Obesity and the metabolic syndrome are increasingly prevalent in society and their complications and response to treatment exhibit sexual dimorphism. Mouse models of high fat diet-induced obesity are ...commonly used for both mechanistic and therapeutic studies of metabolic disease and diabetes. However, the inclusion of female mammals in obesity research has not been a common practice, and has resulted in a paucity of data regarding the effect of sex on metabolic parameters and its applicability to humans.
Here we analyzed male and female C57BL/6 J mice beginning at 4 weeks of age that were placed on a low-fat diet (LFD, 10% calories from fat), a Western Diet (WD, 45% calories from fat), or a high fat diet (HFD, 60% calories from fat). Assessments of body composition, glucose homeostasis, insulin production, and energy metabolism, as well as histological analyses of pancreata were performed.
Both male and female C57BL/6 J mice had similar increases in total percent body weight gain with both WD and HFD compared to LFD, however, male mice gained weight earlier upon HFD or WD feeding compared to female mice. Male mice maintained their caloric food intake while reducing their locomotor activity with either WD or HFD compared to LFD, whereas female mice increased their caloric food intake with WD feeding. Locomotor activity of female mice did not significantly change upon WD or HFD feeding, yet female mice exhibited increased energy expenditure compared to WD or HFD fed male mice. Glucose tolerance tests performed at 4, 12 and 20 weeks of dietary intervention revealed impaired glucose tolerance that was worse in male mice compared to females. Furthermore, male mice exhibited an increase in pancreatic β cell area as well as reduced insulin sensitivity after HFD feeding compared to WD or LFD, whereas female mice did not.
Male and female C57BL/6 J mice exhibited strikingly different responses in weight, food consumption, locomotor activity, energy expenditure and β cell adaptation upon dietary manipulation, with the latter exhibiting less striking phenotypic changes. We conclude that the nature of these responses emphasizes the need to contextualize studies of obesity pathophysiology and treatment with respect to sex.
•Diabetes research has been limited by the historical underrepresentation of females.•Male C57BL/6 mice are more susceptible to diet induced weight gain.•High fat challenge results in decreased activity levels in males not in females.•Female mice were protected from the development of diet induced insulin resistance.•Beta cell mass increases in males in response to diet induced obesity.
Summary
Background
Measurement of disease activity guides treatment of chronic spontaneous urticaria (CSU). A weekly Urticaria Activity Score – here, the average of twice‐daily patient assessment of ...itch and hives scores summed over 1 week (UAS7TD) – measures severity from 0 to 42. Insufficient evidence exists on whether disease activity states, defined by categorical UAS7TD scores, correlate with other patient‐reported outcomes and treatment response.
Objectives
To evaluate and compare categorical UAS7TD scores with selected measures of disease‐related quality of life and impact.
Methods
Data from three randomized clinical trials of omalizumab in CSU were pooled. Continuous UAS7TD scores were categorized into five disease activity states: urticaria‐free, well‐controlled, mild, moderate and severe urticaria. Total scores from the Dermatology Life Quality Index; the Chronic Urticaria Quality of Life questionnaire; and questions on sleep and daily activity interference, presence of angioedema and diphenhydramine use were compared within categorized UAS7TD disease‐state scores, using anova for analysis at different time points and mixed‐effects regressions for analysis of all data pooled.
Results
Pooled analyses showed that categorical UAS7TD disease states accurately predicted differences among treated patients with CSU with different levels of disease activity. A consistent pattern existed between categories, with higher‐activity disease states associated with significantly higher impact and an increase in angioedema frequency. Results at different treatment time points were consistent.
Conclusions
Categorical UAS7TD disease states can discriminate between measures when considering the impact of urticaria activity. Using five categorical disease states could simplify clinical assessment and monitoring of treatment efficacy.
What is already known about this topic?
Increased urticaria disease activity, as measured by the continuous twice‐daily Urticaria Activity Score – the average of twice‐daily patient assessment of itch and hives scores summed over 1 week (UAS7TD) – impacts health‐related quality of life and interferes with sleep and daily activity.
What does this study add?
Categorizing continuous UAS7TD activity scores into disease states defined by UAS7TD score ranges can discriminate between different levels of disease activity, simplify clinical assessment and facilitate evaluation of treatment efficacy.
Linked Comment: Asero. Br J Dermatol 2017; 177:903–904.
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Summary
Background
The appearance and lifelong, chronic nature of psoriasis result in considerable burden to patients, such as sleep impairment, depressive symptoms, negative self‐esteem and reduced ...work productivity.
Objectives
To examine direct and indirect (mediated) effects of secukinumab vs. ustekinumab on quality of life, work productivity and activity impairment based on psoriasis severity and symptoms.
Methods
Analyses were based on data from the CLEAR study. Structural equation modelling examined the effects of secukinumab vs. ustekinumab on the Dermatology Life Quality Index (DLQI) and on the Work Productivity and Activity Impairment (WPAI) questionnaire using Psoriasis Area and Severity Index (PASI) severity and symptoms (pain, itching and scaling) as potential mediators. Analyses were conducted primarily for patients achieving a PASI 90 response (90% or greater reduction in PASI from baseline) at week 16 (repeated at week 52) and for PASI 50, 75 and 100.
Results
Results at weeks 16 and 52 showed that the effect of treatment on change in DLQI score was mediated by the PASI 90 response and by improvements in itching, pain, and scaling. Achieving any PASI response as early as week 16 directly resulted in significantly better WPAI scores. At week 52, both PASI response and improvement in scaling directly resulted in significantly better WPAI scores. Pain, itching and scaling were correlated (r = 0·51–0·68); improvement in any of these had a significant effect (directly or indirectly) on WPAI. All results favoured secukinumab over ustekinumab.
Conclusions
The results underscore the important role of both PASI response and reduction in symptoms on improvements in health‐related quality of life and work and daily activity in favour of secukinumab vs. ustekinumab.
What's already known about this topic?
There are only weak to moderate correlations between Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores.
Factors other than area and severity may play a role in patients’ evaluations of their health‐related quality of life (HRQoL).
Patients perceive pain, itching and scaling to be the most troubling aspects of their psoriasis.
What does this study add?
Both PASI response and improved psoriasis‐related symptoms of pain, itching and scaling have an important role for improvements in HRQoL and work and daily activity.
Improvements in PASI, patient‐reported symptoms, HRQoL, and work and daily activity were greater for those patients on secukinumab vs. ustekinumab.
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The interrogation of beta cell gene expression and function in vitro has squarely shifted over the years from the study of rodent tumorigenic cell lines to the study of isolated rodent islets. ...Primary islets offer the distinct advantage that they more faithfully reflect the biology of intracellular signaling pathways and secretory responses. Whereas the method of islet isolation using tissue dissociating enzyme (TDE) preparations has been well established in many laboratories(1-4), variations in the consistency of islet yield and quality from any given rodent strain limit the extent and feasibility of primary islet studies. These variations often occur as a result of the crude partially purified TDEs used in the islet isolation procedure; TDEs frequently exhibit lot-to-lot variations in activity and often require adjustments to the dose of enzyme used. A small number of reports have used purified TDEs for rodent cell isolations(5, 6), but the practice is not widespread despite the routine use and advantages of purified TDEs for human islet isolations. In collaboration with VitaCyte, LLC (Indianapolis, IN), we developed a modified mouse islet isolation protocol based on that described by Gotoh(7, 8), in which the TDEs are perfused directly into the pancreatic duct of mice, followed by crude tissue fractionation through a Histopaque gradient(9), and isolation of purified islets. A significant difference in our protocol is the use of purified collagenase (CIzyme MA) and neutral protease (CIzyme BP) combination. The collagenase was characterized by the use of a(6) fluorescence collagen degrading activity (CDA) assay that utilized fluorescently labeled soluble calf skin fibrils as substrate(6). This substrate is more predictive of the kinetics of collagen degradation in the tissue matrix because it relies on native collagen as the substrate. The protease was characterized with a sensitive fluorescent kinetic assay(10). Utilizing these improved assays along with more traditional biochemical analysis enable the TDE to be manufactured more consistently, leading to improved performance consistency between lots. The protocol described in here was optimized for maximal islet yield and optimal islet morphology using C57BL/6 mice. During the development of this protocol, several combinations of collagenase and neutral proteases were evaluated at different concentrations, and the final ratio of collagenase:neutral protease of 35:10 represents enzyme performance comparable to Sigma Type XI. Because significant variability in average islet yields from different strains of rats and mice have been reported, additional modifications of the TDE composition should be made to improve the yield and quality of islets recovered from different species and strains.
