Miracle-dz/UniFAR-FTUs huggingface dataset:
Therapies for dopaminergic‐induced dyskinesias in parkinson disease

Existing and emerging strategies for managing L‐dopa–induced dyskinesias (LIDs) in patients with Parkinson disease have involved either delaying the introduction of L‐dopa therapy, treatment with an antidyskinetic agent, using a therapy or delivery system that can provide continuous dopaminergic stimulation, or using novel agents that target receptors implicated in the mechanisms underlying LIDs. Treatment with dopamine agonists such as pramipexole or ropinirole allows levodopa to be delayed, but once levodopa is added to the drug regimen the usual course of onset of dyskinesias is observed. Amantadine, an N‐methyl‐D‐aspartate antagonist, is so far the only approved compound with evidence of providing a sustained antidyskinetic benefit in the absence of unacceptable side effects. These findings support the hypothesis of glutamate overactivity in the development of dyskinesias. More continuous delivery of dopaminergic medication, such as through intraintestinal or subcutaneous routes, is promising but invasive and associated with injection site reactions. As a result of molecular research and elucidation of the role of a variety of neurotransmitters in the mechanism of LIDs, new compounds have been identified, including those that modulate the direct and indirect striatal output pathways; some of these new agents are in the early stages of development or undergoing proof‐of‐concept evaluation as antidyskinetic agents. Ann Neurol 2011;69:919–927
Ranking Functions for Linear-Constraint Loops

In this article, we study the complexity of the problems: given a loop, described by linear constraints over a finite set of variables, is there a linear or lexicographical-linear ranking function for this loop? While existence of such functions implies termination, these problems are not equivalent to termination. When the variables range over the rationals (or reals), it is known that both problems are PTIME decidable. However, when they range over the integers, whether for single-path or multipath loops, the complexity has not yet been determined. We show that both problems are coNP-complete. However, we point out some special cases of importance of PTIME complexity. We also present complete algorithms for synthesizing linear and lexicographical-linear ranking functions, both for the general case and the special PTIME cases. Moreover, in the rational setting, our algorithm for synthesizing lexicographical-linear ranking functions extends existing ones, because our definition for such functions is more general, yet it has PTIME complexity.
Dependent types and multi-monadic effects in F*

We present a new, completely redesigned, version of F*, a language that works both as a proof assistant as well as a general-purpose, verification-oriented, effectful programming language. In support of these complementary roles, F* is a dependently typed, higher-order, call-by-value language with _primitive_ effects including state, exceptions, divergence and IO. Although primitive, programmers choose the granularity at which to specify effects by equipping each effect with a monadic, predicate transformer semantics. F* uses this to efficiently compute weakest preconditions and discharges the resulting proof obligations using a combination of SMT solving and manual proofs. Isolated from the effects, the core of F* is a language of pure functions used to write specifications and proof terms---its consistency is maintained by a semantic termination check based on a well-founded order. We evaluate our design on more than 55,000 lines of F* we have authored in the last year, focusing on three main case studies. Showcasing its use as a general-purpose programming language, F* is programmed (but not verified) in F*, and bootstraps in both OCaml and F#. Our experience confirms F*'s pay-as-you-go cost model: writing idiomatic ML-like code with no finer specifications imposes no user burden. As a verification-oriented language, our most significant evaluation of F* is in verifying several key modules in an implementation of the TLS-1.2 protocol standard. For the modules we considered, we are able to prove more properties, with fewer annotations using F* than in a prior verified implementation of TLS-1.2. Finally, as a proof assistant, we discuss our use of F* in mechanizing the metatheory of a range of lambda calculi, starting from the simply typed lambda calculus to System F-omega and even micro-F*, a sizeable fragment of F* itself---these proofs make essential use of F*'s flexible combination of SMT automation and constructive proofs, enabling a tactic-free style of programming and proving at a relatively large scale.
The performance of community health workers in the management of multiple childhood infectious diseases in Lira, northern Uganda – a mixed methods cross-sectional study

