MECHANISMS IN ENDOCRINOLOGY: Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21

Fibroblast growth factor 21 (FGF21), a 181 amino acid circulating protein, is a member of the FGF superfamily, with relevant metabolic actions. It acts through the interaction with specific FGF receptors and a cofactor called β-Klotho, whose expression is predominantly detected in metabolically active organs. FGF21 stimulates glucose uptake in adipocytes via the induction of glucose transporter-1. This action is additive and independent of insulin. β-Cell function and survival are preserved, and glucagon secretion is reduced by this protein, thus decreasing hepatic glucose production and improving insulin sensitivity. Lipid profile has been shown to be improved by FGF21 in several animal models. FGF21 increases energy expenditure in rodents and induces weight loss in diabetic nonhuman primates. It also exerts favorable effects on hepatic steatosis and reduces tissue lipid content in rodents. Adaptive metabolic responses to fasting, including stimulation of ketogenesis and fatty acid oxidation, seem to be partially mediated by FGF21. In humans, serum FGF21 concentrations have been found elevated in insulin-resistant states, such as impaired glucose tolerance and type 2 diabetes. FGF21 levels are correlated with hepatic insulin resistance index, fasting blood glucose, HbA1c, and blood glucose after an oral glucose tolerance test. A relationship between FGF21 levels and long-term diabetic complications, such as nephropathy and carotid atheromatosis, has been reported. FGF21 levels decreased in diabetic patients after starting therapy with insulin or oral agents. Increased FGF21 serum levels have also been found to be associated with obesity. In children, it is correlated with BMI and leptin levels, whereas in adults, FGF21 levels are mainly related to several components of the metabolic syndrome. Serum FGF21 levels have been found to be elevated in patients with ischemic heart disease. In patients with renal disease, FGF21 levels exhibited a progressive increase as renal function deteriorates. Circulating FGF21 levels seem to be related to insulin resistance and inflammation in dialysis patients. In summary, FGF21 is a recently identified hormone with antihyperglycemic, antihyperlipidemic, and thermogenic properties. Direct or indirect potentiation of its effects might be a potential therapeutic target in insulin-resistant states.     

Weight-Related Quality of Life in Spanish Obese Subjects Suitable for Bariatric Surgery is Lower Than in Their North American Counterparts: a Case–Control Study

Background

Obesity impairs quality of life, but the perception of the impairment could be different from one country to another. The purpose was to compare weight-related quality of life (QOL) between cohorts from Spain and North America.

Methods

A cross-sectional case–control study was performed between two populations. Four hundred Spanish and 400 North American obese subjects suitable for bariatric surgery closely matched for race, gender, age, and body mass index (BMI) were included. Two non-obese control groups matched for gender, age, and BMI from each population were also evaluated (n?=?400 in each group). The participants completed the Impact of Weight on Quality of Life—Lite (IWQOL—Lite) questionnaire, a measure of weight-related QOL.

Results

Spanish morbidly obese patients showed poorer QOL than their North American counterparts in physical function, sexual life, work, and total score. By contrast, Spanish non-obese control subjects reported better QOL in all domains than their North American counterparts. Women, both in Spain and North America, reported reduced QOL compared to men on the domain of self-esteem. In addition, North American women reported reduced QOL on the sexual life domain compared to men. BMI correlated negatively with all domains of QOL except for self-esteem in both national groups.

Conclusions

Spanish obese subjects suitable for bariatric surgery report poorer weight-related quality of life than their North American counterparts, and obese women, regardless of nationality, perceive a reduced quality of life compared to men.     

The role of a mineralocorticoid receptor gene functional polymorphism in the symptom dimensions of persistent ADHD

Attention-deficit/hyperactivity disorder (ADHD) affects approximately 5 % of school-aged children and 2.5 % of adults. Genetic studies in ADHD have pointed to genes in different neurobiological systems, with relatively small individual effects. The mineralocorticoid receptor is the main receptor involved in the initial triggering of stress response. Therefore, its encoding gene (NR3C2) is a candidate for psychiatric disorder studies, including ADHD, and behavioral phenotypes. There is evidence that the Val allele of the MRI180V polymorphism (rs5522) increases the risk of depression, attention and cognitive deficits. We investigated the possible role of the mineralocorticoid receptor gene in the symptom dimensions and susceptibility to persistent ADHD. We compared genotype and allele frequencies in 478 adult patients with ADHD and 597 controls and symptom dimensions in 449 patients and 132 controls. Diagnoses were based on the DSM-IV criteria. ADHD symptom dimensions were investigated with SNAP-IV for ADHD severity and Barkley scales for severity and impairment. Carriers of the Val allele presented higher inattention, hyperactivity/impulsivity and impairment scores, while genotype and allele frequencies did not differ between patients and controls. These results are consistent with a possible link between genetic variations in the HPA axis and inattention and hyperactivity measures.     

