No abstract

Objective To investigate whether symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is non-inferior to antibiotics in the treatment of uncomplicated lower urinary tract infection (UTI) in women, thus offering an opportunity to reduce antibiotic use in ambulatory care. Design Randomised, double blind, non-inferiority trial. Setting 17 general practices in Switzerland. Participants 253 women with uncomplicated lower UTI were randomly assigned 1:1 to symptomatic treatment with the NSAID diclofenac (n=133) or antibiotic treatment with norfloxacin (n=120). The randomisation sequence was computer generated, stratified by practice, blocked, and concealed using sealed, sequentially numbered drug containers. Main outcome measures The primary outcome was resolution of symptoms at day 3 (72 hours after randomisation and 12 hours after intake of the last study drug). The prespecified principal secondary outcome was the use of any antibiotic (including norfloxacin and fosfomycin as trial drugs) up to day 30. Analysis was by intention to treat. Results 72/133 (54%) women assigned to diclofenac and 96/120 (80%) assigned to norfloxacin experienced symptom resolution at day 3 (risk difference 27%, 95% confidence interval 15% to 38%, P=0.98 for non-inferiority, P<0.001 for superiority). The median time until resolution of symptoms was four days in the diclofenac group and two days in the norfloxacin group. A total of 82 (62%) women in the diclofenac group and 118 (98%) in the norfloxacin group used antibiotics up to day 30 (risk difference 37%, 28% to 46%, P<0.001 for superiority). Six women in the diclofenac group (5%) but none in the norfloxacin group received a clinical diagnosis of pyelonephritis (P=0.03). Conclusion Diclofenac is inferior to norfloxacin for symptom relief of UTI and is likely to be associated with an increased risk of pyelonephritis, even though it reduces antibiotic use in women with uncomplicated lower UTI. Trial registration ClinicalTrials.gov NCT01039545.

Congenital thrombotic thrombocytopenic purpura is an autosomal recessive inherited disease with a clinically heterogeneous course and an incompletely understood genotype-phenotype correlation. In 2006, the Hereditary TTP Registry started recruitment for a study which aimed to improve the understanding of this ultra-rare disease. The objective of this study is to present characteristics of the cohort until the end of 2017 and to explore the relationship between overt disease onset and ADAMTS13 activity with emphasis on the recurring ADAMTS13 c.4143_4144dupA mutation. Diagnosis of congenital thrombotic thrombocytopenic purpura was confirmed by severely deficient ADAMTS13 activity (≤10% of normal) in the absence of a functional inhibitor and the presence of ADAMTS13 mutations on both alleles. By the end of 2017, 123 confirmed patients had been enrolled from Europe (n=55), Asia (n=52, 90% from Japan), the Americas (n=14), and Africa (n=2). First recognized disease manifestation occurred from around birth up to the age of 70 years. Of the 98 different ADAMTS13 mutations detected, c.4143_4144dupA (exon 29; p.Glu1382Argfs*6) was the most frequent mutation, present on 60 of 246 alleles. We found a larger proportion of compound heterozygous than homozygous carriers of ADAMTS13 c.4143_4144dupA with overt disease onset at < 3 months of age (50% vs. 37%), despite the fact that ADAMTS13 activity was <1% in 18 of 20 homozygous, but in only 8 of 14 compound heterozygous carriers. An evaluation of overt disease onset in all patients with an available sensitive ADAMTS13 activity assay (n=97) shows that residual ADAMTS13 activity is not the only determinant of age at first disease manifestation. Registered at clinicaltrials.gov identifier NCT01257269.

Etiology and pathogenesis of sarcopenia, the progressive decline in skeletal muscle mass and strength that occurs with aging, are still poorly understood. We recently found that overexpression of the neural serine protease neurotrypsin in motoneurons resulted in the degeneration of their neuromuscular junctions (NMJ) within days. Therefore, we wondered whether neurotrypsin-dependent NMJ degeneration also affected the structure and function of the skeletal muscles. Using histological and functional analyses of neurotrypsin-overexpressing and neurotrypsin-deficient mice, we found that overexpression of neurotrypsin in motoneurons installed the full sarcopenia phenotype in young adult mice. Characteristic muscular alterations included a reduced number of muscle fibers, increased heterogeneity of fiber thickness, more centralized nuclei, fiber-type grouping, and an increased proportion of type I fibers. As in age-dependent sarcopenia, excessive fragmentation of the NMJ accompanied the muscular alterations. These results suggested the destabilization of the NMJ through proteolytic cleavage of agrin at the onset of a pathogenic pathway ending in sarcopenia. Studies of neurotrypsin-deficient and agrin-overexpressing mice revealed that old-age sarcopenia also develops without neurotrypsin and is not prevented by elevated levels of agrin. Our results define neurotrypsin- and age-dependent sarcopenia as the common final outcome of 2 etiologically distinct entities.