uptake after AET was statistically significant (1.13+/-0.32 to 1.26+/-0.27 L/min). These data demonstrate that normal daily activities do not affect exercise performance in lung transplant recipients > or = 6 months after lung transplantation. An AET improves submaximal and peak exercise performance significantly.


Genome Plasticity by Insertion Sequences Learned From a Case of Radiation-Resistant Bacterium Deinococcus geothermalis.
The genome of the radiation-resistant bacterium Deinococcus geothermalis contains 19 types of insertion sequences (ISs), including 93 total transposases (Tpases) in 73 full-length ISs from the main chromosome and 2 mega plasmids. In this study, 68 ISs from the D. geothermalis genome were extracted to implicate the earlier genome before its mutation by transposition of ISs. The total size of eliminated ISs from genome was 78.85 kb. From these in silico corrections of mutation by the ISs, we have become aware of some bioinformatics factualness as follows: (1) can reassemble the disrupted genes if the exact IS region was eliminated, (2) can configure the schematic clustering of major DDE type Tpases, (3) can determine IS integration order across multiple hot spots, and (4) can compare genetic relativeness by the partial synteny analysis between D. geothermalis and Deinococcus strain S9. Recently, we found that several IS elements actively transferred to other genomic sites under hydrogen peroxide-induced oxidative stress conditions, resulting in the inactivation of functional genes. Therefore, the single species genome's mobilome study provides significant support to define bacterial genome plasticity and molecular evolution from past and present progressive transposition events.


Metabolomics and gene expressions revealed the metabolic changes of lipid and amino acids and the related energetic mechanism in response to ovary development of Chinese sturgeon (Acipenser sinensis).
Captive breeding has been explored in Chinese sturgeon (Acipenser sinensis) for species protection. However, gonad development from stage II to IV of cultured female broodstocks is a handicap. This study aimed to explore the physiological and metabolic changes during the ovary development from stage II to IV of female Chinese sturgeon and the related energy regulatory mechanism, which may be helpful to address the developmental obstacle. The results showed that the oocyte volume increased and the muscle lipid content decreased with the ovary development. Ovarian RNA levels of most genes related to lipid and amino acid metabolism were higher in stage II and III than in stage IV. Serum contents of differential metabolites in arginine, cysteine, methionine, purine, tyrosine, lysine, valine, leucine and isoleucine metabolism pathways peaked at stage III, while the contents of sarcosine, alanine and histidine, as well as most oxylipins derived from fatty acids peaked at stage IV. These results indicated the more active amino acids, lipid metabolism, and energy dynamics of fish body in response to the high energy input of ovary developing from stage II to III, and the importance of alanine, histidine, taurine, folate and oxylipins for fish with ovary at stage IV.


Role of actin in platelet function.
Cytochalasin E (CE) was used in this study to evaluate relationships between platelet shape change, pseudopod extension, internal transformation, actin filament assembly, fibrinogen receptor expression, aggregation, clot tension and secretion. Various ratios of G- to F-actin, measured by the DNase inhibition assay, were achieved by using several concentrations of CE in stirred and unstirred thrombin-stimulated platelets. An increased rate of actin polymerization was found in "aggregating" conditions as compared to "activating" conditions, the latter achieved by either absence of stirring or stirring in the presence of the tetrapeptide Arg-Gly-Asp-Ser (RGDS). Larger concentrations of CE were required in aggregated than in activated platelets to obtain G-actin levels analogous to those in resting platelets. Concentrations of polymerizing actin above 20% and 55% for activated and aggregated platelets, respectively, trigger platelet shape change and the extension of pseudopods. Prevention of de novo actin polymerization by CE, added either before or after thrombin stimulation, inhibits fibrinogen binding to platelets. This suggests an involvement of the new actin polymers in fibrinogen receptor exposure. As expected, platelet aggregation and clot tension, which are dependent on fibrinogen receptor exposure, were inhibited by CE. Granular secretion was not dependent on polymerizing actin.


Expectations and satisfaction of pregnant women: unveiling prenatal care in primary care.
To analyze the perception of primiparous women about prenatal care in Basic Health Units in a municipality in southern Brazil. This is a qualitative research from the perspective of Social Representation Theory, from the following question: How has been the pre-natal care for you? Eighteen pregnant women were interviewed. The analysis resulted in three categories: Expectation representation about prenatal care; Rescuing the care offered in prenatal consultation; Unveiling the (dis) satisfaction with prenatal consultation. The prenatal care was apprehended as an essential moment for safe pregnancy, although centered on the doctor's figure and guarantee access to early laboratory and imaging tests. On the other hand, dissatisfaction was revealed from the reception at the entrance to the health unit to the consultations access, although some statements suggest timely satisfaction. Prenatal care did not meet the specific expectations of the study group and unveiled that the nurse did not supply it, as a member of the multidisciplinary team. The organization of the nursing work process in primary care, related to prenatal care, needs to be revisited to promote the effectiveness of its actions.


Charting a course for the future of women's health in the United States: concepts, findings and recommendations.
The JHU Women's and Children's Health Policy Center, with the federal Maternal and Child Health Bureau, undertook a review of the health of women in the United States and invited experts to develop recommendations on health policy, programs, practices and research. The review included published research, program reviews, and policy reports on women's physical health, mental health, and health behaviors, and on the effects of health services, systems and financing on their health. Based on trends in age, ethnic background, education, labor-force participation, marriage and childbearing among women, the results of the reviews, and the experts' consultation, several recommendations were made for a forward looking agenda. They included the need: (1) to focus broadly on women's health, not just during pregnancy; (2) for comprehensive, integrated programs and services addressing women's unique needs; (3) for integrated programs and services across the lifespan; (4) for better provider training about women's unique health needs, the differential effects of particular problems on them, and the consequences of chronic health problems heretofore considered primarily male problems; (5) to eliminate social policies that single out women, particularly pregnant women, for punitive actions; (6) to promote social policies that ensure economic security for women; and (7) for vigorous public health leadership to shape the women's health agenda, recognizing the social and economic context of their lives. The social and economic trends among women in the US and the recommendations for a women's health agenda have relevance to other developed countries as well.


Premature myogenic differentiation and depletion of progenitor cells cause severe muscle hypotrophy in Delta1 mutants.
In vertebrates, skeletal myogenesis is initiated by the generation of myoblasts followed by their differentiation to myocytes and the formation of myofibers. The determination of myoblasts and their differentiation are controlled by muscle regulatory factors that are activated at specific stages during myogenesis. During late embryonic and fetal stages a distinct population of resident proliferating progenitor cells is the major source of myogenic cells. How the differentiation of myoblasts and progenitor cells is regulated is not clear. We show that in mouse embryos the Notch ligand Delta1 (Dll1) controls both differentiation of early myoblasts and maintenance of myogenic progenitor cells. Early dermomyotome-derived myoblasts are determined normally in Dll1 mutant embryos, but their differentiation is accelerated, leading to a transient excess of myotomal muscle fibers. Similarly, migratory hypaxial myogenic cells colonize the limb buds and activate muscle regulatory factor expression normally, but muscle differentiation progresses more rapidly. Resident progenitor cells defined by Pax3/Pax7 expression are formed initially, but they are progressively lost and virtually absent at embryonic day 14.5. Muscle growth declines beginning around embryonic day 12, leading to subsequent severe muscle hypotrophy in hypomorphic Dll1 fetuses. We suggest that premature and excessive differentiation leads to depletion of progenitor cells and cessation of muscle growth, and we conclude that Dll1 provides essential signals that are required to prevent uncontrolled differentiation early and ensure sustained muscle differentiation during development.