Background Community health workers (CHWs) have the potential to reduce child mortality by improving access to care, especially in remote areas. Uganda has one of the highest child mortality rates globally. Moreover, rural areas bear the highest proportion of this burden. The optimal performance of CHWs is critical. In this study, we assess the performance of CHWs in managing malaria, pneumonia, and diarrhea in the rural district of Lira, in northern Uganda. Designs A cross-sectional mixed methods study was undertaken to investigate the performance of 393 eligible CHWs in the Lira district of Uganda. Case scenarios were conducted with a medical officer observing CHWs in their management of children suspected of having malaria, pneumonia, or diarrhea. Performance data were collected using a pretested questionnaire with a checklist used by the medical officer to score the CHWs. The primary outcome, CHW performance, is defined as the ability to diagnose and treat malaria, diarrhea, and pneumonia appropriately. Participants were described using a three group performance score (good vs. moderate vs. poor). A binary measure of performance (good vs. poor) was used in multivariable logistic regression to show an association between good performance and a range of independent variables. The qualitative component comprised seven key informant interviews with experts who had informed knowledge with regard to the functionality of CHWs in Lira district. Results Overall, 347 CHWs (88.3%) had poor scores in managing malaria, diarrhea, and pneumonia, 26 (6.6%) had moderate scores, and 20 (5.1%) had good scores. The factors that were positively associated with performance were secondary-level education (adjusted odds ratio [AOR] 2.72; 95% confidence interval [CI] 1.50–4.92) and meeting with supervisors in the previous month (AOR 2.52; 95% CI 1.12–5.70). Those factors negatively associated with CHW performance included: serving 100–200 households (AOR 0.24; 95% CI 0.12–0.50), serving more than 200 households (AOR 0.22; 95% CI 0.10–0.48), and an initial training duration lasting 2–3 days (AOR 0.13; 95% CI 0.04–0.41). The qualitative findings reinforced the quantitative results by indicating that refresher training, workload, and in-kind incentives were important determinants of performance. Conclusions The performance of CHWs in Lira was inadequate. There is a need to consider pre-qualification testing before CHWs are appointed. Providing ongoing support and supervision, and ensuring that CHWs have at least secondary education can be helpful in improving their performance. Health system managers also need to ensure that the CHWs’ workload is moderated as work overload will reduce performance. Finally, although short training programs are beneficial to some degree, they are not sufficient and should be followed up with regular refresher training.
Blood Iron, Glutathione, and Micronutrient Levels and the Risk of Oral Cancer

The risk of oral cavity cancer was determined in relation to serological levels of iron; vitamins A, B2, C, E; zinc; thiamin; and glutathione (GSH). The study included 65 hospitalized patients with oral cancer and 85 matched controls. In comparing the highest to the lowest tertiles, the risk was odds ratio (OR) = 0.3 [95% confidence interval (CI) = 0.1–0.6] for iron; 3.2 (95% CI = 1.3–8.1) for total iron binding capacity (TIBC), which measures the concentration of the iron delivery protein transferrin; and 0.4 (95% CI = 0.2–0.9) for transferrin saturation (iron/TIBC × 100). These associations were stronger in never smokers than in ever smokers. The risk associated with the iron storage protein ferritin was significantly elevated, but this association could reflect disease-related inflammation or comorbidity. The OR for GSH was 0.4 (95% CI = 0.1–0.9), and the OR for GSH reductase activity coefficient (indicative of riboflavin deficiency) was 1.6 (95% CI = 1.3–3.7). These findings suggest that mild iron deficiency and low GSH levels, which are associated with increased oxidative stress, increase the risk of oral cavity cancer.
Mesenteric Lymphatic-Perilymphatic Adipose Crosstalk: Role in Alcohol-Induced Perilymphatic Adipose Tissue Inflammation.

