Search

We report 2 fatal exacerbations of systemic capillary leak syndrome (SCLS), also known as Clarkson disease, associated with coronavirus disease (COVID-19) in the United States. One patient carried an established diagnosis of SCLS and the other sought treatment for new-onset hypotensive shock, hemoconcentration, and anasarca, classic symptoms indicative of an SCLS flare. Both patients had only mild-to-moderate symptoms of COVID-19. This clinical picture suggests that these patients succumbed to complications of SCLS induced by infection with severe acute respiratory syndrome coronavirus 2. Persons with known or suspected SCLS may be at increased risk for developing a disease flare in the setting of mild-to-moderate COVID-19 infection.

Congenital anomalies of the kidney and urinary tract (CAKUTs) represent the leading cause of chronic kidney disease and end-stage kidney disease in children. Increasing evidence points to critical roles for the urothelium in the developing urinary tract and in the genesis of CAKUTs. The involvement of the urothelium in patterning the urinary tract is supported by evidence that CAKUTs can arise as a result of abnormal urothelial development. Emerging evidence indicates that congenital urinary tract obstruction triggers urothelial remodelling that stabilizes the obstructed kidney and limits renal injury. Finally, the diagnostic potential of radiological findings and urinary biomarkers derived from the urothelium of patients with CAKUTs might aid their contribution to clinical care.

Genetic deletion of Src associated in mitosis of 68kDa (Sam68), a pleiotropic adaptor protein prevents high-fat diet-induced weight gain and insulin resistance. To clarify the role of Sam68 in energy metabolism in the adult stage, we generated an inducible Sam68 knockout mice. Knockout of Sam68 was induced at the age of 7-10 weeks, and then we examined the metabolic profiles of the mice. Sam68 knockout mice gained less body weight over time and at 34 or 36 weeks old, had smaller fat mass without changes in food intake and absorption efficiency. Deletion of Sam68 in mice elevated thermogenesis, increased energy expenditure, and attenuated core-temperature drop during acute cold exposure. Furthermore, we examined younger Sam68 knockout mice at 11 weeks old before their body weights deviate, and confirmed increased energy expenditure and thermogenic gene program. Thus, Sam68 is essential for the control of adipose thermogenesis and energy homeostasis in the adult.

Hepatic gluconeogenesis is essential for glucose homeostasis and also a therapeutic target for type 2 diabetes, but its mechanism is incompletely understood. Here, we report that Sam68, an RNA-binding adaptor protein and Src kinase substrate, is a novel regulator of hepatic gluconeogenesis. Both global and hepatic deletions of Sam68 significantly reduce blood glucose levels and the glucagon-induced expression of gluconeogenic genes. Protein, but not mRNA, levels of CRTC2, a crucial transcriptional regulator of gluconeogenesis, are >50% lower in Sam68-deficient hepatocytes than in wild-type hepatocytes. Sam68 interacts with CRTC2 and reduces CRTC2 ubiquitination. However, truncated mutants of Sam68 that lack the C- (Sam68ΔC) or N-terminal (Sam68ΔN) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68ΔN mice recapitulate the blood-glucose and gluconeogenesis profile of Sam68-deficient mice. Hepatic Sam68 expression is also upregulated in patients with diabetes and in two diabetic mouse models, while hepatocyte-specific Sam68 deficiencies alleviate diabetic hyperglycemia and improves insulin sensitivity in mice. Thus, our results identify a role for Sam68 in hepatic gluconeogenesis, and Sam68 may represent a therapeutic target for diabetes., Hepatic gluconeogenesis is important for glucose homeostasis and a therapeutic target for type 2 diabetes. Here, the authors show that the RNA-binding adaptor protein Sam68 promotes the expression level of gluconeogenic genes and increases blood glucose levels by stabilizing the transcriptional coactivator CRTC2, while hepatic Sam68 deletion alleviates hyperglycemia in mice.

Objectives Under representation of black subjects in trials of hepatitis C virus (HCV) direct-acting antivirals (DAAs) complicates assessment of differential outcomes for black individuals vs non-black individuals. HCV trials submitted to the Food and Drug Administration (2013–2017) to support approval or to expand an indication of 12-week interferon-free DAA regimens with or without ribavirin to treat HCV genotype 1 (GT1) infection were pooled to explore efficacy comparisons by ethnicity. Methods Twenty-six trials were pooled and included 2869 individuals with HCV GT1 alone and 742 individuals with both HCV GT1 and HIV. Results Of the 2869 HCV GT1-mono-infected subjects, 408 (14.2%) were black. Sustained virological response assessed 12 weeks following cessation of treatment (SVR12) was 92%–100% in black individuals and 87.5%–100.0% in non-black individuals. In pooled analyses, SVR12 was numerically similar between black and non-black subjects (97.1% vs 97.3%). Baseline characteristics did not affect SVR12 for the two groups. Of the 742 subjects with both HCV GT1 and HIV, 243 (32.7%) were black: SVR12 was 89.5%–100% in black individuals and 94.4%–100% in non-black individuals. In pooled analyses for HCV GT1/HIV co-infection, black individuals had a 4% (95% confidence interval −7.7% to 0.3%) lower SVR12 than non-black individuals (93.4% vs 97.0%). This difference was driven by ION-4 in which study SVR12 was approximately 10% lower for black than for non-black individuals (89.5% vs 99.1%). Baseline characteristics did not affect SVR12 for the two groups. Conclusion No notable SVR12 differences were seen in between black and non-black individuals with HCV GT1 alone. Although a numerical difference was observed between black and non-black individuals with both HCV GT1 and HIV, this finding was driven by results from a single trial and may be due to reasons other than ethnicity: 19 subgroup analyses showed baseline characteristics did not affect SVR12 for black and non-black individuals with both HCV GT1 and HIV.

Congenital urinary tract obstruction (UTO) is the leading cause of chronic kidney disease in children; however, current management strategies do not safeguard against progression to end-stage renal disease, highlighting the need for interventions to limit or reverse obstructive nephropathy. Experimental UTO triggers renal urothelial remodeling that culminates in the redistribution of basal keratin 5-positive (Krt5+) renal urothelial cells (RUCs) and the generation of uroplakin-positive (Upk)+ RUCs that synthesize a protective apical urothelial plaque. The cellular source of Upk+ RUCs is currently unknown, limiting the development of strategies to promote renal urothelial remodeling as a therapeutic approach. In the present study, we traced the origins of adult Upk+ RUCs during normal development and in response to UTO. Fate mapping analysis demonstrated that adult Upk+ RUCs derive from embryonic and neonatal Krt5+ RUCs, whereas Krt5+ RUCs lose this progenitor capacity and become lineage restricted by postnatal day 14. However, in response to UTO, postnatal day 14-labeled adult Krt5+ RUCs break their lineage restriction and robustly differentiate into Upk+ RUCs. Thus, Krt5+ RUCs drive renal urothelial formation during normal ontogeny and after UTO by differentiating into Upk+ RUCs in a temporally restricted manner.

The hallmark features of allergic asthma are type 2 (eosinophilic) inflammation and airways hyperresponsiveness (AHR). Although these features often comanifest in mouse lungs in vivo, we demonstrate in this study that the serine protease Alp1 from the ubiquitous mold and allergen, Aspergillus fumigatus, can induce AHR in mice unable to generate eosinophilic inflammation. Strikingly, Alp1 induced AHR in mice devoid of protease-activated receptor 2/F2 trypsin-like receptor 1 (PAR2/F2RL1), a receptor expressed in lung epithelium that is critical for allergic responses to protease-containing allergens. Instead, using precision-cut lung slices and human airway smooth muscle cells, we demonstrate that Alp1 directly increased contractile force. Taken together, these findings suggest that Alp1 induces bronchoconstriction through mechanisms that are largely independent of allergic inflammation and point to a new target for direct intervention of fungal-associated asthma.

