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11177674

Adult neurogenesis and neurodegenerative disease.

Advances in stem cell biology of the adult brain and the discovery of adult neurogenesis have raised the hope that neurodegenerative disorders might ultimately become amenable to causal therapy. Stem cells contribute to cellular plasticity during the lifespan, and in some sense, brain development never ends. However, neurodegeneration is not just a lack of neuroregeneration, and cell genesis in the adult brain does not apparently lead to successful endogenous responses to neurodegeneration. The brain heals poorly; nevertheless, the onset, severity and progression of neurodegenerative disorders show large variation and can often be influenced by cognitive training and physical activity. Rather than providing endogenous repair, cellular plasticity, including adult neurogenesis might thus contribute to the 'cognitive reserve' that determines how well an organism can compensate for neurodegeneration. From this perspective, neurodegenerative disorders, such as Alzheimer's, Parkinson's, Lewy body and Huntington's diseases, might share a relevant biological principle that even links them to psychiatric disorders, like depression, which are not considered 'neurodegenerative' in a classical sense. However, the integration of neuroregenerative phenomena and most notably adult neurogenesis into the concepts of neurodegeneration is not without problems and remains speculative at present. Adult neurogenesis might be part of the physiological regenerative response and might thereby alter or alleviate symptoms, but it might also become impaired by the disease mechanism and thereby contribute to the symptoms of neurodegeneration. In any case, the extent to which effects on the level of cellular plasticity, be it degenerative or regenerative, are relevant functionally remains to be determined. The present review gives an overview of what is known about cell genesis and adult neurogenesis in neurodegenerative disorders and discusses how cellular plasticity might be part of concepts that integrate aspects of development and cellular plasticity into neurodegeneration.

Neurons

physiology

23900474

Background severity of asthma in children discharged from the emergency department

Objective:  Attendance at an Emergency Department (ED) with an acute attack of asthma may be indicative of undertreatment of persistent disease. However, many presentations are in children with infrequent episodic asthma. The aim of this study was to characterize the pattern of asthma of children discharged from ED to determine whether there was potential to improve underlying disease control.

Asthma

physiopathology

11951505

Growth after bone marrow transplantation in young children conditioned with chemotherapy alone

Short stature is a potential side-effect of BMT, brought about by the conditioning protocol and/or the complications of BMT. This study evaluates the effects of conditioning by chemotherapy, and BMT complications on growth. Thirty children conditioned for BMT by chemotherapy alone (cyclophosphamide and busulfan) were classified according to the occurrence of serious or prolonged complications after BMT: group 1 (n = 12) had no complication, while group 2 (n = 18) did. Fifteen of them were severely growth retarded (⩽ −2 s.d.) at BMT, because of their initial disease. At the time of BMT, the two groups had similar ages (1.0 ± 0.2, s.e.m. year, in group 1 and 1.7 ± 0.5 year in group 2), height (−1.7 ± 0.5; −1.8 ± 0.3 s.d.) and plasma insulin-like growth factor I (IGFI) levels (0.3 ± 0.1 U/ml in both). Group 1 grew significantly and their plasma IGFI increased but group 2 did not, as assessed 2 years post-BMT. We conclude that conditioning with chemotherapy alone does not prevent the catch-up growth induced by BMT in young children; the lack of catch-up growth is due to complications occurring after BMT, and the change in plasma IGFI suggests that complications of BMT prevent any increase in plasma IGFI, and thereby catch-up growth.

Neoplasms

therapy

31170046

Clinical and angiographic predictors of ST-segment recovery after primary percutaneous coronary intervention.

Important determinants of incomplete ST-segment recovery in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) have been incompletely characterized. Early risk stratification could identify patients with STEMI and incomplete ST-segment recovery who may benefit from adjunctive therapy. For the present study, we analyzed 12-lead electrocardiograms from 2,124 patients with STEMI who underwent primary PCI at our institution from 2000 to 2007. ST-segment recovery was defined as percent change in cumulative ST-segment deviation between preprocedural and immediately postprocedural electrocardiograms and categorized as incomplete when <50%. A total of 1,032 patients (49%) had incomplete ST-segment recovery. After multivariable adjustment, age >60 years (adjusted odds ratio [OR] 1.28, 95% confidence interval [CI] 1.06 to 1.54, p = 0.011), diabetes mellitus (OR 1.36, 95% CI 1.02 to 1.82, p = 0.034), left anterior descending coronary artery-related STEMI (OR 1.92, 95% CI 1.61 to 2.30, p<0.001), and multivessel disease (OR 1.34, 95% CI 1.10 to 1.63, p = 0.004) were independent predictors of incomplete ST-segment recovery. Current smoking (OR 0.79, 95% CI 0.65 to 0.95, p = 0.013) and a preprocedural Thrombolysis In Myocardial Infarction grade <3 flow (OR 0.70, 95% CI 0.53 to 0.93, p = 0.014) were inversely related to ST-segment recovery. Incomplete ST-segment recovery was a strong predictor of long-term mortality (hazard ratio 2.07, 95% CI 1.59 to 2.69, p <0.001) in addition to identified characteristics that independently predicted incomplete ST-segment recovery. In conclusion, incomplete ST-segment recovery at the end of PCI occurred significantly more often in the presence of an age >60 years, nonsmoking, diabetes mellitus, left anterior descending coronary artery-related STEMI, multivessel disease, and preprocedural Thrombolysis In Myocardial Infarction grade 3 flow. Patients with STEMI and these clinical features are at increased risk of impaired myocardial salvage and are appropriate candidates for adjunctive therapy.

Myocardial Infarction

therapy

41712239

Antimicrobial susceptibility tests on anaerobic oral mixed cultures in periodontal diseases.

The ecosystem of the dental plaque in periodontal diseases is very complex: the study of such micro-organisms, which are mostly strict anaerobes, requires the use of specific techniques under conditions of strict anaerobiosis. The aim of the present study was to design a rapid method to evaluate the activity of antimicrobials on mixed bacterial plaque of subjects with periodontal diseases. The study was carried out using a computerised instrument generally used for simultaneous diagnostic tests with aerobic bacteria. Operative and methodological modifications were made to obtain conditions of strict anaerobiosis and the balanced growth of all the microbial forms present in the mixed cultures of the plaque. Penicillins and cephalosporins were active on all the samples, whereas colistin, gentamicin, kanamycin and nalidixic acid showed no activity. Clindamycin, tetracycline, erythromycin and penicillin G were effective only against some samples. The activity of the antimicrobials towards isolated strains was analogous to that towards the corresponding mixed culture.

Anti-Bacterial Agents

pharmacology

23685021

Nuclear factor-kappa B in signal conduction of protein kinase C in T lymphocytes from an asthmatic guinea pig model.

OBJECTIVE To explore the role of nuclear factor-kappa B (NF-kappa B) in the signal conduction of protein kinase C (PKC) regulated proliferation, apoptosis and expression of Th2 cytokines -- interleukin-4 (IL-4) and interleukin-5 (IL-5) of T lymphocytes in the bronchial alveolus lavage fluid (BALF). METHODS T lymphocytes were isolated and purified from BALF of asthmatic guinea pigs in normal and asthmatic groups, and were stimulated with PKC agitator phorbol 12-myristate 13-acetate (PMA) and NF-kappa B inhibitor pyrrolidine dithiocarbamate (PDTC), respectively. The expressions of NF-kappa B, IL-4 and IL-5 mRNA and protein, the proliferation and apoptosis of T lymphocytes were observed by immunohistochemistry, in situ hybridization, ELISA, MTT and TUNEL, respectively. RESULTS The activation of NF-kappa B, proliferation response, and expression of IL-4 and IL-5 mRNA and protein in T lymphocytes stimulated by PMA were significantly higher than those of their blank control (P < 0.01), while those indexes of T lymphocytes stimulated by PMA and PDTC simultaneously were significantly lower than those stimulated by PMA alone (P < 0.01). The apoptotic index of T lymphocytes stimulated with PMA were significantly lower than that of their blank control (P < 0.01), and the apoptotic index of asthmatic guinea pig T lymphocytes stimulated with PMA and PDTC simultaneously were significantly higher than that stimulated by PMA alone (P < 0.01). The significant positive correlations were found between the activation of NF-kappa B and the proliferation (r = 0.64, P < 0.001), and the expression of IL-4 and IL-5 mRNA and protein of T lymphocytes, respectively (r = 0.55 - 0.68, P < 0.001). There was also significant negative correlation between the activation of NF-kappa B and apoptosis of T lymphocytes (r = 0.62, P < 0.001). CONCLUSIONS NF-kappa B may participate in the signal conduction of PKC regulated proliferation, apoptosis and expression of IL-4 and IL-5 of T lymphocytes in asthma. The activation of NF-kappa B in PKC signal conduction pathway of T lymphocytes may play an important role in the pathogenesis of asthma.

Asthma

metabolism

824683

Molecular Pathways: The Complex Roles of Inflammation Pathways in the Development and Treatment of Liver Cancer

Inflammatory signals from the surrounding microenvironment play important roles in tumor promotion. Key inflammatory mediators and pathways that induce and sustain tumorigenesis have recently been identified in many different cancers. Hepatocellular carcinoma is a paradigm for inflammation-induced cancer, as it most frequently develops in the setting of chronic hepatitis, consecutive cellular damage, and compensatory regeneration. Recent studies revealed that liver damage–mediated inflammation and carcinogenesis are triggered by a complex cross-talk between NF-κB, c-jun-NH2-kinase, and STAT3 signaling pathways. Molecular dissection of the mechanisms involved in the interplay between these pathways identified promising new targets for therapeutic intervention. Targeting different components of the signaling cascades may provide efficient means for blocking the apparently irreversible sequence of events initiated by chronic liver inflammation and culminating in liver cancer. Clin Cancer Res; 19(11); 2810–6. ©2013 AACR.

Liver Neoplasms

metabolism

16555848

Effect of emergency major abdominal surgery on CD4 cell count among HIV positive patients in a sub Saharan Africa tertiary hospital - a prospective study

BackgroundSurgery plays a key role in HIV palliative care, specifically in the diagnosis and treatment of HIV related and non-related conditions. Yet major surgery depresses the immune system. Whereas the surgical consequences of HIV infection are well described, there is a paucity of published data, in resource-limited settings, on the effects of major surgery on the immune system. The purpose of this study was to determine the effect of major abdominal surgery on CD4 count in HIV positive and HIV negative patients after emergency major surgery.MethodsA prospective cohort study was done for patients who underwent emergency major abdominal surgery. Their peri-operative CD4 counts were done for both HIV- and HIV + patients. Median CD4s were used in analysis.Mann Whitney test of significance was used for continuous data and Fisher’ exact test used for categorical data. IRB approval was obtained.ResultsA total of 101 patients were recruited, 25 HIV positive and 76 HIV negative. The median CD4 cell reduction was higher in the HIV negative group (−68 cells) than HIV positive group (−29 cells) (p = 0.480).There was a general increase in the median CD4 change by 72 cells for the HIV positives and 95 cells for the HIV negatives (p = 0.44). CD4 change rose in both the HIV positive and negative groups by 27 cells for the HIV positives and 28 cells for the HIV negatives (p = 0.94). Relative Risk was 0.96, {CI 0.60 – 1.53}.ConclusionMajor emergency abdominal surgery had no significant effect on CD4 cell count among HIV positive patients.

Postoperative Complications

pathology

22068891

Does angiotensin‐converting enzyme gene polymorphism affect blood pressure? Findings after 6 years of follow‐up in healthy subjects

There has been an increase in research into the association between angiotensin‐converting enzyme (ACE) gene deletion polymorphism and cardiovascular disease, with conflicting results. The present prospective long‐term study was conducted to evaluate whether the DD genotype could also be associated with a higher prevalence of hypertension in healthy subjects, over 6 years of follow‐up.

Hypertension

genetics

25212346

Treatment with lenalidomide modulates T‐cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia

Lenalidomide, an immunomodulatory agent, has activity in lymphoproliferative disorders. The authors, therefore, evaluated its effects on T‐cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia (CLL).

Antineoplastic Agents

therapeutic use

36685329

Novel therapeutic delivery approaches in development for pediatric gliomas.

Pediatric gliomas are a heterogeneous group of diseases, ranging from relatively benign pilocytic astrocytomas with >90% 5-year survival, to glioblastomas and diffuse intrinsic pontine gliomas with <20% 5-year survival. Chemotherapy plays an important role in the management of these tumors, particularly in low-grade gliomas, but many high-grade tumors are resistant to chemotherapy. A major obstacle and contributor to this resistance is the blood–brain barrier, which protects the CNS by limiting entry of potential toxins, including chemotherapeutic agents. Several novel delivery approaches that circumvent the blood–brain barrier have been developed, including some currently in clinical trials. This review describes several of these novel approaches to improve delivery of chemotherapeutic agents to their site of action at the tumor, in attempts to improve their efficacy and the prognosis of children with this disease.

Antineoplastic Agents

administration & dosage

25304437

Flexible, phase-matched, linear receive arrays for high-field MRI in monkeys.

High signal-to-noise ratios (SNR) are essential for high-resolution anatomical and functional MRI. Phased arrays are advantageous for this but have the drawback that they often have inflexible and bulky configurations. Particularly in experiments where functional MRI is combined with simultaneous electrophysiology, space constraints can be prohibitive. To this end we developed a highly flexible multiple receive element phased array for use on anesthetized monkeys. The elements are interchangeable and different sizes and combinations of coil elements can be used, for instance, combinations of single and overlapped elements. The preamplifiers including control electronics are detachable and can serve a variety of prefabricated and phase matched arrays of different configurations, allowing the elements to always be placed in close proximity to the area of interest. Optimizing performance of the individual elements ensured high SNR at the cortical surface as well as in deeper laying structures. Performance of a variety of arrangements of gapped linear arrays was evaluated at 4.7 and 7T in high-resolution anatomical and functional MRI.

Brain

pathology

29070143

Rapid Identification and Detection of Intracellular Survival Testing of Mycobacterium smegmatis mc2155 that Contains eis Gene from Mycobacterium tuberculosis by Flow Cytometry

Mycobacterium tuberculosis is a facultative intracellular pathogen that has evolved the ability to survive and multiply within human macrophages. The enhanced intracellular survival (eis) gene (Rv2416c) from M. tuberculosis has been identified as a potential factor that can enhance the intracellular survival of Mycobacterium smegmatis in the macrophage cell line. However, the time requirements for intracellular survival testing of Mycobacterium using classical methodologies are still too long. In this study, we used M. smegmatis mc2155 that contains eis to develop and study a rapid method to test intracellular survival using flow cytometry. We demonstrated the success of this technique, which required only a few hours. This assay is rapid, accurate, and reproducible, and it would be valuable for the rapid detection of intracellular survival of mycobacteria.

Bacterial Proteins

metabolism

3832144

Aging With Disability for Midlife and Older Adults

This analysis brings “aging with disability” into middle and older ages. We study U.S. adults ages 51+ and ages 65+ with persistent disability (physical, household management, personal care; physical limitations, instrumental activities of daily living [IADLs], activities of daily living [ADLs]), using Health and Retirement Study data. Two complementary approaches are used to identify persons with persistent disability, one based directly on observed data and the other on latent classes. Both approaches show that persistent disability is more common for persons ages 65+ than ages 51+ and more common for physical limitations than IADLs and ADLs. People with persistent disability have social and health disadvantages compared to people with other longitudinal experiences. The analysis integrates two research avenues, aging with disability and disability trajectories. It gives empirical heft to government efforts to make aging with disability an age-free (all ages) rather than age-targeted (children and youths) perspective.

Aging

physiology

11807417

[Glucose-6-phosphate dehydrogenase as a marker of genetic predisposition to neoplasms].

In the light of reports in the literature the data are presented on the importance of glucose-6-phosphate dehydrogenase in cell metabolism. The effect of decreased enzyme activity or its complete absence on the functions of the cell, and the clinical conditions associated with deficient enzyme activity are described. The influence is discussed of the genetic determination of the enzyme on the occurrence of phenotypic effects, and the use of the mosaicism phenomenon in the study on the pathogenesis of certain disturbances. Several reports from the literature are quoted concerning the study of the reverse relationship between a deficiency of the activity of the enzyme and the incidence of carcinoma. The necessity is stressed of including electrophoretic techniques into the studies.

Neoplasms

etiology

44879965

Mind-body medicine and cancer.

Mind-body medicine, grounded in a respectful, therapeutic partnership, should be a central element in the care of every person diagnosed with cancer. This article reviews some of the physiologic foundations of mind-body medicine, the introduction of mind-body approaches to cancer care in the 1970s, the specific mind-body approaches that have been used, and the evidence that supports their use. The importance of group support for enhancing the effectiveness of these approaches is discussed. Guidelines are offered for integrating mind-body approaches and perspectives in the care of people who have cancer.

