Rapid Response to Cyclosporin A and Favorable Renal Outcome in Nongenetic Versus Genetic Steroid–Resistant Nephrotic Syndrome

Background and objectives

Treatment of congenital nephrotic syndrome (CNS) and steroid–resistant nephrotic syndrome (SRNS) is demanding, and renal prognosis is poor. Numerous causative gene mutations have been identified in SRNS that affect the renal podocyte. In the era of high–throughput sequencing techniques, patients with nongenetic SRNS frequently escape the scientific interest. We here present the long-term data of the German CNS/SRNS Follow-Up Study, focusing on the response to cyclosporin A (CsA) in patients with nongenetic versus genetic disease.

Design, setting, participants, & measurements

Cross–sectional and longitudinal clinical data were collected from 231 patients with CNS/SRNS treated at eight university pediatric nephrology units with a median observation time of 113 months (interquartile range, 50–178). Genotyping was performed systematically in all patients.

Results

The overall mutation detection rate was high at 57% (97% in CNS and 41% in SRNS); 85% of all mutations were identified by the analysis of three single genes only (NPHS1, NPHS2, and WT1), accounting for 92% of all mutations in patients with CNS and 79% of all mutations in patients with SRNS. Remission of the disease in nongenetic SRNS was observed in 78% of patients after a median treatment period of 2.5 months; 82% of nongenetic patients responded within 6 months of therapy, and 98% of patients with nongenetic SRNS and CsA–induced complete remission (normalbuminemia and no proteinuria) maintained a normal renal function. Genetic SRNS, on the contrary, is associated with a high rate of ESRD in 66% of patients. Only 3% of patients with genetic SRNS experienced a complete remission and 16% of patients with genetic SRNS experienced a partial remission after CsA therapy.

Conclusions

The efficacy of CsA is high in nonhereditary SRNS, with an excellent prognosis of renal function in the large majority of patients. CsA should be given for a minimum period of 6 months in these patients with nongenetic SRNS. In genetic SRNS, response to CsA was low and restricted to exceptional patients.     

Surveillance and response: Tools and approaches for the elimination stage of neglected tropical diseases

The presentation of the World Health Organization (WHO)’s roadmap for neglected tropical diseases (NTDs) in January 2012 raised optimism that many NTDs can indeed be eliminated. To make this happen, the endemic, often low-income countries with still heavy NTD burdens must substantially strengthen their health systems. In particular, they need not only to apply validated, highly sensitive diagnostic tools and sustainable effective control approaches for treatment and transmission control, but also to participate in the development and use of surveillance–response schemes to ensure that progress made also is consolidated and sustained. Surveillance followed-up by public health actions consisting of response packages tailored to interruption of transmission in different settings will help to effectively achieve the disease control/elimination goals by 2020, as anticipated by the WHO roadmap. Risk-mapping geared at detection of transmission hotspots by means of geospatial and other dynamic approaches facilitates decision-making at the technical as well as the political level. Surveillance should thus be conceived and developed as an intervention approach and at the same time function as an early warning system for the potential re-emergence of endemic infections as well as for new, rapidly spread epidemics and pandemics.     

HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes

Endothelial progenitor cells (EPCs) play an important role in postnatal neovascularization of ischemic tissue. Ex vivo expansion of EPCs might be useful for potential clinical cell therapy of myocardial ischemia. However, cultivation of primary cells leads to cellular aging (senescence), thereby severely limiting the proliferative capacity. Therefore, we investigated whether statins might be able to prevent senescence of EPCs. EPCs were isolated from peripheral blood and characterized. After ex vivo cultivation, EPCs became senescent as determined by acidic beta-galactosidase staining. Atorvastatin or mevastatin dose-dependently inhibited the onset of EPC senescence in culture. Moreover, atorvastatin increased proliferation of EPCs as assessed by BrdU incorporation and colony-forming capacity. Whereas geranylgeranylpyrophosphate or farnesylpyrophosphate reduced the senescence inhibitory effect of atorvastatin, NO synthase inhibition, antioxidants, or Rho kinase inhibitors had no effect. To get further insights into the underlying downstream effects of statins, we measured telomerase activity and determined the expression of various cell cycle regulatory genes by using a microarray assay. Whereas telomerase activity did not change, atorvastatin modulated expression of cell cycle genes including upregulation of cyclins and downregulation of the cell cycle inhibitor p27Kip1. Taken together, statins inhibited senescence of EPCs independent of NO, reactive oxygen species, and Rho kinase, but dependent on geranylgeranylpyrophosphate. Atorvastatin-mediated prevention of EPC senescence appears to be mediated by the regulation of various cell cycle proteins. The inhibition of EPC senescence and induction of EPC proliferation by statins in vitro may importantly improve the functional activity of EPCs for potential cell therapy.     

