Miracle-dz/UniFAR-FTUs huggingface dataset:
Inflammation of the Hypothalamus Leads to Defective Pancreatic Islet Function*

Type 2 diabetes mellitus results from the complex association of insulin resistance and pancreatic β-cell failure. Obesity is the main risk factor for type 2 diabetes mellitus, and recent studies have shown that, in diet-induced obesity, the hypothalamus becomes inflamed and dysfunctional, resulting in the loss of the perfect coupling between caloric intake and energy expenditure. Because pancreatic β-cell function is, in part, under the control of the autonomic nervous system, we evaluated the role of hypothalamic inflammation in pancreatic islet function. In diet-induced obesity, the earliest markers of hypothalamic inflammation are present at 8 weeks after the beginning of the high fat diet; similarly, the loss of the first phase of insulin secretion is detected at the same time point and is restored following sympathectomy. Intracerebroventricular injection of a low dose of tumor necrosis factor α leads to a dysfunctional increase in insulin secretion and activates the expression of a number of markers of apoptosis in pancreatic islets. In addition, the injection of stearic acid intracerebroventricularly, which leads to hypothalamic inflammation through the activation of tau-like receptor-4 and endoplasmic reticulum stress, produces an impairment of insulin secretion, accompanied by increased expression of markers of apoptosis. The defective insulin secretion, in this case, is partially dependent on sympathetic signal-induced peroxisome proliferator receptor-γ coactivator Δα and uncoupling protein-2 expression and is restored after sympathectomy or following PGC1α expression inhibition by an antisense oligonucleotide. Thus, the autonomic signals generated in concert with hypothalamic inflammation can impair pancreatic islet function, a phenomenon that may explain the early link between obesity and defective insulin secretion.
Clinical and ultrasonography assessment of peripheral enthesitis in ankylosing spondylitis.

OBJECTIVE The aim of this study was to compare clinical examination with power Doppler US (PDUS) in the detection of entheseal abnormalities in patients with AS. METHODS Thirty-six AS patients underwent clinical and PDUS examination of the following bilateral entheseal sites: common extensor tendon at its insertion at the lateral humeral epicondyle; gluteus tendons at their insertion at the greater trochanter; quadriceps tendon at its insertion at the superior pole of the patella; patellar tendon at its proximal insertion at the inferior pole of the patella; patellar tendon at its distal insertion at the tibial tuberosity; Achilles tendon at its insertion at the calcaneus; and plantar aponeuroses at its insertion at the calcaneus. RESULTS Clinical and PDUS examination revealed at least one abnormal enthesis in 23 (63.9%) and 35 (97.2%) AS patients, respectively. Furthermore, of 432 entheses examined in our 36 AS patients, 64 (14.8%) were considered abnormal by clinical examination and 192 (44.4%) by PDUS. US abnormalities most commonly found were enthesophytes (31.7%), calcifications (33.7%), thickening (29.8%) and hypoechogenicity (26.6%). We found erosions and PD signals in 9.7 and 6% of examined entheseal sites, respectively. The evidence of entheseal abnormalities by clinical examination has a poor likelihood ratio (LR) for the presence of US abnormalities with vascularization (LR = 1.61), without vascularization (LR = 1.24) or erosions (LR = 1.51) at all sites. CONCLUSIONS PDUS permits detection of structural and inflammatory abnormalities of the enthesis in AS and may complement the physical examination in order to better evaluate enthesitis.
Lactobacillus acidophilus induces virus immune defence genes in murine dendritic cells by a Toll‐like receptor‐2‐dependent mechanism

