The implications of defining obesity as a disease: a report from the Association for the Study of Obesity 2021 annual conference

Unlike various countries and organisations, including the World Health Organisation and the European Parliament, the United Kingdom does not formally recognise obesity as a disease. This report presents the discussion on the potential impact of defining obesity as a disease on the patient, the healthcare system, the economy, and the wider society. A group of speakers from a wide range of disciplines came together to debate the topic bringing their knowledge and expertise from backgrounds in medicine, psychology, economics, and politics as well as the experience of people living with obesity. The aim of their debate was not to decide whether obesity should be classified as a disease but rather to explore what the implications of doing so would be, what the gaps in the available data are, as well as to provide up-to-date information on the topic from experts in the field. There were four topics where speakers presented their viewpoints, each one including a question-and-answer section for debate. The first one focused on the impact that the recognition of obesity could have on people living with obesity regarding the change in their behaviour, either positive and empowering or more stigmatising. During the second one, the impact of defining obesity as a disease on the National Health Service and the wider economy was discussed. The primary outcome was the need for more robust data as the one available does not represent the actual cost of obesity. The third topic was related to the policy implications regarding treatment provision, focusing on the public's power to influence policy. Finally, the last issue discussed, included the implications of public health actions, highlighting the importance of the government's actions and private stakeholders. The speakers agreed that no matter where they stand on this debate, the goal is common: to provide a healthcare system that supports and protects the patients, strategies that protect the economy and broader society, and policies that reduce stigma and promote health equity. Many questions are left to be answered regarding how these goals can be achieved. However, this discussion has set a good foundation providing evidence that can be used by the public, clinicians, and policymakers to make that happen

Congenic Mesenchymal Stem Cell Therapy Reverses Hyperglycemia in Experimental Type 1 Diabetes

OBJECTIVE - A number of clinical trials are underway to test whether mesenchymal stem cells (MSCs) are effective in treating various diseases, including type 1 diabetes. Although this cell therapy holds great promise, the optimal source of MSCs has yet to be determined with respect to major histocompatibility complex matching. Here, we examine this question by testing the ability of congenic MSCs, obtained from the NOR mouse strain, to reverse recent-onset type 1 diabetes in NOD mice, as well as determine the immunomodulatory effects of NOR MSCs in vivo. RESEARCH DESIGN AND METHODS - NOR MSCs were evaluated with regard to their in vitro immunomodulatory function in the context of autoreactive T-cell proliferation and dendritic cell (DC) generation. The in vivo effect of NOR MSC therapy on reversal of recent-onset hyperglycemia and on immunogenic cell subsets in NOD mice was also examined. RESULTS - NOR MSCs were shown to suppress diabetogenic T-cell proliferation via PD-L1 and to suppress generation of myeloid/inflammatory DCs predominantly through an IL-6-dependent mechanism. NOR MSC treatment of experimental type 1 diabetes resulted in long-term reversal of hyperglycemia, and therapy was shown to alter diabetogenic cytokine profile, to diminish T-cell effector frequency in the pancreatic lymph nodes, to alter antigen-presenting cell frequencies, and to augment the frequency of the plasmacytoid subset of DCs. CONCLUSIONS - These studies demonstrate the inimitable benefit of congenic MSC therapy in reversing experimental type 1 diabetes. These data should benefit future clinical trials using MSCs as treatment for type 1 diabetes

Enhanced diagnostic immunofluorescence using biopsies transported in saline

BACKGROUND: The demonstration of tissue-bound immunoreactants by direct immunofluorescence microscopy (DIF) is a valuable parameter in the diagnosis of various autoimmune and immunecomplex-mediated skin diseases. For preservation of tissue-bound immunoreactants, biopsies are usually fresh-frozen in liquid nitrogen or transported in Michel's fixative. But even optimally preserved tissue specimens are no guarantee for the correct diagnosis by DIF, especially when weak to moderate IgG fluorescence of the epidermal basement membrane zone is involved. In such cases false negative results are easily obtained due to the relatively high dermal "background" fluorescence produced by polyclonal anti-human IgG fluorescein conjugates. METHODS: In the present study we have compared the use of normal saline (0.9% NaCl) with liquid nitrogen and Michel's fixative as transport medium for skin biopsies. From 25 patients with an autoimmune skin disease (pemphigus, pemphigoid, lupus erythematosus and vasculitis) four matched skin biopsies were obtained and transported in either saline for 24 and 48 hours, liquid nitrogen, or Michel's fixative for 48 hours. RESULTS: Direct IF microscopy showed significant reduction of background fluorescence (p < 0.01) and relatively enhanced desired specific (IgG, IgA) staining in biopsies transported in saline. A conclusive or tentative IF diagnosis was reached in 92% after 24 h saline, 83% after 48 h saline, 68% after freezing in liquid nitrogen, and 62% after 48 h Michel's medium (n = 25). CONCLUSIONS: We conclude that transporting biopsies without freezing in normal saline for 24 hours is an adequate and attractive method for routine IF diagnosis in autoimmune and immune complex-mediated dermatoses. The superior results with saline incubation are explained by washing away of IgG background in dermis and epidermis