BACKGROUND The digestive tract lymphatics transport approximately two-thirds of all lymph produced in the body and have a key role in mucosal immunity through their contribution to antigen transport and immune cell trafficking. Mesenteric lymphatic pumping function integrity is critical for maintaining homeostasis and lipid transport. We previously demonstrated that acute alcohol intoxication (AAI) increases mesenteric lymphatic amplitude of contraction and ejection fraction, enhancing the ability of the lymphatic vessels to pump lymph. AAI has been shown to disrupt intestinal barrier integrity, which would be expected to increase the endotoxin content of mesenteric lymph. In this study, we tested the prediction that AAI increases lymphatic permeability directly affecting perilymphatic adipose tissue (PLAT) milieu. METHODS Male Sprague Dawley rats received an intragastric infusion of 2.5 g/kg of alcohol. Isovolumic administration of water (vehicle) served as control. PLAT was isolated for the determination of Evans Blue extravasation (permeability), cytokine content, and immunohistochemistry for inflammatory cell infiltration at 30 minutes and 24 hours after alcohol administration. RESULTS PLAT isolated from AAI animals had greater Evans Blue concentrations and cytokine expression (24 hours post-AAI) and mast cell and neutrophil density than that isolated from controls. AAI resulted in significantly higher plasma lipopolysaccharide (endotoxin) levels, lower plasma adiponectin levels (at 30 minutes), and unchanged plasma visfatin levels. CONCLUSIONS The data indicate that AAI induces mesenteric lymphatic hyperpermeability, promotes PLAT inflammatory milieu and disrupts the systemic adipokine profile. These findings suggest an association between alcohol-induced lymphatic hyperpermeability and early manifestations of metabolic dysfunction as a result of alcohol abuse. We propose that crosstalk between lymph and PLAT results in adipose inflammation and adipokine dysregulation during AAI.
Effect of soy flour on nutritional, physicochemical, and sensory characteristics of gluten‐free bread

Abstract The aim of this study was to assess the effect of soy flour on nutritional, physicochemical, and sensory characteristics of gluten‐free (GF) bread. In this study, corn flour was replaced with soy flour at different levels 5%, 10%, and 15% to produce a more nutritionally balanced GF bread. Physical and chemical properties, sensory evaluation and crust and crumb color were measured in bread samples. The results of evaluations showed that protein content of soy flour‐supplemented GF bread significantly increased from 9.8% to 12.9% as compared to control along with an increased in fat (3.3%–4.1%), fiber (0.29%– 0.38%), and ash (1.7%–2.2%) content. Moisture (27.9%–26.5%) and carbohydrate (58.3–52.3) content decreased with the incremental addition of soybean flour. The highest total score of sensory evaluation was for the bread sample containing 15% soybean flour. The evaluation of crust and crumb showed that bread samples with 15% soy flour were significantly darker than the other bread samples. In conclusion, adding higher levels of soybean flour into GF bread can improve bread quality, sensory characteristics, and nutritional properties of bread. Nutritional status in patients with celiac disease (CD) can be improved through the produce GF bread in this way.
Recent High Incidence of Fulminant Hepatitis in Samara, Russia: Molecular Analysis of Prevailing Hepatitis B and D Virus Strains

ABSTRACT Until 1991, the Russian city of Samara was largely isolated from other parts of Russia and the rest of the world. Very recently, Samara has seen an alarming increase in the incidence of hepatitis. The proportion of fulminant cases is unusually high. We wanted to assess the roles of hepatitis B virus (HBV) and hepatitis D virus (HDV) in acute viral hepatitis in this region by analyzing the prevailing strains of both and by determining their genotypes and possible origin. Serum samples were screened for different serological markers and by PCR followed by direct sequencing. Of the 94 HBV-positive samples (80% of which were acute infections), 37 (39%) were also HDV positive. Sixty-seven percent of the patients had anti-HCV antibodies. Twenty-five percent of all patients in the study had fulminant hepatitis. Statistically significant sex differences were found among fulminant cases. For HBV, the core promoter sequences of 62 strains were determined and all but one were found to be of genotype D. None of these had any deletions. Only one strain, from a patient with fulminant fatal hepatitis, showed multiple mutations. The pre-S2 region sequences of 31 HBV strains were also compared. Phylogenetically, these fell into two distinct groups within genotype D, suggesting different origins. For HDV, part of the region encoding the δ-antigen was sequenced from four strains. All proved to be of genotype I and were similar to Far Eastern and Eastern European strains. The contribution of intravenous drug use to the sharp increase in viral hepatitis in this unique setting is discussed.
Early gene expression divergence between allopatric populations of the house mouse (Mus musculus domesticus)