Lactobacilli are probiotics that, among other health‐promoting effects, have been ascribed immunostimulating and virus‐preventive properties. Certain Lactobacillus spp. have been shown to possess strong interleukin‐12 (IL‐12) ‐inducing properties. As IL‐12 production depends on the up‐regulation of type I interferons (IFNs), we hypothesized that the strong IL‐12‐inducing capacity of Lactobacillus acidophilus NCFM in murine bone‐marrow‐derived dendritic cells (DCs) is caused by an up‐regulation of IFN‐β, which subsequently induces IL‐12 and the double‐stranded RNA binding Toll‐like receptor‐3 (TLR‐3). The expression of the genes encoding IFN‐β, TLR‐3, IL‐12 and IL‐10 in DCs upon stimulation with L. acidophilus NCFM was determined. Lactobacillus acidophilus NCFM induced a much stronger expression of Ifn‐β, Il‐12 and Il‐10 compared with the synthetic double‐stranded RNA ligand Poly I:C, whereas the levels of expressed Tlr‐3 were similar. Whole genome microarray gene expression analysis revealed that other genes related to viral defence were significantly up‐regulated and among the strongest induced genes in DCs stimulated with L. acidophilus NCFM. The ability to induce IFN‐β was also detected in another L. acidophilus strain (X37), but was not a property of other probiotic strains tested, i.e. Bifidobacterium bifidum Z9 and Escherichia coli Nissle 1917. The IFN‐β expression was markedly reduced in TLR‐2−/− DCs, dependent on endocytosis, and the major cause of the induction of Il‐12 and Tlr‐3 in DCs stimulated with L. acidophilus NCFM. Collectively, our results reveal that certain lactobacilli trigger the expression of viral defence genes in DCs in a TLR‐2 manner dependent on IFN‐β.
Temporary workers in Washington state.

BACKGROUND Evidence regarding the unequal burden of occupational injuries between workers employed by temporary agencies and those in standard employment arrangements is unclear. Studies range from no significant differences in risk to substantial increased risk for temporary workers. The purpose of this study is to compare the workers' compensation experience of a large cohort of temporary agency employed workers with those in standard forms of employment. METHODS Washington State Fund workers' compensation data were obtained for claims with injury dates from January 1, 2003 to June 30, 2006, resulting in 342,540 accepted claims. General descriptive statistics, injury rates (per 10,000 FTE), and rate ratios (temp agency/standard employer) were computed by injury type and industry. RESULTS Temporary agency employed workers had higher rates of injury for all injury types, and higher median time loss (40 vs. 27 days) but lower time loss costs (median $1,224 vs. $1,914, P < 0.001) and lower medical costs ($3,026 vs. $4,087, P < 0.001) than standard arrangement workers. Temporary agency workers had substantially higher rates for "caught in" and "struck by" injuries in the construction (IRR 4.93; 95% CI 2.80-8.08) and manufacturing (IRR 4.05; 95% CI 3.25, 5.00) industry sectors. CONCLUSION Temporary agency employed workers have higher claims incidence rates than those in standard employment arrangements. The rate ratios are twofold higher in the construction and manufacturing industry sectors. More research is needed to explore potential reasons for this disparity in occupational injuries. Industry or some measure of job exposure should be included when comparing injury rates in different types of employment in order to better identify areas for prevention.
Tim‐4 inhibition of T‐cell activation and T helper type 17 differentiation requires both the immunoglobulin V and mucin domains and occurs via the mitogen‐activated protein kinase pathway

Emerging experimental data suggest an important role for the T‐cell immunoglobulin mucin 1 (Tim‐1):Tim‐4 pathway in autoimmune and alloimmune responses in vivo. Using a Tim‐4 ectodomain human IgG Fc fusion protein we studied the role of Tim‐4 in T‐cell activation, signalling and differentiation responses in vitro. We demonstrate that Tim‐4Fc can inhibit naive and pre‐activated T‐cell activation, proliferation and cytokine secretion via a Tim‐1‐independent pathway. Tim‐4 contains immunoglobulin variable (IgV) and mucin domains; to identify which domain accounts for the inhibitory effect novel Tim‐4 fusion proteins containing either the IgV or mucin domain were generated. We demonstrate that both IgV and mucin domains are required for the inhibitory effects and that they are mediated at least in part by inhibition of extracellular signal‐regulated kinase pathway activity. Given the emerging interest in the role of the Tim family in T helper type 17 (Th17) cells, which play an important role in autoimmune disease and transplantation tolerance, our data show that Tim‐4Fc can prevent polarization of CD4+ T cells to the Th17 phenotype. Collectively, our results highlight an inhibitory role for Tim‐4Fc in vitro, which we propose is mediated by a receptor other than Tim‐1. In addition, this study provides new insights into the role of Tim‐4Fc in regulating Th17 immune responses and may open a new avenue for autoimmune therapy.
Increased sensitivity to antigen in high avidity CD8+ T cells results from augmented membrane proximal T‐cell receptor signal transduction

