Onset of fulminant type 1 diabetes mellitus following hypophysitis after discontinuation of combined immunotherapy. A case report

Diabetes is a rare, but potentially life-threatening, adverse event of immune checkpoint inhibitors that requires prompt recognition and treatment. It usually occurs in the first 3 months of treatment and is typically related to programmed cell death-1 antibodies, alone or in combined therapy. It has rarely been described developing after immunotherapy cessation. We present a 51-year-old man with metastatic melanoma, who developed acute-onset diabetes 52 days after combined immunotherapy cessation with nivolumab and ipilimumab, and 25.6 months after receiving the first dose. He presented with acute hyperglycemic symptoms, ketosis, complete insulin depletion and negative autoimmunity, fulfilling the criteria of fulminant type 1 diabetes. The patient had previously developed hypophysitis with isolated adrenocorticotropic hormone deficiency during immunotherapy. We describe a case of late-onset fulminant type 1 diabetes developing after immunotherapy cessation. Patient education and active follow up after immunotherapy discontinuation are crucial to warrant a timely intervention.     

Enzymatic Block in the Synthesis of Gangliosides in DNA Virus-Transformed Tumorigenic Mouse Cell Lines

The ganglioside pattern of both SV40- and polyoma virus-transformed mouse cell lines differs from that of the parent cell lines or of cell lines that have transformed spontaneously in tissue culture. This is manifested by a dramatic decrease of gangliosides with an oligosaccharide chain larger than sialyllactose. Present investigations indicate that this change probably cannot be attributed to excessive catabolism of gangliosides, but is caused by impaired synthesis of tri- and tetrahexosyl gangliosides in the virus-transformed cell lines. We present evidence for the block of a required step for the biosynthesis of these ganglioside homologs. The block involves the enzyme catalyzing the transfer of N-acetylgalactosamine from uridine diphosphate N-acetylgalactosamine to hematosides (N-glycolylneuraminyl or N-acetylneuraminylgalactosylglucosyl ceramide). This well-defined enzymatic change opens the way for studies of the biochemical mechanism of the alteration of cell membranes which occurs after transformation by the tumorigenic DNA viruses polyoma and SV40.     

The retained antrum, its endoscopic diagnosis and clinical significance]

A 65-year-old man was admitted to our hospital with gastrointestinal bleeding. Seventeen years previously, he had a Billroth II procedure for a bleeding duodenal ulcer. A gastroscopy performed on admission showed a stomal ulcer with signs of recent haemorrhage. In the proximal end of the afferent loop, we saw retained gastric mucosa. Histological evaluation confirmed the existence of antrum gastric mucosa. Other diagnostic test for retained gastric antrum were normal. The different approaches in the diagnosis of retained gastric antrum, the importance of our findings and the clinic implications are discussed. We conclude that endoscopic management may be the first diagnostic method in the assessment of retained gastric antrum, and it's possible to find gastric mucosa in the proximal end of the afferent loop (antrum retained), without clinic manifestations.     

