Optimal control of HIV/AIDS in the workplace in the presence of careless individuals.
A nonlinear dynamical system is proposed and qualitatively analyzed to study the dynamics of HIV/AIDS in the workplace. The disease-free equilibrium point of the model is shown to be locally asymptotically stable if the basic reproductive number, ℛ0, is less than unity and the model is shown to exhibit a unique endemic equilibrium when the basic reproductive number is greater than unity. It is shown that, in the absence of recruitment of infectives, the disease is eradicated when ℛ0 < 1, whiles the disease is shown to persist in the presence of recruitment of infected persons. The basic model is extended to include control efforts aimed at reducing infection, irresponsibility, and nonproductivity at the workplace. This leads to an optimal control problem which is qualitatively analyzed using Pontryagin's Maximum Principle (PMP). Numerical simulation of the resulting optimal control problem is carried out to gain quantitative insights into the implications of the model. The simulation reveals that a multifaceted approach to the fight against the disease is more effective than single control strategies.


Assessing Proprioception: A Systematic Review of Possibilities.
Proprioception is a vital aspect of motor control and when degraded or lost can have a profound impact on function in diverse clinical populations. This systematic review aimed to identify clinically related tools to measure proprioceptive acuity, to classify the construct(s) underpinning the tools, and to report on the clinimetric properties of the tools. We searched key databases with the pertinent search terms, and from an initial list of 935 articles, we identified 57 of relevance. These articles described 32 different tools or methods to quantify proprioception. There was wide variation in methods, the joints able to be tested, and the populations sampled. The predominant construct was active or passive joint position detection, followed by passive motion detection and motion direction discrimination. The clinimetric properties were mostly poorly evaluated or reported. The Rivermead Assessment of Somatosensory Perception was generally considered to be a valid and reliable tool but with low precision; other tools with higher precision are potentially not clinically feasible. Clinicians and clinical researchers can use the summary tables to make more informed decisions about which tool to use to match their predominant requirements. Further discussion and research is needed to produce measures of proprioception that have improved validity and utility.


Flow-specific trends in river-water quality resulting from the effects of the Clean Air Act in three mesoscale, forested river basins in the northeastern United States through 2002.
Two new methods for assessing temporal trends in stream-solute concentrations at specific streamflow ranges were applied to long (40 to 50-year) but sparse (bi-weekly to quarterly sampling) stream-water quality data collected at three forested mesoscale basins along an atmospheric deposition gradient in the northeastern United States (one in north-central Pennsylvania, one in southeastern New York, and one in eastern Maine). The three data sets span the period since the implementation of the Clean Air Act in 1970 and its subsequent amendments. Declining sulfate (O4(2-)) trends since the mid 1960s were identified for all 3 rivers by one or more of the 4 methods of trend detection used. Flow-specific trends were assessed by segmenting the data sets into 3-year and 6-year blocks, then determining concentration-discharge relationships for each block. Declining sulfate (O4(2-)) trends at median flow were similar to trends determined using a Seasonal Kendall Tau test and Sen slope estimator. The trend of declining O4(2-) concentrations differed at high, median and low flow since the mid 1980s at YWC and NR, and at high and low flow at WR, but the trends leveled or reversed at high flow from 1999 through 2002. Trends for the period of record at high flows were similar to medium- and low-flow trends for Ca2++ Mg2+ concentrations at WR, non-significant at YWC, and were more negative at low flow than at high flow at NR; trends in nitrate (NO3-), and alkalinity (ALK) concentrations were different at different flow conditions, and in ways that are consistent with the hydrology and deposition history at each watershed. Quarterly sampling is adequate for assessing average-flow trends in the chemical parameters assessed over long time periods (approximately decades). However, with even a modest effort at sampling a range of flow conditions within each year, trends at specified flows for constituents with strong concentration-discharge relationships can be evaluated and may allow early detection of ecosystem response to climate change and pollution management strategies.


Evaluation of occult gastrointestinal bleeding.
Occult gastrointestinal bleeding is defined as gastrointestinal bleeding that is not visible to the patient or physician, resulting in either a positive fecal occult blood test, or iron deficiency anemia with or without a positive fecal occult blood test. A stepwise evaluation will identify the cause of bleeding in the majority of patients. Esophagogastroduodenoscopy (EGD) and colonoscopy will find the bleeding source in 48 to 71 percent of patients. In patients with recurrent bleeding, repeat EGD and colonoscopy may find missed lesions in 35 percent of those who had negative initial findings. If a cause is not found after EGD and colonoscopy have been performed, capsule endoscopy has a diagnostic yield of 61 to 74 percent. Deep enteroscopy reaches into the mid and distal small bowel to further investigate and treat lesions found during capsule endoscopy or computed tomographic enterography. Evaluation of a patient who has a positive fecal occult blood test without iron deficiency anemia should begin with colonoscopy; asymptomatic patients whose colonoscopic findings are negative do not require further study unless anemia develops. All men and postmenopausal women with iron deficiency anemia, and premenopausal women who have iron deficiency anemia that cannot be explained by heavy menses, should be evaluated for occult gastrointestinal bleeding. Physicians should not attribute a positive fecal occult blood test to low-dose aspirin or anticoagulant medications without further evaluation.


Elucidation of the conformational free energy landscape in H.pylori LuxS and its implications to catalysis.
One of the major challenges in understanding enzyme catalysis is to identify the different conformations and their populations at detailed molecular level in response to ligand binding/environment. A detail description of the ligand induced conformational changes provides meaningful insights into the mechanism of action of enzymes and thus its function. In this study, we have explored the ligand induced conformational changes in H.pylori LuxS and the associated mechanistic features. LuxS, a dimeric protein, produces the precursor (4,5-dihydroxy-2,3-pentanedione) for autoinducer-2 production which is a signalling molecule for bacterial quorum sensing. We have performed molecular dynamics simulations on H.pylori LuxS in its various ligand bound forms and analyzed the simulation trajectories using various techniques including the structure network analysis, free energy evaluation and water dynamics at the active site. The results bring out the mechanistic details such as co-operativity and asymmetry between the two subunits, subtle changes in the conformation as a response to the binding of active and inactive forms of ligands and the population distribution of different conformations in equilibrium. These investigations have enabled us to probe the free energy landscape and identify the corresponding conformations in terms of network parameters. In addition, we have also elucidated the variations in the dynamics of water co-ordination to the Zn2+ ion in LuxS and its relation to the rigidity at the active sites. In this article, we provide details of a novel method for the identification of conformational changes in the different ligand bound states of the protein, evaluation of ligand-induced free energy changes and the biological relevance of our results in the context of LuxS structure-function. The methodology outlined here is highly generalized to illuminate the linkage between structure and function in any protein of known structure.


Is Social Network a Protective Factor for Cognitive Impairment in US Chinese Older Adults? Findings from the PINE Study.
Social network has been identified as a protective factor for cognitive impairment. However, the relationship between social network and global and subdomains of cognitive function remains unclear. This study aims to provide an analytic framework to examine quantity, composition, and quality of social network and investigate the association between social network, global cognition, and cognitive domains among US Chinese older adults. Data were derived from the Population Study of Chinese Elderly (PINE), a community-engaged, population-based epidemiological study of US Chinese older adults aged 60 and above in the greater Chicago area, with a sample size of 3,157. Social network was assessed by network size, volume of contact, proportion kin, proportion female, proportion co-resident, and emotional closeness. Cognitive function was evaluated by global cognition, episodic memory, executive function, working memory, and Chinese Mini-Mental State Examination (C-MMSE). Linear regression and quantile regression were performed. Every 1-point increase in network size (b = 0.048, p < 0.001) and volume of contact (b = 0.049, p < 0.01) and every 1-point decrease in proportion kin (b = -0.240, p < 0.01) and proportion co-resident (b = -0.099, p < 0.05) were associated with higher level of global cognition. Similar trends were observed in specific cognitive domains, including episodic memory, working memory, executive function, and C-MMSE. However, emotional closeness was only significantly associated with C-MMSE (b = 0.076, p < 0.01). Social network has differential effects on female versus male older adults. This study found that social network dimensions have different relationships with global and domains of cognitive function. Quantitative and structural aspects of social network were essential to maintain an optimal level of cognitive function. Qualitative aspects of social network were protective factors for C-MMSE. It is necessary for public health practitioners to consider interventions that enhance different aspects of older adults' social network.


[Reports of domestic, sexual and other forms of violence against children in Brazil].
The scope of this article is to outline the scenario of domestic, sexual and other forms of violence against children (0-9 years old) in Brazil for the year 2010. It is based on data from reports of domestic, sexual and other forms of violence registered with SINAN - Information System for Notifiable Diseases (Continuous VIVA). Absolute and relative numbers are presented, derived from reported violence, discriminating between children under 1 year of age and those between 1-9 years old, due to the specificities that exist in these age groups. Throughout the country, the number of reports among those under 10 years of age is low (17.1%). Differences were found for the distribution of reports in the different Brazilian States. Few municipalities and few services reported violence to SINAN-Net in 2010 in the country. Some differences were found between children under 1 year of age and those between 1 and 9 years of age, as for instance the relationship between the profile of the violence, the victim and the perpetrator, and the handling of the case. The quality of the reported information is discussed showing the high level of unreported data in some spaces of the reporting form. Lack of information may prejudice comprehension of the phenomenon, interfering with the planning, organization and operation actions of the health services in the country.