The cytoprotective drug amifostine modifies both expression and activity of the pro-angiogenic factor VEGF-A

Peer reviewedPublisher PD

Contrasting Alloreactive CD4 + and CD8 + T Cells: There's More to It Than MHC Restriction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73698/1/j.1600-6143.2003.00036.x.pd

Molecular targets in the discovery and development of novel antimetastatic agents: current progress and future prospects

Tumour invasion and metastasis have been recognized as major causal factors in the morbidity and mortality among cancer patients. Many advances in the knowledge of cancer metastasis have yielded an impressive array of attractive drug targets, including enzymes, receptors and multiple signalling pathways. The present review summarizes the molecular pathogenesis of metastasis and the identification of novel molecular targets used in the discovery of antimetastatic agents. Several promising targets have been highlighted, including receptor tyrosine kinases, effector molecules involved in angiogenesis, matrix metalloproteinases (MMPs), urokinase plasminogen activator, adhesion molecules and their receptors, signalling pathways (e.g. phosphatidylinositol 3-kinase, phospholipase Cγ1, mitogen-activated protein kinases, c-Src kinase, c-Met kinases and heat shock protein. The discovery and development of potential novel therapeutics for each of the targets are also discussed in this review. Among these, the most promising agents that have shown remarkable clinical outcome are anti-angiogenic agents (e.g. bevacizumab). Newer agents, such as c-Met kinase inhibitors, are still undergoing preclinical studies and are yet to have their clinical efficacy proven. Some therapeutics, such as first-generation MMP inhibitors (MMPIs; e.g. marimastat) and more selective versions of them (e.g. prinomastat, tanomastat), have undergone clinical trials. Unfortunately, these drugs produced serious adverse effects that led to the premature termination of their development. In the future, third-generation MMPIs and inhibitors of signalling pathways and adhesion molecules could form valuable novel classes of drugs in the anticancer armamentarium to combat metastasis

The implications of defining obesity as a disease: a report from the Association for the Study of Obesity 2021 annual conference

Unlike various countries and organisations, including the World Health Organisation and the European Parliament, the United Kingdom does not formally recognise obesity as a disease. This report presents the discussion on the potential impact of defining obesity as a disease on the patient, the healthcare system, the economy, and the wider society. A group of speakers from a wide range of disciplines came together to debate the topic bringing their knowledge and expertise from backgrounds in medicine, psychology, economics, and politics as well as the experience of people living with obesity. The aim of their debate was not to decide whether obesity should be classified as a disease but rather to explore what the implications of doing so would be, what the gaps in the available data are, as well as to provide up-to-date information on the topic from experts in the field. There were four topics where speakers presented their viewpoints, each one including a question-and-answer section for debate. The first one focused on the impact that the recognition of obesity could have on people living with obesity regarding the change in their behaviour, either positive and empowering or more stigmatising. During the second one, the impact of defining obesity as a disease on the National Health Service and the wider economy was discussed. The primary outcome was the need for more robust data as the one available does not represent the actual cost of obesity. The third topic was related to the policy implications regarding treatment provision, focusing on the public's power to influence policy. Finally, the last issue discussed, included the implications of public health actions, highlighting the importance of the government's actions and private stakeholders. The speakers agreed that no matter where they stand on this debate, the goal is common: to provide a healthcare system that supports and protects the patients, strategies that protect the economy and broader society, and policies that reduce stigma and promote health equity. Many questions are left to be answered regarding how these goals can be achieved. However, this discussion has set a good foundation providing evidence that can be used by the public, clinicians, and policymakers to make that happen

An early history of T cell-mediated cytotoxicity.

After 60 years of intense fundamental research into T cell-mediated cytotoxicity, we have gained a detailed knowledge of the cells involved, specific recognition mechanisms and post-recognition perforin-granzyme-based and FAS-based molecular mechanisms. What could not be anticipated at the outset was how discovery of the mechanisms regulating the activation and function of cytotoxic T cells would lead to new developments in cancer immunotherapy. Given the profound recent interest in therapeutic manipulation of cytotoxic T cell responses, it is an opportune time to look back on the early history of the field. This Timeline describes how the early findings occurred and eventually led to current therapeutic applications

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project

BACKGROUND: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. METHODS: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. RESULTS: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia