Determining muscle plasticity and meat quality development of low-input extended fed market-ready steers.

In March 2020, the World Health Organization declared COVID-19 a pandemic, which ultimately led to many meat processors temporarily shutting down or reducing processing capacity. This backlog in processing capacity forced many feedlots to retain cattle for longer periods of time and assume the risk of major market fluctuations. The aim of this study was to understand how a dietary insult affects meat quality and muscle metabolism in market-ready steers (590 kg). Sixteen market-ready (590 kg) commercial Angus crossbred steers were subjected to a maintenance diet of either forage or grain for 60 d. Longissimus lumborum (LL) muscle samples were collected immediately postmortem and processed for characteristics reflecting the underlying muscle fiber type and energy state of the tissue. Despite cattle being subjected to a 60-d feeding period, there were no detectable differences (P > 0.05) in carcass characteristics, color of lean, or ultimate pH (pHu). Moreover, our data show that muscle plasticity is rather resilient, as reflected by lack of significance (P > 0.05) in oxidative and glycolytic enzymes, myosin heavy chain isoforms (MyHC), myoglobin, and mitochondrial DNA (mtDNA) contents. These data show that market-ready steers are capable of withstanding a low-input feeding strategy up to 60 d without dramatically impacting underlying muscle characteristics and meat quality development.

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort.

BACKGROUND: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. METHODS: People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). FINDINGS: Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. INTERPRETATION: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. FUNDING: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity.

Intravenous Injection of Sodium Hyaluronate Diminishes Basal Inflammatory Gene Expression in Equine Skeletal Muscle.

Following strenuous exercise, skeletal muscle experiences an acute inflammatory state that initiates the repair process. Systemic hyaluronic acid (HA) is injected to horses routinely as a joint anti-inflammatory. To gain insight into the effects of HA on skeletal muscle, adult Thoroughbred geldings (n = 6) were injected with a commercial HA product weekly for 3 weeks prior to performing a submaximal exercise test. Gluteal muscle (GM) biopsies were obtained before and 1 h after exercise for gene expression analysis and HA localization. The results from RNA sequencing demonstrate differences in gene expression between non-injected controls (CON; n = 6) and HA horses. Prior to exercise, HA horses contained fewer (p < 0.05) transcripts associated with leukocyte activity and cytokine production than CON. The performance of exercise resulted in the upregulation (p < 0.05) of several cytokine genes and their signaling intermediates, indicating that HA does not suppress the normal inflammatory response to exercise. The transcript abundance for marker genes of neutrophils (NCF2) and macrophages (CD163) was greater (p < 0.05) post-exercise and was unaffected by HA injection. The anti-inflammatory effects of HA on muscle are indirect as no differences (p > 0.05) in the relative amount of the macromolecule was observed between the CON and HA fiber extracellular matrix (ECM). However, exercise tended (p = 0.10) to cause an increase in ECM size suggestive of muscle damage and remodeling. The finding was supported by the increased (p < 0.05) expression of CTGF, TGFß1, MMP9, TIMP4 and Col4A1. Collectively, the results validate HA as an anti-inflammatory aid that does not disrupt the normal post-exercise muscle repair process.

Atypical hemolytic uremic syndrome in the era of terminal complement inhibition: an observational cohort study.

Historically, the majority of patients with complement-mediated atypical hemolytic uremic syndrome (CaHUS) progress to end-stage kidney disease (ESKD). Single-arm trials of eculizumab with a short follow-up suggested efficacy. We prove, for the first time to our knowledge, in a genotype matched CaHUS cohort that the 5-year cumulative estimate of ESKD-free survival improved from 39.5% in a control cohort to 85.5% in the eculizumab-treated cohort (hazard ratio, 4.95; 95% confidence interval [CI], 2.75-8.90; P = .000; number needed to treat, 2.17 [95% CI, 1.81-2.73]). The outcome of eculizumab treatment is associated with the underlying genotype. Lower serum creatinine, lower platelet count, lower blood pressure, and younger age at presentation as well as shorter time between presentation and the first dose of eculizumab were associated with estimated glomerular filtration rate >60 ml/min at 6 months in multivariate analysis. The rate of meningococcal infection in the treated cohort was 550 times greater than the background rate in the general population. The relapse rate upon eculizumab withdrawal was 1 per 9.5 person years for patients with a pathogenic mutation and 1 per 10.8 person years for those with a variant of uncertain significance. No relapses were recorded in 67.3 person years off eculizumab in those with no rare genetic variants. Eculizumab was restarted in 6 individuals with functioning kidneys in whom it had been stopped, with no individual progressing to ESKD. We demonstrated that biallelic pathogenic mutations in RNA-processing genes, including EXOSC3, encoding an essential part of the RNA exosome, cause eculizumab nonresponsive aHUS. Recessive HSD11B2 mutations causing apparent mineralocorticoid excess may also present with thrombotic microangiopathy.

A Carnitine-Containing Product Improves Aspects of Post-Exercise Recovery in Adult Horses.

Strenuous exercise can cause tissue damage, leading to an extended recovery period. To counteract delayed post-exercise recovery, a commercial product containing L-carnitine (AID) was tested in adult horses performing consecutive exercise tests to exhaustion. Fit Thoroughbreds were administered an oral bolus of placebo (CON) or AID prior to performing an exercise test to exhaustion (D1). The heart rate (HR) and fetlock kinematics were captured throughout the exercise test. Blood was collected before, 10 min and 1, 4 and 6 h relative to exercise for the quantification of cytokine (IL1ß, IL8, IL10, TNFa) gene expression and lactate concentration. Horses performed a second exercise test 48 h later (D2), with all biochemical and physiological measures repeated. The results demonstrate that the horses receiving AID retained a greater (p < 0.05) amount of flexion in the front fetlock on D2 than the horses given CON. The horses presented a reduced (p < 0.05) rate of HR decline on D2 compared to that on D1. The expression of IL1ß, IL8 and IL10 increased at 1 h post-exercise on D1 and returned to baseline by 6 h; the cytokine expression pattern was not duplicated on D2. These results provide evidence of disrupted cytokine expression, HR recovery and joint mobility in response to consecutive bouts of exhaustive exercise. Importantly, AID may accelerate recovery through an undetermined mechanism.

Assessing the Impact of Prophylactic Eculizumab on Renal Graft Survival in Atypical Hemolytic Uremic Syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare cause of end-stage kidney disease and associated with poor outcomes after kidney transplantation from early disease recurrence. Prophylactic eculizumab treatment at the time of transplantation is used in selected patients with aHUS. We report a retrospective case note review describing transplant outcomes in patients with aHUS transplanted between 1978 and 2017, including those patients treated with eculizumab. METHODS: The National Renal Complement Therapeutics Centre database identified 118 kidney transplants in 86 recipients who had a confirmed diagnosis of aHUS. Thirty-eight kidney transplants were performed in 38 recipients who received prophylactic eculizumab. The cohort not treated with eculizumab comprised 80 transplants in 60 recipients and was refined to produce a comparable cohort of 33 transplants in 32 medium and high-risk recipients implanted since 2002. Complement pathway genetic screening was performed. Graft survival was censored for graft function at last follow-up or patient death. Graft survival without eculizumab treatment is described by complement defect status and by Kidney Disease: Improving Global Outcomes risk stratification. RESULTS: Prophylactic eculizumab treatment improved renal allograft survival ( P = 0.006) in medium and high-risk recipients with 1-y survival of 97% versus 64% in untreated patients. Our data supports the risk stratification advised by Kidney Disease: Improving Global Outcomes. CONCLUSIONS: Prophylactic eculizumab treatment dramatically improves graft survival making transplantation a viable therapeutic option in aHUS.

Safety and impact of eculizumab withdrawal in patients with atypical haemolytic uraemic syndrome: protocol for a multicentre, open-label, prospective, single-arm study.

INTRODUCTION: Atypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening disease caused by excessive activation of part of the immune system called complement. Eculizumab is an effective treatment, controlling aHUS in 90% of patients. Due to the risk of relapse, lifelong treatment is currently recommended. Eculizumab treatment is not without problems, foremost being the risk of severe meningococcal infection, the burden of biweekly intravenous injections and the high cost.This paper describes the design of the Stopping Eculizumab Treatment Safely in aHUS trial that aims to establish whether a safety monitoring protocol, including the reintroduction of eculizumab for those who relapse, could be a safe, alternative treatment strategy for patients with aHUS. METHODS AND ANALYSIS: This is a multicentre, non-randomised, open-label study of eculizumab withdrawal with continuous monitoring of thrombotic microangiopathy-related serious adverse events using the Bayes factor single-arm design. 30 patients will be recruited to withdraw from eculizumab and have regular blood and urine tests for 24 months, to monitor for disease activity. If relapse occurs, treatment will be restarted within 24 hours of presentation. 20 patients will remain on treatment and complete health economic questionnaires only. An embedded qualitative study will explore the views of participants. ETHICS AND DISSEMINATION: A favourable ethical opinion and approval was obtained from the North East-Tyne & Wear South Research Ethics Committee. Outcomes will be disseminated via peer-reviewed articles and conference presentations. TRIAL REGISTRATION NUMBER: EudraCT number: 2017-003916-37 and ISRCTN number: ISRCTN17503205.

Short Communication: Supplementation with calcium butyrate causes an increase in the percentage of oxidative fibers in equine gluteus medius muscle.

Optimal athletic performance requires meeting the energetic demands of the muscle fibers, which are a function of myosin ATPase enzymatic activity. Skeletal muscle with a predominant oxidative metabolism underlies equine athletic success. Sodium butyrate, a short-chain fatty acid, can affect muscle fiber composition in pigs. To determine if a similar scenario exists in horses, 12 adult Thoroughbred geldings (7.4 ± 0.6 yr of age; mean ± SEM) were fed 16 g of calcium butyrate (CB) or an equivalent amount of carrier (CON) daily for 30 d in a crossover design. Middle gluteal muscle biopsies were collected before and after the feeding trial for immunohistochemical determination of fiber type, and RNA and protein isolation. After 30 d, CB increased (P < 0.05) the percentage of type IIA fibers and tended (P = 0.13) to reduce the numbers of type IIX fibers in comparison to control (CON). No changes (P > 0.05) in type I, IIA, or IIX fiber size were observed in response to CB. No differences (P > 0.05) were noted in the abundance of succinate dehydrogenase (SDH) protein or activity between horses receiving CB or CON. Myogenin mRNA abundance was unaffected (P > 0.05) by 30 d of CB supplementation. The increase in type IIA fibers in the absence of altered mitochondrial SDH enzymatic activity suggests that CB affects myosin ATPase expression independent of altered metabolism.

The largest tissue in the body, skeletal muscle, is a heterogeneous mix of fibers that are categorized based on their primary source of energy production and speed of contraction. Evidence suggests that Thoroughbred horses with a greater percentage of type IIA, fast-twitch, oxidative fibers are more successful than those with fewer. Pigs fed a diet supplemented with butyrate contained a greater percentage of oxidative muscle fibers. This study examined the ability of calcium butyrate (CB), a short-chain fatty acid, to alter muscle fiber composition in horses. Adult Thoroughbred geldings were supplemented with a placebo or CB for 30 d, and gluteus medius muscle biopsies were retrieved and analyzed for fiber type, myogenin expression, and succinate dehydrogenase (SDH) activity. Results demonstrate a small increase in the percentage of type IIA fibers without a change in SDH activity, a marker of oxidative metabolism. Myogenin expression remained unaffected by CB supplementation. These efforts underscore the need for further research to validate improved exercise performance in response to CB supplementation and identify a mechanism of action for the fatty acid in the equine skeletal muscle.