Purpose To investigate the effect of femoral cortical notching at different depths on the peak compressive load and energy required to cause a femoral neck fracture in composite femurs. Methods ...Thirty fourth-generation composite femurs were divided into 5 groups: (1) intact with an inherent alpha angle of 61°, (2) resection of inherent cam lesion by reducing the alpha angle from 61° to 45°, (3) cam resection and cortical notching of a 5.5-mm spherical diameter by 2.00-mm (grade I) depth, (4) cam resection with cortical notching of 4.00-mm (grade II) depth, and (5) cam resection with cortical notching of 6.00-mm (grade III) depth. The specimens were loaded in the position of midstance during gait and tested until failure using a dynamic tensile testing machine at a rate of 6 mm/min. Results Grade II and grade III cortical notching depths with cam resections resulted in a significant decrease in the ultimate load to failure and energy ( P < .05) compared with the intact state. The grade II and grade III cortical notching groups with cam resection failed at a significantly lower ultimate load and with significantly lower energy when compared with the cam resection group alone. Conclusions The findings of this study demonstrated significant decreases in ultimate load and energy to failure between the intact group and the grade II and grade III femoral cortical notching groups with cam resection. Clinical Relevance Iatrogenic cortical notching may lead to an increased risk of postsurgical complications, specifically femoral neck fracture. Thus, surgical intervention for a cam lesion femoral osteoplasty should strive for precision, especially around the femoral neck.
A buildup of skeletal muscle plasma membrane (PM) cholesterol content in mice occurs within 1 week of a Western-style high-fat diet and causes insulin resistance. The mechanism driving this ...cholesterol accumulation and insulin resistance is not known. Promising cell data implicate that the hexosamine biosynthesis pathway (HBP) triggers a cholesterolgenic response via increasing the transcriptional activity of Sp1. In this study we aimed to determine whether increased HBP/Sp1 activity represented a preventable cause of insulin resistance.
C57BL/6NJ mice were fed either a low-fat (LF, 10% kcal) or high-fat (HF, 45% kcal) diet for 1 week. During this 1-week diet the mice were treated daily with either saline or mithramycin-A (MTM), a specific Sp1/DNA-binding inhibitor. A series of metabolic and tissue analyses were then performed on these mice, as well as on mice with targeted skeletal muscle overexpression of the rate-limiting HBP enzyme glutamine-fructose-6-phosphate-amidotransferase (GFAT) that were maintained on a regular chow diet.
Saline-treated mice fed this HF diet for 1 week did not have an increase in adiposity, lean mass, or body mass while displaying early insulin resistance. Consistent with an HBP/Sp1 cholesterolgenic response, Sp1 displayed increased O-GlcNAcylation and binding to the HMGCR promoter that increased HMGCR expression in skeletal muscle from saline-treated HF-fed mice. Skeletal muscle from these saline-treated HF-fed mice also showed a resultant elevation of PM cholesterol with an accompanying loss of cortical filamentous actin (F-actin) that is essential for insulin-stimulated glucose transport. Treating these mice daily with MTM during the 1-week HF diet fully prevented the diet-induced Sp1 cholesterolgenic response, loss of cortical F-actin, and development of insulin resistance. Similarly, increases in HMGCR expression and cholesterol were measured in muscle from GFAT transgenic mice compared to age- and weight-match wildtype littermate control mice. In the GFAT Tg mice we found that these increases were alleviated by MTM.
These data identify increased HBP/Sp1 activity as an early mechanism of diet-induced insulin resistance. Therapies targeting this mechanism may decelerate T2D development.