Divergence of gene expression is known to contribute to the differentiation and separation of populations and species, although the dynamics of this process in early stages of population divergence remains unclear. We analyzed gene expression differences in three organs (brain, liver, and testis) between two natural populations of Mus musculus domesticus that have been separated for at most 3000 years. We used two different microarray platforms to corroborate the results at a large scale and identified hundreds of genes with significant expression differences between the populations. We find that although the three tissues have similar number of differentially expressed genes, brain and liver have more tissue–specific genes than testis. Most genes show changes in a single tissue only, even when expressed in all tissues, supporting the notion that tissue–specific enhancers act as separable targets of evolution. In terms of functional categories, in brain and to a smaller extent in liver, we find transcription factors and their targets to be particularly variable between populations, similar to previous findings in primates. Testis, however, has a different set of differently expressed genes, both with respect to functional categories and overall correlation with the other tissues, the latter indicating that gene expression divergence of potential importance might be present in other datasets where no differences in fraction of differentially expressed genes were reported. Our results show that a significant amount of gene expression divergence quickly accumulates between allopatric populations.
Disinfection of swimming pools with chlorine and derivatives: formation of organochlorinated and organobrominated compounds and exposure of pool personnel and swimmers.

Chlorination of pool water leads to the forma-tion of many by-products, chloroform usually being the most abundant. The paper reports the results of a study evaluating exposure of bath-ers and pool employees to trihalomethanes (chloroform, bromodichloromethane, dibromo-chloromethane, bromoform) in four indoor swimming pools with chlorinated water. Chlo-roform concentrations in environmental air samples when the pool was in use (about 9 h), in the range 1-182 μg/m3, were greater near the pool than in the change rooms, passageways and offices. Chloroform concentrations in per-sonal air samples of pool employees were in the range 18-138 μg/m3. Urinary concentrations of chloroform averaged (geometric means) 0.123 and 0.165 μg/l and 0.404 and 0.342 μg/l prior and at the end of exposure during in water and out of water activities, respectively. The significant increase in urinary excretion of chloroform confirms that the source of the contaminant was pool water. Absorption of chloroform, estimated from airborne and water concentrations, was significantly correlated with delta chloroform (after/before exposure) and urinary concentra-tions of chloroform at the end of exposure. As chloroform is a toxic and possibly carcinogenic substance, these observations pose a problem principally for the general population of pool users.
Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis

Objective The mechanisms underlying non-alcoholic steatohepatitis (NASH) are not completely elucidated. In the current study we integrated gene expression profiling of liver biopsies from NASH patients with translational studies in mouse models of steatohepatitis and pharmacological interventions in isolated hepatocytes to identify new molecular targets in NASH. Design and results Using oligonucleotide microarray analysis we identified a significant enrichment of genes involved in the multi-step catalysis of long-chain polyunsaturated fatty acids, namely, Δ-5 desaturase (Δ5D) and Δ6D in NASH. Increased expression of Δ5D and Δ6D at both mRNA and protein level were confirmed in livers from mice with high-fat diet-induced obesity and NASH. Gas chromatography analysis revealed impaired desaturation fluxes toward the ω-6 and ω-3 pathways resulting in increased ω-6 to ω-3 ratio and reduced ω-3 index in human and mouse fatty livers. Restoration of hepatic ω-3 content in transgenic fat-1 mice expressing an ω-3 desaturase, which allows the endogenous conversion of ω-6 into ω-3 fatty acids, produced a significant reduction in hepatic insulin resistance, steatosis, macrophage infiltration, necroinflammation and lipid peroxidation, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were mostly reproduced by feeding obese mice with an exogenous ω-3-enriched diet. A combined Δ5D/Δ6D inhibitor, CP-24879, significantly reduced intracellular lipid accumulation and inflammatory injury in hepatocytes. Interestingly, CP-24879 exhibited superior antisteatotic and anti-inflammatory actions in fat-1 and ω-3-treated hepatocytes. Conclusions These findings indicate that impaired hepatic fatty acid desaturation and unbalanced ω-6 to ω-3 ratio play a role in the pathogenesis of NASH.
Acute pulmonary embolism during warfarin therapy and long-term risk of recurrent fatal pulmonary embolism