Objective Systemic capillary leak syndrome (SCLS) is a rare disorder that presents with episodes of hypovolemic shock. The extent to which genetic abnormalities contribute to SCLS is unknown. We identified pediatric and adult cohorts with characteristic clinical courses. We sought to describe the clinical characteristics of both cohorts, identify a possible genetic contribution to SCLS, and demonstrate that whole-exome sequencing (WES) may be conducted by critical care providers. Design Prospective observational study of WES of nine adult and eight pediatric SCLS patients and available unaffected first-degree relatives. Setting Tertiary children's hospitals and referral research laboratory. Patients Children and adults with SCLS. Interventions None. Measurements Patients and available first-degree relatives underwent WES. Data were analyzed for rare homozygous, biallelic, de novo, and heterozygous variants with allelic enrichment and metabolic pathway analyses. Main results Children with SCLS presented at a younger age with episodes similar to those experienced by adults. All patients and available relatives underwent satisfactory WES. No overlapping gene variants or metabolic pathways were identified across all SCLS patients. Multiple candidate genes with homozygous or biallelic mutations were identified in individual subjects with SCLS. There was no significant enrichment of genes with rare heterozygous variants. Conclusions The clinical characteristics of children and adults with SCLS are similar. We did not identify a uniform germline exomic genetic etiology for SCLS. WES identified several candidate genes in individual patients for future research. WES is a viable way for critical care providers to investigate the etiology of diseases with presumed genetic contributions.

Systemic capillary leak syndrome (SCLS; Clarkson disease) is a rare orphan disorder characterized by transient yet recurrent episodes of hypotension and peripheral oedema due to diffuse vascular leakage of fluids and proteins into soft tissues. Humoral mediators, cellular responses and genetic features accounting for the clinical phenotype of SCLS are virtually unknown. Here, we searched for factors altered in acute SCLS plasma relative to matched convalescent samples using multiplexed aptamer‐based proteomic screening. Relative amounts of 612 proteins were changed greater than twofold and 81 proteins were changed at least threefold. Among the most enriched proteins in acute SCLS plasma were neutrophil granule components including bactericidal permeability inducing protein, myeloperoxidase and matrix metalloproteinase 8. Neutrophils isolated from blood of subjects with SCLS or healthy controls responded similarly to routine pro‐inflammatory mediators. However, acute SCLS sera activated neutrophils relative to remission sera. Activated neutrophil supernatants increased permeability of endothelial cells from both controls and SCLS subjects equivalently. Our results suggest systemic neutrophil degranulation during SCLS acute flares, which may contribute to the clinical manifestations of acute vascular leak.

The development and ultimate approval of tecovirimat for the antiviral treatment of smallpox, a disease that has been eradicated from the world for nearly 40 years, required a unique regulatory approach based on the US Food and Drug Administration's Animal Rule. We summarise the regulatory pathway and describe the challenges involved.

Moyamoya disease (MMD) is a complex and incompletely-understood cerebrovascular pathological entity that requires thorough clinical and imaging evaluation. Moyamoya is rare, thereby making the establishment of an effective, thorough and interdisciplinary patient evaluation protocol challenging, even within specialized referral centers. Nevertheless, implementation of such a protocol is crucial in order to provide the best possible evaluation and treatment for MMD patients. Here, we describe our institution's implementation of, rationale for, and experience with a comprehensive multidisciplinary collaboration and evaluation strategy for adult patients with moyamoya. This evaluation course consists of, first of all, a thorough clinical and laboratory evaluation with a vascular neurologist. This is followed by a comprehensive imaging assessment which evaluates angiographic and parenchymal features, in addition to cerebrovascular functionality. Finally, appropriate referrals are made to consulting services as indicated, which includes vascular neurosurgery. These steps are described in detail herein.

Respiratory virus infections can have long-term effects on lung function that persist even after the acute responses have resolved. Numerous studies have linked severe early childhood infection with respiratory syncytial virus (RSV) to the development of wheezing and asthma, although the underlying mechanisms connecting these observations remain unclear. Here, we examine airway hyperresponsiveness (AHR) that develops in wild-type mice after recovery from symptomatic but sublethal infection with the natural rodent pathogen, pneumonia virus of mice (PVM). We found that BALB/c mice respond to a limited inoculum of PVM with significant but reversible weight loss accompanied by virus replication, acute inflammation, and neutrophil recruitment to the airways. At day 21 post-inoculation, virus was no longer detected in the airways and the acute inflammatory response had largely resolved. However, and in contrast to most earlier studies using the PVM infection model, all mice survived the initial infection and all went on to develop serum anti-PVM IgG antibodies. Furthermore, using both invasive plethysmography and precision-cut lung slices, we found that these mice exhibited significant airway hyperresponsiveness at day 21 post-inoculation that persisted through day 45. Taken together, our findings extend an important and versatile respiratory virus infection model that can now be used to explore the role of virions and virion clearance as well as virus-induced inflammatory mediators and their signaling pathways in the development and persistence of post-viral AHR and lung dysfunction.

Asthma is a highly prevalent disorder characterized by chronic lung inflammation and reversible airways obstruction. Pathophysiological features of asthma include episodic and reversible airway narrowing due to increased bronchial smooth muscle shortening in response to external and host-derived mediators, excessive mucus secretion into the airway lumen, and airway remodeling. The aberrant airway smooth muscle (ASM) phenotype observed in asthma manifests as increased sensitivity to contractile mediators (EC50) and an increase in the magnitude of contraction (Emax); collectively these attributes have been termed “airways hyper-responsiveness” (AHR). This defining feature of asthma can be promoted by environmental factors including airborne allergens, viruses, and air pollution and other irritants. AHR reduces airway caliber and obstructs airflow, evoking clinical symptoms such as cough, wheezing and shortness of breath. G-protein-coupled receptors (GPCRs) have a central function in asthma through their impact on ASM and airway inflammation. Many but not all treatments for asthma target GPCRs mediating ASM contraction or relaxation. Here we discuss the roles of specific GPCRs, G proteins, and their associated signaling pathways, in asthma, with an emphasis on endogenous mechanisms of GPCR regulation of ASM tone and lung inflammation including regulators of G-protein signaling (RGS) proteins, G-protein coupled receptor kinases (GRKs), and β-arrestin.

Despite an ongoing focus on the role of diet in health and disease, we have only a limited understanding of these concepts at the cellular and molecular levels. While obesity has been clearly recognized as contributing to metabolic syndrome and the pathogenesis of adult asthma, recent evidence has linked high sugar intake alone to an increased risk of developing asthma in childhood. In this study, we examined the impact of diet in a mouse model of allergic airways inflammation with a specific focus on eosinophils. As anticipated, male C57BL/6 mice gained weight on a high-calorie, high-fat diet. However, mice also gained weight on an isocaloric high-sucrose diet. Elevated levels of leptin were detected in the serum and airways of mice maintained on the high-fat, but not the high-sucrose diets. We found that diet alone had no impact on eosinophil numbers in the airways at baseline or their recruitment in response to allergen (Alternaria alternata) challenge in either wild-type or leptin-deficient ob/ob mice. However, both bronchoalveolar lavage fluid and eosinophils isolated from lung tissue of allergen-challenged mice exhibited profound diet-dependent differences in cytokine content. Similarly, while all wild-type mice responded to allergen challenge with significant increases in methacholine-dependent total airway resistance (Rrs), airway resistance in mice maintained on the isocaloric high-sucrose (but not the high-calorie/high-fat) diet significantly exceeded that of mice maintained on the basic diet. In summary, our findings revealed that mice maintained on an isocaloric high-sucrose diet responded to allergen challenge with significant changes in both BAL and eosinophil cytokine content together with significant increases in Rrs. These results provide a model for further exploration of the unique risks associated with a high-sugar diet and its impact on allergen-associated respiratory dysfunction.

The authors report a case of a diffuse choroidal hemangioma in the left eye of a 17-year-old girl. No evidence of leptomeningeal angiomatosis was found on magnetic resonance imaging and neither the medical history nor the clinical examination revealed a port wine birthmark on the left side of the face. Fine telangiectatic vessels were found on the bulbar conjunctiva of the ipsilateral eye. Because of the shared destination of the vessel-trigeminal-ectoderm complex that migrates toward the optic placode, forming choriocapillaris, upper facial skin (upper eyelid), and conjunctival vessels, an embryological basis can be offered for ophthalmic angiomatosis of Sturge-Weber syndrome. The authors propose that vascular angiomatosis of upper eyelid skin and conjunctiva are phenotypically equivalent and may be present or absent, independent of each other. Their proposed expansion of Sturge-Weber syndrome diagnostic criteria needs to be validated by a comprehensive review of ophthalmic features of Sturge-Weber syndrome. [ J Pediatr Ophthalmol Strabismus . 2020;57:e43–e47.]

Background Perturbations in myocardial substrate utilization have been proposed to contribute to the pathogenesis of cardiac dysfunction in diabetic subjects. The failing heart in nondiabetics tends to decrease reliance on fatty acid and glucose oxidation, and increases reliance on ketone body oxidation. In contrast, little is known regarding the mechanisms mediating this shift among all 3 substrates in diabetes mellitus. Therefore, we tested the hypothesis that changes in myocardial glucose utilization directly influence ketone body catabolism. Methods and Results We examined ventricular‐cardiac tissue from the following murine models: (1) streptozotocin‐induced type 1 diabetes mellitus; (2) high‐fat‐diet–induced glucose intolerance; and transgenic inducible cardiac‐restricted expression of (3) glucose transporter 4 (transgenic inducible cardiac restricted expression of glucose transporter 4); or (4) dominant negative O ‐GlcNAcase. Elevated blood glucose (type 1 diabetes mellitus and high‐fat diet mice) was associated with reduced cardiac expression of β‐hydroxybutyrate‐dehydrogenase and succinyl‐CoA:3‐oxoacid CoA transferase. Increased myocardial β‐hydroxybutyrate levels were also observed in type 1 diabetes mellitus mice, suggesting a mismatch between ketone body availability and utilization. Increased cellular glucose delivery in transgenic inducible cardiac restricted expression of glucose transporter 4 mice attenuated cardiac expression of both Bdh1 and Oxct1 and reduced rates of myocardial BDH1 activity and β‐hydroxybutyrate oxidation. Moreover, elevated cardiac protein O ‐GlcNAcylation (a glucose‐derived posttranslational modification) by dominant negative O ‐GlcNAcase suppressed β‐hydroxybutyrate dehydrogenase expression. Consistent with the mouse models, transcriptomic analysis confirmed suppression of BDH1 and OXCT1 in patients with type 2 diabetes mellitus and heart failure compared with nondiabetic patients. Conclusions Our results provide evidence that increased glucose leads to suppression of cardiac ketolytic capacity through multiple mechanisms and identifies a potential crosstalk between glucose and ketone body metabolism in the diabetic myocardium.

Polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) are recently described CNS tumors. Classically, PLNTYs are epileptogenic and are a subtype of a heterogeneous group of low-grade neuroepithelial tumors that cause refractory epilepsy, such as angiocentric gliomas, oligodendrogliomas, gangliogliomas, and pleomorphic xanthoastrocytomas. Although they are a relatively new entity, a number of imaging and histologic characteristics of PLNTYs are already known. We present the imaging and pathologic findings of such a tumor as well as the surgical approach and clinical management.

Objective Mice with congenital loss of the glucagon receptor gene (Gcgr−/− mice) remain normoglycemic in insulinopenic conditions, suggesting that unopposed glucagon action is the driving force for hyperglycemia in Type-1 Diabetes Mellitus (T1DM). However, chronic loss of GCGR results in a neomorphic phenotype that includes hormonal signals with hypoglycemic activity. We combined temporally-controlled GCGR deletion with pharmacological treatments to dissect the direct contribution of GCGR signaling to glucose control in a common mouse model of T1DM. Methods We induced experimental T1DM by injecting the beta-cell cytotoxin streptozotocin (STZ) in mice with congenital or temporally-controlled Gcgr loss-of-function using tamoxifen (TMX). Results Disruption of Gcgr expression, using either an inducible approach in adult mice or animals with congenital knockout, abolished the response to a long-acting Gcgr agonist. Mice with either developmental Gcgr disruption or inducible deletion several weeks before STZ treatment maintained normoglycemia. However, mice with inducible knockout of the Gcgr one week after the onset of STZ diabetes had only partial correction of hyperglycemia, an effect that was reversed by GLP-1 receptor blockade. Mice with Gcgr deletion for either 2 or 6 weeks had similar patterns of gene expression, although the changes were generally larger with longer GCGR knockout. Conclusions These findings demonstrate that the effects of glucagon to mitigate diabetic hyperglycemia are not through acute signaling but require compensations that take weeks to develop., Highlights • Congenital or long-term loss of GCGR expression in mice protects from hyperglycemia following STZ treatment. • mTORC signaling does not contribute to the improved glycemic control exhibited by mice with chronic loss of GCGR signaling. • GLP-1R contributes to the modest reduction of hyperglycemia following acute loss of GCGR expression in STZ-treated mice.

Objective Breakthroughs in HIV treatment, especially combination antiretroviral therapy (ART), have massively reduced AIDS-associated mortality. However, ART administration amplifies the risk of non-AIDS defining illnesses including obesity, diabetes, and cardiovascular disease, collectively known as metabolic syndrome. Initial reports suggest that ART-associated risk of metabolic syndrome correlates with socioeconomic status, a multifaceted finding that encompasses income, race, education, and diet. Therefore, determination of causal relationships is extremely challenging due to the complex interplay between viral infection, ART, and the many environmental factors. Methods In the current study, we employed a mouse model to specifically examine interactions between ART and diet that impacts energy balance and glucose metabolism. Previous studies have shown that high-fat feeding induces persistent low-grade systemic and adipose tissue inflammation contributing to insulin resistance and metabolic dysregulation via adipose-infiltrating macrophages. Studies herein test the hypothesis that ART potentiates the inflammatory effects of a high-fat diet (HFD). C57Bl/6J mice on a HFD or standard chow containing ART or vehicle, were subjected to functional metabolic testing, RNA-sequencing of epididymal white adipose tissue (eWAT), and array-based kinomic analysis of eWAT-infiltrating macrophages. Results ART-treated mice on a HFD displayed increased fat mass accumulation, impaired glucose tolerance, and potentiated insulin resistance. Gene set enrichment and kinomic array analyses revealed a pro-inflammatory transcriptional signature depicting granulocyte migration and activation. Conclusion The current study reveals a HFD-ART interaction that increases inflammatory transcriptional pathways and impairs glucose metabolism, energy balance, and metabolic dysfunction., Graphical abstract Image 1, Highlights • Antiretroviral therapy (ART) exacerbates high-fat diet induced obesity and dysregulation of glucose homeostasis. • Transcriptomic and Kinomic analyses identify increased pro-inflammatory, adipose-tissue macrophages after ART-treatment. • ART and high-fat diet synergistically induce the G-protein coupled receptor, Gpr50, in white adipose tissue.

Asthma is a chronic, heterogeneous, and recurring inflammatory disease of the lower airways, with exacerbations that feature airway inflammation and bronchial hyperresponsiveness. Asthma has been modeled extensively via disease induction in both wild-type and genetically manipulated laboratory mice (Mus musculus). Antigen sensitization and challenge strategies have reproduced numerous important features of airway inflammation characteristic of human asthma, notably the critical roles of type 2 T helper cell cytokines. Recent models of disease induction have advanced to include physiologic aeroallergens with prolonged respiratory challenge without systemic sensitization; others incorporate tobacco, respiratory viruses, or bacteria as exacerbants. Nonetheless, differences in lung size, structure, and physiologic responses limit the degree to which airway dynamics measured in mice can be compared to human subjects. Other rodent allergic airways models, including those featuring the guinea pig (Cavia porcellus) might be considered for lung function studies. Finally, domestic cats (Feline catus) and horses (Equus caballus) develop spontaneous obstructive airway disorders with clinical and pathologic features that parallel human asthma. Information on pathogenesis and treatment of these disorders is an important resource. Review on the principles of in vivo modeling together with specific features of animal models for the study of human asthma.

