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Obesity and diabetes are a progressively more and more deleterious hallmark of modern, well fed societies. In order to study the potential impact of strategies designed to obviate the pathological consequences of detrimental lifestyles, a model for the development of Type 2 diabetes geared towards large population simulations would be useful. The present work introduces such a model, representing in simplified fashion the interplay between average glycemia, average insulinemia and functional beta-cell mass, and incorporating the effects of excess food intake or, conversely, of physical activity levels. Qualitative properties of the model are formally established and simulations are shown as examples of its use., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The diagnosis of multiple sclerosis is based on neurological symptoms and signs, alongside evidence of dissemination of CNS lesions in space and time. MRI is often sufficient to confirm the diagnosis when characteristic lesions accompany a typical clinical syndrome, but in some patients, further supportive information is obtained from cerebrospinal fluid examination and neurophysiological testing. Differentiation is important from other diseases in which demyelination is a feature (eg, neuromyelitis optica spectrum disorder and acute disseminated encephalomyelitis) and from non-demyelinating disorders such as chronic small vessel disease and other inflammatory, granulomatous, infective, metabolic, and genetic causes that can mimic multiple sclerosis. Advances in MRI and serological and genetic testing have greatly increased accuracy in distinguishing multiple sclerosis from these disorders, but misdiagnosis can occur. In this Series paper we explore the progress and challenges in the diagnosis of multiple sclerosis with reference to diagnostic criteria, important differential diagnoses, controversies and uncertainties, and future prospects., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Susac's syndrome is the clinical triad of encephalopathy, branch retinal artery occlusions and sensorineural hearing loss (Susac 1994) [1]. It occurs predominantly in young females and is believed to be an immune-mediated endotheliopathy of small vessels of the brain, retina and cochlea (Neumayer et al. 2009) [2]. Early, aggressive, and sustained immunosuppressive therapy has been recommended for Susac's syndrome and anecdotal evidence has suggested a therapeutic role for monoclonal antibodies (Rennebohm et al. 2008, Lee and Amezcua 2009) [3,4]. We report a case of Susac's syndrome in which the patient improved immediately after tumour necrosis factor (TNF) inhibition with the monoclonal antibody, infliximab., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objective: The objective of this study was to evaluate the association of established risk factors for treatment-emergent diabetes (TED) among patients over 65 years of age with dementia who received treatment with olanzapine., Methods: This was a post hoc analysis of data pooled from seven olanzapine clinical trials, which included patients over 65 years of age with dementia. The association of established risk factors for TED was evaluated using categorical and time-to-event analysis. TED was defined as two casual (fasting or nonfasting) glucose values > or =200 mg/dL at any time after baseline or one casual glucose value > or =200 mg/dL at the final visit, initiation of antidiabetic medication, or new clinical diagnosis of diabetes., Results: Elderly patients subsequently identified with TED (N = 29, 2.1%) had similar baseline body mass indices (24 kg/m(2)) and were similar in age (82 versus 80 years) to those who did not have TED. Cox proportional hazards model identified only elevated casual glucose (> or =140 mg/dL) measure at baseline to be significantly associated with the development of TED (hazard ratio [HR] = 11.2, p <0.0001) in this elderly cohort. Other clinical risk factors, like body mass index > or =25 (HR = 0.86), 7% weight gain (HR = 2.26), and antipsychotic treatment (HR = 1.36) were not significant., Conclusion: In elderly patients with dementia enrolled in olanzapine clinical trials, an elevated casual glucose (> or =140 mg/dL) at baseline was the only risk factor significantly associated with subsequent development of TED. Risk of diabetes in these studies was not significantly associated with antipsychotic treatment group assignment.

Objectives: The objective of this study was to investigate risk of diabetes among elderly patients during treatment with antipsychotic medications., Design: We conducted a longitudinal, retrospective study assessing the incidence of new prescription claims for antihyperglycemic agents during antipsychotic therapy., Setting: Prescription claims from the AdvancePCS claim database were followed for 6 to 9 months., Participants: Study participants consisted of patients in the United States aged 60+ and receiving antipsychotic monotherapy. The following cohorts were studied: an elderly reference population (no antipsychotics: n = 1,836,799), those receiving haloperidol (n = 6481) or thioridazine (n = 1658); all patients receiving any conventional antipsychotic monotherapy (n = 11,546), clozapine (n = 117), olanzapine (n = 5382), quetiapine (n = 1664), and risperidone (n = 12,244), and all patients receiving any atypical antipsychotic monotherapy (n = 19,407)., Measurements: We used Cox proportional hazards regression to determine the risk ratio of diabetes for antipsychotic cohorts relative to the reference population. Covariates included sex and exposure duration., Results: New antihyperglycemic prescription rates were higher in each antipsychotic cohort than in the reference population. Overall rates were no different between atypical and conventional antipsychotic cohorts. Among individual antipsychotic cohorts, rates were highest among patients treated with thioridazine (95% confidence interval [CI], 3.1- 5.7), lowest with quetiapine (95% CI, 1.3-2.9), and intermediate with haloperidol, olanzapine, and risperidone. Among atypical cohorts, only risperidone users had a significantly higher risk (95% CI, 1.05-1.60; P = 0.016) than for haloperidol. Conclusions about clozapine were hampered by the low number of patients., Conclusion: These data suggest that diabetes risk is elevated among elderly patients receiving antipsychotic treatment. However, causality remains to be demonstrated. As a group, the risk for atypical antipsychotic users was not significantly different than for users of conventional antipsychotics.

A Saccharomyces cerevisiae gene was identified that would encode a protein similar to the mammalian protein kinase glycogen synthase kinase-3 (GSK-3) and the Drosophila Zeste-White3/Shaggy gene product. The open reading frame predicts a 375 amino acid polypeptide with a putative protein kinase domain that displays 70% and 39% identity, respectively, to two known yeast proteins, Mds1p and Mck1p. The new gene, designated MRK1 (Mds1p Related Kinase), is located on chromosome IV. Disruption of MRK1 was not lethal and did not elicit any alteration in glycogen accumulation. In addition, an mck1 mds1 mrk1 triple disruptant was viable.

M13 DNAs in which carbon 5 of each deoxycytidine residue in one strand is replaced with a bulky group are very good substrates for human DNA (cytosine-5) methyltransferase. Rate enhancements of up to 35 fold are obtained depending on the size of the moiety at C-5. The enzyme appears optimally suited to sense a methyl group in one strand at this position. Alkaline density gradient analyses of the distribution of methyl groups applied to 5-BrdCyd or 5-IdCyd substituted DNA reveal that these groups serve to direct the enzyme to methylate the unsubstituted strand.

Synthetic oligodeoxynucleotides containing a dT.dG mispair at a centrally located d(pCG) dimer are methylated at a moderate rate by highly purified human DNA(cytosine-5)methyltransferase (E.C. 2.1.1.37). The presence of a mispaired dT in one strand induced the enzyme to preferentially methylate the opposite strand.