•Insulin sensitivity is impaired by excess skeletal muscle membrane cholesterol.•De novo cholesterol biosynthesis occurs early in the setting of high-fat feeding.•High-fat feeding triggers an HBP-mediated Sp1 cholesterolgenic response.•Sp1 inhibition prevents muscle membrane cholesterol buildup and insulin resistance.•Targeting the HBP/Sp1 response represents a novel approach to decelerate T2D.
Impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) are polygenic disorders with complex pathophysiologies; recapitulating them with mouse models is challenging. Despite 70% genetic homology, ...C57BL/6J (BL6) and C57BLKS/J (BLKS) inbred mouse strains differ in response to diet- and genetic-induced obesity. We hypothesized these differences would yield insight into IGT and T2DM susceptibility and response to pharmacological therapies. To this end, male 8-wk-old BL6 and BLKS mice were fed normal chow (18% kcal from fat), high-fat diet (HFD; 42% kcal from fat), or HFD supplemented with the PPARγ agonist pioglitazone (PIO; 140 mg PIO/kg diet) for 16 wk. Assessments of body composition, glucose homeostasis, insulin production, and energy metabolism, as well as histological analyses of pancreata were undertaken. BL6 mice gained weight and adiposity in response to HFD, leading to peripheral insulin resistance that was met with increased β-cell proliferation and insulin production. By contrast, BLKS mice responded to HFD by restricting food intake and increasing activity. These behavioral responses limited weight gain and protected against HFD-induced glucose intolerance, which in this strain was primarily due to β-cell dysfunction. PIO treatment did not affect HFD-induced weight gain in BL6 mice, and decreased visceral fat mass, whereas in BLKS mice PIO increased total fat mass without improving visceral fat mass. Differences in these responses to HFD and effects of PIO reflect divergent human responses to a Western lifestyle and underscore the careful consideration needed when choosing mouse models of diet-induced obesity and diabetes treatment.
Chemical reaction networks (CRNs) model the behavior of molecules in a well-mixed solution. The emerging field of molecular programming uses CRNs not only as a descriptive tool, but as a programming ...language for chemical computation. Recently, Chen, Doty and Soloveichik introduced rate-independent continuous CRNs (CCRNs) to study the chemical computation of continuous functions. A fundamental question for any CRN model is
reachability
, the question whether a given target state is reachable from a given start state via a sequence of reactions (a
path
) in the network. In this paper, we investigate CCRN-REACH, the reachability problem for rate-independent continuous chemical reaction networks. Our main theorem is that, for CCRNs, deciding reachability—and constructing a path if there is one—is computable in polynomial time. This contrasts sharply with the known exponential space hardness of the reachability problem for discrete CRNs. We also prove that the related problem Sub-CCRN-REACH, which asks about reachability in a CCRN using only a given number of its reactions, is NP-complete.
Hydrogen peroxide is an inexpensive and effective antimicrobial agent that can be implemented in surgical skin preparations. The purpose of this study was to evaluate the decolonization effect of ...Cutibacterium acnes when adding hydrogen peroxide to a standard sterile preparation for shoulder surgery.
This was a single-institution, prospective, randomized controlled trial of male patients undergoing shoulder arthroscopy (April 2018 and May 2019). Patients were randomized to a standard skin preparation vs. an additional sterile preparation with 3% hydrogen peroxide. After draping, a 3-mm punch biopsy was obtained from the posterior arthroscopic portal site of all patients. Anaerobic and aerobic culture substrates were used and held for 13 days.
Seventy male patients were randomized into the hydrogen peroxide group and 70 male patients were in the traditional group. Twelve (17.1%) patients in the hydrogen peroxide group and 24 (34.2%) patients in the traditional group had positive cultures for C acnes (P = .033). Cultures were positive at a mean of 4.5 days (range 3-7) in the hydrogen peroxide group and 4.1 days (range 3-8) in the traditional group (P = .48). There were no cases of skin reaction to the surgical preparation in either group.
The results of this study suggest that the addition of hydrogen peroxide to preoperative surgical site preparation can reduce the C acnes culture rate. Hydrogen peroxide is inexpensive and can be added to the typical skin preparation used prior to shoulder surgery without substantial risk of skin reactions.
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