The functional avidity of a cytotoxic T lymphocyte (CTL) is known to be a critical determinant of the efficacy with which it clears pathogens. High avidity cells, which are by definition highly sensitive to peptide antigen, are superior for elimination of viruses and tumours. Our studies have established the ability of T cells to undergo avidity modulation as a result of antigen encounter. High and low avidity cells established in this manner exhibit significant differences in the amount of peptide required to elicit effector function. However, how signalling is regulated in these cells as it relates to the control of peptide sensitivity remains to be defined. To address this question, we compared T‐cell receptor (TCR) signal transduction events in high and low avidity CTL generated from OT‐Irag2− TCR transgenic mice. Our data suggest that divergent signalling is initiated at the TCR‐associated CD3ζ, with low avidity CTL requiring higher amounts of pMHC to achieve threshold levels of phosphorylated CD3ζ compared with high avidity CTL. Further, this difference is transduced further downstream to mitogen‐activated protein kinase and Ca2+ signalling pathways. These results suggest that regulated control of the initiation of TCR signalling in high versus low avidity cells determines the amount of peptide required for T‐cell activation.
Cellular and Molecular Mechanisms of Autosomal Dominant Form of Progressive Hearing Loss, DFNA2*

Despite advances in identifying deafness genes, determination of the underlying cellular and functional mechanisms for auditory diseases remains a challenge. Mutations of the human K+ channel hKv7.4 lead to post-lingual progressive hearing loss (DFNA2), which affects world-wide population with diverse racial backgrounds. Here, we have generated the spectrum of point mutations in the hKv7.4 that have been identified as diseased mutants. We report that expression of five point mutations in the pore region, namely L274H, W276S, L281S, G285C, and G296S, as well as the C-terminal mutant G321S in the heterologous expression system, yielded non-functional channels because of endoplasmic reticulum retention of the mutant channels. We mimicked the dominant diseased conditions by co-expressing the wild-type and mutant channels. As compared with expression of wild-type channel alone, the blend of wild-type and mutant channel subunits resulted in reduced currents. Moreover, the combinatorial ratios of wild type:mutant and the ensuing current magnitude could not be explained by the predictions of a tetrameric channel and a dominant negative effect of the mutant subunits. The results can be explained by the dependence of cell surface expression of the mutant on the wild-type subunit. Surprisingly, a transmembrane mutation F182L, which has been identified in a pre-lingual progressive hearing loss patient in Taiwan, yielded cell surface expression and functional features that were similar to that of the wild type, suggesting that this mutation may represent redundant polymorphism. Collectively, these findings provide traces of the cellular mechanisms for DFNA2.
Zastosowanie endocyklofotokoagulacji ciała rzęskowego w leczeniu jaskry

Endocyclophotocoagulation (ECP) is the endoscopic method of glaucoma treatment using a diode laser for cyclodestruction of ciliary processes. Until now it was reserved for advanced cases of refractory glaucoma. The indications for its use are increasing and include patients in earlier stages of the disease, with good visual acuity. Efficacy and safety of ECP is confirmed by many stud-ies on different types of glaucoma.
The 11-item workplace organizational policies and practices questionnaire (OPP-11): examination of its construct validity, factor structure, and predictive validity in injured workers with upper-limb disorders.

BACKGROUND Reliable and valid measurement of workplace organizational policies and practices (OPPs) is needed to evaluate their influences on the prevention and management of occupational injuries. METHODS Injured workers (n = 614) attending an upper-limb specialty clinic operated by the Workplace Safety & Insurance Board of Ontario were recruited for a 1-year study. The OPP-11, completed at baseline, was examined for scaling properties (floor/ceiling effects, internal consistency, and item-convergent/discriminant validity), construct validity, and factor structure. Predictive validity for longitudinal work disability was examined using multivariable logistic regressions. RESULTS Strong scaling properties were observed for the OPP-11. High internal consistency (Cronbach's alpha = 0.80-0.90) and expected associations with comparator constructs were evident. A 4-domain structure (fit statistics: CFI = 0.98, TLI = 0.97, and RMSEA = 0.06) was supported. Higher OPP-11 predicted more favorable 12-month work disability outcomes, after adjusting for demographic and health attributes. CONCLUSIONS The OPP-11 is valid for use in upper-limb disorders. Expanding the ergonomic practices domain could be considered.
Endotoxin Tolerance Impairs IL-1 Receptor-Associated Kinase (IRAK) 4 and TGF-β-activated Kinase 1 Activation, K63-linked Polyubiquitination and Assembly of IRAK1, TNF Receptor-associated Factor 6, and IκB Kinase γ and Increases A20 Expression*

