Involvement of brain-derived neurotrophic factor in early retinal neuropathy of streptozotocin-induced diabetes in rats: therapeutic potential of brain-derived neurotrophic factor for dopaminergic amacrine cells

Although neurotrophins have been assessed as candidate therapeutic agents for neural complications of diabetes, their involvement in diabetic retinopathy has not been fully characterized. We found that the protein and mRNA levels of brain-derived neurotrophic factor (BDNF) in streptozotocin-induced diabetic rat retinas were reduced to 49% (P < 0.005) and 74% (P < 0.05), respectively, of those of normal control animals. In addition, dopaminergic amacrine cells appeared to be degenerating in the diabetic rat retinas, as revealed by tyrosine hydroxylase (TH) immunoreactivity. Overall TH protein levels in the retina were decreased to one-half that of controls (P < 0.01), reflecting reductions in the density of dopaminergic amacrine cells and the intensity of TH immunoreactivity within them. To confirm the neuropathological implications of BDNF reduction, we administered BDNF protein into the vitreous cavities of diabetic rats. Intraocular administration of BDNF rescued dopaminergic amacrine cells from neurodegeneration and counteracted the downregulation of TH expression, demonstrating its therapeutic potential. These findings suggest that the early retinal neuropathy of diabetes involves the reduced expression of BDNF and can be ameliorated by an exogenous supply of this neurotrophin.     

Urinary nerve growth factor in women with overactive bladder syndrome

Study Type – Aetiology (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Urinary nerve growth factor levels were higher in women with OAB‐dry and OAB‐wet compared to the controls. The link between female OAB and risk factors such as obesity and menopause has not been determined yet. This study found ageing, menopause, or higher BMI did not influence the urinary NGF levels in OAB women. Higher urinary NGF levels in OAB women could be an inflammatory disorder unrelated to ageing or obesity.

OBJECTIVE

? To measure urinary nerve growth factor (NGF) in women with overactive bladder (OAB)‐dry and OAB‐wet and investigate the association of urinary NGF expression with these factors.

PATIENTS AND METHODS

? Differentiation between OAB‐wet and OAB‐dry was based on symptoms and a 3‐day voiding diary. ? Urinary NGF levels were measured by enzyme‐linked immunosorbent assay (ELISA). ? The urinary NGF levels were compared among controls, OAB‐dry and OAB‐wet subgroups, and also between OAB patients ≥55 years and <55 years, as well as between patients with a body mass index (BMI, kg/m²) <20, 20–30 and >30.

RESULTS

? A total of 113 women with OAB‐dry, 106 with OAB‐wet and 84 controls were enrolled. The urinary NGF/creatinine (Cr) levels were significantly highest in OAB‐wet (2.13 ± 3.87) and second highest in OAB‐dry (0.265 ± 0.59) compared to controls (0.07 ± 0.21). ? Analysis of urinary NGF or NGF/Cr levels among controls, OAB‐dry and OAB‐wet groups by age and BMI showed no significant differences, except for the OAB‐dry group. ? Urinary NGF/Cr was not significantly correlated with age (P= 0.088) or BMI (P= 0.886) in women with OAB‐dry and OAB‐wet.

CONCLUSIONS

? Urinary NGF levels were significantly higher in women with OAB‐dry and even higher in women with OAB‐wet. ? The urinary NGF level was not associated with ageing, menopause or higher BMI either in controls or OAB patients.     

Urinary nerve growth factor and a variable solifenacin dosage in patients with an overactive bladder

Introduction and hypothesis

We evaluated changes in urinary nerve growth factor (NGF) and NGF/creatinine (NGF/Cr) levels after increasing the dosage of solifenacin in overactive bladder patients.

Methods

The study groups included 59 overactive bladder (OAB) patients and 20 healthy subjects as controls. We measured NGF at baseline for the patients and controls, and used the Overactive Bladder Awareness Tool (OAB-V8) to evaluate urinary symptoms. All patients received a treatment of solifenacin 5 mg for 6 weeks. The responders to treatment served as group 1 and nonresponders received solifenacin 10 mg for an additional 6 weeks. Responders and nonresponders to the 10-mg treatment were defined as groups 2 and 3 respectively. NGF was measured after each treatment using the ELISA method and normalized by the urinary creatinine levels (NGF/Cr).

Results

There were 21, 22 and 16 patients in groups 1, 2, and 3 respectively. At baseline, the NGF and NGF/Cr levels were higher in groups 1, 2, and 3 compared with the controls. After the solifenacin 5 mg treatment, the NGF and NGF/Cr levels of group 1 individuals decreased to those of the control level. After increasing the dosage of solifenacin to 10 mg in group 2, the NGF and NGF/Cr levels decreased to normal levels. In group 3 (patients who did not responded to any treatment), these levels remained unchanged.

Conclusions

Our results suggest that urinary NGF could be a potential biomarker for monitoring the treatment of symptoms in OAB patients who are treated with solifenacin.