The initial delay to mitotic activity in primary cultures of equine satellite cells is reduced by combinations of growth factors.

Satellite cell (SC) activation is defined as the time frame during which the stem cell becomes poised to reenter G1 of the cell cycle. The growth factors and events leading to full mitotic activation in equine SCs remain largely unknown. Insulin-like growth factor I (IGF-I), hepatocyte growth factor (HGF), and fibroblast growth factor 2 (FGF2) are sequentially transcribed during the muscle repair and recovery period following strenuous exercise in adult horses. Expression of IGF-I occurs within 24 h of the postexercise recovery period suggesting it may affect early SC actions. As a first step, gluteus medius muscle cryosections from adult horses (n = 9) were examined for the presence of central nuclei (CN), a marker of SC addition to the fiber. Results demonstrate few CN fibers prior to exercise with a 3-fold increase (P = 0.05) 24 h postexercise. Cultures of SC (n = 4 isolates) were treated with 100 ng/mL IGF-I for varying times prior to measurement of myogenic events. Results demonstrate that IGF-I does not affect the initial lag period, proliferation, or subsequent differentiation of equine SC in vitro (P > 0.05). However, media containing a combination of IGF-I and 10 ng/mL FGF2 and 25 ng/mL HGF hastens (P < 0.05) the time to S-phase entry in fresh isolates of SCs. Media supplementation with optimal concentrations of FGF2, HGF, or a combination of HGF and FGF2 suppresses (P < 0.05) the percentage of myogenin immunopositive SCs to levels below that found in control- or IGF-I-treated SCs. These results provide new insight into the combinatorial roles growth factors play during equine SC myogenesis.

Satellite cells are the resident stem cells found within skeletal muscle. Following strenuous exercise, the cells become mitotically active to supply progenitors for muscle repair. The signals responsible for their exit from the dormant state are largely unknown. Hepatocyte growth factor (HGF), fibroblast growth factor 2 (FGF2), and insulin-like growth factor I (IGF-I) are located within the local environment postexercise suggesting their involvement in mitotic activation. Treatment of satellite cells in vitro with optimal concentrations of HGF, FGF2, or IGF-I did not affect transition into the cell cycle. By contrast, inclusion of all three growth factors in the media caused an increase in the numbers of activated satellite cells. The combination of factors suppressed expression of myogenin, the requisite transcriptional mediator of differentiation. Although IGF-I stimulates myogenin expression in other muscle cell types, a similar response was not observed in equine satellite cells. These results support a role for HGF, FGF2, and IGF-I during the initial postexercise repair period in horses.

Molecular and biochemical regulation of skeletal muscle metabolism.

Skeletal muscle hypertrophy is a culmination of catabolic and anabolic processes that are interwoven into major metabolic pathways, and as such modulation of skeletal muscle metabolism may have implications on animal growth efficiency. Muscle is composed of a heterogeneous population of muscle fibers that can be classified by metabolism (oxidative or glycolytic) and contractile speed (slow or fast). Although slow fibers (type I) rely heavily on oxidative metabolism, presumably to fuel long or continuous bouts of work, fast fibers (type IIa, IIx, and IIb) vary in their metabolic capability and can range from having a high oxidative capacity to a high glycolytic capacity. The plasticity of muscle permits continuous adaptations to changing intrinsic and extrinsic stimuli that can shift the classification of muscle fibers, which has implications on fiber size, nutrient utilization, and protein turnover rate. The purpose of this paper is to summarize the major metabolic pathways in skeletal muscle and the associated regulatory pathways.

Skeletal muscle is a heterogenous population of cells that are classified into muscle types based on contractile speed and metabolism. The various types of muscle cells utilize different biochemical pathways to produce energy to support cellular functions. These complex biochemical pathways are unique in their subcellular localization, substrate source, energy production capacity, and regulatory mechanisms. The purpose of this review is to describe the major metabolic pathways in skeletal muscle and the associated regulatory mechanisms.