Neoplasms

therapy

85542641

Unveiling Integrated Functional Pathways Leading to Enhanced Respiratory Disease Associated With Inactivated Respiratory Syncytial Viral Vaccine

Respiratory syncytial virus (RSV) infection is a severe threat to young children and the elderly. Despite decades of research, no vaccine has been approved. Notably, instead of affording protection, a formalin-inactivated RSV vaccine induced severe respiratory disease including deaths in vaccinated children in a 1960s clinical trial; however, recent studies indicate that other forms of experimental vaccines can also induce pulmonary pathology in pre-clinical studies. These findings suggest that multiple factors/pathways could be involved in the development of enhanced respiratory diseases. Clearly, a better understanding of the mechanisms underlying such adverse reactions is critically important for the development of safe and efficacious vaccines against RSV infection, given the exponential growth of RSV vaccine clinical trials in recent years. By employing an integrated systems biology approach in a pre-clinical cotton rat model, we unraveled a complex network of pulmonary canonical pathways leading to disease development in vaccinated animals upon subsequent RSV infections. Cytokines including IL-1, IL-6 GRO/IL-8, and IL-17 in conjunction with mobilized pulmonary inflammatory cells could play important roles in disease development, which involved a wide range of host responses including exacerbated pulmonary inflammation, oxidative stress, hyperreactivity, and homeostatic imbalance between coagulation and fibrinolysis. Moreover, the observed elevated levels of MyD88 implicate the involvement of this critical signal transduction module as the central node of the inflammatory pathways leading to exacerbated pulmonary pathology. Finally, the immunopathological consequences of inactivated vaccine immunization and subsequent RSV exposure were further substantiated by histological analyses of these key proteins along with inflammatory cytokines, while hypercoagulation was supported by increased pulmonary fibrinogen/fibrin accompanied by reduced levels of plasma D-dimers. Enhanced respiratory disease associated with inactivated RSV vaccine involves a complex network of host responses, resulting in significant pulmonary lesions and clinical manifestations such as tachypnea and airway obstruction. The mechanistic insight into the convergence of different signal pathways and identification of biomarkers could help facilitate the development of safe and effective RSV vaccine and formulation of new targeted interventions.

Lung

immunology

24153108

Mediobasal prosencephalic defects, including holoprosencephaly and cyclopia, in relation to the development of the human forebrain.

Four very early synophthalmic embryos were studied in serial sections and reconstructed graphically by the point-plotting method. Three belonged to stage 16 (5 weeks) and one to stages 19/20 (7 weeks). Recently completed accounts and reconstructions of the normal brains of staged human embryos served as controls for comparison with the abnormal examples. The embryos shared in common: holoprosencephaly, arhinencephaly sensu stricto (absence of olfactory nerve fibers, bulbs, and tracts), presence of a proboscis, synophthalmia with two lens vesicles, a retarded telencephalic wall, absence of the mediobasal part of the telencephalon (the future septal area and the commissural plate: future anterior commissure and corpus callosum), irregularity of the diencephalon, mensural changes in the brain, absence of the rostral part of the notochord and consequent cranial defects, and small ganglia of the cranial nerves. Where it could be determined (at least in the three less advanced specimens), the adenohypophysial primordium was either small and isolated or was absent; a tentorial condensation appeared to be missing; and disturbances of the primordia of the orbital muscles and their innervation were noted. The corpus striatum is single and corresponds to only the diencephalic part (medial eminence) of normal embryos. Interference with induction by the prechordal plate at or before stage 8 (18 days) would be expected to affect the future mediobasal part of the neural plate (median prosencephalic dysgenesis) and the future optic primordium (cyclopia sensu stricto). Insufficient formation of material from the prechordal plate would account for disorders of the orbital musculature and, possibly, for inadequacy of the tentorium cerebelli. Disturbance a couple of days later (stage 9) would result in synophthalmia. Cyclopia and synophthalmia entail arhinencephaly and holoprosencephaly, both of which may arise independently. Defective distribution of the cephalic mesenchyme points to a derangement of the mesencephalic neural crest (stages 10 and 11), causing such features as an incomplete chondrocranium and reduction in size of the ganglia of the cranial nerves. Failure of bilateral division of the telencephalon would occur at or before 4 weeks (stages 13 and 14). It is concluded that all the above conditions arise during the first 4 postovulatory weeks.

Brain

embryology

30787984

Specificity of neuronal factors which aggregate acetylcholine receptors on cultured myotubes.

Neuronal factors from conditioned medium of neuroblastoma X glioma hybrid cells or isolated from embryonic pig brain aggregate acetylcholine receptors (AChR) on cultured chicken and rat myotubes. A membrane surface protein labelled with a fluorescent monospecific antibody was not aggregated with the same treatment. Antibodies against AChR block the action of the aggregating factors but do not produce large aggregates themselves. These findings indicate that the factors specifically react with the AChR on developing myotubes.

Neurons

physiology

73481214

In silico method for identification of novel copper and iron metabolism proteins in various neurodegenerative disorders.

Copper (Cu) and Iron (Fe) has been the subject of intensive research over several decades as numerous seminal studies robustly support the involvement of Cu and Fe metabolism dyshomeostasis as a common denominator in several neurodegenerative disorders (particularly Alzheimer's disease and Parkinson's disease); however, till date, the exact "cause-effect" association has not been elucidated. Thus, there is urgent need to look for newer association/pathways of these redox active elements in different neuropathological conditions. Therefore, in this study, we have used bioinformatics based approach to identify novel Cu and Fe metabolism proteins in neurodegenerative disorders using Cytoscape software. The network biology data demonstrated the association of secreted protein acidic and rich in cysteine (SPARC/osteonectin) protein with Alzheimer's disease, Parkinson's disease, Huntington's disease and neurodegeneration with brain iron accumulation (NBIA) disease, whereas Coagulation factor V may have a role in Brunner Syndrome, Obsessive-Compulsive Disorder, Febrile seizures and Schizophrenia diseases. Further analysis revealed Coagulation factor VII possible role in L1 Syndrome and Congenital hydrocephalus disorders. In conclusion, the present study shows the first evidence in silico that SPARC/osteonectin, Coagulation factor V and VII proteins may have plausible role in the pathogenesis of various neurodegenerative diseases.

Brain

metabolism

20710094

Neurological complications of ankle arthroscopy.

A retrospective review of the first 612 patients undergoing consecutive ankle arthroscopy in the practices of two experienced arthroscopists was under-taken. All inpatient records, outpatient charts, and operative reports were reviewed. Indications for surgery included pain, swelling, locking, and instability that failed to respond to nonoperative management. The results of our investigation revealed an overall complication rate of 9.0% (55 complications). There were 27 neurological complications (4.4% of all arthroscopies) accounting for 49.1% of the complications noted. Specifically, the superficial peroneal nerve was injured in 15 cases, the sural nerve in 6, the saphenous nerve in 5, and the deep peroneal nerve in 1. All nerve injuries occurred through direct injury by portal or distractor pin placement. No cases of neurological injury caused by tourniquet compression or compartment syndrome were seen. Also, 1 case of reflex sympathetic dystrophy was identified.

Postoperative Complications

etiology

33584702

Optimization of culture media for enhanced chitinase production from a novel strain of Stenotrophomonas maltophilia using response surface methodology.

Chitinase is one of the most important mycolytic enzymes with industrial significance. This enzyme is produced by a number of organisms including bacteria. In this study we describe optimization of media components with increased production of chitinase for selected bacteria Stenotrophomonas maltophilia isolated from the soil. Different components of the defined media responsible for influencing chitinase secretion by the bacterial isolate were screened using Plackett-Burman experimental design and were further optimized by Box-Behnken factorial design of response surface methodology (RSM) in liquid culture. Maximum chitinase production was predicted in medium containing chitin 4.94 g/l, maltose 5.56 g/l, yeast extract 0.62 g/l, KH2PO4 1.33 g/l and MgSO4.7H2O 0.65 g/l using Response surface plots and point prediction tool of DESIGN EXPERT 7.1.6 (Statease, USA) software.

Bacterial Proteins

metabolism

7143235

Genetic diversity during the development of Barrett's oesophagus-associated adenocarcinoma: how, when and why?

Recent investigations into Barrett's oesophagus at the level of individual crypts have found significant genetic heterogeneity within a single lesion. Furthermore, this genetic diversity has been shown to predict cancer development. In the present article, we review the genetic alterations implicated in disease progression in Barrett's oesophagus and discuss how genetic diversity could arise during tumorigenesis. Three arguments are discussed: a high mutation rate coupled with strong selection, clonal interaction driving progression, and a hitherto unidentified alteration that disrupts epithelial cell homoeostasis. Suggestions are made for future research to distinguish which of these theories is the predominant mechanism in Barrett's oesophagus-associated tumorigenesis.

Adenocarcinoma

genetics

3282688

Resveratrol prevents the combined maternal plus postweaning high-fat-diets-induced hypertension in male offspring.

Maternal high-fat (HF) diet is believed to induce oxidative stress and activate nutrient-sensing signals, which increase the risk of adult offspring to develop hypertension. We investigated whether resveratrol prevents the combined maternal plus postweaning HF-diets-induced hypertension in adult male offspring, with a focus on the kidney. Female Sprague-Dawley rats received either a normal diet (ND) or HF diet (D12331, Research Diets) for 5 weeks before mating and during gestation and lactation. The male offspring were placed on either the ND or HF diet from weaning to 4 months of age, resulting in four experimental groups (maternal diet/postweaning diet; n=8-10/group): ND/ND, ND/HF, HF/ND and HF/HF. Another group of HF/HF rats (n=10) was treated with 0.5% resveratrol in drinking water between 2 and 4 months of age (HF/HF+R). Rats were killed at 4 months of age. We found that HF/HF-induced hypertension in adult offspring was prevented by resveratrol. Resveratrol mediated its protective effect on HF/HF-induced hypertension in the kidneys of male offspring by diminishing oxidative stress; reducing renal asymmetric dimethylarginine levels; mediating the renin-angiotensin system (RAS) in favor of vasodilatation; restoring nutrient-sensing pathways via increased levels of silent information regulator transcript 1 (SIRT1), AMP-activated protein kinase 2α and peroxisome proliferator-activated receptor gamma coactivator 1-α; and inducing autophagy. Our data implicated an association between oxidative stress, RAS, nitric oxide, and nutrient-sensing signals in HF/HF-induced hypertension. Resveratrol, acting as an antioxidant as well as a SIRT1 activator, might be a therapeutic approach for hypertension.

Hypertension

prevention & control

52041173

Cerebrovascular disease influences functional and structural network connectivity in patients with amnestic mild cognitive impairment and Alzheimer’s disease

BackgroundPatients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) show functional and structural connectivity alterations in the default mode network (DMN) while cerebrovascular disease (CeVD) shows functional and structural connectivity changes in the executive control network (ECN). Such disruptions are associated with memory and executive function impairment, respectively. Concurrent AD and CeVD pathology is associated with a higher rate of cognitive decline and differential neurodegenerative patterns. Together, such findings are likely reflective of different underlying pathology in AD with and without CeVD. However, few studies have examined the effect of CeVD on network functional connectivity (task-free functional magnetic resonance imaging (fMRI)) and structural connectivity (diffusion MRI) of the DMN and ECN in aMCI and AD using a hypothesis-driven multiple seed-based approach.MethodsWe examined functional and structural connectivity network changes in 39 aMCI, 50 aMCI+CeVD, 47 AD, 47 AD+CeVD, and 65 healthy controls (HCs) and their associations with cognitive impairment in the executive/attention and memory domains.ResultsWe demonstrate divergent DMN and ECN functional connectivity changes in CeVD and non-CeVD subjects. Compared with controls, intra-DMN hippocampal functional connectivity reductions were observed in both AD and AD+CeVD, while intra-DMN parietal and medial prefrontal-parietal functional connectivity was higher in AD+CeVD and aMCI+CeVD, but lower in AD. Intra-ECN frontal functional connectivity increases and fronto-parietal functional connectivity decreases occurred in CeVD but not non-CeVD subjects. Such functional connectivity alterations were related with cognitive impairment in a dissociative manner: intra-DMN functional connectivity changes were associated with worse cognition primarily in non-CeVD groups, while intra-ECN functional connectivity changes were associated with worse cognition primarily in CeVD groups. Additionally, CeVD and non-CeVD groups showed overlapping and distinct alterations in inter-network DMN-ECN functional connectivity depending on disease severity. In contrast to functional connectivity, CeVD groups had greater network structural connectivity damage compared with non-CeVD groups in both aMCI and AD patients. Network structural connectivity damage was associated with worse cognition.ConclusionsWe demonstrate differential functional and structural network changes between aMCI and AD patients with and without CeVD through diverging and deleterious network-based degeneration underlying domain-specific cognitive impairment.

Brain

physiopathology

30488875

Composition of individual nucleobases in diets containing different products from bacterial biomass grown on natural gas, and digestibility in mink (Mustela vison).

The objectives of the present study were to quantify the amount of nucleic acids, to examine the nucleobase composition and to determine the digestibility of individual nucleobases in diets containing various products from bacterial biomass grown on natural gas, including autolytic and hydrolytic fractions, using mink (Mustela vison) as a model animal. The diets consisted of cod fillet (control), commercial basic BioProtein, and five experimentally produced autolytic and hydrolytic fractions of the bacterial protein meal as protein sources. Each diet was assigned to four adult male mink, housed individually in cages equipped for controlled feeding and quantitative collection of faeces. Faeces were collected for 4 days, and the individual nucleobases in diet and faeces were analysed by HPLC after hydrolysis using HClO(4). The content of nucleobases in the diets containing bacterial protein meal was 37% to 205% higher than in the control diet. The nucleobase-nitrogen in the control diet amounted to 4.3% of the total nitrogen content, whereas the experimental bacterial protein diets contained from 7.4% to 17.4% of the total N content in the form of nucleic acids. The various methods used to produce the bacterial protein fractions clearly affected both the amount of nucleic acids and the molar proportions of the individual nucleobases. The average digestibility of the nucleobases was 95%, and all the individual nucleobases were highly digestible. Uracil showed the highest digestibility (on average 96.8%), whereas thymine showed the lowest digestibility (on average 93.6%).

Bacterial Proteins

administration & dosage

823311

GM1 ganglioside contributes to retain the neuronal conduction and neuronal excitability in visceral and baroreceptor afferents

GM1 ganglioside has a great impact on the function of nodes of Ranvier on myelinated fiber, suggesting its potential role to maintain the electrical and neuronal excitability of neurons. Here we first demonstrate that visceral afferent conduction velocity of myelinated and unmyelinated fibers are reduced significantly by tetrodotoxin (TTX) or cholera toxin‐B subunits (CTX‐B), and only the effects mediated by CTX‐B are prevented by GM1 pre‐treatment. At soma of myelinated A and unmyelinated C‐type nodose ganglion neurons (NGNs), the action potential spike frequency reduced by CTX‐B is also prevented by GM1. Additionally, the current density of both TTX‐sensitive (TTX‐S) and TTX‐resistant (TTX‐R) Na+ channels were significantly decreased by CTX‐B without changing the voltage‐dependent property. These data confirm that endogenous GM1 may play a dominant role in maintaining the electrical and neuronal excitability via modulation of sodium (Na+) channel around nodes and soma as well, especially TTX‐S Na+ channel, which is also confirmed by the reduction of spike amplitude and depolarization. Similar data are also extended to fluorescently identified and electrophysiologically characterized aortic baroreceptor neurons. These findings suggest that GM1 plays an important role in the neural modulation of electric and neuronal excitability in visceral afferent system.

Neurons

physiology

26759208

Comparative Effects of Alpha Lipoic Acid and Melatonin on Cisplatin-Induced Neurotoxicity

ABSTRACT Cisplatin is a carcinogenic agent having important cytotoxic effects. Cisplatin treatment increases the levels of free oxygen radicals in neurologic tissues. We investigated the effects of alpha lipoic acid (ALA) and melatonin (MEL) on the electrophysiological parameters and on activities of nerve fibers having different conduction properties on cisplatin neurotoxicity. Neurotoxicity was induced by a single injection of 10 mg/kg intraperitoneal (ip) cisplatin. Supplementation was started 1 day before cisplatin injection with either 100 mg/kg/day ip ALA or 4 mg/kg/day ip MEL for 7 days. Compound action potentials were recorded from isolated sciatic nerves in vitro, and numerical analyses were conducted. Cisplatin-induced neurotoxicity resulted in a significant decrease (p <.05) in maximum depolarization (mV), areas (mV·ms), and maximum and minimum upstroke velocity values (mV/ms). Although these decrements were restored by ALA and MEL, ALA was found to be more effective. Conventional conduction velocity measurements and conduction velocity distribution histograms have shown that ALA supplementation can recover the effects of cisplatin while MEL cannot. The conduction velocity distribution histograms have shown that antioxidant supplementation results in a restoration on contribution of fast-conducting fibers (51.8–77.7 m/s), which is deteriorated by cisplatin. Consequently, ALA has more potential to make up for the deleterious effects of cisplatin-induced neurotoxicity.

Antineoplastic Agents

toxicity

11728709

5-HT1D binding sites in various species: similar pharmacological profile in dog, monkey, calf, guinea-pig and human brain membranes

SummaryRadioligand binding studies were performed in membranes of calf caudate, guinea-pig cortex, dog caudate and whole brain, monkey caudate and whole brain, and human caudate using the novel iodinated radioligand, Serotonin-5-O-Carboxymethyl-Glycyl[125I] Tyrosinamide (abbreviated [125I]GTI for the sake of simplicity), a ligand known to label 5-HT 1B and 5-HT 1D sites.In all membrane preparations tested, [125I]GTI labelled high affinity sites with the following rank order of affinity: 5-carboxamidotryptamine > 5-HT = DHE = ergotamine >- sumatriptan >- metergoline = CGS 12066 >- yohimbine = methysergide >- methiothepin > 8-OHDPAT >_ mianserin >- CP 93129 >- (−)pindolol = ketanserin >_ isamoltane = mesulergine >- corynanthine = spiperone > MDL 72222. The affinity profiles were very similar in the membranes of the different species, especially in dog, monkey and human brain. The pharmacological profile of [1251]GTI binding (determined with up to 25 different drugs) was fully comparable to the binding profile reported previously in human substantia nigra (using [1251]GTI) or in a variety of brain preparations known to contain 5-HTID sites using [3H]5-HT as a radioligand.Although, the affinity profiles obtained in the various preparations displayed statistically highly significant correlations with slope values close to one, some drugs displayed slight species-related variations in affinity, as already reported in rabbit brain (see Xiong and Nelson 1989; Hoyer et al. 1992, accompanying report).The present report 1) establishes for the first time the pharmacological profile of 5-HT1D sites in dog and monkey brain, 2) shows that the pharmacological characteristics of these sites is indeed very similar in the brain of a variety of species including man, and 3) demonstrates the advantageous features of [1251]GTI as an iodinated 5-HT1D radioligand which can be used without the need to mask the binding to other 5-HT receptor subtypes.