Background and objectives: Deep brain stimulation (DBS) of the thalamus is a promising therapeutic alternative for treating medically refractory Tourette syndrome (TS). However, few human studies have examined its mechanism of action. Therefore, the networks that mediate the therapeutic effects of thalamic DBS remain poorly understood., Methods: Five participants diagnosed with severe medically refractory TS underwent bilateral thalamic DBS stereotactic surgery. Intraoperative fMRI characterized the blood oxygen level-dependent (BOLD) response evoked by thalamic DBS and determined whether the therapeutic effectiveness of thalamic DBS, as assessed using the Modified Rush Video Rating Scale test, would correlate with evoked BOLD responses in motor and limbic cortical and subcortical regions., Results: Our results reveal that thalamic stimulation in TS participants has wide-ranging effects that impact the frontostriatal, limbic, and motor networks. Thalamic stimulation induced suppression of motor and insula networks correlated with motor tic reduction, while suppression of frontal and parietal networks correlated with vocal tic reduction. These regions mapped closely to major regions of interest (ROI) identified in a nonhuman primate model of TS., Conclusions: Overall, these findings suggest that a critical factor in TS treatment should involve modulation of both frontostriatal and motor networks, rather than be treated as a focal disorder of the brain. Using the novel combination of DBS-evoked tic reduction and fMRI in human subjects, we provide new insights into the basal ganglia-cerebellar-thalamo-cortical network-level mechanisms that influence the effects of thalamic DBS. Future translational research should identify whether these network changes are cause or effect of TS symptoms.

The development and approval of brincidofovir for the treatment of smallpox, a disease that was eradicated from the world over 40 years ago, has resulted in the second antiviral approved via the Medical Countermeasure Initiative (MCMi) to combat this disease. Approval of brincidofovir required a unique regulatory approach based on the FDA Animal Rule, and development was supported by many years of research and collaboration among academic investigators, the pharmaceutical industry and multiple government agencies. This article summarizes the FDA regulatory pathway and describes the challenges involved.

Endocrine Society. In response to an acute threat to homeostasis or well-being, the hypothalamic-pituitary-adrenocortical (HPA) axis is engaged. A major outcome of this HPA axis activation is the mobilization of stored energy, to fuel an appropriate behavioral and/or physiological response to the perceived threat. Importantly, the extent of HPA axis activity is thought to be modulated by an individual’s nutritional environment. In this study, we report that nutritional manipulations signaling a relative depletion of dietary carbohydrates, thereby inducing nutritional ketosis, acutely and chronically activate the HPA axis. Male rats and mice maintained on a low-carbohydrate high-fat ketogenic diet (KD) exhibited canonical markers of chronic stress, including increased basal and stress-evoked plasma corticosterone, increased adrenal sensitivity to adrenocorticotropin hormone, increased stress-evoked c-Fos immunolabeling in the paraventricular nucleus of the hypothalamus, and thymic atrophy, an indicator of chronic glucocorticoid exposure. Moreover, acutely feeding medium-chain triglycerides (MCTs) to rapidly induce ketosis among chow-fed male rats and mice also acutely increased HPA axis activity. Lastly, and consistent with a growing literature that characterizes the hepatokine fibroblast growth factor-21 (FGF21) as both a marker of the ketotic state and as a key metabolic stress hormone, the HPA response to both KD and MCTs was significantly blunted among mice lacking FGF21. We conclude that dietary manipulations that induce ketosis lead to increased HPA axis tone, and that the hepatokine FGF21 may play an important role to facilitate this effect.

In this review of individual patient expanded-access requests to the Center for Drug Evaluation and Research for the period Fiscal Year 2010 to Fiscal Year 2014, we evaluated the number of applications received and the number allowed to proceed. We also evaluated whether drugs and certain biologics obtained under expanded access went on to be approved by the Food and Drug Administration. Finally, we considered concerns that adverse events occurring during expanded access might place sponsors at risk for legal liability. Overall, 98% of individual patient expanded-access requests were allowed to proceed. During the study period, among drugs without a previous approval for any indication or dosage form, 24% of unique drugs (ie, multiple applications for access to the same drug were considered to relate to 1 unique drug), and 20% of expanded-access applications received marketing approval by 1 year after initial submission; 43% and 33%, respectively, were approved by 5 years after initial submission. A search of 3 legal databases and a database of news articles did not appear to identify any product liability cases arising from the use of a product in expanded access. Our analyses seek to give physicians and patients a realistic perspective on the likelihood of a drug's approval as well as certain information regarding the product liability risks for commercial sponsors when providing expanded access to investigational drugs. The US Food and Drug Administration (FDA)'s expanded-access program maintains a careful balance between authorizing patient access to potentially beneficial drugs and protecting them from drugs that may have unknown risks. At the same time, the agency wishes to maintain the integrity of the clinical trials process, ultimately the best way to get safe and effective drugs to patients.

Background/objectives The combination of energy dense diets and reduced energy expenditure in modern society has escalated the prevalence of obesity and obesity-related comorbidities. Among these disease states, type-2 diabetics (T2D) are disproportionately associated with obesity, suggesting a shared etiology. In conjunction with defects in hormonal and inflammatory states, obesity and T2D are also characterized by dysbiosis. Methods We have recently described the beneficial effects of duodenal nutrient exclusion, as induced by the duodenal endoluminal sleeve (DES); including body weight loss, prevented fat mass accumulation, and improved glucose tolerance in the ZDF rat, a rodent model of obesity and type-2 diabetes (T2D). To assess the relative role of DES on hindgut microbiota in the context of these metabolic changes, we analyzed cecal samples from rats implanted with a duodenal endoluminal sleeve (DES), or a sham control of this procedure. A group of pair-fed (pf) sham controls was also included to account for changes induced by reduced body weight and food intake. Results Analysis of hindgut microbiota following DES in the ZDF rat elucidated discrete changes in several microbial populations including a reduction in Paraprevotella family members of the Clostridiales order along with an increase in Akkermansia muciniphila and species of the Allobaculum and Bifidobacterium genera. Conclusions Altogether, these observations suggest that like Roux-en Y gastric bypass (RYGB) and Metformin, regulation of gut microbiota may be a contributing factor to the therapeutic effects of DES.

Glucagon (GCG) is an essential regulator of glucose and lipid metabolism that also promotes weight loss. We have shown that glucagon-receptor (GCGR) signaling increases fatty acid oxidation (FAOx) in primary hepatocytes and reduces liver triglycerides in diet-induced obese (DIO) mice; however, the mechanisms underlying this aspect of GCG biology remains unclear. Investigation of hepatic GCGR targets elucidated a potent and previously unknown induction of leptin receptor (Lepr) expression. Liver leptin signaling is known to increase FAOx and decrease liver triglycerides, similar to glucagon action. Therefore, we hypothesized that glucagon increases hepatic LEPR, which is necessary for glucagon-mediated reversal of hepatic steatosis. Eight-week-old control and liver-specific LEPR-deficient mice (LeprΔliver) were placed on a high-fat diet for 12 weeks and then treated with a selective GCGR agonist (IUB288) for 14 days. Liver triglycerides and gene expression were assessed in liver tissue homogenates. Administration of IUB288 in both lean and DIO mice increased hepatic Lepr isoforms a-e in acute (4 hours) and chronic (72 hours,16 days) (P < 0.05) settings. LeprΔliver mice displayed increased hepatic triglycerides on a chow diet alone (P < 0.05), which persisted in a DIO state (P < 0.001), with no differences in body weight or composition. Surprisingly, chronic administration of IUB288 in DIO control and LeprΔliver mice reduced liver triglycerides regardless of genotype (P < 0.05). Together, these data suggest that GCGR activation induces hepatic Lepr expression and, although hepatic glucagon and leptin signaling have similar liver lipid targets, these appear to be 2 distinct pathways.