Endotoxin tolerance reprograms Toll-like receptor 4 responses by impairing LPS-elicited production of pro-inflammatory cytokines without inhibiting expression of anti-inflammatory or anti-microbial mediators. In septic patients, Toll-like receptor tolerance is thought to underlie decreased pro-inflammatory cytokine expression in response to LPS and increased incidence of microbial infections. The impact of endotoxin tolerance on recruitment, post-translational modifications and signalosome assembly of IL-1 receptor-associated kinase (IRAK) 4, IRAK1, TNF receptor-associated factor (TRAF) 6, TGF-β-activated kinase (TAK) 1, and IκB kinase (IKK) γ is largely unknown. We report that endotoxin tolerization of THP1 cells and human monocytes impairs LPS-mediated receptor recruitment and activation of IRAK4, ablates K63-linked polyubiquitination of IRAK1 and TRAF6, compromises assembly of IRAK1-TRAF6 and IRAK1-IKKγ platforms, and inhibits TAK1 activation. Deficiencies in these signaling events in LPS-tolerant cells coincided with increased expression of A20, an essential deubiquitination enzyme, and sustained A20-IRAK1 associations. Overexpression of A20 inhibited LPS-induced activation of NF-κB and ablated NF-κB reporter activation driven by ectopic expression of MyD88, IRAK1, IRAK2, TRAF6, and TAK1/TAB1, while not affecting the responses induced by IKKβ and p65. A20 shRNA knockdown abolished LPS tolerization of THP1 cells, mechanistically linking A20 and endotoxin tolerance. Thus, deficient LPS-induced activation of IRAK4 and TAK1, K63-linked polyubiquitination of IRAK1 and TRAF6, and disrupted IRAK1-TRAF6 and IRAK1-IKKγ assembly associated with increased A20 expression and A20-IRAK1 interactions are new determinants of endotoxin tolerance.
A Mouse Macrophage Lipidome*♦

We report the lipidomic response of the murine macrophage RAW cell line to Kdo2-lipid A, the active component of an inflammatory lipopolysaccharide functioning as a selective TLR4 agonist and compactin, a statin inhibitor of cholesterol biosynthesis. Analyses of lipid molecular species by dynamic quantitative mass spectrometry and concomitant transcriptomic measurements define the lipidome and demonstrate immediate responses in fatty acid metabolism represented by increases in eicosanoid synthesis and delayed responses characterized by sphingolipid and sterol biosynthesis. Lipid remodeling of glycerolipids, glycerophospholipids, and prenols also take place, indicating that activation of the innate immune system by inflammatory mediators leads to alterations in a majority of mammalian lipid categories, including unanticipated effects of a statin drug. Our studies provide a systems-level view of lipid metabolism and reveal significant connections between lipid and cell signaling and biochemical pathways that contribute to innate immune responses and to pharmacological perturbations.
The relationship between fatigue-related factors and work-related injuries in the Saskatchewan Farm Injury Cohort Study.

BACKGROUND The objective was to examine the relationship between seasonal variations in sleep quantity and work-related injuries on Saskatchewan farms. METHODS A cross-sectional analysis of data from the Saskatchewan Farm Injury Cohort Study was conducted. Analyses were restricted to workers, aged ≥16 years. The primary outcome was work-related injury in the last year. Logistic regression models were used to identify associations between sleep quantity and farm injury. RESULTS After controlling for confounding variables peak production season sleep was not associated with increased odds of injury. However, those obtaining ≤5 hr sleep per night during non-peak production seasons had increased odds of injury (OR 2.42, 95% CI 1.04-5.59) compared with those sleeping ≥7 hr per night. CONCLUSIONS We identified that restricted sleep durations, in certain seasons, placed farmers, and farm workers at risk of injury. Agricultural injury intervention programs need to consider the role of seasonal-related variations in sleep on farm injury.
Vaccine Studies Stymied by Shortage of Animals

The National Institutes of Health doesn9t know how many Indian rhesus macaques its researchers need, nor how many are available. That9s a big problem for AIDS researchers, because the macaques provide the only good animal model researchers have for testing vaccines, measuring the toxicity of various drugs, and exploring the disease9s progression. The shortage of rhesus macaques has highlighted the need for scientists to become more involved in breeding them.
Physical Activity Referral Schemes: Socio-demographic patterning of exposure, uptake and attendance.