Eating behaviors and emotional distress are predicted by treatment and adverse outcome in patients with type 2 diabetes.
Depression and anxiety are hightly prevalent among patients with Type 2 Diabetes (T2D), however not commonly related to outcomes, treatment and comorbidities. Eating behaviors could also have an implication. To evaluate the relation between mood and eating behaviors with demographic, physical, treatment, biochemical profiles and chronic comorbidities in T2D we conducted this exploratory cross sectional study in a population from Mexico. Hospital Anxiety and Depression Scale and the Three Factor Eating Questionnaire Revised 21 (TFEQ-R21) were correlated with age, gender, blood pressure, treatment and comorbidities (nephropathy, neuropathy, retinopathy and cardiopathy). Multi-linear regression models and 2k factorial analyses were conducted. Sixty-one patients (31 male) 55 years old (SD 13) with at least 5 years of T2D were included. Anxiety correlated with depression (r = 0.25, p < 0.05). Gender (women) (std B 0.026, p < 0.001), insulin therapy (std B 0.3, p = 0.11), systolic blood pressure (std B 0.263, p = 0.02) and cardiovascular disease (std B 0.232, p = 0.035) predicted depression. Insulin therapy had a positive effect in cognitive restraint. (std B 0.32, p = 0.001). Age (std B 0.37, p = 0.003) and systolic blood pressure (std B 0.237, p = 0.048) predicted positively emotional eating (not previously published). 2k factorial analyses proved additive interaction between complications and insulin therapy with depression. This study supports the relation between mood disorders and eating behaviors with demographic, physical, treatment, biochemical profiles and chronic comorbidities in T2D and the additive interaction between factors and mood disorders.


[Kidney involvement in rheumatoid arthritis].
Rheumatoid Arthritis (RA) is a widespread disease and its renal involvement, relatively common, is clinically significant because worsens course and mortality of the primary disease. There is still no agreement on the prevalence of renal disorders in RA: data analysis originates from different sources, as death certificates, autopsies, clinical and laboratory findings and kidney biopsies, each with its limitations. Histoimmunological studies on bioptical specimens of patients with RA and kidney damage, led to clarify prevalent pathologies. In order of frequency: glomerulonephritis and amyloidosis (60-65% and 20-30% respectively), followed by acute or chronic interstitial nephritis. Kidney injury during RA includes secondary renal amyloidosis, nephrotoxic effects of antirheumatic drugs and nephropathies as extra-articular manifestations (rheumatoid nephropathy). Amyloidosis affects survival, increases morbidity and is the main cause of end stage renal disease in patients with RA and nephropathy. Strong association between RA activity and amyloidosis needs the use of immunosuppressive and combined therapies, to prevent this complication and reduce risk of dialysis. Long-lasting and combined RA pharmacotherapy involves various renal side effects. In this review we describe NSAIDs and DMARDs (Disease-Modifying Antirheumatic Drugs) nephrotoxicity, particularly by gold compounds, D-penicillamine, cyclosporine A and methotrexate. Rare cases of IgA glomerulonephritis during immunomodulating therapy with leflunomide and TNF blocking receptor (etanercept) are reported; real clinical significance of this drug-related nephropathy will be established by development of RA treatment. In RA nephropathies, mesangial glomerulonephritis is the most frequent histological lesion (35-60 % out of biopsies from patients with urinary abnormalities and/or kidney impairment), followed by minimal change glomerulopathy (3-14%) and p-ANCA positive necrotizing crescentic glomerulonephritis.


Efficacy and Safety of Ferric Carboxymaltose and Other Formulations in Iron-Deficient Patients: A Systematic Review and Network Meta-analysis of Randomised Controlled Trials.
Iron deficiency is very common in a number of medical conditions. Ferric carboxymaltose is a new stable iron preparation that can be administered in single infusions over short periods of time. The aim of this study was to conduct a systematic review of randomised controlled trials (RCTs) regarding the efficacy and safety of the novel complex compared with other iron formulations. In addition, the feasibility of a network meta-analysis for indirect comparisons was investigated. A systematic literature review was performed for published RCTs on the use of ferric carboxymaltose in iron deficiency between July and October 2014. Indirect comparisons were also addressed using terms referring to competing iron formulations. We further supported the qualitative results of the systematic review by a network meta-analysis that allows pooling the evidence around different intervention outcomes in the absence of trials involving a direct comparison. The initial search yielded 1027 citations, which was decreased to 21 studies eligible for inclusion in the review. Studies were heterogeneous in the number of patients randomised, iron deficiency-related conditions addressed, trial inclusion criteria, time horizon, treatment dosage and outcomes assessed. Six studies with the same time horizon (i.e. 6 weeks) were included in the network meta-analysis. Considering the differences between final and initial outcome values for each iron formulation, the mean difference of these differences (delta) was estimated for each couple of treatments involving ferric carboxymaltose. Significant improvements in serum ferritin (µg/l) were obtained with ferric carboxymaltose compared to oral iron (delta 172.8; 95 % CI 66.7-234.4) and in haemoglobin (g/dl) with respect to ferric gluconate (delta 0.6; 95 % CI 0.2-0.9), oral iron (delta 0.8; 95 % CI 0.6-0.9) and placebo (delta 2.1; 95 % CI 1.2-3.0). All currently available intravenous iron preparations appear to be safe and effective, but ferric carboxymaltose seems to provide a better and quicker correction of haemoglobin and serum ferritin levels in iron-deficient patients.


Developing a conceptual framework for an evaluation system for the NIAID HIV/AIDS clinical trials networks.
Globally, health research organizations are called upon to re-examine their policies and practices to more efficiently and effectively address current scientific and social needs, as well as increasing public demands for accountability.Through a case study approach, the authors examine an effort undertaken by the National Institute of Allergy & Infectious Diseases (part of the National Institutes of Health, Department of Health & Human Services, United States Government) to develop an evaluation system for its recently restructured HIV/AIDS clinical trials program. The challenges in designing, operationalizing, and managing global clinical trials programs are considered in the context of large scale scientific research initiatives.Through a process of extensive stakeholder input, a framework of success factors was developed that enables both a prospective view of the elements that must be addressed in an evaluation of this research and a current state assessment of the extent to which the goals of the restructuring are understood by stakeholders across the DAIDS clinical research networks.


Differential effects of theaflavin monogallates on cell growth, apoptosis, and Cox-2 gene expression in cancerous versus normal cells.
Theaflavin (TF-1), theaflavin-3-monogallate and theaflavin-3'-monogallate mixture (TF-2), and theaflavin-3,3'-digallate (TF-3) are the major black tea polyphenols. Here we compared the effects of these polyphenols on cell growth, apoptosis, and gene expression in normal and cancerous cells. We showed that TF-2 (10-50 microM) inhibited the growth of SV40 transformed WI38 human cells (WI38VA) and Caco-2 colon cancer cells but had little effect on the growth of their normal counterparts. The IC50s of TF-2 for the growth inhibition of WI38 and WI38VA cells were, respectively, 300 and 3 microM. The other two black tea polyphenols, TF-1 and TF-3, did not exhibit such differential growth-inhibitory effect. TF-2, but not TF-1 or TF-3, induced apoptosis in transformed WI38VA cells but not in normal WI38 cells, suggesting that apoptosis was responsible, at least in part, for the differential growth-inhibitory effect of TF-2. Cox-2 has been implicated in intestinal carcinogenesis. Among the tea polyphenols tested, TF-2 and, to a lesser degree, (-)-epigallocatechin gallate inhibited cyclooxygenase (Cox)-2 gene expression. TF-2 at 50 microM completely blocked the serum-induced Cox-2 gene expression at both mRNA and protein level. Other genes, including c-fos, c-myc, thymidine kinase, proliferating cell nuclear antigen, BRCA1, BRCA2, and Cox-1, were not significantly affected by TF-2. These findings suggest that TF-2 may be responsible, at least in part, for the chemopreventive activity in black tea extracts.


The evolution of guideline-directed medical therapy among decompensated HFrEF patients in sacubitril/valsartan era: Medical expenses and clinical effectiveness.
Over recent years, new evolution in guideline-directed medical therapy (GDMT) contributes to clinical benefits in patients with heart failure and reduced ejection fraction (HFrEF). The additional medical expenditure may be a concern due to the current financial constraint. This study aimed to investigate the medical costs and clinical effectiveness of contemporary GDMT in recently hospitalized HFrEF patients. Acutely decompensated hospitalized HFrEF patients from two multicenter cohorts of different periods were retrospectively analyzed. A propensity score matching was performed to adjust the baseline characteristics. Annual medication costs, risks of mortality, and recurrent heart failure hospitalizations (HFH) were compared. Following 1:2 propensity score matching, there were 426 patients from the 2017-2018 cohort using sacubitril/valsartan, while 852 patients from 2013 to 2014 did not use so at discharge. Baseline characteristics were similar, whereas the sacubitril/valsartan users were more likely to receive beta-blockers, ivabradine and mineralocorticoid receptor antagonists at discharge (79.3% vs 60.4%, 23.2% vs 0%, and 64.1% vs 49.8%, p < 0.001). The 2017-2018 cohort produced more medication costs by 1277 United States dollar (USD) per person per year, while it resulted in lower rates of HFH and all-cause mortality (10.3 vs 20.3 and 48.8 vs 79.9 per 100 person-year, p < 0.001). Costs of preventing a mortality event and a HFH event with contemporary treatments were 15 758 USD (95% confidence interval [CI] 10 436-29 244) and 5317 USD (95% CI 3388-10 098), respectively. The higher adoption of GDMT was associated with greater medical expenses but better clinical outcomes in recently decompensated HFrEF patients.


Surgical treatment of giant pyogenic granuloma of the upper eyelid.
Pyogenic granuloma (PG), also known as lobular capillary hemangioma, is a benign acquired vascular lesion of the skin and mucous membranes. Diagnosis is aided by history of surgery, trauma or inflammation and characteristic clinical appearance, whereas, definitive diagnosis is made by histopathologic findings. PG is most often located on the head, neck, extremities, and upper trunk. From an ophthalmic perspective, a PG may be located on the eyelids, conjunctiva or rarely on the cornea. We present a case of surgically treated giant pyogenic granuloma of the upper eyelid, and we describe a technique of reconstruction of the upper eyelid skin by bilateral advancement flaps that allows the coverage of small- to medium-sized defects of this region with satisfactory esthetic and functional results.