FreeSurfer-based segmentation of hippocampal subfields: A review of methods and applications,with a novel quality control procedure for ENIGMA studies and other collaborative efforts

Structural hippocampal abnormalities are common in many neurological and psychiatric disorders, and variation in hippocampal measures is related to cognitive performance and other complex phenotypes such as stress sensitivity. Hippocampal subregions are increasingly studied, as automated algorithms have become available for mapping and volume quantification. In the context of the Enhancing Neuro Imaging Genetics through Meta Analysis Consortium, several Disease Working Groups are using the FreeSurfer software to analyze hippocampal subregion (subfield) volumes in patients with neurological and psychiatric conditions along with data from matched controls. In this overview, we explain the algorithm's principles, summarize measurement reliability studies, and demonstrate two additional aspects (subfield autocorrelation and volume/reliability correlation) with illustrative data. We then explain the rationale for a standardized hippocampal subfield segmentation quality control (QC) procedure for improved pipeline harmonization. To guide researchers to make optimal use of the algorithm, we discuss how global size and age effects can be modeled, how QC steps can be incorporated and how subfields may be aggregated into composite volumes. This discussion is based on a synopsis of 162 published neuroimaging studies (01/2013–12/2019) that applied the FreeSurfer hippocampal subfield segmentation in a broad range of domains including cognition and healthy aging, brain development and neurodegeneration, affective disorders, psychosis, stress regulation, neurotoxicity, epilepsy, inflammatory disease, childhood adversity and posttraumatic stress disorder, and candidate and whole genome (epi-)genetics. Finally, we highlight points where FreeSurfer-based hippocampal subfield studies may be optimized.     

Exacerbated pathology of viral encephalitis in mice with central nervous system-specific autoantibodies

We examine here the outcome of viral encephalomyelitis [mouse hepatitis virus (MHV) A59, Theiler's encephalomyelitis virus, and Coxsackievirus B3] in mice with autoantibodies to a central nervous system (CNS)-specific antigen, myelin oligodendrocyte glycoprotein, that usually develop no clinical disease. Morbidity and mortality of the acute viral CNS disease was augmented by the presence of the autoantibodies in all three viral infections. Transfer of serum containing the autoantibodies at the time of infection with MHV was sufficient to reproduce the exacerbated disease. The presence of the autoantibodies was found to result in increased infiltration of mononuclear cells into the brain. Early demyelination was severely augmented in brains and spinal cords of MHV-infected mice with CNS-specific autoantibodies. The antibody-mediated exacerbation was shown to be independent of the complement system but to require expression of Fc receptors, because it was observed in C'-3-deficient but not in Fc receptor-deficient mice. Our study illustrates the possibility that infections can lead to much more profound immunopathology in the presence of an otherwise latent autoimmune condition.     

From transit hub to major supplier of illicit cigarettes to Argentina and Brazil: the changing role of domestic production and transnational tobacco companies in Paraguay between 1960 and 2003

Background

Paraguay has reportedly been a major transit hub for illicit tobacco products since the 1960s, initially to supply markets in Argentina and Brazil and, more recently, other regional markets and beyond. However, to date there has been no systematic analysis, notably independent of the tobacco industry, of this trade including the roles of domestic production and transnational tobacco companies (TTCs). This article fills that gap by detailing the history of Paraguay’s illicit cigarette trade to Brazil and Argentina of TTC products and Paraguayan production between 1960 and 2003. The effective control of illicit cigarette flows, under Article 15 of the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) and the Protocol to Eliminate the Illicit Trade in Tobacco Products, requires fuller understanding of the changing nature of the illicit trade.