ß-Hydroxy ß-methylbutyrate supplementation to adult Thoroughbred geldings increases type IIA fiber content in the gluteus medius.

Consumption of ß-hydroxy ß-methylbutyrate (HMB) alters muscle composition and metabolism leading to strength and agility improvements in human athletes. To determine if HMB affects athletic performance and muscle function in horses, Thoroughbred geldings were fed a control (CON; n = 5) or HMB (n = 6) supplement for 6 wk prior to completing a standardized exercise test (SET). Gluteus medius (GM) muscle biopsies were obtained before the SET for fiber typing. Heart rate, biceps femoris (BF) and semitendinosus (ST) surface electromyograms (EMG), and fore and hind limbs metacarpophalangeal joint angles were captured at the gallop of the SET. Results demonstrate that HMB supplementation increased (P < 0.05) the percentage of type IIA and IIA/X muscle fibers in the GM with a corresponding decrease (P < 0.05) in type IIX fibers. The percentage of type I fibers was unaffected by diet. Supplementation with HMB did not result in any measurable effects on performance or biomechanical properties by comparison to CON. Supplementation with HMB resulted in an increase (P < 0.05) in ST median frequency at speeds of 10 m/s and greater. Increasing treadmill speed resulted in an increase (P < 0.05) in stride length and the maximal proximal forelimb fetlock angle, and a decrease (P < 0.05) in stance phase time of the gait cycle. Integrated EMG (iEMG) increased (P < 0.05) with increasing treadmill speeds for both the BF and ST with the BF exhibiting greater (P < 0.05) iEMG values than the ST. In summary, HMB increased the percentage of type IIA GM fibers, which did not translate into improved performance.

C3 Glomerulopathy and Related Disorders in Children: Etiology-Phenotype Correlation and Outcomes.

BACKGROUND AND OBJECTIVES: Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic data for pediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based on retrospective studies without etiologic data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 80 prevalent pediatric patients with membranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using a Cox proportional hazards model. Kidney and transplant graft survival was determined using the Kaplan-Meier method. RESULTS: Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complex membranoproliferative GN, and ten with immune-complex GN. Patients were aged 2-15 (median, 9; interquartile range, 7-11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired (anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% of patients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18 (interquartile range, 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplants performed in eight patients, two of which failed due to recurrent disease. Presence of >50% crescents on the initial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazard ratio, 6.2; 95% confidence interval, 1.05 to 36.6; P<0.05). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on the initial biopsy specimen. CONCLUSIONS: Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric patients with membranoproliferative GN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.

Identification of LAMA1 mutations ends diagnostic odyssey and has prognostic implications for patients with presumed Joubert syndrome.

Paediatric neurology syndromes are a broad and complex group of conditions with a large spectrum of clinical phenotypes. Joubert syndrome is a genetically heterogeneous neurological ciliopathy syndrome with molar tooth sign as the neuroimaging hallmark. We reviewed the clinical, radiological and genetic data for several families with a clinical diagnosis of Joubert syndrome but negative genetic analysis. We detected biallelic pathogenic variants in LAMA1, including novel alleles, in each of the four cases we report, thereby establishing a firm diagnosis of Poretti-Boltshauser syndrome. Analysis of brain MRI revealed cerebellar dysplasia and cerebellar cysts, associated with Poretti-Boltshauser syndrome and the absence of typical molar tooth signs. Using large UK patient cohorts, the relative prevalence of Joubert syndrome as a cause of intellectual disability was 0.2% and of Poretti-Boltshauser syndrome was 0.02%. We conclude that children with congenital brain disorders that mimic Joubert syndrome may have a delayed diagnosis due to poor recognition of key features on brain imaging and the lack of inclusion of LAMA1 on molecular genetic gene panels. We advocate the inclusion of LAMA1 genetic analysis on all intellectual disability and Joubert syndrome gene panels and promote a wider awareness of the clinical and radiological features of these syndromes.