The C-Type Lectin Receptor SIGNR3 Binds to Fungi Present in Commensal Microbiota and Influences Immune Regulation in Experimental Colitis.
Inflammatory bowel disease is a condition of acute and chronic inflammation of the gut. An important factor contributing to pathogenesis is a dysregulated mucosal immunity against commensal bacteria and fungi. Host pattern-recognition receptors (PRRs) sense commensals in the gut and are involved in maintaining the balance between controlled responses to pathogens and overwhelming innate immune activation. C-type lectin receptors (CLRs) are PRRs recognizing glycan structures on pathogens and self-antigens. Here we examined the role of the murine CLR specific intracellular adhesion molecule-3 grabbing non-integrin homolog-related 3 (SIGNR3) in the recognition of commensals and its involvement in intestinal immunity. SIGNR3 is the closest murine homolog of the human dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) receptor recognizing similar carbohydrate ligands such as terminal fucose or high-mannose glycans. We discovered that SIGNR3 recognizes fungi present in the commensal microbiota. To analyze whether this interaction impacts the intestinal immunity against microbiota, the dextran sulfate sodium-induced colitis model was employed. SIGNR3(-/-) mice exhibited an increased weight loss associated with more severe colitis symptoms compared to wild-type control mice. The increased inflammation in SIGNR3(-/-) mice was accompanied by a higher level of TNF-α in colon. Our findings demonstrate for the first time that SIGNR3 recognizes intestinal fungi and has an immune regulatory role in colitis.


Natural products from resurrection plants: potential for medical applications.
Resurrection species are a group of land plants that can tolerate extreme desiccation of their vegetative tissues during harsh drought stress, and still quickly - often within hours - regain normal physiological and metabolic functions following rehydration. At the molecular level, this desiccation tolerance is attributed to basal cellular mechanisms including the constitutive expression of stress-associated genes and high levels of protective metabolites present already in the absence of stress, as well as to transcriptome and metabolome reconfigurations rapidly occurring during the initial phases of drought stress. Parts of this response are conferred by unique metabolites, including a diverse array of sugars, phenolic compounds, and polyols, some of which accumulate to high concentrations within the plant cell. In addition to drought stress, these metabolites are proposed to contribute to the protection against other abiotic stresses and to an increased oxidative stress tolerance. Recently, extracts of resurrection species and particular secondary metabolites therein were reported to display biological activities of importance to medicine, with e.g. antibacterial, anticancer, antifungal, and antiviral activities, rendering them possible candidates for the development of novel drug substances as well as for cosmetics. Herein, we provide an overview of the metabolite composition of resurrection species, summarize the latest reports related to the use of natural products from resurrection plants, and outline their potential for medical applications.


Regulation of expression of human RNA polymerase II-transcribed snRNA genes.
In addition to protein-coding genes, RNA polymerase II (pol II) transcribes numerous genes for non-coding RNAs, including the small-nuclear (sn)RNA genes. snRNAs are an important class of non-coding RNAs, several of which are involved in pre-mRNA splicing. The molecular mechanisms underlying expression of human pol II-transcribed snRNA genes are less well characterized than for protein-coding genes and there are important differences in expression of these two gene types. Here, we review the DNA features and proteins required for efficient transcription of snRNA genes and co-transcriptional 3' end formation of the transcripts.


Integration with the human genome of peptide sequences obtained by high-throughput mass spectrometry.
A crucial aim upon the completion of the human genome is the verification and functional annotation of all predicted genes and their protein products. Here we describe the mapping of peptides derived from accurate interpretations of protein tandem mass spectrometry (MS) data to eukaryotic genomes and the generation of an expandable resource for integration of data from many diverse proteomics experiments. Furthermore, we demonstrate that peptide identifications obtained from high-throughput proteomics can be integrated on a large scale with the human genome. This resource could serve as an expandable repository for MS-derived proteome information.


Planning for the information age: a survey of microcomputer use in a faculty of health sciences.
Microcomputers can greatly enhance information processing by clinicians and improve the quality of health care. We surveyed 983 full- and part-time faculty members to assess the state of microcomputer use in the Faculty of Health Sciences at McMaster University, Hamilton, Ont. The ratio of faculty members to microcomputers was close to 1; however, 29% of the full-time and 52% of the part-time members who responded indicated that they did not use a computer. Among those who did, the range of applications was generally limited. There was no mention of more advanced uses such as diagnosis, treatment and patient records. Only about 30% of the respondents had taken a computer course, but all indicated a desire to take courses (on average, three of the seven listed in the questionnaire). Our results showed an extensive but unequal distribution of microcomputers and revealed the need for planning and education to put them to optimal use.


Recombination networks as genetic markers in a human variation study of the Old World.
We have analyzed human genetic diversity in 33 Old World populations including 23 populations obtained through Genographic Project studies. A set of 1,536 SNPs in five X chromosome regions were genotyped in 1,288 individuals (mostly males). We use a novel analysis employing subARG network construction with recombining chromosomal segments. Here, a subARG is constructed independently for each of five gene-free regions across the X chromosome, and the results are aggregated across them. For PCA, MDS and ancestry inference with STRUCTURE, the subARG is processed to obtain feature vectors of samples and pairwise distances between samples. The observed population structure, estimated from the five short X chromosomal segments, supports genome-wide frequency-based analyses: African populations show higher genetic diversity, and the general trend of shared variation is seen across the globe from Africa through Middle East, Europe, Central Asia, Southeast Asia, and East Asia in broad patterns. The recombinational analysis was also compared with established methods based on SNPs and haplotypes. For haplotypes, we also employed a fixed-length approach based on information-content optimization. Our recombinational analysis suggested a southern migration route out of Africa, and it also supports a single, rapid human expansion from Africa to East Asia through South Asia.


Cytokine fields and the polarization of the immune response.
Certain cells that participate in the immune response are known to become polarized in their production of cytokines. It is postulated that, after initial polarization at the site of antigenic encounter, the different types of cell arriving at this site are induced to conform to the local cytokine field, implying that they share common regulatory circuits. As they migrate, these cells might, in turn, spread the particular cytokine field. Therefore, the field is 'infectious' in nature. Propagation of the cytokine field must be regulated somehow. The invasion of the cytokine field into an organ or the entire body could have major immunological consequences.


[Retroperitoneal renal hemorrhage: experience of our dialysis center].
The aging of the uremic population, the increasingly common use of anticoagulants, antiplatelet agents e heparin, during hemodialysis, can expose our patients to a greatest risk of bleeding. Spontaneous retroperitoneal hematomas are a fairly rare and potentially fatal condition. We describe 5 clinical cases of retroperitoneal hemorrhage that we observed during 10 years in our department, focusing on modalities of symptom onset, clinical-laboratory picture and treatment modalities.


Effects of self-monitored jogging on physical fitness, blood pressure and serum lipids: a controlled study in sedentary middle-aged men.
To study the effects of long-term, home-based exercise on physical fitness and cardiovascular risk factors of middle-aged nonsmoking males, a controlled study was conducted in 61 sedentary Swiss men. Thirty-nine men were randomly allocated to jog 2 h/week for 4 months on an individually prescribed and heart-rate-controlled basis, whereas 22 men served as controls. Despite varying adherence to the exercise regimen, the 4-month net change (effect in exercise group minus effect in control group) in estimated endurance capacity was significant and positive. Net changes in arterial blood pressure, measured with a random-zero device, were nonsignificant, but after exclusion of low-normotensive men (n = 19) from analysis, a significant net effect of exercise on diastolic blood pressure was seen (-4.3 mmHg; p = .048). The following net changes in serum lipid levels occurred: HDL cholesterol + 0.12 mmol/l (p = .028), total triglycerides -0.21 mmol/l (ns), HDL-C/total cholesterol ratio +0.02 (p = .047). Exploratory analyses revealed that an increase in estimated endurance capacity was associated with a rise in systolic and diastolic blood pressure (r = 0.49 and 0.43, respectively; p less than 0.01 both). Changes in the waist-hip ratio were directly related to the change in diastolic blood pressure (r = 0.27; p less than 0.05). Multivariable analysis indicated that much of the beneficial effect of exercise on diastolic blood pressure was apparently mediated through a decrease in body fat. This study confirms that individually prescribed jogging can reduce cardiovascular risk factors in self-selected nonsmoking males.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of Low-Dose Gestational TCDD Exposure on Behavior and on Hippocampal Neuron Morphology and Gene Expression in Mice.
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent and toxic environmental pollutant. Gestational exposure to TCDD has been linked to cognitive and motor deficits, and increased incidence of autism spectrum disorder (ASD) traits in children. Most animal studies of these neurodevelopmental effects involve acute TCDD exposure, which does not model typical exposure in humans. The aim of the study was to establish a dietary low-dose gestational TCDD exposure protocol and performed an initial characterization of the effects on offspring behavior, neurodevelopmental phenotypes, and gene expression. Throughout gestation, pregnant C57BL/6J mice were fed a diet containing a low dose of TCDD (9 ng TCDD/kg body weight per day) or a control diet. The offspring were tested in a battery of behavioral tests, and structural brain alterations were investigated by magnetic resonance imaging. The dendritic morphology of pyramidal neurons in the hippocampal Cornu Ammonis (CA)1 area was analyzed. RNA sequencing was performed on hippocampi of postnatal day 14 TCDD-exposed and control offspring. TCDD-exposed females displayed subtle deficits in motor coordination and reversal learning. Volumetric difference between diet groups were observed in regions of the hippocampal formation, mammillary bodies, and cerebellum, alongside higher dendritic arborization of pyramidal neurons in the hippocampal CA1 region of TCDD-exposed females. RNA-seq analysis identified 405 differentially expressed genes in the hippocampus, enriched for genes with functions in regulation of microtubules, axon guidance, extracellular matrix, and genes regulated by SMAD3. Exposure to 9 ng TCDD/kg body weight per day throughout gestation was sufficient to cause specific behavioral and structural brain phenotypes in offspring. Our data suggest that alterations in SMAD3-regulated microtubule polymerization in the developing postnatal hippocampus may lead to an abnormal morphology of neuronal dendrites that persists into adulthood. These findings show that environmental low-dose gestational exposure to TCDD can have significant, long-term impacts on brain development and function. https://doi.org/10.1289/EHP7352.


