Miracle-dz/UniFAR-FTUs huggingface dataset:
Fundamentally distinct roles of thyroid hormone receptor isoforms in a thyrotroph cell line are due to differential DNA binding.

Thyroid hormones have a profound influence on human development and disease. The hypothalamic-pituitary-thyroid axis involves finely tuned feedback mechanisms to maintain thyroid hormone (TH) levels. Despite the important role of TH-negative feedback in regulating this axis, the mechanism by which this occurs is not clearly defined. Previous in vivo studies suggest separate roles for the two thyroid hormone receptor isoforms, THRA and THRB, in this axis. We performed studies using a unique pituitary thyrotroph cell line (TαT1.1) to determine the relative roles of THRA and THRB in the regulation of Tshb. Using chromatin immunoprecipitation assays, we found that THRB, not THRA, bound to the Tshb promoter. By selectively depleting THRB, THRA, or both THRA and THRB in TαT1. 1 cells, we found that simultaneous knockdown of both THRB and THRA abolished T(3)-mediated down-regulation of Tshb at concentrations as high as 100 nm T(3). In contrast, THRA knockdown alone had no effect on T(3)-negative regulation, whereas THRB knockdown alone abolished T(3)-mediated down-regulation of Tshb mRNA levels at 10 nm but not 100 nm T(3) concentrations. Interestingly, chromatin immunoprecipitation assays showed that THRA becomes enriched on the Tshb promoter after knockdown of THRB. Thus, a likely mechanism for the differential effects of THR isoforms on Tshb may be based on their differential DNA-binding affinity to the promoter.
Alta prevalencia de factores de riesgo cardiovascular clásicos en una población de estudiantes universitarios de la región centro-sur de Chile

Introduccion y objetivos Las enfermedades cardiovasculares (ECV) son la primera causa de muerte en el mundo. Dichas enfermedades se pueden prevenir mediante el control de los factores de riesgo cardiovascular. Metodos Se estudio a 783 alumnos entre 18 a 26 anos de edad de la Universidad de Talca (VII Region del Maule, Chile), lo que equivale al 14,9% del alumnado. Se registraron sus datos demograficos, los antecedentes familiares de enfermedad cardiovascular, el peso, la talla, la presion arterial y el diametro de cintura, y se determinaron su perfil lipidico y su glucemia. Resultados El 12,8% de los alumnos presento algun grado de hipertension arterial, que fue mayor en varones que en mujeres (p Conclusiones En la poblacion estudiada se encontro una alta prevalencia de los principales factores de riesgo cardiovascular. Parece necesario establecer campanas focalizadas y periodicas que tengan como objetivo mejorar los estilos de vida (disminuir la prevalencia de factores de riesgo cardiovascular) en jovenes que aun no expresan morbimortalidad.
Desigualdades na utilização e no acesso a serviços odontológicos: uma avaliação em nível nacional

Para avaliar a situacao de utilizacao e acesso aos servicos de odontologia no Brasil e estudar diferenciais entre os estratos socioeconomicos, utilizaram-se dados da Pesquisa Nacional por Amostragem de Domicilios (PNAD) de 1998, realizada pelo IBGE. A analise, que levou em conta o desenho amostral, indicou um nivel baixo de utilizacao de servicos odontologicos. Setenta e sete por cento das criancas de 0-6 anos e 4% dos adultos de 20-49 anos nunca haviam consultado um dentista. Entre estes adultos, comparando-se os 20% mais pobres com os 20% mais ricos, observou-se que o numero de desassistidos era 16 vezes maior entre os primeiros. No grupo de 0-6 anos, as criancas ricas consultaram o dentista cinco vezes mais do que as pobres no ano anterior a entrevista. Cerca de 4% dos que procuraram atendimento odontologico nao o obtiveram, 8% dos quais entre os mais pobres e 1% entre os mais ricos. A maioria (68%) dos atendimentos do grupo mais pobre foi financiada pelo SUS, enquanto 63% deles foram pagos pelos mais ricos. As maiores desigualdades no acesso e na utilizacao de servicos odontologicos foram encontradas, exatamente, nos grupos de menor acesso ou utilizacao. A participacao do SUS nos atendimentos odontologicos e muito mais baixa do que na atencao medica.
Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP

The ARRIVE guidelines have been implemented in BJP for 4 years with the aim of increasing transparency in reporting experiments involving animals. BJP has assessed our success in implementing them and concluded that we could do better. This editorial discusses the issues and explains how we are changing our requirements for authors to report their findings in experiments involving animals. This is one of a series of editorials discussing updates to the BJP Instructions to Authors
Protective effects of n‐6 fatty acids‐enriched diet on intestinal ischaemia/reperfusion injury involve lipoxin A4 and its receptor

Long‐term intake of dietary fatty acids is known to predispose to chronic inflammation, but their effects on acute intestinal ischaemia/reperfusion (I/R) injury is unknown. The aim of this study was to determine the consequences of a diet rich in n‐3 or n‐6 polyunsaturated fatty acids (PUFA) on intestinal I/R‐induced damage.
Anaesthetics as cardioprotectants: translatability and mechanism

The pharmacological conditioning of the heart with anaesthetics, such as volatile anaesthetics or opioids, is a phenomenon whereby a transient exposure to an anaesthetic agent protects the heart from the harmful consequences of myocardial ischaemia and reperfusion injury. The cellular and molecular mechanisms of anaesthetic conditioning appear largely to mimic those of ischaemic pre‐ and post‐conditioning. Progress has been made on the understanding of the underlying mechanisms although the order of events and the specific targets of anaesthetics that trigger protection are not always clear. In the laboratory, the protection afforded by certain anaesthetics against cardiac ischaemia and reperfusion injury is powerful and reproducible but this has not necessarily translated into similarly robust clinical benefits. Indeed, clinical studies and meta‐analyses delivered variable results when comparing in the laboratory setting protective and non‐protective anaesthetics. Reasons for this include underlying conditions such as age, obesity and diabetes. Animal models for disease or ageing, human cardiomyocytes derived from stem cells of patients and further clinical studies are employed to better understand the underlying causes that prevent a more robust protection in patients.
Rethinking safety and fidelity: The role of love and intimacy in hepatitis C transmission and prevention

Abstract Hepatitis C (HCV) is a disease of the liver with a range of potentially debilitating symptoms, the severity of which differ from person to person. HCV is a major public health challenge. Globally an estimated one in 12 persons is affected by the virus, and substantial new transmissions occur each year. The vast majority of new transmissions occur among people who inject drugs, particularly through practices such as sharing of needles, syringes and other injecting equipment. Behavioural surveillance data suggest that the majority of equipment sharing occurs between intimate partners. Despite this, very little research has focussed on intimate partnerships as a site of hepatitis C transmission or prevention. This is in part because people who inject drugs are conventionally represented as lacking capacity for romantic love and intimacy; also, drug ‘addiction’ is produced as the antithesis of voluntarity, autonomy and authenticity, all of which feature strongly in Western understandings of romantic love. This study aims to fill existing gaps in the literature about the relationship between romantic love and injecting drug use (IDU) and to explore injecting drug practices among partners in intimate relationships. Fifteen people who inject drugs, currently in long-term heterosexual relationships, were recruited for in-depth interviews, which were recorded, transcribed verbatim and analysed thematically. The main findings of this study are that romantic love and intimacy figure prominently in the lives of people who inject drugs, and that romantic notions such as commitment, trust, care and support shape how individuals who inject drugs talk about serostatus with their partners and how they account for injecting practices. Moreover, injecting practices are co-produced within intimate relationships, shaped by perceptions of risk within and outside the relationship, ideas of intimacy, and the specific levels of skill and expertise within these relationships. These findings have important implications for harm reduction strategies, which, we suggest, have largely failed to take into account the intimate relationship as a source of practice. We conclude with suggestions for future work in this area.
A 3-year Follow-up Study on the Alternating Use of Static Splints after Metacarpophalangeal Joint Arthroplasty in a Patient with Rheumatoid Arthritis