Effects of mid-gestational l-citrulline supplementation to twin-bearing ewes on umbilical blood flow, placental development, and lamb production traits.

The objective of the study was to examine how l-citrulline supplementation to ewes during mid-gestation influences placental activity, placental blood flow, lamb body weight, and carcass characteristics. Two studies were completed. A pharmacokinetic study to compare circulating plasma amino acid concentrations after a single intravenous injection of 155 µmol/kg BW l-citrulline or after an isonitrogenous amount of l-alanine (control; 465 µmol/kg BW). Increases (P < 0.05) in circulating citrulline concentrations were detected for 8 h after l-citrulline injection versus the control. Similarly, increases (P < 0.05) in circulating arginine concentrations were detected for 24 h after l-citrulline treatment. The second study used 12 ewes with twin pregnancies. Daily intravenous injections of either l-citrulline or l-alanine were administered for 39 d from d 42-45 to 81-84 of gestation. Ewes were limit-fed at 85% daily energy requirements during the injection period. A decrease (P < 0.0001) in body weight was observed in both treatment groups during this period. No treatment differences were observed in circulating pregnancy-specific protein B concentrations or placental blood flow during the treatment and post-treatment gestational period. No treatment differences were observed in lamb survival nor in lamb birth, weaning and slaughter weights. Treatment did not influence lamb carcass composition or organ weights. However, there was a tendency (P = 0.10) for an increase in antral follicle numbers in ovaries from ewe lambs derived from ewes treated with l-citrulline. In summary, a daily l-citrulline injection increased both circulating citrulline and arginine concentrations in ewes, but daily l-citrulline injections during mid-gestation did not produce any detectable changes in placental activity and blood flow, neonatal and postnatal lamb development, and lamb carcass composition at slaughter. In conclusion, no benefits in placental function and lamb development were observed after providing l-citrulline during mid-gestation in ewes exposed to a mild energy restriction, but there was an indication that follicle numbers in ewe lambs were positively influenced by l-citrulline treatment during fetal development.

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy.

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.

Satellite cells and their regulation in livestock.

Satellite cells are the myogenic stem and progenitor population found in skeletal muscle. These cells typically reside in a quiescent state until called upon to support repair, regeneration, or muscle growth. The activities of satellite cells are orchestrated by systemic hormones, autocrine and paracrine growth factors, and the composition of the basal lamina of the muscle fiber. Several key intracellular signaling events are initiated in response to changes in the local environment causing exit from quiescence, proliferation, and differentiation. Signals emanating from Notch, wingless-type mouse mammary tumor virus integration site family members, and transforming growth factor-ß proteins mediate the reversible exit from growth 0 phase while those initiated by members of the fibroblast growth factor and insulin-like growth factor families direct proliferation and differentiation. Many of these pathways impinge upon the myogenic regulatory factors (MRF), myogenic factor 5, myogenic differentiation factor D, myogenin and MRF4, and the lineage determinate, Paired box 7, to alter transcription and subsequent satellite cell decisions. In the recent past, insight into mouse transgenic models has led to a firm understanding of regulatory events that control satellite cell metabolism and myogenesis. Many of these niche-regulated functions offer subtle differences from their counterparts in livestock pointing to the existence of species-specific controls. The purpose of this review is to examine the mechanisms that mediate large animal satellite cell activity and their relationship to those present in rodents.

Large-Scale Whole-Genome Sequencing Reveals the Genetic Architecture of Primary Membranoproliferative GN and C3 Glomerulopathy.

BACKGROUND: Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN. METHODS: We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource-Rare Diseases Study. We examined copy number, rare, and common variants. RESULTS: Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (P=3.29×10-8; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 (P=1.21×10-8; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure. CONCLUSIONS: We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.