Maternal smoking, biofuel smoke exposure and child height-for-age in seven developing countries.
Children are at high risk of exposure to environmental tobacco smoke and biofuel smoke at home in developing countries. This study examines whether exposure to cigarette and biofuel smoke is associated with height-for-age of children (0-59 months) in seven developing countries. The data are from Demographic and Health Surveys conducted in Cambodia, Dominican Republic, Haiti, Jordan, Moldova, Namibia and Nepal between 2005 and 2007. The respondents were women (15-49 years) and their children in seven countries (n = 28 439), and men (15-59 years) from four countries. The outcome is a physical measurement of child height-for-age in standard deviation units. Multilevel regression analysis showed that the country of residence modified the association between maternal smoking and child height-for-age. Exposure to maternal smoking was associated negatively with child height-for-age in Cambodia, Namibia and Nepal, whereas it was not in other countries. Multilevel regression analysis revealed that biofuel smoke exposure was associated with a decrease in child height-for-age [b = -0.13, 95% confidence interval (CI) = -0.19 to -0.07, P < 0.001]. No interaction was found between country of residence and biofuel smoke exposure. Multinomial logistic regression results showed that biofuel smoke exposure was associated with both stunting [odds ratio (OR) = 1.25, 95% CI = 1.08-1.44, P = 0.002) and severe stunting (OR = 1.27, 95% CI = 1.02-1.59, P = 0.04), after controlling for covariates. The findings suggest that exposure to maternal smoking and biofuel smoke may contribute to growth deficiencies in young children. Programmes are needed to ensure smoke-free home environments for children.


ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis.
ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice; however, the underlying molecular mechanisms remain unclear. We report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromatid segregation and regulate gene expression. Loss of Asxl1 impairs the cohesin function, as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. Chromatin immunoprecipitation followed by DNA sequencing data revealed that ASXL1, RAD21, and SMC1A share 93% of genomic binding sites at promoter regions in Lin-cKit+ (LK) cells. We have shown that loss of Asxl1 reduces the genome binding of RAD21 and SMC1A and alters the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and regulate gene expression in hematopoietic cells.


Principles and Considerations in the Early Identification and Prehospital Treatment of Thrombocytopenia.
Thrombocytopenia is a common condition characterized by a low platelet count, typically less than 150,000/µL. This article outlines key considerations for field medical providers to effectively identify the early signs of thrombocytopenia and treat different etiologies in the prehospital environment. Following a representative case study, we present a review of basic pathophysiology to include different manifestations of thrombocytopenia as well as diagnostic methods, treatments, and other necessary interventions in this unique setting. With an adequate understanding of typical patient histories and physical presentations leading to this diagnosis, field medics and physicians can be armed with useful information to potentially improve patient outcomes.


P-TEFb: Finding its ways to release promoter-proximally paused RNA polymerase II.
The release of a paused Pol II depends on the recruitment of P-TEFb. Recent studies showed that both active P-TEFb and inactive P-TEFb (7SK snRNP) can be recruited to the promoter regions of global genes by different mechanisms. Here, we summarize the recent advances on these distinct recruitment mechanisms.


Discovery of Compound A--a selective activator of the glucocorticoid receptor with anti-inflammatory and anti-cancer activity.
Glucocorticoids are among the most effective anti-inflammatory drugs, and are widely used for cancer therapy. Unfortunately, chronic treatment with glucocorticoids results in multiple side effects. Thus, there was an intensive search for selective glucocorticoid receptor (GR) activators (SEGRA), which retain therapeutic potential of glucocorticoids, but with fewer adverse effects. GR regulates gene expression by transactivation (TA), by binding as homodimer to gene promoters, or transrepression (TR), via diverse mechanisms including negative interaction between monomeric GR and other transcription factors. It is well accepted that metabolic and atrophogenic effects of glucocorticoids are mediated by GR TA. Here we summarized the results of extensive international collaboration that led to discovery and characterization of Compound A (CpdA), a unique SEGRA with a proven "dissociating" GR ligand profile, preventing GR dimerization and shifting GR activity towards TR both in vitro and in vivo. We outlined here the unusual story of compound's discovery, and presented a comprehensive overview of CpdA ligand properties, its anti-inflammatory effects in numerous animal models of inflammation and autoimmune diseases, as well as its anti-cancer effects. Finally, we presented mechanistic analysis of CpdA and glucocorticoid effects in skin, muscle, bone, and regulation of glucose and fat metabolism to explain decreased CpdA side effects compared to glucocorticoids. Overall, the results obtained by our and other laboratories underline translational potential of CpdA and its derivatives for treatment of inflammation, autoimmune diseases and cancer.


Seasonal childhood anaemia in West Africa is associated with the haptoglobin 2-2 genotype.
Anaemia is a major cause of morbidity and mortality for children in Africa. The plasma protein haptoglobin (Hp) binds avidly to free haemoglobin released following malaria-induced haemolysis. Haptoglobin polymorphisms result in proteins with altered haemoglobin-binding capacity and different antioxidant, iron-recycling, and immune functions. Previous studies examined the importance of haptoglobin polymorphism in malaria and iron homeostasis, but it is unknown whether haptoglobin genotype might be a risk factor for anaemia in children in a malaria-endemic area. A cohort of 780 rural Gambian children aged 2-6 y was surveyed at the start and end of the malaria season. Samples were taken to assess haemoglobin (Hb) concentration, iron status (ferritin, zinc protoporphyrin, transferrin saturation, and soluble transferrin receptor concentration), haptoglobin concentration, alpha-1-antichymotrypsin (a measure of inflammation), and malaria parasites on blood film. We extracted DNA and genotyped for haptoglobin, sickle cell, and glucose-6-phosphate (G6PD) deficiency. Mean Hb levels fell over the malaria season. Children with the haptoglobin 2-2 genotype (17%) had a greater mean drop in Hb level over the malaria season (an 8.9 g/l drop; confidence interval [CI] 5.7, 12.1) compared to other children (a 5.1 g/l drop; CI 3.8, 6.4). In multivariate regression analysis, controlling for baseline Hb level, age group, village, malaria parasites on blood film, iron status, haptoglobin concentration, and G6PD deficiency, haptoglobin genotype predicted Hb level at the end of the malaria season (p = 0.0009, coefficient = -4.2). Iron status was not influenced by haptoglobin genotype. The finding that haptoglobin 2-2 genotype is a risk factor for anaemia in children in a malaria-endemic area may reflect the reduced ability of the Hp2-2 polymer to scavenge free haemoglobin-iron following malaria-induced haemolysis. The magnitude of the effect of haptoglobin genotype (4 g/l Hb difference, p = 0.0009) was comparable to that of G6PD deficiency or HbAS (3 g/l difference, p = 0.03; and 2 g/l difference, p = 0.68, respectively).


GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy.
Radiotherapy is one of the curative treatment options for localized prostate cancer (PCa). The curative potential of radiotherapy is mediated by irradiation-induced oxidative stress and DNA damage in tumor cells. However, PCa radiocurability can be impeded by tumor resistance mechanisms and normal tissue toxicity. Metabolic reprogramming is one of the major hallmarks of tumor progression and therapy resistance. Specific metabolic features of PCa might serve as therapeutic targets for tumor radiosensitization and as biomarkers for identifying the patients most likely to respond to radiotherapy. The study aimed to characterize a potential role of glutaminase (GLS)-driven glutamine catabolism as a prognostic biomarker and a therapeutic target for PCa radiosensitization. Methods: We analyzed primary cell cultures and radioresistant (RR) derivatives of the conventional PCa cell lines by gene expression and metabolic assays to identify the molecular traits associated with radiation resistance. Relative radiosensitivity of the cell lines and primary cell cultures were analyzed by 2-D and 3-D clonogenic analyses. Targeting of glutamine (Gln) metabolism was achieved by Gln starvation, gene knockdown, and chemical inhibition. Activation of the DNA damage response (DDR) and autophagy was assessed by gene expression, western blotting, and fluorescence microscopy. Reactive oxygen species (ROS) and the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) were analyzed by fluorescence and luminescence probes, respectively. Cancer stem cell (CSC) properties were investigated by sphere-forming assay, CSC marker analysis, and in vivo limiting dilution assays. Single circulating tumor cells (CTCs) isolated from the blood of PCa patients were analyzed by array comparative genome hybridization. Expression levels of the GLS1 and MYC gene in tumor tissues and amino acid concentrations in blood plasma were correlated to a progression-free survival in PCa patients. Results: Here, we found that radioresistant PCa cells and prostate CSCs have a high glutamine demand. GLS-driven catabolism of glutamine serves not only for energy production but also for the maintenance of the redox state. Consequently, glutamine depletion or inhibition of critical regulators of glutamine utilization, such as GLS and the transcription factor MYC results in PCa radiosensitization. On the contrary, we found that a combination of glutamine metabolism inhibitors with irradiation does not cause toxic effects on nonmalignant prostate cells. Glutamine catabolism contributes to the maintenance of CSCs through regulation of the alpha-ketoglutarate (α-KG)-dependent chromatin-modifying dioxygenase. The lack of glutamine results in the inhibition of CSCs with a high aldehyde dehydrogenase (ALDH) activity, decreases the frequency of the CSC populations in vivo and reduces tumor formation in xenograft mouse models. Moreover, this study shows that activation of the ATG5-mediated autophagy in response to a lack of glutamine is a tumor survival strategy to withstand radiation-mediated cell damage. In combination with autophagy inhibition, the blockade of glutamine metabolism might be a promising strategy for PCa radiosensitization. High blood levels of glutamine in PCa patients significantly correlate with a shorter prostate-specific antigen (PSA) doubling time. Furthermore, high expression of critical regulators of glutamine metabolism, GLS1 and MYC, is significantly associated with a decreased progression-free survival in PCa patients treated with radiotherapy. Conclusions: Our findings demonstrate that GLS-driven glutaminolysis is a prognostic biomarker and therapeutic target for PCa radiosensitization.