Brain

metabolism

1903364

PURIFICATION OF RAT BRAIN CHOLINE ACETYLTRANSFERASE 1

Abstract— The purification of choline acetyltransferase (ChAc) has been hampered by the increasing instability of the enzyme in the course of purification. By working with a high concentration of protein and by adding glycerol to the enzyme, the stability was increased. The purification was performed by centrifuging twice, at low and high salt concentrations, precipitation by ammonium sulphate and chromatography on carboxymethyl–Sephadex, hydroxylapatite and Sephadex G 100. The final steps were performed by using chromatography on an immunoabsorbent; this consists of agarose‐coupled gammaglobulins of antisera devoid of any activity against ChAc itself and directed against other proteins still present in the purest ChAc preparation achieved by conventional biochemical techniques. The purest rat brain ChAc preparation had a specific activity of 20 μmol/min/mg of protein after a 30,000‐fold purification. The enzyme was not homogeneous in polyacrylamide gel electrophoresis performed either at pH 4.5 or with sodium dodecyl sulphate. Pure ChAc from rat brain would have a specific activity of approximately 100 μmol/min/mg of protein.

Brain

enzymology

46127926

Accelerated partial breast irradiation and posttreatment imaging evaluation.

Accelerated partial breast irradiation (APBI) is a technique that allows irradiation of only that part of the breast that is at greatest risk for recurrence of breast cancer. Because only a portion of the breast is irradiated, APBI can be performed in a relatively short period of time, usually in 5 days rather than the traditional 6 weeks. When used in carefully selected patients, APBI also allows normal portions of the breast parenchyma and regional vital organs to be spared from unnecessary irradiation. Common post-APBI imaging findings include focal skin thickening, seroma, scar, and skin retraction. Studies are underway that will compare a cohort of patients who underwent whole-breast irradiation with a cohort who underwent APBI to help determine whether the two techniques lead to significantly different imaging findings. Additional multicenter studies will be needed to document and analyze any such differences. In the future, APBI may play a significant role in selected patients, with pretherapy dynamic contrast material-enhanced magnetic resonance imaging of the breast possibly aiding in the selection process.

Breast Neoplasms

radiotherapy

22313881

Development of an MRM assay panel with application to biobank samples from patients with myocardial infarction.

UNLABELLED As part of a Swedish national cardiological research initiative, the development of a quantitative MRM assay is reported for the quantification of eleven putative cardiovascular disease markers. Within the study, patient samples from the LUNDHEARTGENE biobank were processed and nanoLC-MS/MS analysis was performed together with a stable isotope dilution strategy for absolute quantification of the target proteins. Excellent linear regressions were achieved for 9 of the 11 peptides with LOQ ranged in the attomolar range. We have utilized the assay for the screening of plasma samples from patients with chest pain, and performed a comparative analysis of patients with ST-segment elevation myocardial infarction and chest pain due to other causes. The assay demonstrates high reproducibility and correlate with clinical findings. Strong correlations were found for several of the apolipoproteins and their respective lipid subfractions (LDL, HDL or triglycerides). APOC1, APOC2 and APOE were elevated in patients with STEMI. BIOLOGICAL SIGNIFICANCE An MRM assay were developed for putative cardiovascular disease markers as target proteins, and applied to biobanking sample material. The comparative analysis of patients with ST-segment elevation myocardial infarction and chest pain due to other causes showed elevated levels of APOC1, APOC2 and APOE in patients with STEMI. These observations raise interesting novel hypotheses about the role of apolipoproteins C1, C2 and E in the pathophysiology of acute myocardial infarction, which merits further studies.

Myocardial Infarction

blood

8802889

Essential cysteines in 3-deoxy-D-manno-octulosonic acid 8-phosphate synthase from Escherichia coli: analysis by chemical modification and site-directed mutagenesis.

The enzyme 3-deoxy-D-manno-octulosonic acid 8-phosphate synthase (EC 4.1. 2.16) (KDO 8-P synthase) that catalyzes the condensation of D-arabinose 5-phosphate (A 5-P) with phosphoenolpyruvate (PEP) to give 3-deoxy-D-manno-octulosonic acid 8-phosphate (KDO 8-P) and inorganic phosphate (Pi) was inactivated by the thiol-modifying reagents 5,5-dithiobis (2-nitrobenzoate) (DTNB) and methyl methanethiosulfonate (MMTS). Reaction of cloned native KDO 8-P synthase with DTNB correlated with modification of two of the four cysteine sulfhydryls per monomer of enzyme and total loss of enzymatic activity which could be partially restored by treatment with dithiothreitol (DTT). Cyanolysis of the DTNB-inactivated enzyme with KCN led to the elimination of 2 equiv of 5-thio-2-nitrobenzoate and partial recovery of activity. The presence of either substrate(s) or product(s) provided no protection against inactivation nor affected the number of cysteines modified, indicating that the cysteines modified are most likely not at the active site of KDO 8-P synthase. Titration of denatured enzyme with DTNB resulted in the modification of all four cysteines. After treatment of native enzyme with MMTS, no cysteines could be titrated with DTNB and no enzymatic activity could be detected. Treatment of the MMTS-inactivated KDO 8-P synthase with DTT resulted in restoration of enzymatic activity and the presence of two DTNB-titratable cysteine residues. Based on these observations and a report that KDO 8-P synthase is inactivated in a time-dependent manner with 3-bromopyruvate and that the substrate PEP protects against this inactivation, all four cysteines (38, 166, 206, and 249) were individually mutated to alanines via a modified PCR methodology. The C206A and C249A mutants were both enzymatically active with K(m) and Vmax values approximately identical to those of wild-type KDO 8-P synthase, and both native mutants reacted with DTNB to modify only one of the three remaining cysteine sulfhydryls per monomer of enzyme. Titration of denatured C206A and C249A mutants resulted in the modification of three cysteines. The C38A and C166A mutants were both for the most part enzymatically inactive. Titration of native C38A and C166A with DTNB resulted in modification of two cysteines while titration of the denatured mutant protein resulted in modification of the three remaining cysteines. Circular dichroism measurements of wild-type KDO 8-P synthase and the four C --> A mutants indicate modest but significant changes in the structure of the mutants. These results indicate that C206 and C249 in native KDO 8-P synthase are readily accessible to the modification reagent DTNB and therefore inactivation may result from structural changes in the DTNB-modified KDO 8-P synthase or blockage of access of substrates to the active site. The C38 and C166 in native KDO 8-P synthase are inaccessible to the modification reagent DTNB, indicating that they are located in the interior of KDO 8-P synthase, and loss of activity in the C38A and C166A mutants suggests their essentiality in the KDO 8-P synthase reaction.

Escherichia coli

enzymology

1428089

Nanowire electrodes for high-density stimulation and measurement of neural circuits

Brain-machine interfaces (BMIs) that can precisely monitor and control neural activity will likely require new hardware with improved resolution and specificity. New nanofabricated electrodes with feature sizes and densities comparable to neural circuits may lead to such improvements. In this perspective, we review the recent development of vertical nanowire (NW) electrodes that could provide highly parallel single-cell recording and stimulation for future BMIs. We compare the advantages of these devices and discuss some of the technical challenges that must be overcome for this technology to become a platform for next-generation closed-loop BMIs.

Brain

physiology

6344676

RHOB expression controls the activity of serine/threonine protein phosphatase PP2A to modulate mesenchymal phenotype and invasion in non-small cell lung cancers

ABSTRACT Metastatic dissemination is the cause of death in the vast majority of cancers, including lung cancers. In order to metastasize, tumor cells must undergo a well-known series of changes, however the molecular details of how they manage to overcome the barriers at each stage remain incomplete. One critical step is acquiring the ability to migrate through the extracellular matrix. Loss of expression of the RAS-related small GTPase RHOB is a common feature of lung cancer progression, and we recently reported that this induces an epithelial-to-mesenchymal transition (EMT) that is dependent on SLUG overexpression and E-Cadherin inhibition and is characterized by 3-dimensional cell shape reorganization and the increased invasiveness of bronchial cells. RHOB loss was found to induce AKT1 activation, which in turn activates RAC1 through its GEF TRIO. Further investigation of this pathway revealed that RHOB interacts with and positively regulates PP2A, one of the major cellular serine-threonine phosphatases, by recruiting its regulatory subunit B55. Here we discuss the role of this newly discovered RHOB/PP2A/AKT1/RAC1 pathway in relation to mesenchymal migration and invasion in lung cancer.

Lung Neoplasms

pathology

1896991

Temporal structure in neuronal activity during working memory in macaque parietal cortex

Many cortical structures have elevated firing rates during working memory, but it is not known how the activity is maintained. To investigate whether reverberating activity is important, we studied the temporal structure of local field potential (LFP) activity and spiking from area LIP in two awake macaques during a memory-saccade task. Using spectral analysis, we found spatially tuned elevated power in the gamma band (25–90 Hz) in LFP and spiking activity during the memory period. Spiking and LFP activity were also coherent in the gamma band but not at lower frequencies. Finally, we decoded LFP activity on a single-trial basis and found that LFP activity in parietal cortex discriminated between preferred and anti-preferred direction with approximately the same accuracy as the spike rate and predicted the time of a planned movement with better accuracy than the spike rate. This finding could accelerate the development of a cortical neural prosthesis.

Neurons

physiology

19184435

Associations between cardiovascular disease risk factors and IL-6 and hsCRP levels in the elderly

BACKGROUND Age-related diseases, including cardiovascular diseases (CVD) may be stimulated by microinflammation, marked by increased level of IL-6 and high-sensitivity CRP (hsCRP). We aimed to investigate whether aging "per se" independently contributes to the microinflammation, in addition to traditional and novel CVD risk factors. METHODS/RESULTS The research sample included 4979 participants from PolSenior Study, aged over 65years. The study consisted of three visits and included questionnaire survey, geriatric assessment and blood/urine sampling in 4101 participants (83.2% of the sample). Serum hsCRP and plasma IL-6 were measured in 4093 (99.8%) and 3895 (95.0%) subjects. Multiple logistic regression showed that advanced age (over 80years), obesity, actual/former smoking, decreased HDL-cholesterol, chronic kidney disease (CKD) and depression were associated with occurrence of increased level of IL-6 (>2.4pg/ml). For hsCRP we found that advanced age, overweight/obesity, decreased HDL-cholesterol, actual/former smoking and CKD were associated with increased level of hsCRP (>3mg/l), while high income and statins treatment were related to lower level of hsCRP. CONCLUSIONS Microinflammation in the elderly is not fully explained by traditional and novel CVD risk factors. Active smoking, obesity and low HDL-cholesterol among traditional risk factors, along with CKD, depression and low income among novel risk factors, are the strongest determinants of microinflammation. Also we found that statin therapy decreases hsCRP levels, which indicates a potential role of inflammation in CVD as a target for intervention in the elderly (e.g. statin use).

Cardiovascular Diseases

blood

29900352

Scanning electrochemical microscopy of living cells: different redox activities of nonmetastatic and metastatic human breast cells.

Electrochemical methods have been widely used to monitor physiologically important molecules in biological systems. This report describes the first application of the scanning electrochemical microscope (SECM) to probe the redox activity of individual living cells. The possibilities of measuring the rate and investigating the pathway of transmembrane charge transfer are demonstrated. By this approach, significant differences are detected in the redox responses given by nonmotile, nontransformed human breast epithelial cells, breast cells with a high level of motility (engendered by overexpression of protein kinase Calpha), and highly metastatic breast cancer cells. SECM analysis of the three cell lines reveals reproducible differences with respect to the kinetics of charge transfer by several redox mediators.

Breast Neoplasms

physiopathology

2002452

Risk of radiation-induced secondary rectal and bladder cancer following radiotherapy of prostate cancer

ABSTRACT Background. An elevated risk of radiation-induced secondary cancer (SC) has been observed in prostate cancer patients after radiotherapy (RT), rising to as high as one in 70 patients with more than 10 years follow-up. In this study we have estimated SC risks following RT with both previous and contemporary techniques, including proton therapy, using risk models based on different dose-response relationships. Material and methods. RT plans treating the prostate and seminal vesicles with either conformal radiotherapy (CRT), volumetric modulated arc therapy (VMAT) or intensity-modulated proton therapy (IMPT) were created for 10 patients. The risks of radiation-induced cancer were estimated for the bladder and rectum using dose-response models reflecting varying degrees of cell sterilisation: a linear model, a linear-plateau model and a bell-shaped model also accounting for fractionated RT. Results. The choice of risk models was found to rank the plans quite differently, with the CRT plans having the lowest SC risk using the bell-shaped model, while resulting in the highest risk applying the linear model. Considering all dose-response scenarios, median relative risks of VMAT versus IMPT were 1.1–1.7 for the bladder and 0.9–1.8 for the rectum. Risks of radiation-induced bladder and rectal cancers were lower from VMAT if exposed at 80 years versus IMPT if exposed at 50 years. Conclusions. The SC risk estimations for the bladder and rectum revealed no clear relative relationship between the contemporary techniques and CRT, with divergent results depending on choice of model. However, the SC risks for these organs when using IMPT were lower or comparable to VMAT. SC risks could be assessed when considering referral of prostate cancer patients to proton therapy, taking also general patient characteristics, such as age, into account.

Prostatic Neoplasms

radiotherapy

924913

Cholecystokinin2 receptor-deficient mice display altered function of brain dopaminergic system

Abstract.Rationale: Cholecystokinin (CCK) has been shown to coexist and interact with dopamine in the regulation of behaviour. Two different CCK receptors (CCK1 and CCK2) have an opposite influence on the activity of dopamine neurons. Stimulation of CCK2 receptors decreases the release of dopamine and that receptor could mediate the neuroleptic-like effect of CCK. Objective: To investigate the activity of the dopaminergic system in pharmacological experiments on CCK2 receptor (CCK2R)-deficient mice. Methods: We used age- and sex-matched littermates in all our experiments. To evaluate the behavioural differences, we performed the rotarod test and measured the locomotor activity of animals using computer-connected photoelectric motility boxes. Amphetamine and apomorphine, two dopaminergic drugs with different pharmacodynamic properties, were used to influence the activity of the dopaminergic system in the brain. Neurochemical differences related to the different genotype were analysed by means of high-performance liquid chromatography and radioligand binding studies. Results: Motor co-ordination was significantly impaired in the rotarod test of CCK2R receptor-deficient mice. Moreover, the locomotor activity of heterozygous (+/–) and homozygous (–/–) CCK2R receptor-deficient mice was somewhat reduced. A low dose of apomorphine (0.1 mg/kg), an unselective agonist of dopamine receptors, suppressed locomotor activity significantly more in homozygous (–/–) and heterozygous (+/–) mutant mice than in their wild-type (+/+) littermates. Amphetamine (3–6 mg/kg), increasing release of dopamine from the presynaptic terminals, caused a dose-dependent motor stimulation in wild-type (+/+) mice. In heterozygous (+/–) and homozygous (–/–) mice, a lower dose of amphetamine (3 mg/kg) did not alter the locomotor activity, whereas the higher dose of (6 mg/kg) induced a significantly stronger increase in locomotor activity in homozygous (–/–) mice than in their heterozygous (+/–) and wild-type (+/+) littermates. Despite the changes in the action of apomorphine and amphetamine in homozygous (–/–) mice, we did not find any significant differences in the concentration of dopamine and their metabolites in the striatum or cortex. However, the density of dopamine D2 receptors was significantly increased in the striatum of homozygous (–/–) animals compared with wild-type (+/+) mice. Conclusions: The targeted mutation of the CCK2 receptor gene induced gene dose-dependent changes in the activity of the dopaminergic system. The sensitivity of presynaptic dopamine receptors was increased in heterozygous (+/–) and homozygous (–/–) animals, whereas the increase in sensitivity of postsynaptic dopamine receptors was apparent only in homozygous (–/–) mice.

Brain

metabolism

28577214

Tumour-associated eosinophilia in the bladder.

Tumour eosinophilia is an uncommon but striking phenomenon which has been found in many tumours, mostly of large cell type or squamous differentiation. The incidence, appearance and importance of tumour eosinophilia in the bladder are described. Eosinophilia is commoner in deeply invasive tumours and in tumours showing squamous metaplasia. Transitional cell carcinomas with eosinophilia have a better prognosis than those without, but this improvement is not seen in squamous cell carcinomas of the bladder. When eosinophilia is found on superficial biopsies of a bladder tumour, the possibility of muscle invasion should be considered.

Carcinoma, Squamous Cell

pathology

21435666

The family experience in cultural context: implications for further research and practice.

Cross-cultural studies of families' experience of mental illness are discussed, in terms of uniformities in and differences between belief systems and values, caregiving norms, perceived burden and distress, and expectations, with suggestions for further research and applications to practice.

Mental Disorders

psychology

1583904

A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Panobinostat, an HDAC Inhibitor, Combined with Erlotinib in Patients with Advanced Aerodigestive Tract Tumors

Purpose: Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non–small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer. Experimental Design: Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre and posttherapy tumor biopsies for checkpoint kinase 1 (CHK1) expression were assessed. Results: Of 42 enrolled patients, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1–3), and rash and anorexia (grades 1–2). Disease control rates were 54% for NSCLC (n = 26) and 43% for head and neck cancer (n = 7). Of 7 patients with NSCLC with EGF receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P = 0.43) and overall survival was 41 (estimated) versus 5.2 months (P = 0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat's pharmacodynamic effect in blood, FPB, and tumor samples. Low CHK1 expression levels correlated with PFS (P = 0.006) and response (P = 0.02). Conclusions: We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore the benefits of HDAC inhibitors in patients with EGFR-mutant NSCLC, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1's predictive role. Clin Cancer Res; 20(6); 1644–55. ©2014 AACR.