Tropical pyomyositis: an update

Tropical pyomyositis (TP) is a life‐threatening bacterial infection of the skeletal muscle that occurs particularly among children, young adults and those with immunocompromised conditions. The appropriate diagnosis and treatment are often delayed due to its non‐specific signs, leading to fatal consequences. Staphylococcus aureus, especially methicillin‐susceptible S. aureus, is responsible for most TP cases. However, other bacteria (i.e. streptococci, Pseudomonas aeruginosa, Escherichia coli, Klebsiella spp., Candida spp., Mycobacterium spp.) have been reported. This narrative review provides an update on the epidemiology and clinical course of TP. A special focus is laid on the role of toxins (i.e. Panton‐Valentine Leucocidin and α‐toxin) in the pathogenesis of TP and their implication for the clinical management of infection.     

Asymmetric Cell–Matrix and Biomechanical Abnormalities in Elastin Insufficiency Induced Aortopathy

Aortopathy is characterized by vascular smooth muscle cell (VSMC) abnormalities and elastic fiber fragmentation. Elastin insufficient (Eln ^+/? ) mice demonstrate latent aortopathy similar to human disease. We hypothesized that aortopathy manifests primarily in the aorto-pulmonary septal (APS) side of the thoracic aorta due to asymmetric cardiac neural crest (CNC) distribution. Anatomic (aortic root vs. ascending aorta) and molecular (APS vs. non-APS) regions of proximal aorta tissue were examined in adult and aged wild type (WT) and mutant (Eln ^+/? ) mice. CNC, VSMCs, elastic fiber architecture, proteoglycan expression, morphometrics and biomechanical properties were examined using histology, 3D reconstruction, micropipette aspiration and in vivo magnetic resonance imaging (MRI). In the APS side of Eln ^+/? aorta, Sonic Hedgehog (SHH) is decreased while SM22 is increased. Elastic fiber architecture abnormalities are present in the Eln ^+/? aortic root and APS ascending aorta, and biglycan is increased in the aortic root while aggrecan is increased in the APS aorta. The Eln ^+/? ascending aorta is stiffer than the aortic root, the APS side is thicker and stiffer than the non-APS side, and significant differences in the individual aortic root sinuses are observed. Asymmetric structure–function abnormalities implicate regional CNC dysregulation in the development and progression of aortopathy.     

Speech‐perception training for older adults with hearing loss impacts word recognition and effort

The current pupillometry study examined the impact of speech‐perception training on word recognition and cognitive effort in older adults with hearing loss. Trainees identified more words at the follow‐up than at the baseline session. Training also resulted in an overall larger and faster peaking pupillary response, even when controlling for performance and reaction time. Perceptual and cognitive capacities affected the peak amplitude of the pupil response across participants but did not diminish the impact of training on the other pupil metrics. Thus, we demonstrated that pupillometry can be used to characterize training‐related and individual differences in effort during a challenging listening task. Importantly, the results indicate that speech‐perception training not only affects overall word recognition, but also a physiological metric of cognitive effort, which has the potential to be a biomarker of hearing loss intervention outcome.     

S151A δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice

So far, the role of mutations in the δ-sarcogylcan (Sgcd) gene in causing autosomal dominant dilated cardiomyopathy (DCM) remains inconclusive. A p.S151A missense mutation in exon 6 of the Sgcd gene was reported to cause severe isolated autosomal dominant DCM without affecting skeletal muscle. This is controversial to our previous findings in a large consanguineous family where this p.S151A mutation showed no relevance for cardiac disease. In this study, the potential of the p.S151A mutation to cause DCM was investigated by using two different approaches: (1) engineering and characterization of heterozygous knock-in (S151A-) mice carrying the p.S151A mutation and (2) evaluation of the potential of adeno-associated virus (AAV) 9-based cardiac-specific transfer of p.S151A-mutated Sgcd cDNA to rescue the cardiac phenotype in Sgcd-deficient (Sgcd-null) mice as it has been demonstrated for intact, wild-type Sgcd cDNA. Heterozygous S151A knock-in mice developed a rather mild phenotype of cardiomyopathy. Increased heart to body weight suggests cardiac enlargement in 1-year-old S151A knock-in mice. However, at this age cardiac function, assessed by echocardiography, is maintained and histopathology completely absent. Myocardial expression of p.S151A cDNA, similar to intact Sgcd cDNA, restores cardiac function, although not being able to prevent myocardial histopathology in Sgcd-null mice completely. Our results suggest that the p.S151A mutation causes a mild, subclinical phenotype of cardiomyopathy, which is prone to be overseen in patients carrying such sequence variants. Furthermore, this study shows the suitability of an AAV-mediated cardiac gene transfer approach to analyze whether a sequence variant is a disease-causing mutation.