Steered molecular dynamics simulation on the binding of NNRTI to HIV-1 RT.
HIV-1 reverse transcriptase (RT) is the primary target for anti-AIDS chemotherapy. Nonnucleoside RT inhibitors (NNRTIs) are very potent and most promising anti-AIDS drugs that specifically inhibit HIV-1 RT. The binding and unbinding processes of alpha-APA, an NNRTI, have been studied using nanosecond conventional molecular dynamics and steered molecular dynamics simulations. The simulation results show that the unbinding process of alpha-APA consists of three phases based on the position of alpha-APA in relation to the entrance of the binding pocket. When alpha-APA is bound in the binding pocket, the hydrophobic interactions between HIV-1 RT and alpha-APA dominate the binding; however, the hydrophilic interactions (both direct and water-bridged hydrogen bonds) also contribute to the stabilizing forces. Whereas Tyr-181 makes significant hydrophobic interactions with alpha-APA, Tyr-188 forms a strong hydrogen bond with the acylamino group (N14) of alpha-APA. These two residues have very flexible side chains and appear to act as two "flexible clamps" discouraging alpha-APA to dissociate from the binding pocket. At the pocket entrance, two relatively inflexible residues, Val-179 and Leu-100, gauge the openness of the entrance and form the bottleneck of the inhibitor-unbinding pathway. Two special water molecules at the pocket entrance appear to play important roles in inhibitor recognition of binding and unbinding. These water molecules form water bridges between the polar groups of the inhibitor and the residues around the entrance, and between the polar groups of the inhibitor themselves. The water-bridged interactions not only induce the inhibitor to adopt an energetically favorable conformation so the inhibitor can pass through the pocket entrance, but also stabilize the binding of the inhibitor in the pocket to prevent the inhibitor's dissociation. The complementary steered molecular dynamics and conventional molecular dynamics simulation results strongly support the hypothesis that NNRTIs inhibit HIV-1 RT polymerization activity by enlarging the DNA-binding cleft and restricting the flexibility and mobility of the p66 thumb subdomain that are believed to be essential during DNA translocation and polymerization.


Ferrocene-decorated nanocrystalline cellulose with charge carrier mobility.
Ferrocene-decorated cellulose nanowhiskers were prepared by the grafting of ethynylferrocene onto azide functionalized cotton-derived cellulose nanowhiskers using azide-alkyne cycloaddition. Successful surface modification and retention of the crystalline morphology of the nanocrystals was confirmed by elemental analysis, inductively coupled plasma-atomic emission spectroscopy, X-ray photoelectron spectroscopy, and X-ray diffraction. The coverage with ferrocenyl is high (approximately 1.14 × 10(-3) mol g(-1) or 4.6 × 10(13) mol cm(-2) corresponding to a specific area of 61 Å(2) per ferrocene). Cyclic voltammetry measurements of films formed by deposition of ferrocene-decorated nanowhiskers showed that this small spacing of redox centers along the nanowhisker surface allowed conduction hopping of electrons. The apparent diffusion coefficient for electron (or hole) hopping via Fe(III/II) surface sites is estimated as Dapp = 10(-19) m(2)s(-1) via impedance methods, a value significantly less than nonsolvated ferrocene polymers, which would be expected as the 1,2,3-triazole ring forms a rigid linker tethering the ferrocene to the nanowhisker surface. In part, this is believed to be also due to "bottleneck" diffusion of charges across contact points where individual cellulose nanowhiskers contact each other. However, the charge-communication across the nanocrystal surface opens up the potential for use of cellulose nanocrystals as a charge percolation template for the preparation of conducting films via covalent surface modification (with applications similar to those using adsorbed conducting polymers), for use in bioelectrochemical devices to gently transfer and remove electrons without the need for a solution-soluble redox mediator, or for the fabrication of three-dimensional self-assembled conducting networks.


Laminin β2 variants associated with isolated nephropathy that impact matrix regulation.
Mutations in LAMB2, encoding laminin β2, cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense mutations that have been identified affect primarily the N-terminus of laminin β2. On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the β2 LEa-LF-LEb domains are exclusively found in cases with isolated nephropathy. Here we report the clinical features of mild isolated nephropathy associated with 3 LAMB2 variants in the LEa-LF-LEb domains (p.R469Q, p.G699R, and p.R1078C) and their biochemical characterization. Although Pierson syndrome missense mutations often inhibit laminin β2 secretion, the 3 recombinant variants were secreted as efficiently as WT. However, the β2 variants lost pH dependency for heparin binding, resulting in aberrant binding under physiologic conditions. This suggests that the binding of laminin β2 to negatively charged molecules is involved in glomerular basement membrane (GBM) permselectivity. Moreover, the excessive binding of the β2 variants to other laminins appears to lead to their increased deposition in the GBM. Laminin β2 also serves as a potentially novel cell-adhesive ligand for integrin α4β1. Our findings define biochemical functions of laminin β2 variants influencing glomerular filtration that may underlie the pathogenesis of isolated nephropathy caused by LAMB2 abnormalities.


Parameter estimation by descent and genetic algorithm methods of an in-vitro stenosis bypass model.
The development of improved hemodynamic impedance models can greatly aid the understanding of arterial disease progression and its remediation. This paper leverages the recent progress in advanced manufacturing techniques to engage in in-vitro experimentation with physiologically relevant geometries and flows that correspond to arterial stenosis. The measurements of pressures and flow obtained by these experiments were then used to estimate flow-to-pressure transfer functions, aimed at determining a lumped-parameter impedance model of the physical system, by applying conventional descent as well as recently developed Genetic Algorithm methods. The resulting transfer functions can now be utilized for further studies with regard to the hemodynamics relevant to arterial stenosis.


Novel germline GJA5/connexin40 mutations associated with lone atrial fibrillation impair gap junctional intercellular communication.
Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia worldwide. Here, we investigate the molecular and cellular mechanisms of lone AF-linked germline mutations in the connexin40 (Cx40) gene, GJA5. The entire coding region of GJA5 was sequenced in 68 unrelated patients with lone AF. A novel germline heterozygous missense mutation in Cx40 (p.I75F) was identified in one index patient. The mutation was also present in the proband's father with lone AF but was not found in the unaffected family members who were examined and 200 unrelated healthy control individuals. Electrophysiological studies revealed no electrical coupling of the cell pairs expressing the mutant alone and a significant reduction in gap junction coupling conductance when the mutant was coexpressed with wild-type (wt) Cx40 or Cx43. Interestingly, another lone AF-linked Cx40 mutant p.L229M did not show any apparent coupling defect when expressed alone or together with wt Cx40 but specifically reduced the gap junction coupling when coexpressed with wt Cx43. This study is the first to demonstrate that the germline familial mutations in Cx40 impair the gap junctions through different mechanisms, which may predispose the mutant carriers to AF.


Central or peripheral catheters for initial venous access of ICU patients: a randomized controlled trial.
The vast majority of ICU patients require some form of venous access. There are no evidenced-based guidelines concerning the use of either central or peripheral venous catheters, despite very different complications. It remains unknown which to insert in ICU patients. We investigated the rate of catheter-related insertion or maintenance complications in two strategies: one favoring the central venous catheters and the other peripheral venous catheters. Multicenter, controlled, parallel-group, open-label randomized trial. Three French ICUs. Adult ICU patients with equal central or peripheral venous access requirement. Patients were randomized to receive central venous catheters or peripheral venous catheters as initial venous access. The primary endpoint was the rate of major catheter-related complications within 28 days. Secondary endpoints were the rate of minor catheter-related complications and a composite score-assessing staff utilization and time spent to manage catheter insertions. Analysis was intention to treat. We randomly assigned 135 patients to receive a central venous catheter and 128 patients to receive a peripheral venous catheter. Major catheter-related complications were greater in the peripheral venous catheter than in the central venous catheter group (133 vs 87, respectively, p=0.02) although none of those was life threatening. Minor catheter-related complications were 201 with central venous catheters and 248 with peripheral venous catheters (p=0.06). 46% (60/128) patients were managed throughout their ICU stay with peripheral venous catheters only. There were significantly more peripheral venous catheter-related complications per patient in patients managed solely with peripheral venous catheter than in patients that received peripheral venous catheter and at least one central venous catheter: 1.92 (121/63) versus 1.13 (226/200), p<0.005. There was no difference in central venous catheter-related complications per patient between patients initially randomized to peripheral venous catheters but subsequently crossed-over to central venous catheter and patients randomized to the central venous catheter group. Kaplan-Meier estimates of survival probability did not differ between the two groups. In ICU patients with equal central or peripheral venous access requirement, central venous catheters should preferably be inserted: a strategy associated with less major complications.


Stochastic resonances in a distributed genetic broadcasting system: the NFκB/IκB paradigm.
Gene regulatory networks must relay information from extracellular signals to downstream genes in an efficient, timely and coherent manner. Many complex functional tasks such as the immune response require system-wide broadcasting of information not to one but to many genes carrying out distinct functions whose dynamical binding and unbinding characteristics are widely distributed. In such broadcasting networks, the intended target sites are also often dwarfed in number by the even more numerous non-functional binding sites. Taking the genetic regulatory network of NFκB as an exemplary system we explore the impact of having numerous distributed sites on the stochastic dynamics of oscillatory broadcasting genetic networks pointing out how resonances in binding cycles control the network's specificity and performance. We also show that active kinetic regulation of binding and unbinding through molecular stripping of DNA bound transcription factors can lead to a higher coherence of gene-co-expression and synchronous clearance.