Lung Neoplasms

drug therapy

46806671

Effect of ageing on the nerve fibre population of rat optic nerve.

The age-related changes in the number and density of optic nerve fibres were studied in 3-month-old (young), 12-month-old (adult), 20-month-old (senescent) and 30-month-old (aged) male Wistar rats. Two-micrometer-thick resin-embedded transverse sections of the optic nerve of animals of the different age groups were stained with toluidine blue and examined under a light microscope at low (X5) and high (X500) magnification. The optic nerve cross-sectional area and the number of nerve fibres with diameters shorter or longer than 1 micron were assessed by means of computerized image analysis. Optic nerve cross-sectional area is constant in young and adult rats, but is increased in senescence. The number of optic nerve fibres with a diameter less than 1 micron is decreased by about 18 and 12% in 20-month-old rats versus 3- and 12-month-old rats, respectively. The number of these nerve fibres is decreased by about 43, 39 and 30% in 30-month-old rats versus 3-, 12- and 20-month-old animals, respectively. In contrast no age-dependent changes were observed in nerve fibres with diameters greater than 1 micron. The present data suggest that age-related impairment of nerve cell population described by other authors in rat retina and visual cortex occurs also at the level of the optic nerve.

Aging

pathology

19550508

Diagnostic accuracy of magnetic resonance imaging in the assessment of mandibular involvement in oral-oropharyngeal squamous cell carcinoma: a prospective study.

OBJECTIVE To evaluate the sensitivity, specificity, accuracy, and predictive values of magnetic resonance imaging (MRI) in the assessment of mandibular involvement in oral-oropharyngeal squamous cell carcinoma. DESIGN Prospective study. SETTING University hospital. PATIENTS Forty-three patients with oral or oropharyngeal squamous cell carcinoma undergoing marginal or segmental mandibulectomy between January 1, 1994, and January 31, 2003. INTERVENTIONS Indications for mandibulectomy were MRIs suggestive of bony invasion, tumor involving the retromolar trigone or the alveolar ridge, recurrent or persistent lesion, or intraoperative suspicion of periosteal invasion. Detection of tumor signal replacing the hypointense cortical rim was considered the main radiologic finding for mandibular invasion. MAIN OUTCOME MEASURES The MRI findings were subsequently compared with histopathologic data of surgical specimens with reference to the presence of cortical and/or medullary mandibular involvement. RESULTS Sixteen patients had MRI findings suggestive of mandibular involvement. Segmental mandibulectomy was performed in 15 cases and marginal resection in the remaining case. In 14 patients, bony invasion was confirmed. All of the other 27 patients who underwent marginal or segmental mandibulectomy with negative MRI findings had no histopathologic evidence of mandibular involvement, except in 1 patient: on histopathologic examination, despite cortical integrity, neoplastic vascular embolization into the bony lacunae was detected. Sensitivity of MRI in detecting mandibular involvement was 93%; specificity, 93%; accuracy, 93%; and negative and positive predictive values, 96% and 87.5%, respectively. CONCLUSIONS Magnetic resonance imaging is commonly considered the technique of choice for treatment planning in advanced oral and oropharyngeal squamous cell carcinoma because of its accuracy in depicting soft-tissue involvement. This study demonstrates the additional diagnostic value of MRI in detecting bone invasion.

Carcinoma, Squamous Cell

pathology

52914526

Event-related desynchronization during movement attempt and execution in severely paralyzed stroke patients: An artifact removal relevance analysis

The electroencephalogram (EEG) constitutes a relevant tool to study neural dynamics and to develop brain-machine interfaces (BMI) for rehabilitation of patients with paralysis due to stroke. However, the EEG is easily contaminated by artifacts of physiological origin, which can pollute the measured cortical activity and bias the interpretations of such data. This is especially relevant when recording EEG of stroke patients while they try to move their paretic limbs, since they generate more artifacts due to compensatory activity. In this paper, we study how physiological artifacts (i.e., eye movements, motion artifacts, muscle artifacts and compensatory movements with the other limb) can affect EEG activity of stroke patients. Data from 31 severely paralyzed stroke patients performing/attempting grasping movements with their healthy/paralyzed hand were analyzed offline. We estimated the cortical activation as the event-related desynchronization (ERD) of sensorimotor rhythms and used it to detect the movements with a pseudo-online simulated BMI. Automated state-of-the-art methods (linear regression to remove ocular contaminations and statistical thresholding to reject the other types of artifacts) were used to minimize the influence of artifacts. The effect of artifact reduction was quantified in terms of ERD and BMI performance. The results reveal a significant contamination affecting the EEG, being involuntary muscle activity the main source of artifacts. Artifact reduction helped extracting the oscillatory signatures of motor tasks, isolating relevant information from noise and revealing a more prominent ERD activity. Lower BMI performances were obtained when artifacts were eliminated from the training datasets. This suggests that artifacts produce an optimistic bias that improves theoretical accuracy but may result in a poor link between task-related oscillatory activity and BMI peripheral feedback. With a clinically relevant dataset of stroke patients, we evidence the need of appropriate methodologies to remove artifacts from EEG datasets to obtain accurate estimations of the motor brain activity.

Brain

physiopathology

45538071

My Sister, Myself

African American women are bearing an excess burden of HIV/AIDS, becoming infected at a rate 25 times that of White American women. This places African American girls at the highest risk for becoming infected with HIV/AIDS. Culturally appropriate prevention strategies are indicated to suppress this trend. Two qualitative research methods were used to evaluate a culture- and gender-based HIV prevention intervention: My Sister, Myself. Community action participatory research was used to engage the community in the development of the intervention for early-adolescent girls. Eight girls participated in the 8-week intervention. Data were collected about culture and gender identification, sexual health knowledge, and future intentions throughout the intervention. Focus groups and observation participation data revealed three major themes: “high aspirations,” “needing to know the truth,” and “internal, external, and eternal resources.” Findings indicate promise for intervention strategies that utilize culture- and gender-based strategies for HIV/AIDS prevention with young girls.

HIV Infections

prevention & control

893517

Should tissue structure suppress or amplify selection to minimize cancer risk?

BackgroundIt has been frequently argued that tissues evolved to suppress the accumulation of growth enhancing cancer inducing mutations. A prominent example is the hierarchical structure of tissues with high cell turnover, where a small number of tissue specific stem cells produces a large number of specialized progeny during multiple differentiation steps. Another well known mechanism is the spatial organization of stem cell populations and it is thought that this organization suppresses fitness enhancing mutations. However, in small populations the suppression of advantageous mutations typically also implies an increased accumulation of deleterious mutations. Thus, it becomes an important question whether the suppression of potentially few advantageous mutations outweighs the combined effects of many deleterious mutations.ResultsWe argue that the distribution of mutant fitness effects, e.g. the probability to hit a strong driver compared to many deleterious mutations, is crucial for the optimal organization of a cancer suppressing tissue architecture and should be taken into account in arguments for the evolution of such tissues.ConclusionWe show that for systems that are composed of few cells reflecting the typical organization of a stem cell niche, amplification or suppression of selection can arise from subtle changes in the architecture. Moreover, we discuss special tissue structures that can suppress most types of non-neutral mutations simultaneously.ReviewersThis article was reviewed by Benjamin Allen, Andreas Deutsch and Ignacio Rodriguez-Brenes. For the full reviews, please go to the Reviewers’ comments section.

Neoplasms

genetics

3278481

Age-Related Left Ventricular Remodeling and Associated Risk for Cardiovascular Outcomes: The Multi-Ethnic Study of Atherosclerosis

Background—Age-related alterations of left ventricular (LV) structure and function that may predispose to cardiovascular events are not well understood. Methods and Results—We used cardiac MRI to examine age-related differences in LV structure and function in 5004 participants without overt cardiovascular disease when enrolled in the Multi-Ethnic Study of Atherosclerosis; 1099 participants received additional strain analyses by MRI tagging. We also assessed the relation of age-associated remodeling with cardiovascular outcomes using Cox proportional hazard models adjusting for cardiovascular risk factors. Although LV mass decreased with age (−0.3 g per year), the mass-to-volume ratio markedly increased (+5 mg/mL per year, P<0.0001), driven by a substantial reduction in end-diastolic volume (−0.8 mL per year, P<0.0001). Age was also associated with a significant fall in stroke volume (−0.4 mL per year, P<0.0001), along with strain patterns reflecting systolic (P<0.0001) as well as diastolic (P<0.01) myocardial dysfunction—despite a modestly enhanced ejection fraction (+0.1% per year, P<0.0001). Increased mass-to-volume ratio conferred a significant risk for total cardiovascular events; this trend was strongest among younger (<65 years; hazard ratio, 3.69 [CI, 1.34 to 10.10]) versus older (≥65 years; hazard ratio, 1.68 [CI 0.77 to 3.68]) individuals with the highest compared to lowest mass-to-volume ratio quintile (Pinteraction=0.013). Conclusions—Age is associated with a phenotype of LV remodeling marked by increased mass-to-volume ratio and accompanied by systolic as well as diastolic myocardial dysfunction that is not reflected by preserved ejection fraction. This pattern of ventricular remodeling confers significant cardiovascular risk, particularly when present earlier in life.

Cardiovascular Diseases

etiology

46518404

[Sentinel lymph node identification in the staging of cutaneous melanoma. Blue dye vs. radioguided localization].

BACKGROUND The purpose of this study is to emphasize the usefulness of combined intraoperative gamma-detecting-probe (C-Trak) and blue dye guided research of sentinel nodes (SN) in the treatment of cutaneous melanoma. METHODS At the Department of General Surgery of Macerata Hospital, after informed consent, 22 consecutive patients (10 males and 12 females) with mean age 53 years (20-78 years) affected by histologically proved cutaneous malignant melanoma in stage I (TC, ultrasonography and bone scintigraphy) were studied by dynamic lymphoscintigraphy with 10.8-22.2 MBq of 99mTc albumin microcolloids 18-22 hours before surgery and by intradermal injection of blue dye at induction of anaesthesia. Intraoperative mapping technique to localize SN has been done by using a combination of a vital blue dye and a radioactive tracer. RESULTS A total of 42 SN were identified. Micrometastases were found in 2 (9.1%) patients; 13 SN were well-coloured (31%), 23 SN were poorly-coloured (55%), and 6 SN were not coloured (14%). Overall localization with blue dye was 86%. All SN were radiolabeled, but identification with gamma detecting probe was possible only in 41 cases (95%). Combined techniques was effective in 100% of cases. CONCLUSIONS Combined use of radiocolloids and blue dye is the gold standard for correct identification and biopsy of SN with 100% of favourable results. The technique is simple, fast and effective and permits to select the patients that need other surgical and oncologic procedures.

Skin Neoplasms

pathology

41603929

Right ventricular failure due to late embolic RV infarction during continuous flow LVAD support

This report describes a 63-year-old man with a dilated cardiomyopathy, who was supported with a continuous flow left ventricular assist device (LVAD), and on the waiting list for heart transplantation. After a long period of stability, he presented with recurrent ventricular tachycardia and rapidly developed progressive right ventricular (RV) failure. He required implantation of a temporary RV assist device to regain stability and subsequently underwent urgent heart transplantation. The explanted heart showed multiple areas of ischaemic damage to the RV myocardium, but there was no significant underlying coronary artery disease. It appears that the ventricular arrhythmias and subsequent RV failure were due to an embolic event in the territory of the right coronary artery. The case highlights that coronary embolism is a rare cause of RV failure during LVAD support and demonstrates the utility of temporary RV assist device support as a bridge to heart transplantation.

Myocardial Infarction

physiopathology

24772423

Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity.

BACKGROUND IL-4, IL-5, and IL-13 are thought to be central to the allergic asthmatic response. Previous work supposed that the essential source of these cytokines was CD4(+) T(H)2 cells. However, more recent studies have suggested that other innate production of type 2 cytokines might be as important. OBJECTIVES Nuocytes are a novel population of IL-13-producing innate cells, which are critical for protective immunity in Nippostrongylus brasiliensis infection. Given this, we investigated the potential existence and functional importance of nuocytes in experimental allergic asthma. METHODS We generated Il4(+/eGFP)Il13(+/Tomato) dual-reporter mice to study cytokine-producing cells during allergic inflammation. We adoptively transferred innate IL-13-producing cells to investigate their role in airways hyperreactivity (AHR). RESULTS We show that allergen-induced nuocytes infiltrate the lung and are a major innate source of IL-13. CD4(+) T cells in the lung almost exclusively express only IL-13, whereas IL-4-producing T cells were restricted to the draining lymph nodes. Intranasal administration of IL-25 or IL-33 induced IL-13-producing nuocytes in the BAL fluid. Strikingly, adoptive transfer of wild-type nuocytes, but not Il13(-/-) nuocytes, into Il13(-/-) mice, which are normally resistant to IL-25-induced AHR, restored airways resistance and lung cell infiltration. CONCLUSIONS These findings identify nuocytes as a novel cell type in allergic lung inflammation and an innate source of IL-13 that can directly induce AHR in the absence of IL-13-producing CD4(+) T cells. These data highlight nuocytes as an important new consideration in the development of future allergic asthma therapy.

Asthma

immunology

9332176

Antihypoxidotic and nootropic drugs: proof of their encephalotropic and pharmacodynamic properties by quantitative EEG investigations.

Abstract 1. 1. In several double-blind placebo-controlled studies the encephalotropic and pharmacodynamic properties of antihypoxidotics and nootropics such as dihydroergotoxine, nicergoline, Instenon forte (a hexobendine-combination), cinnarizine, isoxsuprine, pirazetam and etirazetam- a new pirazetam analogue — were investigated by means of quantitative EEG analysis in normal young and geriatric subjects. 2. 2. Power pectral density analysis of the EEG demonstrated after the ergot alkaloids HydergineR and nicergoline as well as after Instenon forte statistically significant changes as compared with placebo. The latter were characterized by an increase in alpha and slow beta activity as well as by a decrease in delta and theta activity, which indicates an increase in vigilance. 3. 3. Pirazetam and the new pirazetam analogue etirazetam — produced a significant increase in beta activity as well, while alpha activity was augmented or attenuated according to the given dosage. After chronic administration of UCB 6474 and especially after high doses, an increase in theta activity was observed. Psychometric tests showed also activating qualities in low doses and slight sedative properties in high doses. 4. 4. Cinnarizine and isoxsuprine produced in the R-EEG different alterations typified by an increase of slow and decrease of fast waves. 5. 5. Time-efficacy and dose-efficacy relationships in various EEG parameters give valuable information about the pharmacodynamics of such substances in man already at an early stage of drug development.

Brain

drug effects

17626595

Glycemic Control and Health Disparities in Older Ethnically Diverse Underserved Adults With Diabetes

OBJECTIVE The Informatics for Diabetes Education and Telemedicine (IDEATel) project randomized ethnically diverse underserved older adults with diabetes to a telemedicine intervention or usual care. Intervention participants had lower A1C levels over 5 years. New analyses were performed to help better understand this difference. RESEARCH DESIGN AND METHODS IDEATel randomized Medicare beneficiaries with diabetes (n = 1,665) to receive home video visits with a diabetes educator and upload glucose levels every 4–6 weeks or usual care (2000–2007). Annual measurements included BMI, A1C (primary outcome), and completion of questionnaires. Mixed-model analyses were performed using random effects to adjust for clustering within primary care physicians. RESULTS At baseline, A1C levels (mean ± SD) were 7.02 ± 1.25% in non-Hispanic whites (n = 821), 7.58 ± 1.78% in non-Hispanic blacks (n = 248), and 7.79 ± 1.68% in Hispanics (n = 585). Over time, lower A1C levels were associated with more glucose uploads (P = 0.02) and female sex (P = 0.002). Blacks, Hispanics, and insulin-users had higher A1C levels than non-Hispanic whites (P < 0.0001). BMI was not associated with A1C levels. Blacks and Hispanics had significantly fewer uploads than non-Hispanic whites over time. Hispanics had the highest baseline A1C levels and showed the greatest improvement in the intervention, but, unlike non-Hispanic whites, Hispanics did not achieve A1C levels <7.0% at 5 years. CONCLUSIONS Racial/ethnic disparities were observed in this cohort of underserved older adults with diabetes. The IDEATel telemedicine intervention was associated with improvement in glycemic control, particularly in Hispanics, who had the highest baseline A1C levels, suggesting that telemedicine has the potential to help reduce disparities in diabetes management.

Diabetes Mellitus, Type 2

drug therapy

37504124

Is a decline in offspring quality a necessary consequence of maternal age?

Recent studies in two species of Drosophila have demonstrated a negative effect of parental age on offspring fitness, including a reduced hatch rate of eggs and larval-to-adult viability. This has led to a call to consider the decline of offspring quality as a function of parental age in theoretical considerations of the evolution of ageing. We have tested whether a decline in egg and larval quality of older mothers is a general feature of senescence by examining it in the cockroach Nauphoeta cinerea. We also tested whether maternal age affected the reproductive potential of daughters. Although maternal age at first reproduction profoundly affected maternal fitness, there was no difference in hatch rate or larval viability between the offspring of young and old mothers. Likewise, the reproductive potential of the daughters of young and old mothers was the same. Thus, while maternal age effects may be important aspects of ageing in some systems, the generality and overall importance for theories of ageing remain unclear.