: Burr et al. (2002) reported the results of a 19-month follow-up study on a static splinting regimen as an alternative to dynamic extension splinting after metacarpophalangeal (MCP) joint arthroplasty. However, the long-term results of static splinting therapy have not been reported. Therefore, we conducted a 3-year follow-up study on the use of alternating static splinting in extension and flexion after MCP joint arthroplasty. Active flexion and extension of the MCP joints and grip strength were evaluated before surgery and at 12 weeks and 3 years after surgery. The range of motion (ROM) of the MCP joints and grip strength improved at 12 weeks and 3 years postoperatively. The efficacy of dynamic extension splinting after MCP joint arthroplasty indicated no change in the ROM and grip strength. The findings in this case indicate the positive long-term results of a static splinting regimen.
The endoplasmic reticulum stress and the HIF‐1 signalling pathways are involved in the neuronal damage caused by chemical hypoxia

Hypoxia inducible factor‐1 (HIF‐1) promotes transitory neuronal survival suggesting that additional mechanisms such as the endoplasmic reticulum (ER) stress might be involved in determining neuronal survival or death. Here, we examined the involvement of ER stress in hypoxia‐induced neuronal death and analysed the relationship between ER stress and the HIF‐1 pathways.
The Akt inhibitor, triciribine, ameliorates chronic hypoxia‐induced vascular pruning and TGFβ‐induced pulmonary fibrosis

Interstitial lung disease accounts for a group of chronic and progressive disorders associated with severe pulmonary vascular remodelling, peripheral vascular rarefaction and fibrosis, thus limiting lung function. We have previously shown that Akt is necessary for myofibroblast differentiation, a critical event in organ fibrosis. However, the contributory role of the Akt‐mTOR pathway in interstitial lung disease and the therapeutic benefits of targeting Akt and mTOR remain unclear.
Fulminant hepatic failure

Fulminant hepatic failure (FHF) is an acute and eventually fatal illness, caused by a severe hepatocyte damage with massive necrosis. Its hallmarks are hepatic encephalopathy and a prolonged prothrombin time (<40%). FHF is currently defined as hyperacute (encephalopathy appearing within 7 days of the onset of jaundice), acute (encephalopathy appearing between 8 and 28 days) or subacute (encephalopathy appearing between 5 and 12 weeks). FHF can be caused by viruses, drugs, toxins, and miscellaneous conditions such as Wilson’s disease, Budd-Chiari syndrome, ischemia and others. However, a single most common etiology is still not defined. Factors that are valuable in assessing the likelihood of spontaneous recovery are age, etiology, degree of encephalopathy, prothrombin time and serum bilirubin. The management is based in the early treatment of infections, hemodynamic abnormalities, cerebral edema, and other associated conditions. Liver transplant has emerged as the most important advance in the therapy of FHF, with a survival rate that ranges between 60 and 80%. The use of hepatic support systems, extracorporeal liver support and auxiliary liver transplantation are innovative therapies (Rev Med Chile 2002; 130: 691-698).
Diacylglycerol lipase β inhibition reverses nociceptive behaviour in mouse models of inflammatory and neuropathic pain

Inhibition of diacylglycerol lipase (DGL)β prevents LPS‐induced pro‐inflammatory responses in mouse peritoneal macrophages. Thus, the present study tested whether DGLβ inhibition reverses allodynic responses of mice in the LPS model of inflammatory pain, as well as in neuropathic pain models.
Relaxant action mechanism of berberine identified as the active principle of Argemone ochroleuca Sweet in guinea‐pig tracheal smooth muscle

In this study we investigated the relaxant effect of the aerial parts of Argemone ochroleuca (Papaveraceae), which is used in Mexican traditional medicine for the treatment of various respiratory diseases such as cough, bronchitis and asthma. The alkaloid berberine was identified as one of the active relaxant principles (EC50 = 118.50 ± 3.91 μM) in the dichloromethane extract of A. ochroleuca (EC50 = 78.03 ± 2.15 μg mL−1 with 95.12 ± 3.56% of relaxation). Berberine concentration‐dependently relaxed the carbachol‐induced precontractions but not histamine‐ or KCl‐induced precontraction. The relaxant effect of berberine was unaffected by the presence of propranolol (3 μM), glibenclamide (10 μM) or ODQ (10 μM). However, 2′, 5′‐dideoxyadenosine (10 μM) blocked the log concentration‐response curves of berberine. On the other hand, berberine produced a leftward shift of the log concentration‐response curves of isoproterenol, forskolin and nitroprusside. Additionally, berberine produced a parallel rightward shift of the concentration‐response curve of carbachol in a competitive manner with a pA2 of 3.87 ± 0.045. The above results suggest that the relaxant effect of berberine on tracheal muscle is due to its antagonistic effect on muscarinic acetylcholine receptors.
Faster clearance of omeprazole in rats with acute renal failure induced by uranyl nitrate: contribution of increased expression of hepatic cytochrome P450 (CYP) 3A1 and intestinal CYP1A and 3A subfamilies