Clinical characteristics of neuropathic pain in leprosy and associated somatosensory profiles: a deep phenotyping study in India.
This study investigated the clinical characteristics and somatosensory profiles of patients suffering from leprosy in Mumbai, India. A cross-sectional deep profiling study was conducted in 86 patients with leprosy (with and without pain) using an extensive battery of phenotyping measures including structured clinical examination, psychological state (General Health Questionnaire [GHQ-12]), and a quality-of-life condition-specific instrument (Brief Pain Inventory-short form). Quantitative sensory testing was performed according to the protocol of the German Research Network on Neuropathic Pain (DFNS) to assess the somatosensory profiles in the ulnar nerve innervation territory of all participants (dorsum of the hand). Reference data from 50 healthy Indian subjects were within the range of published DFNS values. Somatosensory profiles in leprosy patients with clinically or electroneurographically diagnosed neuropathy (with and without pain) revealed a profile of sensory loss to thermal and tactile stimuli combined with preservation of vibration and deep pressure detection. Sensory gain phenomena were not generally observed in patients with leprosy. In the group of subclinical neuropathy, a high degree of impaired thermal sensation was found, which could be clinically deployed to enhance identification of leprosy neuropathy at an early stage. Quantitative sensory testing can effectively document leprosy-associated neuropathy but does not distinguish between patients with or without pain. Patients with leprosy and neuropathic pain reported a poor quality of life and less psychological well-being compared with the pain-free patients with leprosy neuropathy.


Temporal performance fields: visual and attentional factors.
This study is the first to investigate: (a) 'temporal performance fields,' whether the speed of information accrual differs for different locations at a fixed eccentricity, and (b) whether covert attention modulates temporal dynamics differentially at isoeccentric locations. Using the speed accuracy tradeoff (SAT) procedure, we derived conjoint measures of how isoeccentric locations and precueing targets location affect speed and accuracy in a search task. The results demonstrate the existence of temporal performance fields, analogous to spatial performance fields: information accrual was fastest for target on the horizontal meridian, intermediate for targets at the intercardinal locations, slow for targets on the vertical meridian, and slowest for targets at the North (N) location (accrual time pattern: E&W<intercardinal<S<N). Surprisingly, in contrast to spatial performance fields, where covert attention enhanced discriminability at all locations to a similar degree, attention differentially sped up processing at the slower locations, with a greater benefit evident along the vertical than the horizontal meridian, particularly at the N location, and an intermediate benefit at intercardinal locations (viz., N>S>intercardinal>E&W). Hence, the compensatory effect of attention eliminated the temporal asymmetries across isoeccentric locations.


Dapagliflozin and Liraglutide Therapies Rapidly Enhanced Bone Material Properties and Matrix Biomechanics at Bone Formation Site in a Type 2 Diabetic Mouse Model.
The aim of this study is to compare head-to-head the effects of dapagliflozin and liraglutide on bone strength and bone material properties in a pre-clinical model of diabetes-obesity. Combined low-dose streptozotocin and high fat feeding were employed in mice to promote obesity, insulin resistance, and hyperglycaemia. Mice were administered daily for 28 days with saline vehicle, 1 mg/kg dapagliflozin or 25 nmol/kg liraglutide. Bone strength was assessed by three-point bending and nanoindentation. Bone material properties were investigated by Fourier transform infrared microspectroscopy/imaging. Although diabetic controls presented with dramatic reductions in mechanical strength, no deterioration of bone microarchitecture was apparent. At the tissue level, significant alterations in phosphate/amide ratio, carbonate/phosphate ratio, tissue water content, crystal size index, collagen maturity and collagen glycation were observed and linked to alteration of matrix biomechanics. Dapagliflozin and liraglutide failed to improve bone strength by 3-point bending or bone microarchitecture during the 28-day-treatment period. At bone formation site, dapagliflozin enhanced phosphate/amide ratio, mineral maturity, and reduced tissue water content, crystal size index, and collagen glycation. Liraglutide had significant effects on phosphate/amide ratio, tissue water content, crystal size index, mature collagen crosslinks, collagen maturity, and collagen glycation. At bone formation site, both drugs modulated matrix biomechanics. This study highlighted that these two molecules are effective in improving bone material properties and modulating matrix biomechanics at bone formation site. This study also highlighted that the resulting effects on bone material properties are not identical between dapagliflozin and liraglutide and not only mediated by lower blood glucose.


Next Generation Driver for Attosecond and Laser-plasma Physics.
The observation and manipulation of electron dynamics in matter call for attosecond light pulses, routinely available from high-order harmonic generation driven by few-femtosecond lasers. However, the energy limitation of these lasers supports only weak sources and correspondingly linear attosecond studies. Here we report on an optical parametric synthesizer designed for nonlinear attosecond optics and relativistic laser-plasma physics. This synthesizer uniquely combines ultra-relativistic focused intensities of about 1020 W/cm2 with a pulse duration of sub-two carrier-wave cycles. The coherent combination of two sequentially amplified and complementary spectral ranges yields sub-5-fs pulses with multi-TW peak power. The application of this source allows the generation of a broad spectral continuum at 100-eV photon energy in gases as well as high-order harmonics in relativistic plasmas. Unprecedented spatio-temporal confinement of light now permits the investigation of electric-field-driven electron phenomena in the relativistic regime and ultimately the rise of next-generation intense isolated attosecond sources.


Wavelength anomalies in ultraviolet-visible spectrophotometry.
Spectral scans of atomic line emission sources with a Shimadzu UV2101PC spectrophotometer show that the nominal wavelength depends upon the instrumental slit width, the wavelength sampling interval, and for some slit widths, also on the specified spectral range. The range dependence is manifested as a smoothing that occurs when the range includes >65 sampled wavelengths, and it affects both the wavelength and the line shape. For spectra not subject to this smoothing, the wavelength error looks like a one-sample misassociation of the wavelength and photometric readings. However, the instrument does reliably move to a specified wavelength, independent of the scan parameter settings. These behaviors do not seem to be documented anywhere but have been present in the software for operating this instrument for about two decades.


Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase.
Disruption of synapses underlies a plethora of neurodevelopmental and neurodegenerative disease. Presynaptic specialization called the active zone plays a critical role in the communication with postsynaptic neuron. While the role of many proteins at the active zones in synaptic communication is relatively well studied, very little is known about how these proteins are transported to the synapses. For example, are there distinct mechanisms for the transport of active zone components or are they all transported in the same transport vesicle? Is active zone protein transport regulated? In this report we show that overexpression of Par-1/MARK kinase, a protein whose misregulation has been implicated in Autism spectrum disorders (ASDs) and neurodegenerative disorders, lead to a specific block in the transport of an active zone protein component- Bruchpilot at Drosophila neuromuscular junctions. Consistent with a block in axonal transport, we find a decrease in number of active zones and reduced neurotransmission in flies overexpressing Par-1 kinase. Interestingly, we find that Par-1 acts independently of Tau-one of the most well studied substrates of Par-1, revealing a presynaptic function for Par-1 that is independent of Tau. Thus, our study strongly suggests that there are distinct mechanisms that transport components of active zones and that they are tightly regulated.


Achromatic wide-view circular polarizers for a high-transmittance vertically-aligned liquid crystal cell.
We propose an optical compensation scheme through which we can eliminate the off-axis light leakage in a vertically-aligned liquid crystal cell with circular polarizers. In this scheme, four uniaxial films with complementary dispersion characteristics are used to compensate one another, resulting in achromatic effective phase retardation for off-axis angles. By using the proposed optical compensation, a contrast ratio higher than 2000:1 can be realized over the entire 55° viewing cone in a multi-domain vertical-alignment liquid crystal cell with circular polarizers.


A Broader Understanding of Moral Distress.
On the traditional view, moral distress arises only in cases where an individual believes she knows the morally right thing to do but fails to perform that action due to various constraints. We seek to motivate a broader understanding of moral distress. We begin by presenting six types of distress that fall outside the bounds of the traditional definition and explaining why they should be recognized as forms of moral distress. We then propose and defend a new and more expansive definition of moral distress and examine how it can enable the development of a taxonomy of moral distress.


Mitochondrial diversity in linguistic isolates of the Alps: a reappraisal.
In Stenico et al. (1996) we reported unusually high levels of mitochondrial diversity in the Alps. In particular, two communities of Ladin speakers appeared the most extreme European mitochondrial outliers at that time. Recently, it has been observed that some rare nucleotide substitutions occur repeatedly among those sequences, raising the possibility of systematic sequencing errors. No biological material was left from the previous study, and hence we had to sample new individuals from the same communities. Here, we present the HVSI sequence variation, along with haplogroup assignment based on restriction fragment length polymorphism (RFLP), in 20 Ladin speakers of Colle Santa Lucia. None of the new sequences displays substitutions at the sites viewed as problematic. However, Ladins still show high levels of mtDNA diversity, both within their community and with respect to other Europeans, and they can still be considered one of the main European mitochondrial outliers.


A New Approach to Reducing Disorder and Improving Well-Being.
Psychological science has usually approached the treatment of disorder through research on individual combinations of risk and protective factors (including life experiences, thinking styles, behaviors, social relationships and genes) and the application of interventions that focus on improvements in the individual. However, we can do better than this. Not only should we be aiming to enhance well-being rather than merely reducing disorder, but we should also be doing so for the majority of people rather than the few who have a disorder. In this article, I focus on the mental health spectrum and make the case for a broad population-based approach. I argue that a very small shift in the population mean of the underlying symptoms or risk factors can do more to enhance well-being and reduce disorder than would any amount of intervention with individuals who need help. Examples from research on alcohol abuse and psychological distress are presented to illustrate the value of a population-based approach.