Aging

physiology

29024217

Effects of a brief media intervention on expectations, attitudes, and intentions of mental health help seeking.

This study examined the effects of a mass-media video intervention on expectations, attitudes, and intentions to seek help from professional mental health care services. A public service announcement-style, mass-media video intervention was developed, with prior empirical research on help-seeking behaviors organized according to the theory of reasoned action/planned behavior. In total, 228 participants were randomly assigned to 1 of 2 conditions: (a) the media-exposed intervention group, who watched programming in which the media intervention was inserted, and (b) the control group, who watched the same programming without the media intervention. The media intervention was not influential on expectation and belief-based barrier variables. However, the media intervention was effective at increasing positive attitudes toward help seeking. Findings regarding the intervention's ability to increase help-seeking intentions for interpersonal problems were complex. Implications of these findings for future research are discussed.

Mental Disorders

rehabilitation

202747914

Fruit and vegetable import duty reduction in Fiji to prevent obesity and non-communicable diseases: a case study

Abstract Objective: To describe the development of Fiji’s fruit and vegetable fiscal policies between 2010 and 2014 and explore the impact they have had on import volumes. Design: Qualitative case study and in-depth analysis of policy process. Policy impact was assessed using publicly available import volume data and prices of food products. Setting: Fiji. Participants: Senior government policy makers, non-communicable disease officers from the Ministry of Health and Medical Services (MoHMS) and supermarket managers. Results: In 2011, the Fijian Government introduced an import excise of 10 % on vegetables and reduced the import fiscal duty on fruit that was also grown in Fiji by 10 %. The import tax on vegetables was removed in 2012 in response to a MoHMS request. Policy makers from several sectors supported the MoHMS request, recognized their leadership and acknowledged the importance of collaboration in achieving the removal of the excise. Tariff reductions appear to have contributed to increases in the volume of vegetables (varieties not grown in Fiji) and fruit (varieties grown in Fiji) imported, but it is not clear if this increased population consumption. Conclusions: Reductions in import duties appear to have contributed to increases in volumes of vegetables and fruit imported into Fiji. This case study has demonstrated that governments can use fiscal policy to meet the needs of a range of sectors including health, agriculture and tourism.

Obesity

prevention & control

30861460

Nervous influences on the pulmonary circulation

SummaryThe intravenous injection of veratridine in anesthetized dogs caused a reflex vasoconstriction of the perfused lung. A similar vasoconstriction could be elicited by increased intracranial pressure. The vasoconstriction was dependent on thoracic (T1 to T4) sympathetic ganglia.

Lung

blood supply

25469896

Surgical excision for B3 breast lesions diagnosed by vacuum-assisted core biopsy.

UNLABELLED The aim of this retrospective study was to assess whether open surgical excision is required following a B3 diagnosis on 11-gauge vacuum-assisted core biopsy (VACB) of radiologically indeterminate breast lesions. PATIENTS AND METHODS Twenty-four women with a histological diagnosis of the B3 category on VACB of radiologically indeterminate breast lesions were identified over a 3-year period. The VACB procedure was performed under stereotactic (n=21), ultrasound (n=2) or magnetic resonance imaging (MRI) (n=1) guidance using the Suros system. Nineteen patients underwent open surgical excision. The remaining 5 patients who had 'complete' removal of the radiological abnormality using VACB under ultrasound (n=2, papilloma) or stereotactic (n=4, atypical ductal hyperplasia) guidance were followed up clinically and radiologically. RESULTS The median patient age was 49 years. The disease status in three patients was upgraded to ductal carcinoma in situ at open surgical excision. The VACB showed atypical lobular hyperplasia in these 3 patients, associated with microcalcification (n=2) or mass lesion (n=1). No single case of upgrading to invasive breast cancer was identified in our series. The remaining patients (16 out of 19) had a benign biopsy. The upgrade to malignancy was significantly associated with the presence of atypical lobular hyperplasia, a BI-RADS category of 4 and incomplete removal of the radiological abnormality by VACB. After a mean follow-up of 18 months, no malignancy was detected in the 5 patients who did not undergo open surgical biopsy. CONCLUSION Open surgical excision is strongly recommended for atypical lobular hyperplasia identified in VACB specimens. VACB can be a safe alternative to surgery in the treatment of B3 lesions in selected cases, providing thorough multidisciplinary discussion has taken place.

Breast Neoplasms

surgery

229279261

PERCEPTION Trial protocol

Abstract Background: Triple negative breast cancer affects 10% to 20% of all women diagnosed with breast cancer. Due to its characteristics, treatment strategies are limited and metastatic recurrences are common in the first 5 years after treatment. However, not all patients affected by this disease develop metastases. Tumor-infiltrating lymphocytes have shown to be reliable predictive biomarkers of treatment response and metastatic recurrences. However, we need to develop simpler and faster ways to predict response to cytotoxic treatment and the possibility of eventual cancer relapse by identifying new biomarkers. Recently, new studies are emerging, suggesting a predictive role of circulating blood cells in different types of cancer. In this study, we will assess the correlation between tumor-infiltrating lymphocytes and different elements of the blood count in patients diagnosed with triple negative breast cancer. Methods: The main objective of this study is to evaluate the correlation between the peripheral neutrophil-to-lymphocyte ratio and the amount of tumor-infiltrating lymphocytes, assessed in triple negative breast cancer patients at diagnosis. Secondary objectives include evaluation of the correlation between tumor-infiltrating lymphocytes at diagnosis and the baseline absolute neutrophil, lymphocyte, and platelet counts, as well as the platelet-to-lymphocyte ratio. The triple negative breast cancer patients will be enrolled in the PERCEPTION trial during the first year after the treatment completion. Two supplementary blood tests, at 12 months after the end of treatment and at the time of the first metastatic recurrence, will be performed. Discussion: The discovery of new prognostic and predictive biomarkers is crucial for triple negative breast cancer. We set up the PERCEPTION clinical trial in order to evaluate certain blood counts as early biomarkers and to assess their correlation with tumor-infiltrating lymphocytes. Demonstration of comparative predictive and/or prognostic capacities of peripheral blood counts and tumor-infiltrating lymphocytes would allow introduction of the former as simple and cheap biomarkers in triple negative breast cancer patient management. Trial registration: The PERCEPTION study has been registered in the French National Agency of Medical Security registry on the 2nd of July 2019 under the number 2019-A01861-56 and in the ClinicalTrials.org registry under the number NCT04068623.

Breast Neoplasms

blood

33919706

Effect of a peptide leukotriene receptor antagonist, ONO-1078, on guinea-pig models of asthma.

Peptide leukotrienes have been suggested to play an important role in bronchial asthma. As antigen-induced bronchoconstrictions, airway hyperreactivity, and pulmonary eosinophil accumulation are characteristics of the pathology of asthma, we investigated the effect of a peptide leukotriene receptor antagonist, ONO-1078, on these responses using guinea-pig models of asthma. Oral administration of ONO-1078 (3 mg/kg) significantly inhibited slow-reacting substance of anaphylaxis-mediated bronchoconstriction induced by i.v. administered ovalbumin. ONO-1078 (30-100 mg/kg), when administered orally both 1 h before and 4 h after ovalbumin challenge, significantly reduced immediate- and late-phase asthmatic responses, with peak responses occurring immediately and 5-11 h after challenge with inhaled ovalbumin. Oral administration of ONO-1078 significantly reduced the airway hyperreactivity (10-30 mg/kg) and the pulmonary eosinophil accumulation (30-100 mg/kg) observed 4 and 24 h after ovalbumin challenge, respectively. These results suggest that ONO-1078 may be of therapeutic use for bronchial asthma.

Asthma

drug therapy

3637675

Association of Modifiable Risk Factors in Young Adulthood With Racial Disparity in Incident Type 2 Diabetes During Middle Adulthood

Importance In the United States, black individuals are twice as likely to develop type 2 diabetes compared with white individuals, and these disparities are particularly pronounced in young and middle age. Prior studies have identified differences in traditional risk factors that may be associated with racial disparities in diabetes incidence but have not simultaneously adjusted for risk factors measured across multiple domains (eg, the individual and the environment) and updated over time. Objective To determine the relative associations of modifiable biological, neighborhood, psychosocial, socioeconomic, and behavioral factors in young adulthood with the observed racial disparity in diabetes incidence between middle-aged black and white individuals. Design, Setting, and Participants Black and white men and women from the observational Coronary Artery Risk Development in Young Adults study, aged 18 to 30 years, without diabetes at baseline (1985-1986; N = 4251) were observed through 2015-2016. Sex-stratified multivariable-adjusted Cox proportional hazards modeling, with adjustment for time-updated covariates, was used to estimate risk for incident diabetes. Percent reduction in the &bgr; coefficient (the logarithm used to calculate the hazard ratio [HR]) was calculated to compare black to white participants. Exposures Self-identified race and factors including biological (eg, fasting glucose, body mass index), neighborhood (racial segregation and tract-level poverty), psychosocial (depressive symptoms), socioeconomic (eg, personal and parental educational attainment, current employment), and behavioral (eg, regular alcohol consumption, smoking) domains. Main Outcomes and Measures Incident type 2 diabetes mellitus. Results The mean (SD) age at baseline was 25 (3.6) years, 49% (n = 2066) of the sample was black, and 54% (n = 2304) were women. Over a mean follow-up of 24.5 years, 504 cases of incident diabetes were identified. Using sex-stratified multivariable-adjusted Cox proportional hazards models, black women and men were more likely to develop diabetes than white men and women (black women: HR, 2.86 [95% CI, 2.19-3.72] and risk difference [RD], 89 cases/1000 people [95% CI, 61-117]; black men: HR, 1.67 [95% CI, 1.28-2.17] and RD, 47 cases/1000 people [95% CI, 15-78]) after adjustment for age and center. Biological factors were most strongly associated with the disparity in diabetes risk between black and white individuals for women (percent reduction in &bgr;, 112%) and men (percent reduction in &bgr;, 86%). There was no longer disparity in diabetes risk between black and white middle-aged adults after adjustment for biological, neighborhood, psychosocial, socioeconomic, and behavioral factors measured over time (HR for women, 0.79 [95% CI, 0.55-1.14]; HR for men, 0.92 [95% CI, 0.62-1.38]). Conclusions and Relevance In this cohort study comparing black and white participants, there was a statistically significant increased risk of incident type 2 diabetes among black women and men. However, after adjustment for modifiable risk factors during young adulthood, the disparity was no longer statistically significant.

Diabetes Mellitus, Type 2

ethnology

5927758

Measures of bioavailable serum sex hormone levels in aging Chinese by protein chip

The purpose of this study was to develop a protein chip technique based on receptor binding assays to measure bioavailable serum sex hormone levels (BSSHL). 224 aging healthy Chinese were investigated to get the referenced values of BSSHL for the first time. In the assays recombined sex hormone receptor proteins were jointed to polysaccharide coated slides to make protein chip, and the dose-dependence curves of sex hormone on chip were prepared. The data showed that this method had good precision (CV<16%) and accuracy (Bias<10%), and the sensitivity could reach 1 pmol/L. From the results, BSSHL of men and women declined with aging, but no significant differences were observed. The BSSHL of aging men were higher than those of women. The bioavailable serum androgen level of men was 52–112 pmol/L, women’s was 3–70 pmol/L and the whole group was 41.9–81.4 pmol/L. The bioavailable serum estrogen level of men was 0.8–3.0 pmol/L, women’s was 1.2–2.5 pmol/L and the whole group was 0.6–2.64 pmol/L. Based on the assays, BSSHL measurement by protein chip can meet the needs of epidemiological studies in terms of speed, accuracy and sample volume required, and was helpful in quantitative assessment of aging people’s health.

Aging

blood

23777395

Platinum phenanthroimidazole complexes as G-quadruplex DNA selective binders.

Complexes that bind and stabilize G-quadruplex DNA structures are of significant interest due to their potential to inhibit telomerase and halt tumor cell proliferation. We here report the synthesis of the first Pt(II) G-quadruplex selective molecules, containing pi-extended phenanthroimidazole ligands. Binding studies of these complexes with duplex and quadruplex d(T(4)G(4)T(4))(4) DNA were performed. Intercalation to duplex DNA was established through UV/Vis titration, CD spectroscopy, and thermal denaturation studies. Significantly stronger binding affinity of these phenanthroimidazole Pt(II) complexes to G-quadruplex DNA was observed by UV/Vis spectroscopy and competitive equilibrium dialysis studies. Observed binding constants to quadruplex DNA were nearly two orders of magnitude greater than for duplex DNA. Circular dichroism studies show that an increase in pi-surface leads to a significant increase in the thermal stability of the Pt(II)/quadruplex DNA complex. The match in the pi-surface of these phenanthroimidazole Pt(II) complexes with quadruplex DNA was further substantiated by molecular modeling studies. Numerous favorable pi-stacking interactions with the large aromatic surface of the intermolecular G-quadruplex, and unforeseen hydrogen bonds between the ancillary ethylenediamine ligands and the quadruplex phosphate backbone are predicted. Thus, both biological and computational studies suggest that coupling the square-planar geometry of Pt(II) with pi-extended ligands results in a simple and modular method to create effective G-quadruplex selective binders, which can be readily optimized for use in telomerase-based antitumor therapy.

DNA

chemistry

23601426

A stepwise approach for peroral endoscopic myotomy for treating achalasia: from animal models to patients

Abstract Objectives. Peroral endoscopic myotomy (POEM) was initially developed for the treatment of achalasia. This study aimed to investigate the feasibility and safety of a stepwise approach for POEM in the management of achalasia. Methods. A total of five ex-vivo porcine esophagus-stomach training models were created and POEM was performed. Then, 25 patients with achalasia were treated similarly. The Eckardt score, barium esophagrams, and high-resolution manometry were used to evaluate its efficacy. Results. POEM procedures were completed in five stomach-esophagus models, with perforations in the initial three and success in the last two. A total of 36 achalasia patients (22 males, 14 females) with achalasia successfully underwent POEM. The mean operation time was 72.0 min (range, 45–180 min). There were two complications in three patients: one case of severe bleeding and two cases of pneumothorax, which were treated successfully. During the follow-up period, the median Eckardt score decreased dramatically from 8 to 1 (p = 0.000). The lower basal esophageal sphincter pressure (36.1 ± 14.3 vs. 11.9 ± 4.6 mmHg, p = 0.000), as well as the 4-s integrated relaxation pressure (12.9 ± 13.0 vs. 6.6 ± 2.9 mmHg, p = 0.000). Additionally, the maximum esophagus width was significantly reduced (mean reduced width: 1.6 ± 1.1 cm, p = 0.000). Conclusions. The ex-vivo porcine esophagus-stomach can be used as a simple and cheap training model that mimics the POEM procedure. POEM is a safe and effective therapy for achalasia patients.

Postoperative Complications

therapy

210131857

Light-Controlled, Toehold-Mediated Logic Circuit for Assembly of DNA Tiles.

Inspired by cytoskeletal structures that respond sensitively to environmental changes and chemical inputs, we report a strategy to trigger and finely control the assembly of stimulus-responsive DNA nanostructures with light under isothermal conditions. The strategy is achieved via integrating an upstream light-controlled, toehold-mediated DNA strand displacement circuit with a downstream DNA tile self-assembly process. By rationally designing upstream DNA strands module, we further transform the upstream DNA strand displacement circuit to an "AND gate" circuit to control the assembly of DNA nanostructures. This example represents the demonstration of the spatially and temporally assembly of DNA nanostructures using a non-invasive chemical input. Such light-controlled DNA logic circuit not only adds a new element to the tool box of DNA nanotechnology but also inspires us to assemble complex and responsive nanostructures.

DNA

chemistry

11259309

Chemical Composition of the Essential Oil from Croton Oblongifolius and its Antibacterial Activity Against Propionibacterium Acnes

The essential oil of C. oblongifolius Roxb. stem bark was obtained by hydrodistillation. Chemical analysis by GC-MS identified 29 compounds. Terpinen-4-ol (17.8%) was a major component, together with α-guaiene (7.9%), E-caryophyllene (7.0%), myrcene (6.7%), (+)-cyclosativene (5.1%), sabinene (4.8%), aciphyllene (4.7%), pogostol (4.6%), γ-terpinene (3.4%), α-muurolol (3.2%) and germecrene D (3.2%). The essential oil exhibited antibacterial activity against Propionibacterium acnes ATCC 6919 with an MIC of 0.125%, v/v.

Anti-Bacterial Agents

chemistry

23953179

Don't ask, don't tell: parental nondisclosure of complementary and alternative medicine and over-the-counter medication use in children's asthma management.

INTRODUCTION Parent-health care provider (HCP) communication is an important component of pediatric asthma management. Given the high prevalence of complementary and alternative medicine (CAM) and over-the-counter (OTC) medication use among this population, it is important to examine parental nondisclosure of these asthma management strategies. METHOD One-time interview and 1-year retrospective medical record review with 228 parents of 5- to 12-year-old children with asthma enrolled from six pediatric primary care practices examining parental nondisclosure of CAM and OTC medication use, reasons for nondisclosure, medical record documentation of CAM usage, and association between parent-HCP relationship and nondisclosure. RESULTS Seventy-one percent of parents reported using CAM and/or OTC medication for children's asthma management, and 54% of those parents did not disclose usage. Seventy-five percent "did not think" to discuss it. Better parent-HCP relationship led to decreased nondisclosure. DISCUSSION HCPs can play an important role in creating an environment where parents feel comfortable sharing information about their children's asthma management strategies in order to arrive at a shared asthma management plan for the child, leading to improved asthma health outcomes.

