Diagnostic challenges of early Lyme disease: Lessons from a community case series

<p>Abstract</p> <p>Background</p> <p>Lyme disease, the most common vector-borne infection in North America, is increasingly reported. When the characteristic rash, erythema migrans, is not recognized and treated, delayed manifestations of disseminated infection may occur. The accuracy of diagnosis and treatment of early Lyme disease in the community is unknown.</p> <p>Methods</p> <p>A retrospective, consecutive case series of 165 patients presenting for possible early Lyme disease between August 1, 2002 and August 1, 2007 to a community-based Lyme referral practice in Maryland. All patients had acute symptoms of less than or equal to 12 weeks duration. Patients were categorized according to the Centers for Disease Control and Prevention criteria and data were collected on presenting history, physical findings, laboratory serology, prior diagnoses and prior treatments.</p> <p>Results</p> <p>The majority (61%) of patients in this case series were diagnosed with early Lyme disease. Of those diagnosed with early Lyme disease, 13% did not present with erythema migrans; of those not presenting with a rash, 54% had been previously misdiagnosed. Among those with a rash, the diagnosis of erythema migrans was initially missed in 23% of patients whose rash was subsequently confirmed. Of all patients previously misdiagnosed, 41% had received initial antibiotics likely to be ineffective against Lyme disease.</p> <p>Conclusion</p> <p>For community physicians practicing in high-risk geographic areas, the diagnosis of Lyme disease remains a challenge. Failure to recognize erythema migrans or alternatively, viral-like presentations without a rash, can lead to missed or delayed diagnosis of Lyme disease, ineffective antibiotic treatment, and the potential for late manifestations.</p

Zanamivir Conjugated to Poly-L-Glutamine is Much More Active Against Influenza Viruses in Mice and Ferrets Than the Drug Itself

Purpose: Previously, polymer-attached zanamivir had been found to inhibit influenza A viruses in vitro far better than did small-molecule zanamivir (1) itself. The aim of this study was to identify in vitro—using the plaque reduction assay—a highly potent 1-polymer conjugate, and subsequently test its antiviral efficacy in vivo. Methods: By examining the structure-activity relationship of 1-polymer conjugates in the plaque assay, we have determined that the most potent inhibitor against several representative influenza virus strains has a neutral high-molecular-weight backbone and a short alkyl linker. We have examined this optimal polymeric inhibitor for efficacy and immunogenicity in the mouse and ferret models of infection. Results: 1 attached to poly-L-glutamine is an effective therapeutic for established influenza infection in ferrets, reducing viral titers up to 30-fold for 6 days. There is also up to a 190-fold reduction in viral load when the drug is used as a combined prophylactic/therapeutic in mice. Additionally, we see no evidence that the drug conjugate stimulates an immune response in mice upon repeat administration. Conclusions: 1 attached to a neutral high-molecular-weight backbone through a short alkyl linker drastically reduced both in vitro and in vivo titers compared to those observed with 1 itself. Thus, further development of this polymeric zanamivir for the mitigation of influenza infection seems warranted.National Institutes of Health (U.S.) (Grant U01-AI074443

Noisy-threshold control of cell death

<p>Abstract</p> <p>Background</p> <p>Cellular responses to death-promoting stimuli typically proceed through a differentiated multistage process, involving a lag phase, extensive death, and potential adaptation. Deregulation of this chain of events is at the root of many diseases. Improper adaptation is particularly important because it allows cell sub-populations to survive even in the continuous presence of death conditions, which results, among others, in the eventual failure of many targeted anticancer therapies.</p> <p>Results</p> <p>Here, I show that these typical responses arise naturally from the interplay of intracellular variability with a threshold-based control mechanism that detects cellular changes in addition to just the cellular state itself. Implementation of this mechanism in a quantitative model for T-cell apoptosis, a prototypical example of programmed cell death, captures with exceptional accuracy experimental observations for different expression levels of the oncogene Bcl-x_Land directly links adaptation with noise in an ATP threshold below which cells die.</p> <p>Conclusions</p> <p>These results indicate that oncogenes like Bcl-x_L, besides regulating absolute death values, can have a novel role as active controllers of cell-cell variability and the extent of adaptation.</p

Myostatin Inhibition in Muscle, but Not Adipose Tissue, Decreases Fat Mass and Improves Insulin Sensitivity

Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn−/− mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn−/− mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn−/− mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn−/− mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn−/− mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn−/− mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes

The effect of resistance training interventions on weight status in youth:a meta-analysis