Background. Despite the prevalence of Physical Activity Referral Schemes (PARS) in Britain, to date, there has been no attempt to elucidate their public health role. The nature of this role will depend upon who schemes are accessible to, and appropriate for. Objective. The aim of the present research was to provide a rigorous account of sociodemographic bias in referral to, and attendance of a county-wide PARS by tracking participant progress, from point of referral to the end of their involvement with the scheme. Methods. Epidemiological methods were applied to analyse data from people referred to the Somerset-wide ProActive PARS over a three-year period. For all Somerset residents referred, age, gender, and the deprivation level (measured by the Townsend score) and urban-rural character of their area of residence were used to make socio-demographic comparisons with the county population as a whole. Mann-Whitney and Kruskal-Wallis difference tests were used to compare socio-economic characteristics. Binary logistic regression analysis was used to identify sociodemographic characteristics associated with referral uptake (attending ≥1 session) and completion of physical activity programmes (≥80% attendance). Results. The proportion of referred participants (n=3569) who were female was above the county average (61.1 vs. 51.4%). Referrals increased markedly with age from 6.6% (≤30 yrs) to 22.7% (50-59 yrs), dropping off sharply thereafter (≥60 yrs). The mean Townsend deprivation score for participant area of residence was greater than the county average (0.33 vs. 0.00, p<0.001). These patterns indicated that, with the exception of older adults, those groups most likely to consult primary care were referred most frequently. Regression analysis (n=2864) revealed that increasing age (Exp(B)=1.014, p<0.001) and urban residency (Exp(B)=1.317, p<0.001) increased the likelihood of referral uptake. Uptake was less likely for those living in more deprived areas (Exp(B)=0.933, p<0.001). In participants who took up referral, the likelihood of completion was lower in women than men (Exp(B)=0.818, p=0.041) but increased with age (Exp(B)=1.018, P<0.001). Conclusion. Younger people, residents of deprived and rural areas, and women appear less likely to progress through schemes or complete PARS programmes, regardless of relative scheme exposure. PARS appear more appropriate for adults of middle-to-old age who are more likely to require supervision and should be targeted accordingly. To promote physical activity in a preventive capacity and to increase activity across the socio-economic strata is likely to require broader and multi-faceted environmental and policy-led interventions to promote habitual activity, rather than attempting to increase recreational activity through individual-orientated such as PARS.
INCIDENCE RATE OF GASTROINTESTINAL TRACT CANCERS IN TEHRAN – IRAN (1998-2001)

Incidence rate of gastrointestinal tract cancers in Tehran – Iran (1998-2001) Mehdi khabazkhoob (MSc), Mohammad Ali Mohagheghi (MD) Alireza Mosavi Jarrahi (PhD)*, Ali Javaher Foroushzadeh (MD) Mohsen Pedram Far (MS), Ali Moradi (MSc), Bijan Rezvan (DDS) Ali Khalafi (MSc), Nikoo Kiasat Fard 9 MSc of Epidemiology, Cancer Research Center, The Cancer Institute, Imam Khomeini Medical Center, Tehran University of Medical Sciences,Tehran, Iran. Associate Professor, Department of Cancer Surgery, Cancer Research Center, The Cancer Institute, Imam Khomeini Medical Center, Tehran University of Medical Sciences,Tehran, Iran. Associate Professor, Department of Epidemiology, School of Public Health, Shaheed Beheshti University of Medical Sciences and Health Services, Tehran, Iran. General Physician. Master of Public Health. MSc of Phisiology, Department of Laboratory Science Technology, Faculty of Health and Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran. Dentist, Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iran. MSc of Nursing, Azad Universityof Dezful, Dezful, Iran. Nursing Student, Azad University of Dezful, Dezful, Iran. ________________________________________________________________________ Abstract