Quantifying selection in immune receptor repertoires

The efficient recognition of pathogens by the adaptive immune system relies on the diversity of receptors displayed at the surface of immune cells. T-cell receptor diversity results from an initial random DNA editing process, called VDJ recombination, followed by functional selection of cells according to the interaction of their surface receptors with self and foreign antigenic peptides. Using high-throughput sequence data from the β-chain of human T-cell receptors, we infer factors that quantify the overall effect of selection on the elements of receptor sequence composition: the V and J gene choice and the length and amino acid composition of the variable region. We find a significant correlation between biases induced by VDJ recombination and our inferred selection factors together with a reduction of diversity during selection. Both effects suggest that natural selection acting on the recombination process has anticipated the selection pressures experienced during somatic evolution. The inferred selection factors differ little between donors or between naive and memory repertoires. The number of sequences shared between donors is well-predicted by our model, indicating a stochastic origin of such public sequences. Our approach is based on a probabilistic maximum likelihood method, which is necessary to disentangle the effects of selection from biases inherent in the recombination process.The T-cell response of the adaptive immune system begins when receptor proteins on the surface of these cells recognize a pathogen peptide displayed by an antigen-presenting cell. The immune cell repertoire of a given individual is comprised of many clones, each with a distinct surface receptor. This diversity, which is central to the ability of the immune system to defeat pathogens, is initially created by a stochastic process of germline DNA editing (called VDJ recombination) that gives each new immune cell a unique surface receptor gene. This initial repertoire is subsequently modified by selective forces, including nonpathogen-related thymic selection against excessive (or insufficient) recognition of self proteins, which are also stochastic in nature. Because of this stochasticity and the large T-cell diversity, these repertoires are best described by probability distributions. In this paper, we apply a probabilistic approach to sequence data to obtain quantitative measures of the overall (not necessarily pathogenic) selection pressures that shape T-cell receptor repertoires.New receptor genes are formed by randomly choosing alleles from a set of genomic templates for the subregions (V, D, and J) of the complete gene. Insertion and deletion of nucleotides in the junctional regions between the V and D and D and J genes greatly enhance diversity beyond pure VDJ combinatorics (1). The most variable region of the gene is between the last amino acids of the V segment and the beginning of the J segment; it codes for the Complementarity Determining Region 3 (CDR3) loop of the receptor protein, a region known to be functionally important in recognition (2). Previous studies have shown that immune cell receptors are not uniform in terms of VDJ gene segment use (3–6) or probability of generation (1) and that certain receptors are more likely than others to be shared by different individuals (4, 7). The statistical properties of the immune repertoire are, thus, rather complex, and their accurate determination requires sophisticated methods.Recent advances in sequencing technology have made it possible to sample the T-cell receptor diversity of individual subjects in great depth (8). The availability of such data has, in turn, led to the development of sequence statistics-based approaches to the study of immune cell diversity (9, 10). In particular, we recently quantitatively characterized the preselection diversity of the human T-cell repertoire by learning the probabilistic rules of VDJ recombination from out-of-frame DNA sequences that cannot be subject to functional selection and whose statistics therefore reflect only the recombination process (1). After generation, T cells undergo a somatic selection process in the thymus (11) and later in the periphery (12). Cells that pass thymic selection enter the peripheral repertoire as naive T cells, and the subset of naive cells that eventually engage in an immune response will survive as a long-lived memory pool. Although we now understand the statistical properties of the initial repertoire of immune receptors (1) and despite some theoretical studies of thymic selection at the molecular level (13, 14), a quantitative understanding of how selection modifies those statistics to produce the naive and memory repertoires is lacking.In this paper, we build on our understanding of the preselection distribution of T-cell receptors to derive a statistical method for identifying and quantifying selection pressures in the adaptive immune system. We apply this method to naive and memory DNA sequences of human T-cell β-chains obtained from peripheral blood samples of nine healthy individuals. Our goal is to characterize the likelihood that any given sequence, after it is generated, will survive selection for the ensemble of properties needed to pass into the peripheral repertoire(s). Our analysis reveals strong and reproducible signatures of selection on specific amino acids in the CDR3 sequence and on the usage of V and J genes. Most strikingly, we find significant correlation between the generation probability of a sequence and the probability that it will pass selection. This correlation suggests that natural selection, which acts on very long timescales to shape the generation mechanism itself, may have tuned it to anticipate somatic selection, which acts on single cells throughout the lifetime of an individual. The quantitative features of selection inferred from our model vary very little between donors, indicating that these features are universal. In addition, our measures of selection pressure on the memory and naive repertoires are statistically indistinguishable, consistent with the hypothesis that the memory pool is a random subsample of the naive pool.     

Very Low Levels of Atherogenic Lipoproteins and the Risk for Cardiovascular Events : A Meta-Analysis of Statin Trials

Background

Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented.

Objectives

The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk.

Methods

This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up.

Results

Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB.

Conclusions

The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.     

Muscle intrusion as a potential cause of carpal tunnel syndrome

Introduction: The aim of this study was to determine whether there is an association between flexor digitorum and lumbrical muscle intrusion into the carpal tunnel and carpal tunnel syndrome (CTS). Methods: Five hundred thirteen manual laborers (1026 wrists) were evaluated with ultrasound to determine whether those with CTS had more muscle intrusion into the carpal tunnel than those without CTS. One hundred ninety of the participants without CTS at baseline (363 wrists) were followed over 1 year to determine whether muscle intrusion at baseline predicted the development of CTS. Results: Participants with CTS had more muscle within the carpal tunnel with the wrist in the neutral (P = 0.026) and flexed (P = 0.018) positions than those without CTS. Baseline muscle intrusion did not predict development of CTS at 1 year. Conclusions: Muscle intrusion into the carpal tunnel is associated with CTS, but muscle intrusion alone does not predict the development of CTS over the course of a year. Muscle Nerve 50: 517–522, 2014     

Sonication did not provide reliability to Maki technique for catheter related bloodstream infection diagnosis

ObjectiveThe aim of our study was to analyze sonication and Maki techniques for diagnosis of catheter tip colonization and catheter-related bloodstream infection (CRBSI) on patients admitted to ICU.Material and methodsObservational and prospective study in one Intensive Care Unit. Patients with some central venous catheter (CVC) at least for 7 days and catheter-related infection (CRI) suspicion (new episode of fever or sepsis) were included. We performed Maki technique followed by sonication of catheter tip. We compared area under the curve (AUC) of Maki, sonication, and techniques combination to diagnosis catheter tip colonization and CRBSI.ResultsWe included 94 CVC from 87 CRI suspicion episodes. We found 14 cases of catheter tip colonization and 10 cases of CRBSI. Of the 14 catheter tip colonization cases, 7 (50.0%) were detected by Maki and sonication techniques, 6 (42.9%) were detected only by Maki technique, and 1 (7.1%) was detected only by sonication technique. Of the 10 CRBSI, 6 (60.0%) were detected by Maki and sonication techniques, 4 (40.0%) were detected only by Maki technique, and any only by sonication technique. We found higher AUC in Maki technique than in sonication technique to diagnosis of CRBSI (p=0.02) and to diagnosis of catheter tip colonization (p=0.03). No significant differences were found in AUC between Maki technique and combination techniques for diagnosis of catheter tip colonization (p=0.32) and of CRBSI (p=0.32).Conclusion.:Sonication did not provide reliability to Maki technique for diagnosis of catheter tip colonization and CRBSI.