Asthma

drug therapy

36169317

Triglycerides as vascular risk factors: new epidemiologic insights

Purpose of review Targeting triglycerides as a vascular risk factor is justified because of the role of triglyceride-rich lipoproteins in atherogenesis. This review examines recent evidence connecting triglycerides with cardiovascular disease (CVD) in the context of advances in insights concerning the pathophysiology, population burden and prognostic impact of fasting versus nonfasting values. Recent findings Cross-sectional surveys indicate that mean triglyceride levels in the United States have increased in recent decades. Although elevated fasting triglycerides are consistently associated with increased CVD risk, adjustment for other risk factors (especially high-density lipoprotein cholesterol (HDL-C)) substantially attenuates this relationship. A recent meta-analysis of 27 prospective studies of western populations reported a triglyceride impact on CVD in both sexes, for both fasting and nonfasting values. Nonfasting triglycerides maintained an independent graded relationship with CVD in fully adjusted analyses, with elevated 4 h postprandial triglyceride imposing a 4.5-fold increment relative to lower levels. Summary Evidence supports a potential role for both fasting and nonfasting triglycerides as vascular risk factors, owing in part to the accompanying burden of atherogenic remnant particles, small dense low-density lipoprotein, reduced HDL-C and a high frequency of accompanying insulin resistance. Triglyceride-associated CVD risk occurs even in patients with low low-density lipoprotein cholesterol (LDL-C), and lowering both lipids provides more benefit than reducing LDL-C alone.

Cardiovascular Diseases

epidemiology

18860563

Increasing prevalence of HIV infection among first time clients in Italian drug treatment services – is it sexual transmission?

BackgroundOver the last two decades, the proportion of people who inject drugs among newly reported HIV cases in Italy has been continuously declining. This trend is reflected in the prevalence of HIV infection among problem drug users followed in drug treatment services. We report nationwide trends in the prevalence of HIV and HCV among tested clients in charge to drug addiction services from 2005 to 2011.MethodsData on the prevalence of HIV and HCV among drug users from public drug treatment services across Italy were collected and analyzed for the period from 2005 to 2011. Prevalence of HIV and HCV were compared between clients returning to treatment and those entering treatment for the first time, and by gender. Due to the high percentage of missing data, the “inverse probability weight” method was used. Trends in testing uptake were also analysed.ResultsA significant decrease of HIV and HCV prevalence is observed among all PDUs entering treatment (from 14.7% to 11.1% and from 61.6% to 50%, respectively, in 2005–2011). By contrast, among those entering the services for the first time, after an initial decline the prevalence of HIV infection steadily increased in both sexes, from 2.2% in 2009 to 5.3% in 2011. Self-reported injecting rates in this group decreased over time, and in 2011 the proportion reporting drug injecting was lower among new clients than in people returning to services (14.5 vs. 34.4%). We also observed a progressive and significant reduction in HIV and HCV testing in drug treatment services.ConclusionsChanges in injection practice and type of drugs used, coupled with a concurrent reduction in HCV prevalence, do not support drug injection as the main explanation for an increased HIV transmission in people entering drug treatment services for the first time. While reductions in testing rates raise concerns over data quality, the possibility of increased sexual transmission needs to be considered.

HIV Infections

epidemiology

37967032

Nitric oxide in hypertension and renal diseases.

Nitric oxide (NO) is intimately involved in the regulation of vascular tone, renal haemodynamics and sodium balance. The physiological actions of NO suggest important vascular and renal protective roles for NO. When produced in large amounts, however, NO may also mediate cytotoxic effects. Increasing evidence suggests that endothelial function, notably the NO pathway, may be compromised in hypertension. It is not known, however, whether changes in endothelial function are primary or secondary to the development of hypertension. In renal diseases evidence for both excessive and deficient activity of NO pathway has been found. Increased glomerular production of NO via inducible NO synthase (NOS) with potential cytotoxic consequences has been demonstrated in experimental acute glomerulonephritis. On the other hand, indirect evidence obtained by means of NOS inhibitors point out to an important renoprotective role for NO in renal diseases. NO may counteract disease progression in renal diseases by preventing glomerular microthrombi, maintaining renal perfusion and medullary oxygenation, and via its anti-inflammatory/antiproliferative effects. However, these beneficial effects of NO may be compromised (endothelial and/or tubular dysfunction) in chronic nephropathies resulting in an accelerated course of renal disease. In future, more specific inhibitors and activators of different NOS isoforms are needed to elucidate the role of NO in various renal diseases in detail, and for treatment strategies aimed at modifying the NO pathway.

Hypertension

physiopathology

40267514

Does Neuronal Synchrony Underlie Visual Feature Grouping?

Previous research suggests that synchronous neural activity underlies perceptual grouping of visual image features. The generality of this mechanism is unclear, however, as previous studies have focused on pairs of neurons with overlapping or collinear receptive fields. By sampling more broadly and employing stimuli that contain partially occluded objects, we have conducted a more incisive test of the binding by synchrony hypothesis in area MT. We find that synchrony in spiking activity shows little dependence on feature grouping, whereas gamma band synchrony in field potentials can be significantly stronger when features are grouped. However, these changes in gamma band synchrony are small relative to the variability of synchrony across recording sites and do not provide a robust population signal for feature grouping. Moreover, these effects are reduced when stimulus differences nearby the receptive fields are eliminated using partial occlusion. Our findings suggest that synchrony does not constitute a general mechanism of visual feature binding.

Neurons

physiology

35805169

PPARG2 Pro12Ala and ADAMTS9 rs4607103 as “insulin resistance loci” and “insulin secretion loci” in Italian individuals. The GENFIEV study and the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 4

We investigated cross-sectionally whether the type 2 diabetes (T2DM) risk alleles of rs1801282 (PPARG2) and rs4607103 (ADAMTS9) were associated with T2DM and/or insulin sensitivity (IS) and beta cell function (βF) in Italians without and with newly diagnosed T2DM. In 676 nondiabetic subjects (336 NGR and 340 IGR) from the GENFIEV study and in 597 patients from the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS), we (1) genotyped rs1801282 and rs4607103, (2) assessed βF by C-peptide/glucose modeling after OGTT, and (3) assessed IS by HOMA-IR in both studies and by euglycemic insulin clamp in VNDS only. Logistic, linear, and two-stage least squares regression analyses were used to test (a) genetic associations with T2DM and with pathophysiological phenotypes, (b) causal relationships of the latter ones with T2DM by a Mendelian randomization design. Both SNPs were associated with T2DM. The rs4607103 risk allele was associated to impaired βF (p < 0.01) in the GENFIEV study and in both cohorts combined. The rs1801282 genotype was associated with IS both in the GENFIEV study (p < 0.03) and in the VNDS (p < 0.03), whereas rs4607103 did so in the VNDS only (p = 0.01). In a Mendelian randomization design, both HOMA-IR (instrumental variables: rs1801282, rs4607103) and βF (instrumental variable: rs4607103) were related to T2DM (p < 0.03–0.01 and p < 0.03, respectively). PPARG2 and ADAMTS9 variants are both associated with T2DM and with insulin resistance, whereas only ADAMTS9 may be related to βF. Thus, at least in Italians, they may be considered bona fide “insulin resistance genes”.

Diabetes Mellitus, Type 2

genetics

3325271

Opposite changes of pituitary and ovarian receptors for LHRH in ageing rats: further evidence for a direct neural control of ovarian LHRH receptor activity.

Hypophyseal and ovarian receptors for the neurohormone LHRH (LHRH-R) have been measured in young (3-4 months), middle-aged (8-11 months), constant estrous (CE, 10-14 months) and pseudopregnant (PR, 16-18 months) rats in order to study whether changes in hypothalamic and/or peripheral LHRH-like peptide production might precede and/or accompany the onset of reproductive failure observed in aging rats. Furthermore, we have investigated whether the neural efferent system from the brain to the ovary is affected with aging. The pattern of pituitary LHRH-R modifications during the estrous cycle of middle-aged rats shows lower LHRH-R levels on the second day of diestrus, resulting in a shift of the maximal LHRH binding capacity in the morning of proestrus. On the other hand, when comparing pituitary LHRH-R of animals exhibiting constant vaginal cornification (CVC) or repetitive PP with young estrus rats, no significant difference could be observed. Young rats responded to electrical stimulation (ES) of the medial preoptic area with an acute elevation of LHRH-R while ES performed in CVC, or PP animals resulted in a significant increase of hypophyseal LHRH binding capacity similar to the one observed in young estrous controls, indicating an impairment in the neural signals impinging in the pulse generating system, in old rats, and not an intrinsic defect of the LHRH-R per se. Ovarian LHRH-R concentration is higher in middle-aged cycling animals on the day of vaginal proestrus, compared to levels measured in young animals at any phase of the estrous cycle. Similarly, CE rats displaying CVC as well as PP animals show significantly higher numbers of LHRH-R with no change in affinity, than young estrus rats. CVC and PP rats receiving unilaterally an intraovarian injection of the potent LHRH antagonist, Ac-D-Cl-Phe1,2, D-Trp3, D-Phe6, D-Ala10, LHRH, showed an acute drop of LHRH-R measured within the treated ovary with no significant changes taking place in the vehicle-treated contralateral gland, suggesting that changes of endogenous ovarian LHRH-like peptide might participate in the mechanism(s) responsible for LHRH receptor increase observed in aging rats. In order to investigate the participation of a direct neural efferent pathway in ovarian LHRH-R regulation, young and old rats were subjected to spinal cord transection (above T10-T11). Bilateral transection of the spinal cord in young animals in the morning of proestrous markedly increased ovarian LHRH-R concentration in the afternoon (17.00 h) of the same day.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging

metabolism

41080863

Coordination of cell cycle exit and differentiation of neuronal progenitors

During development, co-ordinate regulation of cell cycle exit and differentiation of neuronal precursors is essential for generation of appropriate number of neurons and proper wiring of neuronal circuits. Recent studies have identified some of the molecules implicated in the regulation of these cellular events, but the complex machinery that orchestrates these processes into a coherent developmental program remains unclear. BM88/Cend1 is a neuronal protein associated in vivo with terminal neuron-generating divisions, marking the exit of proliferative cells from the cell cycle. Genetic studies in neural cell lines, neural stem/progenitor cells using the neurosphere system and in the developing chicken neural tube in vivo have shown that BM88/Cend1 is a dual function molecule co-ordinating cell cycle exit and differentiation of neuronal progenitors. These studies have thus shed light on a molecular determinant that participates, along with other known and possibly still unknown regulators, in the complex processes by which a progenitor cell becomes a mature neuron.

Neurons

physiology

15171856

Thigh Circumference and Diabetes: Obesity as a Potential Effect Modifier

Background Thigh circumference is associated with diabetes risk; however, the role of obesity as a potential effect modifier has not been well studied. Methods We examined the association between thigh circumference and diabetes in a cross-sectional study of 384 612 Koreans aged 30 to 79 years. The association between diabetes and thigh circumference in relation to body mass index (BMI) was analyzed among 315 628 participants, using multivariate logistic regression. Thigh circumference was categorized into 9 percentile categories—namely, the 2.5th, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 97.5th percentiles—and the 50th percentile was used as the reference value for thigh circumference. Separate analyses were performed for men and women. Results The association of thigh circumference with diabetes showed contradictory patterns before and after adjustment for BMI and waist circumference. Small thigh circumference was associated with greater risk of diabetes among men and women. This relationship was stronger among participants younger than 50 years, although age was not a significant effect modifier. BMI was a significant effect modifier among men with a BMI of less than 25 kg/m2. Among women, diabetes risk increased with smaller thigh circumference. Conclusions Small thigh circumference was associated with diabetes, and this association was stronger among participants with a BMI of less than 25 kg/m2. Thigh circumference might be a useful diabetes marker in lean populations.

Obesity

epidemiology

11839263

From Homodimer to Heterodimer and Back: Elucidating the TonB Energy Transduction Cycle

ABSTRACT The TonB system actively transports large, scarce, and important nutrients through outer membrane (OM) transporters of Gram-negative bacteria using the proton gradient of the cytoplasmic membrane (CM). In Escherichia coli, the CM proteins ExbB and ExbD harness and transfer proton motive force energy to the CM protein TonB, which spans the periplasmic space and cyclically binds OM transporters. TonB has two activity domains: the amino-terminal transmembrane domain with residue H20 and the periplasmic carboxy terminus, through which it binds to OM transporters. TonB is inactivated by all substitutions at residue H20 except H20N. Here, we show that while TonB trapped as a homodimer through its amino-terminal domain retained full activity, trapping TonB through its carboxy terminus inactivated it by preventing conformational changes needed for interaction with OM transporters. Surprisingly, inactive TonB H20A had little effect on homodimerization through the amino terminus and instead decreased TonB carboxy-terminal homodimer formation prior to reinitiation of an energy transduction cycle. That result suggested that the TonB carboxy terminus ultimately interacts with OM transporters as a monomer. Our findings also suggested the existence of a separate equimolar pool of ExbD homodimers that are not in contact with TonB. A model is proposed where interaction of TonB homodimers with ExbD homodimers initiates the energy transduction cycle, and, ultimately, the ExbD carboxy terminus modulates interactions of a monomeric TonB carboxy terminus with OM transporters. After TonB exchanges its interaction with ExbD for interaction with a transporter, ExbD homodimers undergo a separate cycle needed to re-energize them. IMPORTANCE Canonical mechanisms of active transport across cytoplasmic membranes employ ion gradients or hydrolysis of ATP for energy. Gram-negative bacterial outer membranes lack these resources. The TonB system embodies a novel means of active transport across the outer membrane for nutrients that are too large, too scarce, or too important for diffusion-limited transport. A proton gradient across the cytoplasmic membrane is converted by a multiprotein complex into mechanical energy that drives high-affinity active transport across the outer membrane. This system is also of interest since one of its uses in pathogenic bacteria is for competition with the host for the essential element iron. Understanding the mechanism of the TonB system will allow design of antibiotics targeting iron acquisition.

Escherichia coli

metabolism

35924218

Abnormalities of basophil "releasability" in atopic and asthmatic individuals.

47. Pandey JP, Ambroscht F, Fudenberg HH, Staniki G, Wiedermann G. Immunoglobulin allotypes and immune response to meningococcal polysaccharides A and C. J Immunogenet 1982;9:25-9. 48. Salier JP, Goust JM, Pandey JP, Fudenberg HH. Preferential synthesis of the Glm(l) allotype of IgGl in the central nervous system of multiple sclerosis patients. Science 1981;213: 1400. 49. Wilcox H, Marsh D. Genetic regulation of antibody heterogeneity. Immunogenetics 1978;6:209. 50. Blumenthal MN, Yunis E, Gleich G, et al. Lack of association of the immune response to ragweed antigen E, Ra3 and Ra5 with the HLA system. J Immunogenet 1981;8:379-86. 51. Marsh D, Hsu SH, Roebber M, et al. HLA-Dw2-A genetic marker for human immune response to short ragweed allergen RAS: I. Response resulting primarily from natural antigenic exposure. J Exp Med 1982;155:1439-51. 52. Coulter KM, Dorval G, Yang WH, Drouin MA, Del Carpio J, Goodfriend L. Presented at the American Academy of Allergy, Chicago, February 1985. 53. Marsh D, Meyers D, Freidhoff L, et al. HLA-Dw2-A genetic marker for human immune response to short ragweed allergen RAS. II. Response after ragweed immunotherapy. J Exp Med 1982;155:1452-63. 54. Levine B, Stember R, Fotino M. Ragweed hay fever: genetic control and linkagae to HL-A haplotypes. Science 1972; 178:1201. 55. Blumenthal M, Amos D, Noreen H, Mendell N, Yunis E. Genetic mapping of Ir locus in man: linkage to second locus of HL-A. Science 1974;184:1301. 56. Mendell NR, Blumenthal MN, Amos DB, Yunis EJ, Elston RC. Ragweed sensitivity: segregation analysis and linkage to HLA-B. Cytogenetics 1978;22:330-4. 57. Blumenthal MN, Yunis EJ, Mendell NR, Amos B. HLA and ragweed allergy. Monogr Allergy 1977; 11:83-8. 58. Awdeh ZL, Raum D, Yunis EJ, Alper CA. Extended HLA/complement allele haplotypes: evidence for T/t-like complex in man. Proc Nat1 Acad Sci USA 1983;80:259-63. 59. Alper CA, Awdeh ZL, Raum DD, Yunis EJ. Extended major histocompatibility complex haplotypes in man: role of alleles analogous to murine t mutants. Clin Immunol Immunopathol 1982;24:276-85.

Asthma

immunology

25863201

Risk factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependent diabetes mellitus: prospective, observational study

Abstract Objective: To evaluate putative risk factors for the development of incipient diabetic nephropathy (persistent microalbuminuria) and overt diabetic nephropathy (persistent macroalbuminuria) in patients with non-insulin dependent diabetes. Design: Prospective, observational study of a cohort of white, non-insulin dependent diabetic patients followed for a median period of 5.8 years. Setting: Outpatient clinic in tertiary referral centre. Subjects: 191 patients aged under 66 years with non-insulin dependent diabetes and normoalbuminuria (urinary albumin excretion rate<30 mg/24 h) who attended the clinic during 1987. Main outcome measures: Incipient and overt diabetic nephropathy. Results: Fifteen patients were lost to follow up. Thirty six of the 176 remaining developed persistent microalbuminuria (30-299 mg/24 h in two out of three consecutive 24 hour urine collections) and five developed persistent macroalbuminuria (≥300 mg/24 h in two out of three consecutive collections) during follow up. The five year cumulative incidence of incipient diabetic nephropathy was 23% (95% confidence interval 17% to 30%). Cox's multiple stepwise regression analysis revealed the following risk factors for the development of incipient or overt diabetic nephropathy: increased baseline log urinary albumin excretion rate (relative risk 11.1 (3.4 to 35.9); P<0.0001); male sex (2.6 (1.2 to 5.4); P<0.02); presence of retinopathy (2.4 (1.3 to 4.7); P<0.01); increased serum cholesterol concentration (1.4 (1.1 to 1.7); P<0.01); haemoglobin A 1c concentration (1.2 (1.0 to 1.4); P<0.05); and age (1.07 (1.02 to 1.12); P<0.01). Known duration of diabetes, body mass index, arterial blood pressure, serum creatinine concentration, pre-existing coronary heart disease, and history of smoking were not risk factors. Conclusion: Several potentially modifiable risk factors predict the development of incipient and overt diabetic nephropathy in normoalbuminuric patients with non-insulin dependent diabetes.