Abstract Background There has been a rise in research into obesity prevention and treatment programmes in youth, including the effectiveness of resistance-based exercise. The purpose of this meta-analysis was to examine the effect of resistance training interventions on weight status in youth. Methods Meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered on PROSPERO (registration number CRD42016038365). Eligible studies were from English language peer-reviewed published articles. Searches were conducted in seven databases between May 2016 and June 2017. Studies were included that examined the effect of resistance training on weight status in youth, with participants of school age (5–18 years). Results There were 24 complete sets of data from 18 controlled trials (CTs) which explored 8 outcomes related to weight status. Significant, small effect sizes were identified for body fat% (Hedges’ g = 0.215, 95% CI 0.059 to 0.371, P = 0.007) and skinfolds (Hedges’ g = 0.274, 95% CI 0.066 to 0.483, P = 0.01). Effect sizes were not significant for: body mass (Hedges’ g = 0.043, 95% CI − 0.103 to 0.189, P = 0.564), body mass index (Hedges’ g = 0.024, 95% CI − 0.205 to 0.253, P = 0.838), fat-free mass (Hedges’ g = 0.073, 95% CI − 0.169 to 0.316, P = 0.554), fat mass (Hedges’ g = 0.180, 95% CI − 0.090 to 0.451, P = 0.192), lean mass (Hedges’ g = 0.089, 95% CI − 0.122 to 0.301, P = 0.408) or waist circumference (Hedges’ g = 0.209, 95% CI − 0.075 to 0.494, P = 0.149). Conclusions The results of this meta-analysis suggest that an isolated resistance training intervention may have an effect on weight status in youth. Overall, more quality research should be undertaken to investigate the impact of resistance training in youth as it could have a role to play in the treatment and prevention of obesity

A Multi-Variant, Viral Dynamic Model of Genotype 1 HCV to Assess the in vivo Evolution of Protease-Inhibitor Resistant Variants

Variants resistant to compounds specifically targeting HCV are observed in clinical trials. A multi-variant viral dynamic model was developed to quantify the evolution and in vivo fitness of variants in subjects dosed with monotherapy of an HCV protease inhibitor, telaprevir. Variant fitness was estimated using a model in which variants were selected by competition for shared limited replication space. Fitness was represented in the absence of telaprevir by different variant production rate constants and in the presence of telaprevir by additional antiviral blockage by telaprevir. Model parameters, including rate constants for viral production, clearance, and effective telaprevir concentration, were estimated from 1) plasma HCV RNA levels of subjects before, during, and after dosing, 2) post-dosing prevalence of plasma variants from subjects, and 3) sensitivity of variants to telaprevir in the HCV replicon. The model provided a good fit to plasma HCV RNA levels observed both during and after telaprevir dosing, as well as to variant prevalence observed after telaprevir dosing. After an initial sharp decline in HCV RNA levels during dosing with telaprevir, HCV RNA levels increased in some subjects. The model predicted this increase to be caused by pre-existing variants with sufficient fitness to expand once available replication space increased due to rapid clearance of wild-type (WT) virus. The average replicative fitness estimates in the absence of telaprevir ranged from 1% to 68% of WT fitness. Compared to the relative fitness method, the in vivo estimates from the viral dynamic model corresponded more closely to in vitro replicon data, as well as to qualitative behaviors observed in both on-dosing and long-term post-dosing clinical data. The modeling fitness estimates were robust in sensitivity analyses in which the restoration dynamics of replication space and assumptions of HCV mutation rates were varied

The effects of progressive resistance training combined with a whey-protein drink and vitamin D supplementation on glycaemic control, body composition and cardiometabolic risk factors in older adults with type 2 diabetes: study protocol for a randomized controlled trial