Methods

We systematically searched internal industry documents to understand the activities and strategies of leading TTCs in Paraguay and subregion over time. We also mapped illicit trade volume and patterns using US government and UN data on the cigarette trade involving Paraguay. We then estimated Paraguay’s cigarette production from 1989 to 2003 using tobacco leaf flows from the United Nations Commodity Trade Statistics Database (UN Comtrade).

Results

We identify four phases in the illicit tobacco trade involving Paraguay: 1) Paraguay as a transit hub to smuggle BAT and PMI cigarettes from the U.S. into Argentina and Brazil (from the 1960s to the mid-1970s); 2) BAT and PMI competing in north-east Argentina (1989–1994); 3) BAT and PMI competing in southern and southern-east Brazil (mid to late 1990s); and 4) the growth in the illicit trade of Paraguayan manufactured cigarettes (from the mid- 1990s onwards). These phases suggest the illicit trade was seeded by TTCs, and that the system of supply and demand on lower priced brands they developed in the 1990s created a business opportunity for manufacturing in Paraguay. Brazil’s efforts to fight this trade, with a 150% tax on exports to Latin American countries in 1999, further prompted supply of the illicit trade to shift from TTCs to Paraguayan manufacturers.

Conclusion

This paper extends evidence of the longstanding complicity of TTCs in the illicit trade to this region and the consequent growth of Paraguayan production in the 1990s. Our findings confirm the need to better understand the factors influencing how the illicit tobacco trade has changed over time, in specific regional contexts, and amid tobacco industry globalization. In Paraguay, the changing roles of TTC and domestic production have been central to shifting patterns of illicit supply and distribution since the 1960s. Important questions are raised, in turn, about TTCs efforts to participate as legitimate partners in global efforts to combat the problem, including a leading role in data gathering and analysis.

     

Using case management in a universal health coverage system to improve quality of life of frequent Emergency Department users: a randomized controlled trial

Purpose

Frequent Emergency Department users are likely to experience poor quality of life (QOL). Case management interventions are efficient in responding to the complex needs of this population, but their effects on QOL have not been tested yet. Therefore, the aim of our study was to examine to what extent a case management intervention improved frequent Emergency Department users’ QOL in a universal health coverage system.

Methods

Data were part of a randomized controlled trial designed to improve frequent Emergency Department users’ QOL at the Lausanne University Hospital, Switzerland. A total of 250 frequent Emergency Department users (≥?5 attendances during the previous 12 months) were randomly assigned to the control (n?=?125) or the intervention group (n?=?125). The latter benefited from case management intervention. QOL was evaluated using the WHOQOL-BREF at baseline, two, five and a half, nine, and twelve months later. It included four dimensions: physical health, psychological health, social relationship, and environment. Linear mixed-effects models were used to analyze the change in the patients’ QOL over time.

Results

Patients’ QOL improved significantly (p?<?0.001) in both groups for all dimensions after two months. However, environment QOL dimension improved significantly more in the intervention group after 12 months.

Conclusions

Environment QOL dimension was the most responsive dimension for short-term interventions. This may have been due to case management’s assistance in obtaining income entitlements, health insurance coverage, stable housing, or finding general health care practitioners. Case management in general should be developed to enhance frequent users’ QOL.Trial registration: http://www.clinicaltrials.gov, Unique identifier: NCT01934322

     

Vasculitis during immunotherapy treatment in a patient with allergy to Cupressus arizonica

Allergen immunotherapy dates back to 1911 and has been used successfully to treat large numbers of patients throughout the last century. CASE REPORT: a 66-year-old woman presented with symptoms of allergic rhinitis and asthma due to sensitization to Cupressus arizonica. Specific immunotherapy was prescribed as a continuous 2-year treatment with a depot preparation of standarized and characterized allergen extracts of Cupressus arizonica pollen. Forty-eight hours after one maintenance dose of 0.8 cc, the patient presented palpable violaceous purpuric lesions and pruritus on both legs. We performed skin prick and intradermal tests with Cupressus arizonica. Twenty-four hours later, the 1/1 dilution intradermal skin test was positive. Biopsy showed leukocytoclastic vasculitis. CONCLUSIONS: A middle-aged woman experienced cutaneous non-necrotizing vasculitis after 2 years of maintenance immunotherapy. The interval between injections and the first appearance of cutaneous lesions suggests a type III hypersensitivity immune reaction. Skin biopsy of the positive intradermal test also supports this hypothesis.