Antihyperalgesic Properties of Honokiol in Inflammatory Pain Models by Targeting of NF-κB and Nrf2 Signaling.
The present study investigates the possible anti-nociceptive effect of intraperitoneal (i.p.) honokiol: a phenolic compound originally isolated from Magnolia officinalis, in acute and chronic inflammatory pain models. Doses of 0.1, 5, and 10 mg/kg honokiol were administered in carrageenan induced pain and the dose (honokiol 10 mg/kg i.p.) with most significant response among behavioral tests was selected for further experiments. The i.p. administration of honokiol inhibits mechanical hyperalgesia, mechanical allodynia, and thermal hyperalgesia, without causing any apparent toxicity. To elucidate the effect of honokiol on various cytokines and antioxidant enzymes, quantitative real-time-PCR was performed to determine the expression levels of pro-inflammatory cytokines and antioxidant enzymes. It is demonstrated that honokiol significantly reduced the expression levels of tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF). Similarly, honokiol was also found to potentiate the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), and heme oxygenase-1 (HO-1) levels. Additionally, honokiol significantly reduced plasma nitrite levels as compared to complete Freund's adjuvant (CFA) induced group. X-ray analysis and hematoxylin and eosin (H&E) staining of inflamed and treated paws showed that honokiol reduced the inflammation with significantly less leukocyte infiltration and soft tissue inflammation. In order to explore the possible mechanism of action of honokiol, agonists [piroxicam (5 mg/kg), tramadol (50 mg/kg), and gabapentin (5 mg/kg) i.p.] as well as antagonists [naloxone (4 mg/kg), olanzapine (10 mg/kg), and flumazenil (0.2 mg/kg) i.p.] were used to study involvement of various receptors on the anti-nociceptive effect of honokiol. The potential side effects of honokiol on muscle activity were assessed. An adverse effect testing of honokiol by liver and renal functions were also carried out. The effect of oral honokiol was also assessed on gastrointestinal (GIT) mucosa. Our results demonstrate that honokiol has a significant anti-nociceptive activity through inhibition of anti-inflammatory mediators.


The Concise Guide to PHARMACOLOGY 2013/14: G protein-coupled receptors.
The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. G protein-coupled receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.


Solvent-dependent transition states for decarboxylations.
The rate constants and kinetic isotope effects for decarboxylation of 4-pyridylacetic acid depend strongly on whether the solvent is water or dioxane, and the present paper interprets this finding. We calculate the solvent dependence of the free energy barrier and of the (13)C and (18)O kinetic isotope effects using a quantum mechanical solvation model based on class IV charges and semiempirical atomic surface tensions. The calculations provide a consistent interpretation of the experimental results, which provides a striking confirmation of the soundness of the solvation modeling. Even more significantly, the agreement of theory and experiment gives us confidence in the physical picture of the reaction provided by the model. This indicates that the location of the transition state, as measured by the length of the breaking C--C bond, is 0.24 A later than the gas phase in dioxane and 0.37 A later than the gas phase in water. Charge development at the transition state also depends strongly on the solvent; in particular the CO(2) moiety is 0.07 electronic charge units more negative at the transition state in dioxane than in water.


Autonomous roles for the cytoplasmic domains of the CD2 and CD4 T cell surface antigens.
CD2 and CD4 are single chain transmembrane T cell surface molecules that are involved in signal transduction. Chimaeric constructs from rat CD2 and CD4 antigens were expressed in the Jurkat human T cell line to examine the role of extracellular, transmembrane and cytoplasmic domains in mediating functions controlled by CD2 and CD4. The results show that the large rise in concentration of cytoplasmic free Ca2+ mediated via CD2 crosslinking is controlled by the cytoplasmic domain and does not require the CD2 transmembrane and extracellular domains. Similarly the CD4 cytoplasmic domain alone was shown to encode the specificity for binding to the p56lck tyrosine kinase and to control down-modulation of CD4 after treatment with phorbol ester. Evidence was obtained that down-modulation of CD4 occurs when p56lck dissociates from the cytoplasmic domain due to phosphorylation of Ser 405.


Why do lean hypertensives have higher mortality rates than other hypertensives? Findings of the Hypertension Detection and Follow-up Program.
Specific causes of death were analyzed for 10,908 participants in the Hypertension Detection and Follow-up Program, to explore possible explanations for the observed excess 8.3-year mortality from all causes in hypertensives with low body mass. Although the cardiovascular mortality rate among men in the lowest decile of body mass (body mass index 21.96 or less) was 50% higher than that of men in the median class (body mass index 26.4-28.8), death rate for noncardiovascular deaths was more than 2 1/2 times higher in men with lean versus median body mass. The pattern was similar among women. Among noncardiovascular causes, striking differences in mortality rates between lean hypertensives and those of average body mass were observed for cirrhotic death (relative risk of 12+ in men and 11+ in women), for nonmalignant respiratory disease in men (relative risk of 7+), for violent death (both sexes), and for malignant neoplasms in men. Prevalence of smoking was almost twice as high in the lowest compared with the median body mass group; among the lean, excess deaths, particularly noncardiovascular deaths, were concentrated among smokers. Thus, male smokers in the lowest decile of body mass constituted only 3% of the study population, but contributed 8% of all deaths, 11% of all noncardiovascular deaths, and 22% of all cirrhotic deaths. A larger proportion of deaths occurred early in follow-up in the lean versus other hypertensives, suggesting occult disease among the lean at baseline. There was no evidence that more severe or treatment-resistant hypertension was present in or could explain excess mortality among the hypertensives with low body mass. The inference from the findings is not that overweight is protective for hypertensives nor that excess risk is due to leanness per se. Rather, a reasonable hypothesis, particularly from findings on specific causes of death, is that excess mortality in lean hypertensives is due to deleterious lifestyles, particularly smoking and excess alcohol intake, contributing to both leanness and risk of death.


The Enhanced Liver Fibrosis (ELF) Panel: Analyte Stability Under Common Sample Storage Conditions Used in Clinical Practice.
The enhanced liver fibrosis (ELF) blood test has recently been recommended by the National Institute for Health and Care Excellence to test for advanced fibrosis in nonalcoholic fatty liver disease. The ELF test involves calculating a score from the concentrations of serum biomarkers: tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), aminoterminal propeptide of procollagen type III (P3NP), and hyaluronic acid (HA). Blood samples for the ELF score are often acquired in primary care and may be stored before analysis. However, the effect of preanalytical storage on the ELF test is not known. We conducted experiments to assess the stabilities of the ELF score, P3NP, HA, and TIMP-1 under medium- to long-term storage at -80 °C, repeated freeze-thawing, and refrigeration at 4 °C for days. Mean TIMP-1 concentrations increased during medium- to long-term storage (+16.5%) and refrigeration (+4.9%), but were stable during freeze-thawing. Mean P3NP concentrations were stable under medium- to long-term storage, but increased during refrigeration (+7.4%) and freeze-thawing (+9.3%). Mean HA concentrations decreased during medium- to long-term storage (-12.3%) but were stable during refrigeration and freeze-thawing. Despite changes in biomarker concentrations, the changes in the mean ELF score were not clinically significant and not >0.1 U (0.7%). The ELF score was stable, with no clinically significant changes under common storage conditions. These findings demonstrate that the ELF score is robust in situations where analysis may be delayed.


Palladium-catalyzed tandem addition/cyclization in aqueous medium: synthesis of 2-arylindoles.
An efficient protocol to construct 2-arylindoles was developed through palladium-catalyzed tandem addition/cyclization of potassium aryltrifluoroborates with aliphatic nitriles in aqueous medium. The use of water as the reaction medium makes the synthesis process environmentally benign. A plausible mechanism for the formation of 2-arylindoles involving sequential nucleophilic addition followed by an intramolecular cyclization is proposed. Moreover, the utility of this catalytic tandem transformation was also demonstrated in an efficient gram-scale synthesis. This method provides an alternative synthetic tool for accessing a more diverse array of 2-arylindoles.


Thyroid function in lung cancer.
Thyroid function was assessed at the time of initial diagnosis in 204 patients with lung cancer and compared with that of age and sex-matched patients with non-malignant lung disease. Abnormalities in thyroid function were found in 67 patients (33%). The most prevalent abnormality was a low T3 concentration; this was not associated with other clinical or biochemical evidence of hypothyroidism, but the short-term prognosis of these patients was worse than that of matched patients with lung cancer having normal T3 concentrations. Primary hypothyroidism occurred in three patients, low T4 concentrations and free thyroxine index (FTI) with normal thyrotrophin (TSH) concentrations in four patients, and moderately raised TSH with normal thyroid hormone concentrations in six patients; nine patients had a raised FTI with or without raised T4 concentration as the sole abnormality.Overall, the pattern of thyroid hormone metabolism in lung cancer was a tendency towards reduced T3 concentrations with significantly increased T4/T3 ratios and modestly increased 3,3',5'-triiodothyronine (rT3) concentrations. The altered T4/T3 ratio was particularly noticeable in patients with anaplastic tumours of small ("oat cell") and large cell types, but was not apparently related to detectable extrathoracic metastases.These data suggest that thyroid hormone metabolism is altered in patients with lung cancer by decreased 5'-monodeiodination of T4. The resulting low T3 concentrations and altered T4/T3 ratio may be partly responsible for the reduced ratio of androsterone to aetiocholanolone observed in lung cancer, which is known to be a poor prognostic sign.


Comparison of serum 1,25-dihydroxycholecalciferol concentrations in rheumatoid arthritis and osteoarthrosis.
We have previously compared 25-hydroxycholecalciferol levels in the serum of patients with osteoarthrosis and rheumatoid arthritis, finding no significant difference between the circulating levels of this hormone. We have now estimated 1,25-dihydroxycholecalciferol levels on stored sera from the same groups of patients and found no significant difference in the levels of this hormone between the 2 groups. The osteopenia that distinguishes rheumatoid arthritis from osteoarthrosis is not the result of altered levels of systemic 25OHD3 or of 1,25(OH)2D3. Local factors may be more important in its pathogenesis.