Background - While physical activity, energy restriction and weight loss are the cornerstone of type 2 diabetes management, less emphasis is placed on optimizing skeletal muscle mass. As muscle is the largest mass of insulin-sensitive tissue and the predominant reservoir for glucose disposal, there is a need to develop safe and effective evidence-based, lifestyle management strategies that optimize muscle mass as well as improve glycaemic control and cardiometabolic risk factors in people with this disease, particularly older adults who experience accelerated muscle loss. Methods/Design - Using a two-arm randomized controlled trial, this 6-month study builds upon the community-based progressive resistance training (PRT) programme Lift for Life® to evaluate whether ingestion of a whey-protein drink combined with vitamin D supplementation can enhance the effects of PRT on glycaemic control, body composition and cardiometabolic health in older adults with type 2 diabetes. Approximately 200 adults aged 50 to 75 years with type 2 diabetes, treated with either diet alone or oral hypoglycaemic agents (not insulin), will be recruited. All participants will be asked to participate in a structured, supervised PRT programme based on the Lift for Life® programme structure, and randomly allocated to receive a whey-protein drink (20 g daily of whey-protein plus 20 g after each PRT session) plus vitamin D supplements (2000 IU/day), or no additional powder and supplements. The primary outcome measures to be collected at baseline, 3 and 6 months will be glycated haemoglobin (HbA1c) and insulin sensitivity (homeostatic model assessment). Secondary outcomes will include changes in: muscle mass, size and intramuscular fat; fat mass; muscle strength and function; blood pressure; levels of lipids, adipokines and inflammatory markers, serum insulin-like growth factor-1 and 25-hydroxyvitamin D; renal function; diabetes medication; health-related quality of life, and cognitive function. Discussion - The findings from this study will provide new evidence on whether increased dietary protein achieved through the ingestion of a whey-protein drink combined with vitamin D supplementation can enhance the effects of PRT on glycaemic control, muscle mass and size, and cardiometabolic risk factors in older adults with type 2 diabetes

Persistent Cell-Autonomous Circadian Oscillations in Fibroblasts Revealed by Six-Week Single-Cell Imaging of PER2::LUC Bioluminescence

Biological oscillators naturally exhibit stochastic fluctuations in period and amplitude due to the random nature of molecular reactions. Accurately measuring the precision of noisy oscillators and the heterogeneity in period and strength of rhythmicity across a population of cells requires single-cell recordings of sufficient length to fully represent the variability of oscillations. We found persistent, independent circadian oscillations of clock gene expression in 6-week-long bioluminescence recordings of 80 primary fibroblast cells dissociated from PER2::LUC mice and kept in vitro for 6 months. Due to the stochastic nature of rhythmicity, the proportion of cells appearing rhythmic increases with the length of interval examined, with 100% of cells found to be rhythmic when using 3-week windows. Mean period and amplitude are remarkably stable throughout the 6-week recordings, with precision improving over time. For individual cells, precision of period and amplitude are correlated with cell size and rhythm amplitude, but not with period, and period exhibits much less cycle-to-cycle variability (CV 7.3%) than does amplitude (CV 37%). The time series are long enough to distinguish stochastic fluctuations within each cell from differences among cells, and we conclude that the cells do exhibit significant heterogeneity in period and strength of rhythmicity, which we measure using a novel statistical metric. Furthermore, stochastic modeling suggests that these single-cell clocks operate near a Hopf bifurcation, such that intrinsic noise enhances the oscillations by minimizing period variability and sustaining amplitude

Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states

Cells respond dynamically to pulsatile cytokine stimulation. Here we report that single, or well-spaced pulses of TNFα (>100 min apart) give a high probability of NF-κB activation. However, fewer cells respond to shorter pulse intervals (<100 min) suggesting a heterogeneous refractory state. This refractory state is established in the signal transduction network downstream of TNFR and upstream of IKK, and depends on the level of the NF-κB system negative feedback protein A20. If a second pulse within the refractory phase is IL-1β instead of TNFα, all of the cells respond. This suggests a mechanism by which two cytokines can synergistically activate an inflammatory response. Gene expression analyses show strong correlation between the cellular dynamic response and NF-κB-dependent target gene activation. These data suggest that refractory states in the NF-κB system constitute an inherent design motif of the inflammatory response and we suggest that this may avoid harmful homogenous cellular activation

Exercise therapy in Type 2 diabetes

Structured exercise is considered an important cornerstone to achieve good glycemic control and improve cardiovascular risk profile in Type 2 diabetes. Current clinical guidelines acknowledge the therapeutic strength of exercise intervention. This paper reviews the wide pathophysiological problems associated with Type 2 diabetes and discusses the benefits of exercise therapy on phenotype characteristics, glycemic control and cardiovascular risk profile in Type 2 diabetes patients. Based on the currently available literature, it is concluded that Type 2 diabetes patients should be stimulated to participate in specifically designed exercise intervention programs. More attention should be paid to cardiovascular and musculoskeletal deconditioning as well as motivational factors to improve long-term treatment adherence and clinical efficacy. More clinical research is warranted to establish the efficacy of exercise intervention in a more differentiated approach for Type 2 diabetes subpopulations within different stages of the disease and various levels of co-morbidity