Myopic children have larger ciliary muscles than non-myopic children, suggesting that the ciliary muscle may have an impact on or be affected by refractive error development. The guinea pig represents an attractive model organism for myopia development research. The purpose of the study was to investigate whether form deprivation-induced myopia in one or more strains of guinea pig causes thickening of the ciliary muscle as seen in human myopia. Thirty-nine guinea pigs were bred from in-house progenitors obtained from Cincinnati Children's Hospital (Cincinnati) and the United States Army (Strain 13). At 2–4 days of age the right eyes of animals were exposed to form deprivation for 7 days while the fellow eyes served as controls. Refractive error was determined with retinoscopy while vitreous chamber depth (VCD) and axial length (AL) were determined with A-scan ultrasound. Ciliary muscle characteristics (ciliary muscle length, cross-sectional area, volume, cell number, cell size, and smooth muscle actin concentration) were determined histologically with antibody labeling and analyzed according to whether the animal developed axial myopia (anisometropia > −2.00 D with VCD and/or AL differences > 0.1 mm) or was unresponsive. This analysis method yielded four groups with Group 1 having no induced myopia but with axial elongation (n = 11), Group 2 having myopia without vitreous or axial elongation (n = 8), Group 3 having myopia with either vitreous or axial elongation (n = 11), and Group 4 having myopia with both vitreous and axial elongation (n = 8). There were no post-treatment inter-ocular differences between strains or for the overall group of animals for any ciliary muscle variable; however, a higher response group number in multivariate ordinal regression was related to having a treated compared to fellow eye that had a lower smooth muscle actin concentration (p = 0.006), with a shorter ciliary muscle length (p = 0.042), and a less oblate eye shape (p = 0.010). Guinea pig ciliary muscle length and smooth muscle actin concentration were significantly less in the treated eyes of axially myopic animals suggesting that 7 days of form deprivation induced ciliary muscle cellular atrophy or inhibited ciliary muscle growth. Form deprivation myopia in the guinea pig does not result in the increase in ciliary muscle thickness associated with human juvenile and adult myopia.

Vesicoureteral reflux (VUR) is a complex, heritable disorder. Genome-wide linkage analyses of families affected by VUR have revealed multiple genomic loci linked to VUR. These loci normally harbor a number of genes whose biologically functional variant is yet to be identified. DNA copy number variations (CNVs) have not been extensively studied at high resolution in VUR patients. In this study, we performed array comparative genomic hybridization (aCGH) on a cohort of patients with a history of both VUR and urinary tract infection (UTI) with the objective of identifying genetic variations responsible for VUR and/or UTI susceptibility. UTI/VUR-associated CNVs were identified by aCGH results from the 192 Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) patients compared to 683 controls. Rare, large CNVs that are likely pathogenic and lead to VUR development were identified using stringent analysis criteria. Because UTI is a common affliction with multiple risk factors, we utilized standard analysis to identify potential disease-modifying CNVs that can contribute to UTI risk. Gene ontology analysis identified that CNVs in innate immunity and development genes were enriched in RIVUR patients. CNVs affecting innate immune genes may contribute to UTI susceptibility in VUR patients and may provide the first step in assisting clinical medicine in determining adverse outcome risk in children with VUR.

Background Allergens elicit host production of mediators acting on G-protein–coupled receptors to regulate airway tone. Among these is prostaglandin E2 (PGE2), which, in addition to its role as a bronchodilator, has anti-inflammatory actions. Some patients with asthma develop bronchospasm after the ingestion of aspirin and other nonsteroidal anti-inflammatory drugs, a disorder termed aspirin-exacerbated respiratory disease. This condition may result in part from abnormal dependence on the bronchoprotective actions of PGE2. Objective We sought to understand the functions of regulator of G protein signaling 4 (RGS4), a cytoplasmic protein expressed in airway smooth muscle and bronchial epithelium that regulates the activity of G-protein–coupled receptors, in asthma. Methods We examined RGS4 expression in human lung biopsies by immunohistochemistry. We assessed airways hyperresponsiveness (AHR) and lung inflammation in germline and airway smooth muscle–specific Rgs4−/− mice and in mice treated with an RGS4 antagonist after challenge with Aspergillus fumigatus. We examined the role of RGS4 in nonsteroidal anti-inflammatory drug–associated bronchoconstriction by challenging aspirin-exacerbated respiratory disease–like (ptges1−/−) mice with aspirin. Results RGS4 expression in respiratory epithelium is increased in subjects with severe asthma. Allergen-induced AHR was unexpectedly diminished in Rgs4−/− mice, a finding associated with increased airway PGE2 levels. RGS4 modulated allergen-induced PGE2 secretion in human bronchial epithelial cells and prostanoid-dependent bronchodilation. The RGS4 antagonist CCG203769 attenuated AHR induced by allergen or aspirin challenge of wild-type or ptges1−/− mice, respectively, in association with increased airway PGE2 levels. Conclusions RGS4 may contribute to the development of AHR by reducing airway PGE2 biosynthesis in allergen- and aspirin-induced asthma.

Glucagon is an essential regulator of glucose and lipid metabolism that also promotes weight loss. We have shown that GCGR signaling increases fatty acid oxidation (FAOx) in primary hepatocytes and reduces liver triglycerides in DIO mice; however, the mechanisms underlying this aspect of glucagon biology remains unclear. Investigation of downstream GCGR targets elucidated potent and previously unknown regulation of liver leptin receptor (Lepr) expression. Intriguingly, we found GCGR agonism induces hepatic Lepr expression in vivo and in vitro. Liver leptin signaling is known to increase FAOx and decrease liver triglycerides, similar to glucagon action. Therefore, we hypothesized that glucagon increases hepatic LEPR, which is necessary for glucagon-mediated reversal of hepatic steatosis. Administration of the selective GCGR agonist IUB288 in both lean and diet-induced obese (DIO) mice increases both total hepatic Lepr (p Disclosure S. Nason: None. T. Kim: None. J.P. Antipenko: None. B. Finan: Employee; Self; Novo Nordisk A/S. R. DiMarchi: Employee; Self; Novo Nordisk Inc. K.M. Habegger: Consultant; Self; Glyscend, Inc., Novo Nordisk Inc. Research Support; Self; Glyscend, Inc. Stock/Shareholder; Self; Glyscend, Inc. Funding National Institutes of Health (T32HL1053491, R011DK112934-01)

Background: We compared resting-state functional connectivity (RSFC) among limbic and temporal lobe regions between patients with medial temporal lobe epilepsy (mTLE) and healthy control subjects to identify imaging evidence of functional networks related to seizure frequency, age of seizure onset, and duration of epilepsy. Methods: Twelve patients with drug-resistant, unilateral medial temporal lobe epilepsy and twelve healthy control subjects matched for age, sex, and handedness participated in the imaging experiments. We used network-based statistics to compare functional connectivity graphs in patients with mTLE and healthy controls to investigate the relationship between functional connectivity abnormalites and seizure frequency. Results: Among mTLE patients, we found functional network abnormalities throughout the limbic system, but primarily in the hemisphere ipsilateral to the seizure focus. The RSFCs between ipsilateral hypothalamus and ventral anterior cingulate cortex and between ipsilateral subiculum and contralateral posterior cingulate cortex were highly correlated with seizure frequency. Discussion: These findings suggest that in mTLE, changes in limbic networks ipsilateral to the epileptic focus are common. The pathological changes in connectivity between cingulate cortex, hypothalamus and subiculum ipsilateral to the seizure focus were correlated with increased seizure frequency. This also suggests that cingulate and limbic networks are progressively impacted by increased frequency of seizures, and could even play a central role in the progression of epilepsy.