Diabetes Mellitus, Type 2

complications

7413454

Renal function in Palestine sunbirds: elimination of excess water does not constrain energy intake

SUMMARY Although the renal responses of birds to dehydration have received significant attention, the consequences of ingesting and processing large quantities of water have been less studied. Nectar-feeding birds must often deal with exceptionally high water intake rates in order to meet their high mass-specific energy demands. Birds that ingest large volumes of water may either eliminate excess water in the kidney or regulate the volume of water absorbed in the gastrointestinal tract. Because water absorption in the gastrointestinal tract of Palestine sunbirds (Nectarinia osea) decreases with increasing water ingestion rate, we predicted that glomerular filtration rate (GFR) in these birds would not be unusually high in spite of large ingested water loads. When feeding on dilute sucrose solutions, sunbirds ingested between 4 and 6 times their body mass in nectar per day, yet they were able to compensate for varying nectar energy density and increased thermoregulatory energy demands with no apparent difficulty. GFR was lower than predicted (1976.22±91.95 μl h-1), and was not exceptionally sensitive to water loading. Plasma glucose concentrations were high, and varied 1.8-fold between fasted (16.08± 0.75 mmol l-1) and fed (28.18±0.68 mmol l-1) sunbirds, but because GFR was low, glucose filtered load also remained relatively low. Essentially the entire glucose filtered load (98%) was recovered by the kidney. Renal fractional water reabsorption (FWR) decreased from 0.98 to 0.64 with increasing water intake. The ability of Palestine sunbirds to reduce the absorption of ingested water in the gastrointestinal tract may resolve the potential conflict between filtering a large excess of absorbed water in the kidney and simultaneously retaining filtered metabolites.

Kidney

physiology

222256325

Prophylaxis of thromboembolism during therapy with asparaginase in adults with acute lymphoblastic leukaemia.

BACKGROUND The risk of venous thromboembolism is increased in adults and enhanced by asparaginase-based chemotherapy, and venous thromboembolism introduces a secondary risk of treatment delay and premature discontinuation of key anti-leukaemic agents, potentially compromising survival. Yet, the trade-off between benefits and harms of primary thromboprophylaxis in adults with acute lymphoblastic leukaemia (ALL) treated according to asparaginase-based regimens is uncertain.  OBJECTIVES: The primary objectives were to assess the benefits and harms of primary thromboprophylaxis for first-time symptomatic venous thromboembolism in adults with ALL receiving asparaginase-based therapy compared with placebo or no thromboprophylaxis. The secondary objectives were to compare the benefits and harms of different groups of primary systemic thromboprophylaxis by stratifying the main results per type of drug (heparins, vitamin K antagonists, synthetic pentasaccharides, parenteral direct thrombin inhibitors, direct oral anticoagulants, and blood-derived products for antithrombin substitution). SEARCH METHODS We conducted a comprehensive literature search on 02 June 2020, with no language restrictions, including (1) electronic searches of Pubmed/MEDLINE; Embase/Ovid; Scopus/Elsevier; Web of Science Core Collection/Clarivate Analytics; and Cochrane Central Register of Controlled Trials (CENTRAL) and (2) handsearches of (i) reference lists of identified studies and related reviews; (ii) clinical trials registries (ClinicalTrials.gov registry; the International Standard Randomized Controlled Trial Number (ISRCTN) registry; the World Health Organisation's International Clinical Trials Registry Platform (ICTRP); and pharmaceutical manufacturers of asparaginase including Servier, Takeda, Jazz Pharmaceuticals, Ohara Pharmaceuticals, and Kyowa Pharmaceuticals), and (iii) conference proceedings (from the annual meetings of the American Society of Hematology (ASH); the European Haematology Association (EHA); the American Society of Clinical Oncology (ASCO); and the International Society on Thrombosis and Haemostasis (ISTH)). We conducted all searches from 1970 (the time of introduction of asparaginase in ALL treatment). We contacted the authors of relevant studies to identify any unpublished material, missing data, or information regarding ongoing studies. SELECTION CRITERIA Randomised controlled trials (RCTs); including quasi-randomised, controlled clinical, cross-over, and cluster-randomised trial designs) comparing any parenteral/oral preemptive anticoagulant or mechanical intervention with placebo or no thromboprophylaxis, or comparing two different pre-emptive anticoagulant interventions in adults aged at least 18 years with ALL treated according to asparaginase-based chemotherapy regimens. For the description of harms, non-randomised observational studies with a control group were eligible for inclusion.  DATA COLLECTION AND ANALYSIS: Using a standardised data collection form, two review authors independently screened and selected studies, extracted data, assessed risk of bias for each outcome using standardised tools (RoB 2.0 tool for RCTs and ROBINS-I tool for non-randomised studies) and the certainty of evidence for each outcome using the GRADE approach. Primary outcomes included first-time symptomatic venous thromboembolism, all-cause mortality, and major bleeding. Secondary outcomes included asymptomatic venous thromboembolism, venous thromboembolism-related mortality, adverse events (i.e. clinically relevant non-major bleeding and heparin-induced thrombocytopenia for trials using heparins), and quality of life. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. For non-randomised studies, we evaluated all studies (including studies judged to be at critical risk of bias in at least one of the ROBINS-I domains) in a sensitivity analysis exploring confounding.  MAIN RESULTS: We identified 23 non-randomised studies that met the inclusion criteria of this review, of which 10 studies provided no outcome data for adults with ALL. We included the remaining 13 studies in the 'Risk of bias' assessment, in which we identified invalid control group definition in two studies and judged outcomes of nine studies to be at critical risk of bias in at least one of the ROBINS-I domains and outcomes of two studies at serious risk of bias. We did not assess the benefits of thromboprophylaxis, as no RCTs were included. In the main descriptive analysis of harms, we included two retrospective non-randomised studies with outcomes judged to be at serious risk of bias. One study evaluated antithrombin concentrates compared to no antithrombin concentrates. We are uncertain whether antithrombin concentrates have an effect on all-cause mortality (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.26 to 1.19 (intention-to-treat analysis); one study, 40 participants; very low certainty of evidence). We are uncertain whether antithrombin concentrates have an effect on venous thromboembolism-related mortality (RR 0.10, 95% CI 0.01 to 1.94 (intention-to-treat analysis); one study, 40 participants; very low certainty of evidence). We do not know whether antithrombin concentrates have an effect on major bleeding, clinically relevant non-major bleeding, and quality of life in adults with ALL treated with asparaginase-based chemotherapy, as data were insufficient. The remaining study (224 participants) evaluated prophylaxis with low-molecular-weight heparin versus no prophylaxis. However, this study reported insufficient data regarding harms including all-cause mortality, major bleeding, venous thromboembolism-related mortality, clinically relevant non-major bleeding, heparin-induced thrombocytopenia, and quality of life. In the sensitivity analysis of harms, exploring the effect of confounding, we also included nine non-randomised studies with outcomes judged to be at critical risk of bias primarily due to uncontrolled confounding. Three studies (179 participants) evaluated the effect of antithrombin concentrates and six studies (1224 participants) evaluated the effect of prophylaxis with different types of heparins. When analysing all-cause mortality; venous thromboembolism-related mortality; and major bleeding (studies of heparin only) including all studies with extractable outcomes for each comparison (antithrombin and low-molecular-weight heparin), we observed small study sizes; few events; wide CIs crossing the line of no effect; and substantial heterogeneity by visual inspection of the forest plots. Although the observed heterogeneity could arise through the inclusion of a small number of studies with differences in participants; interventions; and outcome assessments, the likelihood that bias due to uncontrolled confounding was the cause of heterogeneity is inevitable. Subgroup analyses were not possible due to insufficient data.  AUTHORS' CONCLUSIONS: We do not know from the currently available evidence, if thromboprophylaxis used for adults with ALL treated according to asparaginase-based regimens is associated with clinically appreciable benefits and acceptable harms. The existing research on this question is solely of non-randomised design, seriously to critically confounded, and underpowered with substantial imprecision. Any estimates of effect based on the existing insufficient evidence is very uncertain and is likely to change with future research.

Antineoplastic Agents

adverse effects

39978623

Manganese Dipyridoxal Diphosphate-Enhanced Magnetic Resonance Imaging in the Evaluation of Hepatocyte Function

RATIONALE AND OBJECTIVES.To determine whether contrast-enhanced magnetic resonance imaging can detect ethanol hepatotoxicity in rats. METHODS.Rats were treated with a single high dose of ethanol (acute) intraperitoneally or with a 36% ethanol diet (chronic) for up to 5.5 months. Magnetic resonance imaging was performed before and after intravenous administration of manganese dipyridoxal diphosphate (Mn-DPDP). RESULTS.Enhancement (acute group) was significantly lower in ethanol treated animals on T1-weighted scans (P < .02). Precontrast, a significant difference in intensity was seen on T2-weighted scans (P < .01). Electron microscopy revealed severe hepatocyte damage. In the chronic groups, there was no significant difference in intensity precontrast. Postcontrast, enhancement (ethanol group) was significantly lower on T1-weighted scans only at 2 weeks (P < .05). Electron microscopy demonstrated progressive ethanol hepatotoxicity. CONCLUSIONSMagnetic resonance imaging can distinguish between normal and certain types of ethanol damaged livers on T1-weighted scans. Enhancement, however, does not correlate with progressive microscopic chronic liver damage.

Liver

pathology

22134602

Epac/Rap and PKA are novel mechanisms of ANP‐induced Rac‐mediated pulmonary endothelial barrier protection

Acute lung injury, sepsis, lung inflammation, and ventilator‐induced lung injury are life‐threatening conditions associated with lung vascular barrier dysfunction, which may lead to pulmonary edema. Increased levels of atrial natriuretic peptide (ANP) in lung circulation reported in these pathologies suggest its potential role in the modulation of lung injury. Besides well recognized physiological effects on vascular tone, plasma volume, and renal function, ANP may exhibit protective effects in models of lung vascular endothelial cell (EC) barrier dysfunction. However, the molecular mechanisms of ANP protective effects are not well understood. The recently described cAMP‐dependent guanine nucleotide exchange factor (GEF) Epac activates small GTPase Rap1, which results in activation of small GTPase Rac‐specific GEFs Tiam1 and Vav2 and Rac‐mediated EC barrier protective responses. Our results show that ANP stimulated protein kinase A and the Epac/Rap1/Tiam/Vav/Rac cascade dramatically attenuated thrombin‐induced pulmonary EC permeability and the disruption of EC monolayer integrity. Using pharmacological and molecular activation and inhibition of cAMP‐and cGMP‐dependent protein kinases (PKA and PKG), Epac, Rap1, Tiam1, Vav2, and Rac we linked ANP‐mediated protective effects to the activation of Epac/Rap and PKA signaling cascades, which dramatically inhibited the Rho pathway of thrombin‐induced EC hyper‐permeability. These results suggest a novel mechanism of ANP protective effects against agonist‐induced pulmonary EC barrier dysfunction via inhibition of Rho signaling by Epac/Rap1‐Rac and PKA signaling cascades. J. Cell. Physiol. 215: 715–724, 2008. © 2007 Wiley‐Liss, Inc.

Lung

enzymology

27700261

Synthesis, uptake and release of taurine in astrocytes treated with 8-Br-cAMP

Taurine is one of the most abundant free amino acids in the mammalian central nervous system, where it is crucial for proper development. Moreover, taurine has been related with epilepsy, as it can reduce or prevent seizures. It is also a neuroprotectant in other experimental conditions. Glial cultures were analysed to determine the changes in taurine synthesis and traffic that occur in a more differentiated state of these cells. The cultures were treated with 8-Br-cAMP, an analogue of cAMP that induces differentiation in astrocytes. We observed an increase in immunoreactivity for GFAP, as well as an alteration in uptake-release kinetics in these cells. Moreover, we noted an increase in taurine levels and in cysteine sulfinic decarboxylase, which is the rate-limiting enzyme in taurine synthesis. The data indicate that taurine synthesis and traffic kinetics vary according to the differentiation state of the astrocytes. Thus, our results highlight the importance of astrocytes in modulating taurine levels in the brain.

Brain

metabolism

24180898

Antibiotic-Resistant Gram-Positive Cocci: Implications for Surgical Practice

Abstract. Gram-positive infections are causing more serious infections than ever before in surgical patients, who are increasingly aged, ill, and debilitated. Invasive procedures disrupt natural barriers to bacterial invasion, and indwelling catheters may act as conduits for infection. The use of broad-spectrum antibiotics selects for the emergence of resistant pathogens. Potential sites of nosocomial gram-positive infections include the urinary tract, surgical site (including prosthetic devices), intravascular loci, lung and pleural space, facial sinuses, and peritoneal cavity. Responsible organisms include species from the generaEnterococcus andStaphylococcus. Methicillin-resistant strains ofStaphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) emerged during the 1970s, leading to a marked increase in the use of vancomycin as the treatment of choice. Vancomycin use, in turn, has been implicated (along with widespread cephalosporin use) in the emergence of vancomycin-resistant enterococci (VRE) during the 1990s. Of great concern is the likely emergence of vancomycin-resistant staphylococci, which would constitute a public health emergency. Vancomycin remains the treatment of choice for infections caused by MRSA/MRSE, but rampant inappropriate use (e.g., prophylaxis in non-penicillin-allergic patients, treatment of methicillin-sensitive strains) must be curtailed. Chloramphenicol is increasingly the treatment of choice for serious VRE infections. Infection control policy must also minimize the possibility of transmission. All infected or colonized patients should be isolated and all environmental surfaces considered contaminated. Disposable gloves are mandatory for all patient contact, even incidental contact, and must be disposed of after each patient encounter. Hand-washing (the single most effective infection control measure) is mandatory after glove disposal. Gowns should be worn for direct contact with infected patients and masks used when aerosolization or splashing of secretions is likely.

Postoperative Complications

drug therapy

58568665

Dual Targeting of EGFR and IGF1R in the TNFAIP8 Knockdown Non–Small Cell Lung Cancer Cells

Aberrant regulation of EGFR is common in non–small cell lung carcinomas (NSCLC), and tumor resistance to targeted therapies has been attributed to emergence of other co-occurring oncogenic events, parallel bypass receptor tyrosine kinase pathways including IGF1R, and TNFα-driven adaptive response via NF-κB. TNFAIP8, TNFα-inducible protein 8, is an NF-κB–activated prosurvival and oncogenic molecule. TNFAIP8 expression protects NF-κB–null cells from TNFα-induced cell death by inhibiting caspase-8 activity. Here, we demonstrate that knockdown of TNFAIP8 inhibited EGF and IGF-1–stimulated migration in NSCLC cells. TNFAIP8 knockdown cells showed decreased level of EGFR and increased expression of sorting nexin 1 (SNX1), a key regulator of the EGFR trafficking through the endosomal compartments, and treatment with SNX1 siRNA partially restored EGFR expression in these cells. TNFAIP8 knockdown cells also exhibited downregulation of IGF-1–induced pIGF1R and pAKT, and increased expression of IGF-1–binding protein 3 (IGFBP3), a negative regulator of the IGF-1/IGF1R signaling. Consistently, treatment of TNFAIP8 knockdown cells with IGFBP3 siRNA restored pIGF1R and pAKT levels. TNFAIP8 knockdown cells had enhanced sensitivities to inhibitors of EGFR, PI3K, and AKT. Furthermore, IHC expression of TNFAIP8 was associated with poor prognosis in NSCLC. These findings demonstrate TNFAIP8-mediated regulation of EGFR and IGF1R via SNX1 and IGFBP3, respectively. We posit that TNFAIP8 is a viable, multipronged target downstream of the TNFα/NF-κB axis, and silencing TNFAIP8 may overcome adaptive response in NSCLC. Implications: TNFAIP8 and its effectors SNX1 and IGFBP3 may be exploited to improve the efficacy of molecular-targeted therapies in NSCLC and other cancers. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/5/1207/F1.large.jpg. Visual Overview

Lung Neoplasms

genetics

24279231

Turnover of env Variable Region 1 and 2 Genotypes in Subjects with Late-Stage Human Immunodeficiency Virus Type 1 Infection

ABSTRACT The env gene of human immunodeficiency virus type 1 (HIV-1) includes some of the most genetically diverse regions of the viral genome, which are called variable regions 1 through 5 (V1 through V5). We have developed a heteroduplex tracking assay to detect changes in variable regions 1 and 2 of env (V1/V2-HTA). Using sequences from two molecular clones as probes, we have studied the nature of longitudinal virus population changes in a cohort of HIV-1-infected subjects. Viral sequences present in 21 subjects with late-stage HIV-1 infection were initially screened for stability of the virus population by V1/V2-HTA. The virus populations at entry comprised an average of five coexisting V1/V2 genotypic variants (as identified by HTA). Eight of the 21 subjects were examined in detail because of the dynamic behavior of their env variants over an approximately 9-month period. In each of these cases we detected a single discrete transition of V1/V2 genotypes based on monthly sampling. The major V1/V2 genotypes (those present at >10% abundance) from the eight subjects were cloned and sequenced to define the nature of V1/V2 variability associated with a discrete transition. Based on a comparison of V1/V2 genotypic variants present at entry with the newly emerged variants we categorized the newly emerged variants into two groups: variants without length differences and variants with length differences. Variants without length differences had fewer nucleotide substitutions, with the changes biased to either V1 or V2, suggestive of recent evolutionary events. Variants with length differences included ones with larger numbers of changes that were distributed, suggestive of recall of older genotypes. Most length differences were located in domains where the codon motif AVT (V = A, G, C) had become enriched and fixed. Finally, recombination events were detected in two subjects, one of which resulted in the reassortment of V1 and V2 regions. We suggest that turnover in V1/V2 populations was largely driven by selection on either V1 or V2 and that escape was accomplished either through changes focused in the region under selection or by the appearance of a highly divergent variant.