It has been reported that omeprazole is mainly metabolized via hepatic cytochrome P450 (CYP) 1A1/2, CYP2D1 and CYP3A1/2 in male Sprague‐Dawley rats, and the expression of hepatic CYP3A1 is increased in male Sprague‐Dawley rats with acute renal failure induced by uranyl nitrate (U‐ARF rats). Thus, the metabolism of omeprazole would be expected to increase in U‐ARF rats. After intravenous administration of omeprazole (20 mgkg−1) to U‐ARF rats, the area under the plasma concentration‐time curve from time zero to infinity (AUC) was significantly reduced (371 vs 494 μg min mL−1), possibly due to the significantly faster non‐renal clearance (56.6 vs 41.2 mL min−1 kg−1) compared with control rats. This could have been due to increased expression of hepatic CYP3A1 in U‐ARF rats. After oral administration of omeprazole (40 mg kg−1) to U‐ARF rats, the AUC was also significantly reduced (89.3 vs 235 μg min mL−1) compared with control rats. The AUC difference after oral administration (62.0% decrease) was greater than that after intravenous administration (24.9% decrease). This may have been primarily due to increased intestinal metabolism of omeprazole caused by increased expression of intestinal CYP1A and 3A subfamilies in U‐ARF rats, in addition to increased hepatic metabolism.
Retinal microvascular changes and MRI signs of cerebral atrophy in healthy, middle-aged people

Objective: To examine the relation of retinal microvascular abnormalities and MRI signs of cerebral atrophy in healthy middle-aged people. Methods: A population-based, cross-sectional study involved 1,684 persons aged 51 to 72 years who had cerebral MRI and retinal photography in 1993 to 1995. Sulcal and ventricular size were quantified from the MRI scans and coded as grades 0 to 9, with sulcal widening (SW) and ventricular enlargement (VE) defined as grades 3 or higher. The presence or absence of retinopathy, microaneurysms, hemorrhages, and other characteristics were defined from retinal photographs using a standardized protocol. Generalized arteriolar narrowing was defined from a computer-assisted measurement of arteriolar diameters from digitized photographs. Results: Persons with retinopathy had higher sulcal (p = 0.001) and ventricular (p = 0.03) grades than persons without retinopathy. After adjusting for age, gender, race, mean arterial blood pressure, diabetes, cigarette smoking, common carotid artery intima–media thickness, and other vascular risk factors, retinopathy was significantly associated with SW (odds ratio [OR], 1.9; 95% CI, 1.2, 3.0) and VE (OR, 1.5; 95% CI, 1.0, 2.3). These associations persisted even in people without diabetes or hypertension (OR 1.9, 95% CI, 0.8, 4.4 for SW; OR 2.7, 95% CI, 1.2, 6.5 for VE). Other retinal arteriolar characteristics (arteriovenous nicking, focal and generalized arteriolar narrowing) were not related to sulcal or ventricular grade. Conclusions: In healthy, middle-aged people, retinopathy is independently associated with sulcal and ventricular enlargement on MRI. This finding is compatible with the hypothesis that microvascular characteristics may influence the development of cerebral atrophic changes.
Xenobiotic‐metabolizing enzymes in Bacillus anthracis: molecular and functional analysis of a truncated arylamine N‐acetyltransferase isozyme

The arylamine N‐acetyltransferases (NATs) are xenobiotic‐metabolizing enzymes that play an important role in the detoxification and/or bioactivation of arylamine drugs and xenobiotics. In bacteria, NATs may contribute to the resistance against antibiotics such as isoniazid or sulfamides through their acetylation, which makes this enzyme family a possible drug target. Bacillus anthracis, a bacterial species of clinical significance, expresses three NAT isozymes with distinct structural and enzymatic properties, including an inactive isozyme ((BACAN)NAT3). (BACAN)NAT3 features both a non‐canonical Glu residue in its catalytic triad and a truncated C‐terminus domain. However, the role these unusual characteristics play in the lack of activity of the (BACAN)NAT3 isozyme remains unclear.
Cannabimimetic phytochemicals in the diet – an evolutionary link to food selection and metabolic stress adaptation?