Background Members of the regulator of G‐protein signaling ( RGS ) family inhibit G‐protein coupled receptor signaling by modulating G‐protein activity. In platelets, there are 3 different RGS isoforms that are expressed at the protein level, including RGS 16. Recently, we have shown that CXCL 12 regulates platelet function via RGS 16. However, the role of RGS 16 in platelet function and thrombus formation is poorly defined. Methods and Results We used a genetic knockout mouse model approach to examine the role(s) of RGS 16 in platelet activation by using a host of in vitro and in vivo assays. We observed that agonist‐induced platelet aggregation, secretion, and integrin activation were much more pronounced in platelets from the RGS 16 knockout ( Rgs16 −/− ) mice relative to their wild type ( Rgs16 +/+ ) littermates. Furthermore, the Rgs16 −/− mice had a markedly shortened bleeding time and were more susceptible to vascular injury–associated thrombus formation than the controls. Conclusions These findings support a critical role for RGS 16 in regulating hemostatic and thrombotic functions of platelets in mice. Hence, RGS 16 represents a potential therapeutic target for modulating platelet function.

Background and objectives We assessed correlations between the resting state functional connectivity (RSFC) of different thalamic nuclei and seizure frequency in patients with drug-resistant medial temporal lobe epilepsy (mTLE). Methods Seventeen patients with mTLE and 17 sex-/age-/handedness-matched controls participated. A seed-based correlation method for the resting-state FMRI data was implemented to get RSFC maps of 70 thalamic nuclei seed masks. Group statistics for individual RSFC for subjects and seed masks were performed to obtain within-group characteristics and between-group differences with age covariates. A linear regression was applied to test whether seizure frequency correlated with thalamic nuclear RSFC with the whole brain in mTLE patients. Results RSFC of thalamic nuclei showed spatially distinguishable connectivity patterns that reflected principal inputs and outputs that were derived from priori anatomical knowledge. We found group differences between normal control and mTLE groups in RSFC for nuclei seeds located in various subdivisions of thalamus. The RSFCs in some of those nuclei were strongly correlated with seizure frequency. Conclusions Mediodorsal thalamic nuclei may play important roles in seizure activity or in the regulation of neuronal activity in the limbic system. The RSFC of motor- and sensory-relay nuclei may help elucidate sensory-motor deficits associated with chronic seizure activity. RSFC of the pulvinar nuclei of the thalamus could also be a key reflection of symptom-related functional deficits in mTLE., Highlights • We assessed the functional connectivity for 70 thalamic nuclei of temporal lobe epilepsy subjects. • Each nucleus showed distinguishable connectivity along its known pathological preference. • Especially, the mediodorsal thalamic nuclei may play important roles in seizure frequency.

Exercise is an effective therapy against the metabolic syndrome. However, the molecular pathways underlying the advantageous effects of exercise are elusive. Glucagon receptor signaling is essential for exercise benefits, and recent evidence indicates that a downstream effector of glucagon, fibroblast growth factor 21 (FGF21), is implicated in this response. Therefore, we tested the hypothesis that FGF21 action is necessary in mediating metabolic effects of exercise. We utilized acute exhaustive treadmill exercise in Wistar rats to identify a putative, concomitant increase in plasma glucagon and FGF21 with the increase in glucose and lactate following exercise. To test the necessity of FGF21 action in the exercise response, we exposed FGF21 congenitally deficient mice ( Fgf21 −/−) and their wild-type (Wt) littermates to chronic high-fat (HF) feeding and inoperable (sedentary) or operable (exercise) voluntary running wheels. Physiological tests were performed to assess the role of FGF21 in the beneficial effect of exercise on glucose metabolism. Wt and Fgf21 −/− littermates exhibited similar running behavior, and exercise was effective in suppressing weight and fat mass gain and dyslipidemia independently of genotype. However, exercise failed to positively affect hepatic triglyceride content and glucose tolerance in HF diet-fed Fgf21 −/− mice. Furthermore, Fgf21 −/− mice exhibited an impaired adaptation to exercise training, including reduced AMP-activated protein kinase activity in skeletal muscle. This study demonstrates that FGF21 action is necessary to achieve the full metabolic benefits of exercise during chronic HF feeding.

Thalamic deep brain stimulation (DBS) is an effective therapy for essential tremor. Gibson et al. use functional MRI to reveal patterns of activation that correlate with stimulation-induced therapeutic and adverse effects. Their results suggest that thalamic DBS controls tremor, and induces paraesthesias, through distal modulation of tremor-related network nodes., Deep brain stimulation is an established neurosurgical therapy for movement disorders including essential tremor and Parkinson’s disease. While typically highly effective, deep brain stimulation can sometimes yield suboptimal therapeutic benefit and can cause adverse effects. In this study, we tested the hypothesis that intraoperative functional magnetic resonance imaging could be used to detect deep brain stimulation-evoked changes in functional and effective connectivity that would correlate with the therapeutic and adverse effects of stimulation. Ten patients receiving deep brain stimulation of the ventralis intermedius thalamic nucleus for essential tremor underwent functional magnetic resonance imaging during stimulation applied at a series of stimulation localizations, followed by evaluation of deep brain stimulation-evoked therapeutic and adverse effects. Correlations between the therapeutic effectiveness of deep brain stimulation (3 months postoperatively) and deep brain stimulation-evoked changes in functional and effective connectivity were assessed using region of interest-based correlation analysis and dynamic causal modelling, respectively. Further, we investigated whether brain regions might exist in which activation resulting from deep brain stimulation might correlate with the presence of paraesthesias, the most common deep brain stimulation-evoked adverse effect. Thalamic deep brain stimulation resulted in activation within established nodes of the tremor circuit: sensorimotor cortex, thalamus, contralateral cerebellar cortex and deep cerebellar nuclei (FDR q < 0.05). Stimulation-evoked activation in all these regions of interest, as well as activation within the supplementary motor area, brainstem, and inferior frontal gyrus, exhibited significant correlations with the long-term therapeutic effectiveness of deep brain stimulation (P < 0.05), with the strongest correlation (P < 0.001) observed within the contralateral cerebellum. Dynamic causal modelling revealed a correlation between therapeutic effectiveness and attenuated within-region inhibitory connectivity in cerebellum. Finally, specific subregions of sensorimotor cortex were identified in which deep brain stimulation-evoked activation correlated with the presence of unwanted paraesthesias. These results suggest that thalamic deep brain stimulation in tremor likely exerts its effects through modulation of both olivocerebellar and thalamocortical circuits. In addition, our findings indicate that deep brain stimulation-evoked functional activation maps obtained intraoperatively may contain predictive information pertaining to the therapeutic and adverse effects induced by deep brain stimulation.

The clinical and financial impact of chronic kidney disease (CKD) is significant, while its progression and prognosis is variable and often poor. Studies using the megabladder (mgb−/−) model of CKD show that renal urothelium plays a key role in modulating early injury responses following the development of congenital obstruction. The aim of this review is to examine the role that urothelium has in normal urinary tract development and pathogenesis. We discuss normal morphology of renal urothelium and then examine the role that uroplakins (Upks) play in its development. Histologic, biochemical, and molecular characterization of Upk1bRFP/RFP mice indicated Upk1b expression is essential for normal urinary tract development, apical plaque/asymmetric membrane unit (AUM) formation, and differentiation and functional integrity of the renal urothelium. Our studies provide the first evidence that Upk1b is directly associated with the development of congenital anomalies of the urinary tract (CAKUT), spontaneous age-dependent hydronephrosis, and dysplastic urothelia. These observations demonstrate the importance of proper urothelial differentiation in normal development and pathogenesis of the urinary tract and provide a unique working model to test the hypothesis that the complex etiology associated with CKD is dependent upon predetermined genetic susceptibilities that establish pathogenic thresholds for disease initiation and progression.