HIV Infections

virology

30654280

Effect of Amifostine to prevent radiotherapy-induced acute and late toxicity in head and neck cancer patients who had normal or mild impaired salivary gland function.

BACKGROUND Amifostine has a potential role for salivary gland protection in head and neck cancer patients who had radiotherapy. MATERIAL AND METHOD Sixty-seven head and neck cancer patients were randomized to receive radiotherapy or radiotherapy plus Amifostine. The efficacy of the treatment was determined by a questionnaire evaluating dryness of mouth and the oral comfort, the RTOG/EORTC acute/late radiation morbidity scoring criteria, collection of the whole saliva and the 99mTc-pertecnetate scintigraphy of the salivary glands. RESULTS Amifostine significantly reduced the mean questionnaire scores from 6.49 to 3.73, the incidence of grade > or = 2 mucositis from 75% to 36% and acute xerostomia from 82% to 39%. The salivary gland function returned to normal at a rate of 36.3% in the Amifostine group versus 9.1% in the control group. CONCLUSION Amifostine is effective in reducing the incidence and severity of acute mucositis, acute and late xerostomia in head and neck cancer patients.

Carcinoma, Squamous Cell

radiotherapy

1234266

Identification of NUB1 as a suppressor of mutant Huntingtin toxicity via enhanced protein clearance

Huntington's disease is caused by expanded CAG repeats in HTT, conferring toxic gain of function on mutant HTT (mHTT) protein. Reducing mHTT amounts is postulated as a strategy for therapeutic intervention. We conducted genome-wide RNA interference screens for genes modifying mHTT abundance and identified 13 hits. We tested 10 in vivo in a Drosophila melanogaster Huntington's disease model, and 6 exhibited activity consistent with the in vitro screening results. Among these, negative regulator of ubiquitin-like protein 1 (NUB1) overexpression lowered mHTT in neuronal models and rescued mHTT-induced death. NUB1 reduces mHTT amounts by enhancing polyubiquitination and proteasomal degradation of mHTT protein. The process requires CUL3 and the ubiquitin-like protein NEDD8 necessary for CUL3 activation. As a potential approach to modulating NUB1 for treatment, interferon-β lowered mHTT and rescued neuronal toxicity through induction of NUB1. Thus, we have identified genes modifying endogenous mHTT using high-throughput screening and demonstrate NUB1 as an exemplar entry point for therapeutic intervention of Huntington's disease.

Neurons

metabolism

9608508

Amnion as a surrogate tissue reporter of the effects of maternal preeclampsia on the fetus

BackgroundPreeclampsia, traditionally characterized by high blood pressure and proteinuria, is a common pregnancy complication, which affects 2–8 % of all pregnancies. Although children born to women with preeclampsia have a higher risk of hypertension in later life, the mechanism of this increased risk is unknown. DNA methylation is an epigenetic modification that has been studied as a mediator of cellular memory of adverse exposures in utero. Since each cell type in the body has a unique DNA profile, cell subtype composition is a major confounding factor in studies of tissues with heterogeneous cell types. The best way to avoid this confounding effect is by using purified cell types. However, using purified cell types in large cohort translational studies is difficult. The amnion, the inner layer of the fetal membranes of the placenta, is derived from the epiblast and consists of two cell types, which are easy to isolate from the delivered placenta. In this study, we demonstrate the value of using amnion samples for DNA methylation studies, revealing distinctive patterns between fetuses exposed to proteinuria or hypertension and fetuses from normal pregnancies.ResultsWe performed a genome-wide DNA methylation analysis, HpaII tiny fragment Enrichment by Ligation-mediated PCR (HELP)-tagging, on 62 amnion samples from the placentas of uncomplicated, normal pregnancies and from those with complications of preeclampsia or hypertension. Using a regression model approach, we found 123, 85, and 99 loci with high-confidence hypertension-associated, proteinuria-associated, and hypertension- and proteinuria-associated DNA methylation changes, respectively. A gene ontology analysis showed DNA methylation changes to be selecting genes with different biological processes in exposure status. We also found that these differentially methylated regions overlap loci previously reported as differentially methylated regions in preeclampsia.ConclusionsOur findings support prior observations that preeclampsia is associated with changes of DNA methylation near genes that have previously been found to be dysregulated in preeclampsia. We propose that amniotic membranes represent a valuable surrogate fetal tissue on which to perform epigenome-wide association studies of adverse intrauterine conditions.

Hypertension

genetics

20754695

Dietary factors influencing calcium and bone metabolism: introduction.

Although the nutritional need of calcium for ade quate bone mineralization and maintenance is widely appreciated, the impact of other nutrients on bone health is less understood. Dietary sodium, potassium, phosphate and caffeine are each known to alter calcium metabolism, and thus could potentially affect bone. For example, increases in dietary intakes of sodium and caffeine increase urinary calcium, whereas increased consumption of phosphate and potassium decreases urinary calcium. Concerns have arisen that overly generous consumption of sodium, caffeine and phosphate may be detrimental to bone, as may be low dietary intakes of potassium, especially when dietary calcium intakes are simultaneously in adequate. Although the changes in urinary calcium excretion and calcium metabolism caused by these four dietary factors seem to be small, these small changes over long times of exposure may have a significant impact on bone. For example, Heaney and Recker (1982) noted that "a negative calcium balance of 1.0 mmol/

Calcium

metabolism

34196854

Failure of salt restriction to modify blood pressure in the accelerated phase of primary hypertension.

Excerpt Salt restriction in the treatment of hypertension was first advocated more than a half-century ago.1The subsequent history of this therapeutic measure has been reviewed,2, 3and it has also ...

Hypertension

therapy

22522367

Occupation and lung cancer in two industrialized areas of northern Italy

A population‐based case‐control study on lung cancer was conducted in 2 industrialized areas of northern Italy. Cases (126) were all males who died from lung cancer between 1976 and 1980. Controls (384) were a random sample of males dying from other causes during the same period. Jobs held during working life have been analyzed according to a list of occupations already known to be causally associated with lung cancer (list A) and a list of occupations suspected of being so (list B). Attributable risk percentages in the population for occupations included in either list A or B were about 36% and 12% in the 2 areas. Welders or workers in industries in which welding is common showed elevated odds ratios: 2.9 for welders (95% Cl 0.9–9.8); 4.9 (1.1–22.9) for structural metal workers; 11.4 (2.6–49.9) for workers in structural metal production. Other job categories associated with lung cancer included: electricians and workers in electrical machine production, woodworker (in furniture or cabinet making, but not in carpentry or joinery) and cleaning services. Smoking did not seem to exert a substantial confounding effect. Attributable risk percentages for tobacco smoking were about 78% and 76% in the population of the 2 areas.

Lung Neoplasms

etiology

8600294

Cell, tissue and organ culture as in vitro models to study the biology of squamous cell carcinomas of the head and neck

In vitro models are currently being used to study head and neck squamous cell carcinoma (HNSCC). Several hundred HNSCC cell lines have been established by various investigators and used to study a broad spectrum of questions related to head and neck cancer. The head and neck model with respect to multistage carcinogenesis is now complete. Several techniques exist for the culture of normal epithelial cells from the upper aerodigestive tract (UADT). The biology of these UADT cells (oral cavity, oropharynx, hypopharynx and larynx) is being studied. Successful culture of premalignant lesions (dysplastic mucosa, leukoplakia, erythroplakia) has resulted in establishment of a limited number of premalignant cell lines and cell cultures. HPV infection of normal oral epithelial cells for immortalization (∼ premalignant cells) coupled with transformation with carcinogens (malignant cells) has established an experimental model for progression. Two in vivo models for oral carcinogenesis, the 7,12 dimethylbenz(a)anthracene-induced hamster cheek pouch model and the 4-nitroquinoline-N-oxide rat oral model, have been established in culture. Thus, multistage carcinogenesis models have been established from both human tissues and animal models and include cultures of normal, premalignant and malignant cells. Culture techniques for growing dissociated primary tumor cells for short term experimental analysis are being used. The culture of normal or tumor tissue as organ/explant cultures allows for the maintenance of normal cell-cell and cell-matrix interactions, but limits experimentation since these cultures cannot be propagated. Several three dimensional model systems are being used to obtain this histological complexity but allow for experimentation. The ability to culture normal, premalignant and malignant cells coupled with the use of a variety of culture techniques, should allow for the continued growth and experimentation in head and neck cancer research.

Carcinoma, Squamous Cell

pathology

22943986

Immune complexes, complement, and anti-DNA in exacerbations of systemic lupus erythematosus (SLE).

The usefulness of serological parameters in assessing clinical exacerbations of SLE was examined. Patients with active renal disease tend to have lower levels of CH50 and C3 and highest levels of immune complexes detected by C1qBA than those patients with extrarenal manifestations only. Patients with a combination of both active extrarenal and renal disease are more likely to demonstrate the lowest levels of CH50, C4, and C3. However, immune complex levels are not higher than levels detected in patients with only active nephritis. A normal C3 level argues against active nephritis. Low complement levels without appreciably elevated levels of C1qBA suggest that significant renal disease is unlikely. The serial measurements that best reflect evolving clinical activity and which may serve as markers of impending exacerbation are, in decreasing order of usefulness: C4, CH50, C1qBA, C4, C3 and ADA. However, a combination of CH50, C4, C3 and C1qBA appeared to be the most useful. Given various serologic changes, guidelines for following patients are offered.

DNA

immunology

13626731

The effect of a myocardial infarction on the normalized time-varying elastance curve.

It has been suggested that the shape of the normalized time-varying elastance curve [E(n)(t(n))] is conserved in different cardiac pathologies. We hypothesize, however, that the E(n)(t(n)) differs quantitatively after myocardial infarction (MI). Sprague-Dawley rats (n = 9) were anesthetized, and the left anterior descending coronary artery was ligated to provoke the MI. A sham-operated control group (CTRL) (n = 10) was treated without the MI. Two months later, a conductance catheter was inserted into the left ventricle (LV). The LV pressure and volume were measured and the E(n)(t(n)) derived. Slopes of E(n)(t(n)) during the preejection period (alpha(PEP)), ejection period (alpha(EP)), and their ratio (beta = alpha(EP)/alpha(PEP)) were calculated, together with the characteristic decay time during isovolumic relaxation (tau) and the normalized elastance at end diastole (E(min)(n)). MI provoked significant LV chamber dilatation, thus a loss in cardiac output (-33%), ejection fraction (-40%), and stroke volume (-30%) (P < 0.05). Also, it caused significant calcium increase (17-fold), fibrosis (2-fold), and LV hypertrophy. End-systolic elastance dropped from 0.66 +/- 0.31 mmHg/microl (CTRL) to 0.34 +/- 0.11 mmHg/microl (MI) (P < 0.05). Normalized elastance was significantly reduced in the MI group during the preejection, ejection, and diastolic periods (P < 0.05). The slope of E(n)(t(n)) during the alpha(PEP) and beta were significantly altered after MI (P < 0.05). Furthermore, tau and end-diastolic E(min)(n) were both significantly augmented in the MI group. We conclude that the E(n)(t(n)) differs quantitatively in all phases of the heart cycle, between normal and hearts post-MI. This should be considered when utilizing the single-beat concept.

Myocardial Infarction

physiopathology

7350830

[Clinical evaluation for sublingual immunotherapy of allergic asthma and atopic rhinitis with Dermatophagoides Farinae Drops].

OBJECTIVE To evaluate the safety and efficacy of sublingual immunotherapy with 'Dermatophagoides Farinae Drops' in D. farinae allergic asthma and/or rhinitis patients. METHODS A 25-week double-blind, placebo-controlled, multi-centered trail was conducted in 278 children (aged 4 - 18 yr) with mite-induced asthma and/or rhinitis. Patients were randomly assigned to receive sublingual immunotherapy (SLIT) with 'Dermatophagoides Farinae Drops' (n = 139) or placebo (n = 139) for 25 weeks and the dosage and administration strictly followed the manufacturer's instructions. At the beginning of the 2nd, 3rd, 4th, 6th, 10th, 14th, 18th, 22nd week of the treatment, the patients were asked to accept follow-up visit, during the clinical trial all patients and parents were asked to keep a daily record of their asthma symptom scores, rescue medicine use, rhinitis symptom scores, morning and evening peak expiratory flow. Asthma symptom scores, reduction in use of rescue medicine, rhinitis symptom scores, lung function tests, skin sensitivity to mite, mite-specific immunoglobulin (Ig) E and IgG4, and quality of life and adverse effect were assessed during the study. RESULT (1) Of the 278 children, 27 dropped out before the study completion. (2) After 25 weeks of treatment, the median variability of PEFR was -1.38 for SLIT group and -0.90 for the placebo (P < 0.05). (3) Besides, the mean variability of medicine score of asthma was -0.08 for SLIT group and 0.52 for the plcebo (P < 0.05). (4) The median variability of rhinitis symptom score was -1.96 for SLIT group and -1.03 for the placebo (P < 0.01). (5) The rescue medicine usage of SLIT reduced but did not show significant differences between SLIT and placebo. (6) After 25 weeks treatment, the increase of D. farinae specific IgE antibody of two groups were similar, while specific IgG4 increased significantly in SLIT compared to the patients in control one (P < 0.01); (7) No severe adverse events happened in the trial and the most-likely adverse events were mild asthma and local rash. CONCLUSION Dermatophagoides Farinae Drops is safe and effective in treating allergic asthma and atopic rhinitis.

Asthma

therapy

9273374

Comparison of postoperative intraocular pressure in patients with Densiron-68 vs conventional silicone oil: a case–control study

A solution of perfluorohexyloctane and silicone oil with a specific gravity of 1.06 g/cm3 (Densiron-68) has similar properties as conventional silicone oil (SO) in terms of the shape of the bubble and its ability to act as an internal tamponade agent. We conducted a case–control study to compare the postoperative intraocular pressure (IOP) in patients treated with Densiron-68 with those treated with SO.MethodsSeventy-one eyes of 71 patients and 57 eyes of 57 patients who had received Densiron-68 and SO, respectively, were included in our study. Both groups were found to have matched for their preoperative comorbidities (diabetes, glaucoma, phakic status, and refractive errors). IOP at first day, between seventh and fourteenth day, and at 4 week postoperatively was recorded.ResultsThe mean IOP was higher in patients treated with Densiron-68 at day 1 and between seventh and fourteenth day postoperatively (P=0.05 and 0.01, respectively). By the 4th week, the IOP difference between the two groups was insignificant (P=0.17). The difference in the two groups could still be clinically significant and the raised IOP in Densiron-68 group was more difficult to treat in some cases.On day 1, nine eyes (12.7%) in the Densiron-68 group and two eyes (3.5%) in the SO group had IOP greater than 30 mmHg. At 4 weeks, IOP of more than 30 mmHg was seen in nine eyes (12.7%) in the Densiron-68-treated group and in one eye (1.8%) in the SO group.ConclusionThe use of Densiron-68 was associated with a higher IOP in the early postoperative period when compared with SO.

Postoperative Complications

drug therapy

219755301

Prevalence of type 2 diabetes mellitus (T2DM) in India: A systematic review (1994-2018).

AIM To conduct a systematic and critical review of published studies on prevalence of Type 2 diabetes mellitus (T2DM) in urban and rural areas of India. METHODS We conducted a literature search in PubMed, EMBASE and Web of Science using the terms 'prevalence', 'Type 2 diabetes, 'India', 'urban' and 'rural' for English language articles published during January 1994-December 2018. We selected articles that reported the results of original studies that randomly sampled adults aged 15-80 years, and which reported T2DM prevalence based on the actual examination of blood samples. RESULTS Of 1751 articles screened by titles and abstracts, 37 fulfilled our inclusion criteria. Majority (28 of 37; 76%) of studies were from South India, especially from the states of Tamil Nadu, Andhra Pradesh, Kerala and Karnataka. The prevalence of T2DM showed a wide range from 1.9% to 25.2%. Only 11 studies covering 24 regions separately reported the data by urban or rural location. Albeit inconsistent, 17 studies reported prevalence of T2DM by age group. CONCLUSION In this systematic review, we show that there remains an ambiguity about the actual prevalence of T2DM from India due to several factors. The findings underscore a strong need for having periodic regional surveillance involving appropriate epidemiological methods.

Diabetes Mellitus, Type 2

epidemiology

33657983

Interfaces Between the Detection, Signaling, and Repair of DNA Damage

Left unrepaired, the myriad types of damage that can occur in genomic DNA pose a serious threat to the faithful transmission of the correct complement of genetic material. Defects in DNA damage signaling and repair result in genomic instability, a hallmark of cancer, and often cause lethality, underlining the importance of these processes in the cell and whole organism. The past decade has seen huge advances in our understanding of how the signal transduction pathways triggered by DNA damage radically alter cell behavior. In contrast, it is still unclear how primary DNA damage is detected and how this interfaces with signal transduction and DNA repair proteins.

DNA

metabolism