The benefit of conversion from mycophenolate mofetil (MMF) to enteric-coated sodium (EC-MPS) in terms gastrointestinal symptom burden has been evaluated previously using patient-reported outcomes. However, data are lacking concerning the sustained effect over time, and potential impact concomitant calcineurin inhibitor.In this 3-month, prospective, multicenter, longitudinal, open-label trial, MMF-treated renal transplant patients with symptoms receiving cyclosporine or tacrolimus were...

Although the genetic causes of hypertrophic cardiomyopathy (HCM) are widely recognized, considerable lag in development targeted therapeutics has limited interventions to symptom palliation. This is part attributable an incomplete understanding how point mutations trigger pathogenic remodeling. As a further complication, similar within sarcomeric genes can result differential disease severity, highlighting need understand mechanism progression at molecular level. One pathway commonly linked...

The progression of genetically inherited cardiomyopathies from an altered protein structure to clinical presentation disease is not well understood. One the main roadblocks mechanistic insight remains a lack high-resolution structural information about multiprotein complexes within cardiac sarcomere. example tropomyosin (Tm) overlap region thin filament that crucial for function To address this central question, we devised coupled experimental and computational modalities characterize...

Renal dysfunction is one of the most significant problems following orthotopic liver transplantation (OLTx). Since major risk factor for delayed renal OLTx presumed to be cyclosporine (CsA) nephrotoxicity, it has been suggested that CsA probably cause end‐stage disease (ESRD) in this population patients. To test hypothesis records patients our center who developed ESRD requiring dialysis were reviewed. There 132 consecutive adult with (ESLD) received 146 OLTxs between 1990 and 2000. Five...

Introduction: Pancreatic transplantation (PTx) with portal venous delivery of insulin and enteric drainage the exocrine secretion is more physiologic than bladder‐systemic (BS) drainage. With portal‐enteric (PE) PTx, diagnosis acute rejection (AR) requires a percutaneous biopsy. The roux‐en‐y (RNY) venting jejunostomy in patients PEPTx offers novel approach to monitor prevent anastomatic leaks. Methods. From January 1996 December 1998, we performed 17 simultaneous kidney/pancreas transplants...

The structural analysis of large protein complexes has been greatly enhanced through the application electron microscopy techniques. One such multiprotein complex, cardiac thin filament (cTF), cyclic interactions with thick proteins to drive contraction heart that recently subject studies. As important as these studies are, they provide limited or no information on highly flexible regions in isolation would be characterized inherently disordered. region is extended troponin T (cTnT) linker...

Point mutations within sarcomeric proteins have been associated with altered function and cardiomyopathy development. Difficulties remain, however, in establishing the pathogenic potential of individual mutations, often limiting use genotype management affected families. To directly address this challenge, we utilized our all-atom computational model human full cardiac thin filament (CTF) to predict how sequence substitutions CTF might affect structure dynamics on an atomistic level....

This article reports a coupled computational experimental approach to design small molecules aimed at targeting genetic cardiomyopathies. We begin with fully atomistic model of the cardiac thin filament. To this we dock using accepted drug binding methodologies. The candidates are screened for their ability repair alterations in biophysical properties caused by mutation. Hypertrophic and dilated cardiomyopathies mutation initially nature, take is correct insult prior irreversible damage....

BACKGROUND: Impaired left ventricular relaxation, high filling pressures, and dysregulation of Ca 2+ homeostasis are common findings contributing to diastolic dysfunction in hypertrophic cardiomyopathy (HCM). Studies have shown that impaired relaxation is an early observation the sarcomere-gene-positive preclinical HCM cohort, which suggests potential involvement myofilament regulators relaxation. A molecular-level understanding mechanism(s) at level lacking. We hypothesized...

Familial dilated cardiomyopathy (DCM) is a genetic heart disorder characterized by enlargement of one or both ventricles, rendering the unable to pump blood efficiently. Mutations in cardiac thin filament (CTF) proteins have been associated with clinical manifestations DCM. Genetic segregation identified mutation α-Tropomyosin (Tm) at residue 230 (D230N-Tm) two unrelated, multigenerational families linked severe, early onset To meaningfully link genotype phenotype our group sought...

In the heart, Ca/Calmodulin Kinase IIδ (CaMKIIδ) functions to maintain electromechanical and calcium homeostasis. Post-translational modifications (PTMs) of CaMKIIδ render its activity autonomous Ca/CaM. hypertrophic cardiomyopathy (HCM), increased levels are linked disease progression. We have shown that pathogenic role in HCM is mutation-specific: elevated cardiac troponin T (cTnT)-R92W mice, but not cTnT-R92L mice. These results pose a clinically relevant critical question: what trigger...

Anthracyclines are a key component in the management of pediatric cancers long recognized to carry significant risk dose-dependent cardiotoxicity. Despite advancements clinical management, considerable variation incidence cardiotoxicity persists across dosing regimens suggesting modifiers exist. Recently, changes splicing TNNT2, gene encoding cardiac troponin T (cTnT), were postulated contribute anthracycline cardiotoxicity, potentially providing direct link myofilament. Previous studies our...

An oft-noted component of sarcomeric DCM is the observation that patients within families carrying same primary mutation exhibit significant phenotypic variability. This lack a distinct link between genotype and phenotype has complicated clinical management. In recent study two unrelated multigenerational with tropomyosin (Tm) Asp230Asn (D230N), striking “bimodal” distribution severity was observed. these families, many children (<1 year) presented severe form led to sudden, often fatal...

An oft-noted component of sarcomeric HCM and DCM is the observation that patients within families, carrying same primary mutation, often exhibit significant phenotypic variability. This lack a distinct link between genotype phenotype has greatly complicated clinical management. In recent study two large unrelated multigenerational families tropomyosin (Tm) mutation Asp230Asn (D230N), striking “bimodal” distribution severity was observed. these many children (<1 year) with presented severe...

An oft noted component of sarcomeric DCM is the observation that patients within families carrying same primary mutation exhibit significant phenotypic variability. This lack a distinct link between genotype and phenotype has complicated clinical management. Recently two unrelated multigenerational were identified with tropomyosin (Tm) Asp230Asn (D230N), exhibiting striking “bimodal” distribution severity. In these families, many children (<1 year) D230N Tm presented severe form led to...