Discussion of how CRF1 activation augments systemic MC degranulation via mobilization of intracellular calcium stores, to promote gastrointestinal leakage and systemic anaphylaxis in mice.

Summary Introduction In the pediatric patient whose ureteropelvic junction obstruction (UPJO) is not always symptomatic, imaging is the most common means of detecting surgical success. There is interest, however, in other means of post-operative monitoring. A panel of antimicrobial peptides (AMPs) has been previously found to be elevated in UPJO, but the impact of surgical correction on these AMPs is unknown. Objective To determine if elevated levels of candidate urinary AMP biomarkers of urinary tract obstruction decrease following UPJO repair. Study design Pediatric patients undergoing surgical correction of an UPJO were recruited for participation. Bladder urine from uninfected consenting/assenting patients was collected immediately prior to surgery and then at least 6 months afterward. Based on prior studies demonstrating significant elevation of beta defensin 1 (BD-1), hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP), cathelicidin (LL-37), and neutrophil gelatinase-associated lipocalin (NGAL) in patients with UPJO versus control patients, we performed enzyme-linked immunosorbent assays on these four AMPs to compare their expression before and after surgical intervention. If found to significantly decrease, AMP levels were compared to healthy controls. AMP levels were normalized to urine creatinine. Results were analyzed with paired t test or Wilcoxon test using Graphpad software. Correlation was calculated using Pearson or Spearman correlation. A p-value of Results 13 UPJO patients were included in this study; 9 were male (69%). Age at surgery was a median of 4.3 years (average 6.1, range 0.4–18.4 years). Follow-up urine samples were collected a median of 27.4 months after surgery (average 27.4; range 7.8–45.3 months). All 13 patients had clinical improvement and/or signs of improved hydronephrosis on post-operative imaging. HIP/PAP and BD-1 significantly decreased in post-surgical samples compared to pre-surgical samples (p = 0.02 and 0.01, respectively); NGAL and LL-37 did not significantly change. Overall, HIP/PAP decreased in 12 patients (92%) and BD-1 decreased in 11 patients (85%). BD-1 levels after successful repair were not different from healthy controls (p = 0.06). Discussion Urinary biomarkers of obstruction should detect significant obstructive pathology as well as reflect its resolution. This would enable their use in post-operative monitoring and augment current methods of determining successful surgical outcome through imaging. Conclusions The AMPs HIP/PAP and BD-1 are significantly elevated in UPJO but then significantly decrease after pyeloplasty, with BD-1 returning to healthy control levels. As a result, these AMPs could serve as markers of successful surgical intervention. Download : Download high-res image (282KB) Download : Download full-size image Summary Figure . Urinary markers before (Pre) and after (Post) successful surgical correction. HIP/PAP and BD-1 expression significantly decrease upon paired analysis after successful surgical correction for ureteropelvic junction obstruction (∗p = 0.0215; ∗∗p = 0.0052).

Aims Emerging evidence suggests that during gestation the in utero environment programs metabolism and can increase risk of obesity in adult offspring. Our aim was to study how alterations in maternal diets during gestation might alter body weight evolution, circulating leptin levels and caloric intake in offspring, leading to changes in body composition. Materials and methods We fed gestating rats either a control diet (CD), high fat diet (HFD) or an isocaloric low protein diet (LPD), and examined the repercussions in offspring fed similar diets post-weaning on birth weight, body weight evolution, body composition, insulin sensitivity, glucose tolerance and in the relationship between plasma leptin concentration and caloric intake in offspring during growth and development. Key finds Offspring from dams fed LPD maintained reduced body weight with greater % lean mass and consumed fewer calories despite having leptin levels similar to controls. On the other hand, offspring from dams fed a HFD were insulin resistant and maintained increased body weight and % fat mass, while consuming more calories than controls despite elevated leptin concentrations. Therefore the uterine environment, modulated primarily through maternal nutrition, modified the relationship between circulating leptin levels, body fat, and caloric intake in the offspring, and dams fed a HFD produced offspring with excess adiposity, insulin resistance, and leptin resistance into adulthood. Significance Our data indicates that in utero environmental factors affected by maternal diet program alterations in the set point around which leptin regulates body weight in offspring into adulthood contributing to obesity.

The systemic capillary leak syndrome (SCLS, Clarkson disease) is a disorder of unknown etiology characterized by recurrent episodes of vascular leakage of proteins and fluids into peripheral tissues, resulting in whole-body edema and hypotensive shock. The pathologic mechanisms and genetic basis for SCLS remain elusive. Here we identify an inbred mouse strain, SJL, which recapitulates cardinal features of SCLS, including susceptibility to histamine- and infection-triggered vascular leak. We named this trait “Histamine hypersensitivity” (Hhs/Hhs) and mapped it to Chromosome 6. Hhs is syntenic to the genomic locus most strongly associated with SCLS in humans (3p25.3), revealing that the predisposition to develop vascular hyperpermeability has a strong genetic component conserved between humans and mice and providing a naturally occurring animal model for SCLS. Genetic analysis of Hhs may reveal orthologous candidate genes that contribute not only to SCLS, but also to normal and dysregulated mechanisms underlying vascular barrier function more generally., Raza et al. report a naturally occurring animal model that recapitulates cardinal features of Systemic Capillary Leak Syndrome and map its histamine-triggered vascular leak trait to Chromosome 6. They suggest that the predisposition to develop vascular hyperpermeability has a strong genetic component conserved between humans and mice.

BACKGROUND: Obstructive uropathy (OU) is a common cause of end-stage renal disease (ESRD) in children. Children who escape the newborn period with mild-to-moderate chronic kidney disease (CKD) continue to be at increased risk. The predictive ability of clinically available markers throughout childhood is poorly defined. METHODS: Patients with OU were identified in the Chronic Kidney Disease in Children Study. The primary outcome of interest was renal replacement therapy (RRT) (cases). Controls were age matched and defined as patients within the OU cohort who did not require RRT during study follow-up. RESULTS: In total, 27 cases and 41 age-matched controls were identified. Median age at baseline and age at outcome measurement were 10 vs. 16 years, respectively. First available glomerular filtration rate (GFR) (36.9 vs. 53.5 mL/min per 1.73 m(2)), urine protein/creatinine (Cr) (0.40 vs. 0.22 mg/mg) and microalbumin/Cr (0.58 vs. 0.03 mg/mg), and serum CO(2) (20 vs. 22 mmol/L) and hemoglobin (12.4 vs. 13.2 g/dL) differed significantly between cases and controls, respectively. GFR declined 3.07 mL/min per 1.73 m(2)/year faster in cases compared to that in controls (p < 0.0001). Urine protein/Cr and microalbumin/Cr increased by 0.16 and 0.11 per year more in cases compared to those in controls, respectively (p ≤ 0.001 for both). Serum phosphate increased by 0.11 mg/dL and serum albumin and hemoglobin decreased by 0.04 (g/dL) and 0.14 (g/dL) per year more for cases compared to those for controls, respectively (p < 0.05 for all). CONCLUSIONS: Age-specific baseline and longitudinal measures of readily available clinical measures predict progression to ESRD in children with mild-to-moderate CKD from OU.