Summary The clinical characteristics and long-term outcomes of patients presenting with acute pulmonary embolism (PE) during treatment with warfarin have not been described. Clinical details of all patients admitted to a tertiary institution from 2000-2007 with acute PE were retrieved retrospectively, baseline warfarin status and the international normalised ratio (INR) were recorded, and their outcomes tracked using a statewide death registry. Of 923 patients with clearly documented warfarin status included in this study, 83 (9%) were taking warfarin. Mean (± standard deviation) day-1 INR of those taking warfarin was 2.3 ± 0.9, with 67% of patients therapeutically anti-coagulated (INR ≥2.0) at presentation (49 patients with INR <2.5 and 34 with INR ≥2.5). Patients taking warfarin on admission were more likely to have heart failure, atrial fibrillation and valvular heart disease, with similar prevalence of malignancy and ischaemic heart disease, compared to patients not on warfarin. Total mortality of the cohort (mean follow-up 4.0 ± 2.5 years) was 31.6% (in-hospital mortality 1.5%), and was similar between warfarin and no warfarin groups. There was however a greater than four-fold increased risk of post-discharge death due to recurrent PE for the patients taking warfarin on admission (hazard ratio [HR] 4.43, 95% confidence interval [CI] 1.36-14.42, p=0.01). Among patients taking warfarin on admission, day-1 INR <2.5 significantly increased long-term all-cause mortality compared to INR ≥2.5 (adjusted HR 2.51, 95% CI 1.08-5.86, p=0.03). In conclusion, patients presenting with PE during treatment with warfarin have an increased risk of death from recurrent PE. Admission INR appears to have independent long-term prognostic importance in these patients.
Concomitant down regulation of glycolytic enzymes, upregulation of gluconeogenic enzymes and potential hepato-nephro-protective effects following the chronic administration of the hypoglycemic, insulinotropic Citrullus colocynthis pulp extract.

Background Citrullus colocynthis pulp seedless extract has been demonstrated to have antihyperglycemic and insulinotropic effects. Problem statement: The mechanism(s) underlying the antihyperglycemic and insulinotropic effects have not been investigated to date. Approach: The influence of Citrullus colocynthis pulp extract administered orally was studied in alloxan diabetic white albino rats. Rats were divided into four groups, the first group was normal non diabetic rats given normal saline orally and was named control group, the second group was diabetic rats given normal saline orally and were named normal saline treated-diabetic rats, the third and fourth group were diabetic rats treated with the pulp extract or glybenclamide (a positive control) orally. Plasma glucose, glycosylated hemoglobin and insulin were determined in all groups. The effect of pulp extract of this plant on liver and kidney tissues was also studied. The amount of insulin in β-cells of the Islets of Langerhans in all groups was assessed using immunohistochemistry procedure. Results: Treatment of diabetic rats with Citrullus colocynthis pulp extract (300 mg kg-1 body weight) resulted in a significant decrease in plasma glucose, glygosylated Hb and increased insulin levels. This significant increase in insulin may explain the increase in the activity of liver hexokinase, with concomitant decrease of glucose 6-phosphatase and fructose-1,6-bisphosphatase. Immunohistochemistry procedure showed that the amount of insulin in β-cells of the islets of Langerhans is greater in Citrullus colocynthis treated-diabetic rats in comparison to non-treated diabetic rats. Conclusion: The present study clearly demonstrated that the folk medicinal plant Citrullus colocynthis pulp extract possesses a hypoglycemic effect, through an increase in insulin production and the subsequent increase in activity of glycolytic enzyme and decrease in activity of enzymes of gluconeogenesis. The present study also showed that the pulp extract of this plant to may have protective effects on the liver and kidney.