Self-drying: a gecko's innate ability to remove water from wet toe pads.
When the adhesive toe pads of geckos become wet, they become ineffective in enabling geckos to stick to substrates. This result is puzzling given that many species of gecko are endemic to tropical environments where water covered surfaces are ubiquitous. We hypothesized that geckos can recover adhesive capabilities following exposure of their toe pads to water by walking on a dry surface, similar to the active self-cleaning of dirt particles. We measured the time it took to recover maximum shear adhesion after toe pads had become wet in two groups, those that were allowed to actively walk and those that were not. Keeping in mind the importance of substrate wettability to adhesion on wet surfaces, we also tested geckos on hydrophilic glass and an intermediately wetting substrate (polymethylmethacrylate; PMMA). We found that time to maximum shear adhesion recovery did not differ in the walking groups based on substrate wettability (22.7±5.1 min on glass and 15.4±0.3 min on PMMA) but did have a significant effect in the non-walking groups (54.3±3.9 min on glass and 27.8±2.5 min on PMMA). Overall, we found that by actively walking, geckos were able to self-dry their wet toe pads and regain maximum shear adhesion significantly faster than those that did not walk. Our results highlight a unexpected property of the gecko adhesive system, the ability to actively self-dry and recover adhesive performance after being rendered dysfunctional by water.


A combined 3D and 2D light scattering study on aqueous colloidal model systems with tunable interactions.
In this article we report on the synthesis and characterization of a system of colloidal spheres suspended in an aqueous solvent which can be refractive index-matched, thus allowing for investigations of the particle near-wall dynamics by evanescent wave dynamic light scattering at concentrations up to the isotropic to ordered transition and beyond. The particles are synthesized by copolymerization of a fluorinated acrylic ester monomer with a polyethylene-glycol (PEG) oligomer by surfactant free emulsion polymerization. Static and dynamic light scattering experiments in combination with cryo transmission electron microscopy reveal that the particles have a core shell structure with a significant enrichment of the PEG chains on the particles surface. In index-matching DMSO/water suspensions the particles arrange in an ordered phase at volume fraction above 7%, if no additional electrolyte is present. The near-wall dynamics at low volume fraction are quantitatively described by the combination of electrostatic repulsion and hydrodynamic interaction between the particles and the wall. At volume fractions close to the isotropic to ordered transition, the near-wall dynamics are more complex and qualitatively reminiscent of the behaviour which was observed in hard sphere suspensions at high concentrations.


Association of physical activity and sitting time with incident colorectal cancer in postmenopausal women.
Findings from epidemiological studies have found that physical activity (PA) is associated with a lower risk of colorectal cancer (CRC). Recent studies have found an increased CRC risk with higher sitting time (ST); however, many studies did not include PA as a potential confounder. The objective of this project was to investigate the independent and combined associations of ST and PA with the risk of incident CRC, specifically colon and rectal cancer. Participants in the Women's Health Initiative Observational Study (n=74 870), 50-79 years of age self-reported ST and PA at baseline, years 3 and 6. Incident CRC was the primary outcome; colon and rectal cancers were the secondary outcomes, which were centrally adjudicated. Over a 13-year follow-up period, 1145 incident cases of CRC were documented. A positive age-adjusted association was found between higher ST (≥10 vs. <5 h/day) and CRC (P for trend=0.04) and colon cancer (P for trend=0.05); however, these associations were attenuated and no longer significant in multivariable-adjusted models. Compared with inactive women (≤1.7 MET-h/week), the multivariable risk of CRC in the high PA (>20 MET-h/week) group was 0.81 (95% confidence interval: 0.66-1.00; P for trend 0.04). Compared with inactive women with high ST (≥10 h/day), there was a trend toward reduced multivariable CRC risks with higher PA irrespective of ST level (interaction=0.64). We observed an inverse association between leisure time PA and the risk of CRC, particularly for rectal cancer. There was no association between ST and CRC in multivariable models.


Socioeconomic status during lifetime and cognitive impairment no-dementia in late life: the population-based aging in the Chianti Area (InCHIANTI) Study.
Thousand and twelve dementia-free elderly (60–98 years old) enrolled in the InChianti Study (Italy) were evaluated at baseline (1998–2000) and at 3-year follow-up (2001–2003) with the aim of analyzing the association of lifetime socioeconomic status (SES) with prevalent and incident cognitive impairment no-dementia (CIND). SES was defined from information on formal education, longest held occupation, and financial conditions through life. CIND was defined as age-adjusted Mini-Mental State Examination score one standard deviation below the baseline mean score of participants without dementia. Logistic regression and Cox proportional-hazards models were used to estimate the association of SES with CIND. Demographics,occupation characteristics (i.e., job stress and physical demand), cardiovascular diseases, diabetes, apolipoprotein E (APOE)genotype, smoking, alcohol consumption, depressive symptoms, and C-reactive protein were considered potential confounders.Prevalence of CIND was 17.7%. In the fully adjusted model, low education (OR = 2.1; 95% confidence intervals, CI = 1.4 to 3.2)was associated with prevalent CIND. Incidence rate of CIND was 66.0 per 1000 person-years. Low education (HR = 1.7; 95% CI = 1.04 to 2.6) and manual occupation (HR = 1.9; 95% CI = 1.0 to 3.6) were associated with incident CIND. Among covariates,high job-related physical demand was associated with both prevalent and incident CIND (OR = 1.6; 95% CI = 1.1 to 2.4 and HR= 1.5; 95% CI = 1.0 to 2.3). After stratification for education, manual occupation was still associated with CIND among participants with high education (HR = 2.2; 95% CI = 1.2 to 4.3 versus HR= 1.4; 95% CI = 0.2 to 10.4 among those with low education). Proxy markers of lifetime SES (low education, manual occupation and high physical demand) are cross-sectional correlates of CIND and predict incident CIND over a three-year follow-up.


NFI-B3, a novel transcriptional repressor of the nuclear factor I family, is generated by alternative RNA processing.
Nuclear factor I (NFI) proteins constitute a family of sequence-specific transcription factors whose functional diversity is generated through transcription from four different genes (NFI-A, NFI-B, NFI-C, and NFI-X), alternative RNA splicing, and protein heterodimerization. Here we describe a naturally truncated isoform, NFI-B3, which is derived from the human NFI-B gene, in addition to characterizing further human NFI-B1 and NFI-B2, two differentially spliced variants previously isolated from hamster and chicken. Although NFI-B1 and NFI-B2 proteins are translated from an 8. 7-kilobase message, the mRNA for NFI-B3 has a size of only 1.8 kilobases. The NFI-B3 message originates from the failure to excise the first intron downstream of the exons encoding the DNA binding domain and subsequent processing of this transcript at an intron-internal polyadenylation signal. The translation product includes the proposed DNA binding and dimerization domain and terminates after translation of two additional "intron" encoded codons. In SL-2 cells, which are void of endogenous NFI, NFI-B3 by itself had no effect on transcriptional regulation and failed to bind DNA. Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. Gel shift analysis indicated that NFI-B3 disrupts the function of other NFI proteins by reducing their DNA binding activity by heterodimer formation. The efficiency of NFI-B3 heterodimers to bind to DNA correlated with the degree of transcriptional repression. The abundance of NFI-B transcripts varied significantly between different human cell lines and tissues, suggesting a potential involvement of these factors in the complex mechanisms that generate cell type specificity.


Suppression of leptin during lactation: contribution of the suckling stimulus versus milk production.
Lactation in the rat is characterized by the suppression of pulsatile LH secretion, a large increase in food intake, and changes in energy balance due to the metabolic drain of milk production. The change in energy balance may be a major component in altering reproductive function. A number of factors may contribute to changing energy balance of a lactating animal; one is leptin, the product of adipose tissue, which is known to act partly as a satiety factor to decrease food intake. The aims of the present study were to determine whether there are changes in leptin levels during lactation, a state of high energy demand, and during periods of acute suckling in the presence or absence of changes in energy demand. Our goals were to determine whether lactation and the suckling stimulus influenced serum leptin levels and whether there was a potential role for leptin in the suppression of LH secretion during lactation. The first experiment was performed during diestrus of the estrous cycle, and chronic lactation, (day 9 post partum) in animals suckling 8 pups. The results showed that leptin levels were significantly decreased in both ovarian intact or ovariectomized lactators; this decrease parallels the suppression of pulsatile LH secretion. Serum insulin levels were not altered in the lactating animals. The second experiment was performed in ovariectomized lactators whose 8 pup litters were removed for 48 h, starting on day 9. On day 11, mothers received no pups or pups that were either nonfostered (resulting in no milk production) or fostered (resulting in milk production). The pups were allowed to suckle for 24 h. Following 24 h of acute suckling, serum leptin, and insulin levels correlated with the energy drain on the mother. The levels of leptin were normal and of insulin were elevated in mothers producing no milk. Conversely, leptin levels were suppressed and insulin levels normal in mothers producing milk. The third experiment used the same groups as described for the second experiment except that serial blood samples were collected for measurement of pulsatile LH secretion following 24 h of acute suckling. The results showed that regardless of whether leptin levels remained normal or were suppressed in response to acute suckling, pulsatile LH secretion was significantly inhibited compared with the nonsuckled control animals. In summary, these data suggest that the metabolic drain of milk production, and not the suckling stimulus itself, is the most likely factor responsible for the suppression of leptin secretion during lactation. Furthermore, although the decreased levels of leptin may be causally related to the inhibition of pulsatile LH secretion during chronic lactation, changes in leptin are not a prerequisite for the suppression of LH secretion in response to suckling.


Variable attenuator for intense unpolarized laser beams.
Utilization of polarizing optics for dynamic attenuation of intense unpolarized laser beams is reported. The new family of variable attenuator is composed of a retardation plate mounted between two identical polarization splitters placed in tandem. By varying the retardation, or by rotating the plate, the transmission is varied. These attenuators are characterized by a high transmission and a high optical damage threshold. A transmission dynamic range as large as 1 to 10(-5) is achievable with polarization splitters made of crystals such as sapphire. These attenuators are applicable in laser material processing and in Q switching of unpolarized lasers.