INTRODUCTION Our purpose was to determine whether the chronic use of preoperative narcotics adversely affected clinical and/or radiographic outcomes. METHODS Seventy-three patients (79 shoulders) with primary total shoulder arthroplasty for osteoarthritis were evaluated clinically and radiographically at preoperative visits and postoperatively at a minimum follow-up of 2 years: 26 patients (28 shoulders) taking chronic narcotic pain medication for at least 3 months before surgery and 47 patients (51 shoulders) who were not taking narcotics preoperatively. RESULTS Postoperatively, significant differences were noted between the narcotic and nonnarcotic groups regarding American Shoulder and Elbow Surgeons scores and visual analog scale scores, as well as forward elevation, external rotation, and all strength measurements (P < 0.01). The nonnarcotic group had markedly higher American Shoulder and Elbow Surgeons scores, better overall range of motion and strength, and markedly lower visual analog scale scores than the narcotic group. CONCLUSION Chronic preoperative narcotic use seems to be a notable indicator of poor outcomes of anatomic total shoulder arthroplasty for glenohumeral osteoarthritis.

Systemic capillary leak syndrome (SCLS), also known as Clarkson syndrome, is a rare disease with potential fatal outcome. The clinical picture involves leakage of fluid and protein from the bloodstream into peripheral tissues, resulting in hypoalbuminaemia, elevated haematocrit, oedema and hypotension. The spectrum of the symptoms ranges from discrete swelling/oedema of extremities to fulminant cardiogenic shock. We present a case with a 52-year-old man diagnosed with SCLS after being resuscitated from cardiac arrest, which was complicated by compartment syndrome. The severe episode of capillary leak was potentially triggered by influenza virus infection. With the benefit of hindsight, he presented with symptoms of SCLS 2 years prior the major acute episode. Here we describe this case and review some aspects of the literature on SCLS, with particular focus on the pathogenesis, treatment/prophylaxis and long-term physical and psychological complications.

There is emerging evidence supporting fetal metabolism is determined in utero, and the programmed metabolism persists into adulthood. Understanding how metabolic dysfunction is transmitted through generations will help identify the biological mechanisms underlying obesity and cardiometabolic disease, and provide insight regarding rational strategies for treatment and prevention. Metabolic parameters were assessed in offspring from dams fed different diets for 4 weeks before pregnancy and during pregnancy and lactation; open standard (OSD), isocaloric low protein (LPD, 8% protein) and high-fat diets (HFD, 60% fat). After weaning, offspring had OSD. Offspring from dams fed LPD showed 31% reduced birthweights compared to offspring from dams fed OSD, and the difference persisted into 6 months of age. At 3 and 6 months, they exhibited significantly smaller perigonadal fat pad than offspring from dams fed OSD. In addition, they showed significantly higher blood glucose concentration than offspring from dams fed OSD at birth (52.35mg/dl vs. 63.71 mg/dl). In case of offspring from dams fed HFD, they exhibited significantly higher body weights (5.99g vs. 6.56g) and blood glucose level at birth (52.35mg/dl vs. 64.64 mg/dl) compared to offspring from dams fed OSD. The difference of body weights continued to 3week-old at weaning, and they showed significantly impaired glucose tolerance compared to offspring from dams fed OSD at the same age. Maternal dietary manipulation strongly influenced metabolic phenotypes such as birthweight, blood glucose concentration at birth and glucose tolerance, and the programed phenotypes persisted into adulthood. Therefore, maternal nutrition programs a glucose intolerant phenotype in offspring indicating that in utero stress augments diabetes risk not only childhood but also adulthood. We expect our findings in this study to help clarify the mechanism how the utero environment affects offspring’s metabolism, which would explain in part the intergenerational transmission of obesity. Disclosure M. Kang: None. J.P. Antipenko: None. X. Liu: None. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc. W. Garvey: Advisory Panel; Self; Novo Nordisk Inc., Merck & Co., Inc.. Research Support; Self; Sanofi, Pfizer Inc., Novo Nordisk Inc., AstraZeneca, Merck & Co., Inc., Elcelyx Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Eisai Inc..

Urinary tract obstruction represents a common cause of kidney injury across the human life span, resulting in chronic kidney disease and end-stage renal disease. Yet, the extent of obstructive renal damage can be heterogeneous between individuals, implying the existence of unknown mechanisms that protect against or accelerate kidney injury. In this study, we investigated the role of urothelial remodeling in renal adaptation during congenital and acquired obstruction. In the Megabladder ( Mgb−/−) model of congenital obstruction and unilateral ureteral ligation model of acute obstruction, progressive hydronephrosis is strongly associated with dynamic reorganization of the renal urothelium, which elaborates a continuous uroplakin (Upk) plaque. This led us to postulate that the Upk plaque prevents parenchymal injury during urinary tract obstruction. To test this hypothesis, we interbred Mgb−/− and Upk1b−/− mice, which lack the critical Upk1b subunit for Upk plaque formation. Upk1b−/−; Mgb−/− mice experienced an accelerated onset of bilateral hydronephrosis with severe (>67%) parenchymal loss, leading to renal failure and mortality in adolescence. To investigate the function of the renal Upk plaque during acute obstruction, we destabilized the Upk plaque by Upk1b deletion or genetically depleted Upk+ cells following unilateral ureteral obstruction. Both of these strategies accelerated renal parenchymal loss following ureteral ligation, attesting to a conserved, stabilizing role for Upk plaque deposition in the acutely obstructed kidney. In aggregate, these complementary experiments provide the first evidence that the Upk plaque confers an essential, protective adaptation to preserve renal parenchymal integrity during congenital and acquired urinary tract obstruction.

BACKGROUND: Systemic capillary leak syndrome (SCLS) (Clarkson’s disease) is a rare disorder of unknown etiology, characterized by transient episodes of hypotension, and the microvascular leak of fluids into the peripheral tissues, resulting in edema. Between 80–90% of patients with SCLS have a concomitant monoclonal gammopathy. Although translational in vitro studies have implicated vascular endothelial barrier dysfunction in the etiology of SCLS, the etiology and disease associations in clinical cases remain unknown. CASE REPORT: We report a case of SCLS in a 49-year-old woman who initially presented with an upper respiratory tract infection, which was complicated by edema and compartment syndromes in the extremities that required fasciotomies. Serum levels of the cell surface heparan sulfate proteoglycan, syndecan-1 (CD138), a measure of endothelial surface glycocalyx (ESG) damage, were measured by enzyme-linked immunoassay (ELISA), peaked at up to 500 ng/mL (reference range, 50–100 ng/mL) and normalized on disease remission. CONCLUSIONS: This case report supports the view that damage to the microvascular endothelium, has a role in the pathogenesis of acute SCLS. This case also indicated that monitoring serum levels of syndecan-1 (CD138) might be used to monitor the progression and resolution of episodes of SCLS. Open Access. This paper has been published under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.

Ketogenic diets (KDs) have increasingly gained attention as effective means for weight loss and potential adjunctive treatment of cancer. The metabolic benefits of KDs are regularly ascribed to enhanced hepatic secretion of fibroblast growth factor 21 (FGF21) and its systemic effects on fatty-acid oxidation, energy expenditure (EE) and body weight. Ambiguous data from Fgf21-knockout animal strains and low FGF21 concentrations reported in humans with ketosis have nevertheless cast doubt regarding the endogenous function of FGF21. We here aimed to elucidate the causal role of FGF21 in mediating the therapeutic benefits of KDs on metabolism and cancer. We established a dietary model of increased vs decreased FGF21 by feeding C57BL/6J mice with KDs, either depleted of protein or enriched with protein. We furthermore used wild-type and Fgf21-knockout mice that were subjected to the respective diets, and monitored energy and glucose homeostasis as well as tumour growth after transplantation of Lewis lung carcinoma cells. Hepatic and circulating, but not adipose tissue, FGF21 levels were profoundly increased by protein starvation, independent of the state of ketosis. We demonstrate that endogenous FGF21 is not essential for the maintenance of normoglycaemia upon protein and carbohydrate starvation and is therefore not needed for the effects of KDs on EE. Furthermore, the tumour-suppressing effects of KDs were independent of FGF21 and, rather, driven by concomitant protein and carbohydrate starvation. Our data indicate that the multiple systemic effects of KD exposure in mice, previously ascribed to increased FGF21 secretion, are rather a consequence of protein malnutrition.