The endocannabinoid system (ECS) is a major lipid signalling network that plays important pro‐homeostatic (allostatic) roles not only in the nervous system but also in peripheral organs. There is increasing evidence that there is a dietary component in the modulation of the ECS. Cannabinoid receptors in hominids co‐evolved with diet, and the ECS constitutes a feedback loop for food selection and energy metabolism. Here, it is postulated that the mismatch of ancient lipid genes of hunter‐gatherers and pastoralists with the high‐carbohydrate diet introduced by agriculture could be compensated for via dietary modulation of the ECS. In addition to the fatty acid precursors of endocannabinoids, the potential role of dietary cannabimimetic phytochemicals in agriculturist nutrition is discussed. Dietary secondary metabolites from vegetables and spices able to enhance the activity of cannabinoid‐type 2 (CB2) receptors may provide adaptive metabolic advantages and counteract inflammation. In contrast, chronic CB1 receptor activation in hedonic obese individuals may enhance pathophysiological processes related to hyperlipidaemia, diabetes, hepatorenal inflammation and cardiometabolic risk. Food able to modulate the CB1/CB2 receptor activation ratio may thus play a role in the nutrition transition of Western high‐calorie diets. In this review, the interplay between diet and the ECS is highlighted from an evolutionary perspective. The emerging potential of cannabimimetic food as a nutraceutical strategy is critically discussed.
Relaxin‐like peptides in male reproduction – a human perspective

The relaxin family of peptide hormones and their cognate GPCRs are becoming physiologically well‐characterized in the cardiovascular system and particularly in female reproductive processes. Much less is known about the physiology and pharmacology of these peptides in male reproduction, particularly as regards humans. H2‐relaxin is involved in prostate function and growth, while insulin‐like peptide 3 (INSL3) is a major product of the testicular Leydig cells and, in the adult, appears to modulate steroidogenesis and germ cell survival. In the fetus, INSL3 is a key hormone expressed shortly after sex determination and is responsible for the first transabdominal phase of testicular descent. Importantly, INSL3 is becoming a very useful constitutive biomarker reflecting both fetal and post‐natal development. Nothing is known about roles for INSL4 in male reproduction and only very little about relaxin‐3, which is mostly considered as a brain peptide, or INSL5. The former is expressed at very low levels in the testes, but has no known physiology there, whereas the INSL5 knockout mouse does exhibit a testicular phenotype with mild effects on spermatogenesis, probably due to a disruption of glucose homeostasis. INSL6 is a major product of male germ cells, although it is relatively unexplored with regard to its physiology or pharmacology, except that in mice disruption of the INSL6 gene leads to a disruption of spermatogenesis. Clinically, relaxin analogues may be useful in the control of prostate cancer, and both relaxin and INSL3 have been considered as sperm adjuvants for in vitro fertilization.
Dendrimers as therapeutic agents: a systematic review.

OBJECTIVES Dendrimers by virtue of their therapeutic value have recently generated enormous interest among biomedical scientists. This review describes the therapeutic prospects of the dendrimer system. KEY FINDINGS Their bioactivity suggests them to be promising therapeutic agents, especially in wound healing, bone mineralisation, cartilage formation and tissue repair, and in topical treatments to prevent HIV transmission. Findings also demonstrate their potential as anti-prion, anti-Alzheimer's, anticoagulant, antidote, anti-inflammatory and anticancer agents. One of the dendrimer-based formulations with activity against herpes simplex virus (VivaGel from Starpharma) has successfully completed phase I clinical trials and is expected to be available on the market soon. SUMMARY All reports cited in this review demonstrate the use of dendrimers as medical therapeutics in different ailments. The review focuses on the current state of therapeutic potential of the dendrimer system.