Vaginal treatment with lactic acid gel delays relapses in recurrent urinary tract infections: results from an open, multicentre observational study.

PURPOSE: The main objective of this open, prospective, multicentre, observational study is to investigate the relapse rate and tolerability of lactic acid gels in adult female patients with recurrent urinary tract infections during routine practice. METHODS: Data were collected from patients undergoing intermittent short courses of intravaginal treatment with lactic acid gel for prevention of recurrent urinary tract infections. The observation period for individual patients was 4 months, aimed at covering four short courses of intravaginal treatment. Data on UTI relapses, tolerability, handling and satisfaction with the treatment were collected via patient diaries and physician assessments and comprised any adverse events (AEs). RESULTS: In total, 72 patients were treated. During the last 12 months prior to the study, patients had on average 4.0 UTIs. In the 4 months after commencing treatment, 63.5% of patients had no recurrence of UTI symptoms. Overall efficacy was rated by physicians as 'excellent/good' for 96.7% of patients. The patients' overall acceptance of local treatment was high with 94.1% being '(very) satisfied'. Similarly, handling was rated as '(very) easy' by 94.2% of patients. The tolerability was assessed as 'highly tolerable/tolerable' by over 98% of patients and physicians alike. Safety analyses reported six AEs of mild intensity, all of which had resolved by the end of the study. CONCLUSION: Treatment with lactic acid gel may increase resilience against uropathogens, possibly preventing the need for antibiotic prevention of recurrent urinary tract infections. Treatment was positively assessed by the patients. The physician assessments corroborate these findings. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: DRKS00016760, 18.02.2019.

Effectiveness of varenicline as an aid to smoking cessation in primary care: an observational study.

AIMS: Although varenicline is commonly prescribed in primary care, information on smoking-related comorbidities and the effectiveness of varenicline in this context in Germany is scarce. This study assessed the efficacy and safety of varenicline in a large sample of patients seeking smoking cessation treatment through their general practitioners. The frequency of comorbidities was also evaluated. METHODS: This was a 12-week, prospective, observational, non-comparative phase IV trial conducted in Germany. Abstinence rates at week 12 were evaluated by verbal reporting using the nicotine use inventory. RESULTS: Overall, 1,391 subjects were enrolled; 1,177 received study medication and were evaluated for effectiveness and safety. At the end of the study, 71.1% (95% confidence interval 68.5-73.7) of subjects were abstinent. There were a total of 205 all-causality adverse events; 2.2% were classified as serious or severe. There were no fatal adverse events. At inclusion, 66.7% of participants had at least 1 concurrent comorbidity, with chronic obstructive pulmonary disease (35.5%), hypertension (29.6%) and depression (10.4%) being the most commonly reported. CONCLUSION: These real-world data indicate that varenicline is an effective and well-tolerated smoking cessation treatment when used in the primary care setting including patients with smoking-related comorbidities.

Role of NF2 haploinsufficiency in NF2-associated polyneuropathy.

Neurofibromatosis 2 (NF2) is a hereditary tumor disease characterized by bilateral vestibular schwannomas. Polyneuropathy seems to occur quite frequently in NF2 and in most cases, the etiology of this neuropathy is unclear, especially when the neuropathy is symmetric. NF2 is believed to follow the two-hit hypothesis. According to this, one allele is mutated in the germline, and the second hit is somatic and results in tumor formation. The second hit most frequently is a loss of the NF2 locus, often the entire chromosome 22. We set out to investigate the underlying genetics in peripheral nerve of NF2 patients with polyneuropathy. We identified NF2 patients with polyneuropathy in which we could detect the germline mutation and analyzed NF2 gene dosage in archived nerve biopsies from these patients using a newly developed method. We observed merlin haploinsufficiency in peripheral nerves of two different patients with NF2-related polyneuropathy. This finding was further supported by showing that approximately 50% merlin expression in a cell line using shRNA results in altered gene expression as previously shown in schwannomas. Thus, we suggest that reduced merlin gene dosage is relevant in NF2-associated polyneuropathy.

Sensitive detection of deletions of one or more exons in the neurofibromatosis type 2 (NF2) gene by multiplexed gene dosage polymerase chain reaction.

Mutation detection in the neurofibromatosis type 2 (NF2) gene is challenging because when combining mutation detection methods such as single-strand conformational polymorphism and heteroduplex analysis, denaturing gradient gel electrophoresis, and direct sequencing of aberrant polymerase chain reaction (PCR) fragments only 30 to 60% of the constitutional mutations are detected. Because large deletions and complete chromosome rearrangements are also described methods such as microarray-comparative genomic hybridization and fluorescence in situ hybridization are also used. The one type of mutation often missed corresponds to deletions encompassing one or few exons. To detect this type we have developed a swift and reliable method. We perform a gene dosage analysis with two fluorescent multiplex PCR assays that amplify 15 of the 17 NF2 exons. The labeled PCR products are quantified and gene dose is calculated with respect to controls. We tested the reliability of this method with DNA from eight NF2 patients with known heterozygous NF2 deletions, eight controls and four unknown NF2 patients. In all of the patients with known heterozygous deletions we found in several exons a reduction of gene dosage to 50 to 69%. In one NF2 patient with previously unknown mutation and a severe phenotype we found the gene dosage of two exons reduced by 50% indicating a deletion of these two exons on one allele. This finding was validated by reverse transcriptase-PCR on fibroblast and schwannoma cell cultures of this patient and cDNA sequencing. Our gene dosage assay will detect deletions of one or more exons as well as gross deletions of the whole coding region of the gene. It can complement the existing screening methods because it is faster and easier.

The branched-chain amino acid transaminase gene family in Arabidopsis encodes plastid and mitochondrial proteins.

Branched-chain amino acid transaminases (BCATs) play a crucial role in the metabolism of leucine, isoleucine, and valine. They catalyze the last step of the synthesis and/or the initial step of the degradation of this class of amino acids. In Arabidopsis, seven putative BCAT genes are identified by their similarity to their counterparts from other organisms. We have now cloned the respective cDNA sequences of six of these genes. The deduced amino acid sequences show between 47.5% and 84.1% identity to each other and about 30% to the homologous enzymes from yeast (Saccharomyces cerevisiae) and mammals. In addition, many amino acids in crucial positions as determined by crystallographic analyses of BCATs from Escherichia coli and human (Homo sapiens) are conserved in the AtBCATs. Complementation of a yeast Deltabat1/Deltabat2 double knockout strain revealed that five AtBCATs can function as BCATs in vivo. Transient expression of BCAT:green fluorescent protein fusion proteins in tobacco (Nicotiana tabacum) protoplasts shows that three isoenzymes are imported into chloroplasts (AtBCAT-2, -3, and -5), whereas a single enzyme is directed into mitochondria (AtBCAT-1).