     

The overactive bladder in children: a potential future indication for tolterodine

OBJECTIVE: To determine the safety, efficacy and pharmacokinetics of tolterodine in children with an overactive bladder. PATIENTS AND METHODS: Thirty-three children (20 boys and 13 girls, aged 5-10 years) with an overactive bladder and symptoms of urgency, frequency and/or urge incontinence were enrolled in an open, dose-escalation study. Patients were treated with oral tolterodine 0.5 mg (n = 11), 1 mg (n = 10) or 2 mg (n = 12) twice daily for 14 days. The primary safety endpoint was the change in residual urinary volume, as determined by ultrasonography. In addition, voiding diary variables (frequency and incontinence episodes) and pharmacokinetics were evaluated. Other safety endpoints included laboratory variables, electrocardiogram recordings and reported adverse events. RESULTS: There were no safety concerns in terms of the change in residual urinary volume for any of the three dosage groups; values were comparable with baseline after 2 weeks of treatment for all three dosages. Adverse events were reported by 20 patients (six on 0.5 mg, five on 1 mg, and nine on 2 mg). Most adverse events were not considered to be drug-related; of the 13 possibly related events, 10 occurred in those taking 2 mg. Headache was the most commonly reported adverse event. No serious adverse events were reported and there were no general safety concerns. There was an improvement in voiding diary variables in all treatment groups after 2 weeks of treatment, although the efficacy was greatest in those taking 1 mg and 2 mg. Pharmacokinetic findings were consistent with dose linearity over the range 0.5-2 mg. CONCLUSION: The results support the use of 1 mg twice daily as the optimal dose of tolterodine for treating children aged 5-10 years with an overactive bladder.     

Urinary urgency outcomes after propiverine treatment for an overactive bladder: the ‘Propiverine study on overactive bladder including urgency data’

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To investigate the effects of a daily regimen of propiverine 20 mg in patients with an overactive bladder (OAB), focused on improving urgency, as the clinical efficacy of treatment for OAB should be measured in terms of urgency, the cornerstone symptom of OAB.

PATIENTS AND METHODS

Eligible patients aged ≥18 years with symptoms of OAB were enrolled in this multicentre, prospective, parallel, double‐blind, placebo‐controlled trial. Of 264 patients (mean age 52.2 years), 221 who had efficacy data available from baseline and at least one on‐treatment visit with >75% compliance with medication were analysed (142 in the propiverine group and 79 in the placebo group). All patients were randomized to receive a placebo or 20 mg propiverine once daily in a 12‐week study. They completed a 3‐day voiding diary before visits during the study period, including the severity of urgency associated with every voiding, using the Indevus Urgency Severity Scale and the Urgency Perception Score. The patients’ overall self‐evaluation of treatment benefits at the end of the study, and safety data, were also collected.

RESULTS

The daily urgency episodes reduced significantly from baseline to 12 weeks on propiverine treatment, compared with placebo (?46.0% vs ?31.3%, P = 0.005). Secondary endpoints, including sum of urgency severity per 24 h, urgency severity per void, and daytime voiding frequency, were also improved significantly in the propiverine group. Overall, of those patients treated with propiverine, 38.7% rated their treatment as providing ‘much benefit’, compared with 15.2% of the placebo group (P = 0.025). Adverse events reported by 32 (22.5%) and 10 (12.7%) patients in the propiverine and placebo group were all tolerable. However, this is a short‐term study using only one fixed regimen.

CONCLUSIONS

Propiverine 20 mg once‐daily could be an effective treatment for patients with OAB, by improving urgency.     

脑源性神经营养因子在生殖细胞发育过程中的作用

脑源性神经营养因子（BDNF）是神经营养因子家族成员，不仅在神经系统广泛表达，也在非神经组织如心血管系统、免疫系统、内分泌和生殖系统表达。本文综述了BDNF在生殖细胞发育过程中的表达和作用的研究进展，重点讨论了BDNF在卵泡发育和成熟过程中的表达和可能作用。     

脑源性神经营养因子在大鼠炎性痛中的作用

目的 评价脑源性神经营养因子(BDNF)在大鼠炎性痛中的作用.方法 鞘内置管成功的雌性未交配SD大鼠60只,体重150～180 g,随机分为5组(n=12):假手术组(Ⅰ组)、假手术+BDNF中和抗体组(Ⅱ组)、炎性痛组(Ⅲ组)、炎性痛+IgG对照抗体组(Ⅳ组)和炎性痛+BDNF中和抗体组(Ⅴ组).Ⅲ组、Ⅳ组和Ⅴ组于左后肢外踝关节腔内注射完全弗式佐剂50μl,制备炎性痛模型;Ⅰ组和Ⅱ组于左后肢外踝关节腔内注射生理盐水50μl.造模后第1天时Ⅱ组、Ⅳ组和Ⅴ组分别鞘内注射BDNF中和抗体、IgG对照抗体和BDNF中和抗体15 .μg/10μl,1次/d,连续3 d.分别于造模前及造模后第3、5、7、10、14天时,测定大鼠热缩足反射潜伏期(PWTL).于造模后第3天PWTL测定结束后处死大鼠,取L4～6脊髓背角,采用荧光免疫组化法和Western blot法测定BDNF和p-ERK1/2的蛋白表达水平.结果 与Ⅰ组比较,Ⅱ组PWTL、脊髓背角BDNF和p-ERK1/2的蛋白表达差异无统计学意义(P＞0.05),Ⅲ组和Ⅳ组PWTL缩短,脊髓背角BDNF和p-ERK1/2的蛋白表达上调,Ⅴ组PWTL缩短(P＜0.01),脊髓背角BDNF和p-ERK1/2的蛋白表达差异无统计学意义(P＞0.05);与Ⅲ组比较,Ⅳ组PWTL、脊髓背角BDNF和p-ERK1/2的蛋白表达差异无统计学意义(P＞0.05),Ⅴ组PWTL延长,脊髓背角BDNF和p-ERK1/2的蛋白表达下调(P＜0.01).结论 脊髓背角BDNF可通过其下游的p-ERK1/2信号转导通路参与大鼠炎性痛的形成.     

Urinary urgency: a review of its assessment as the key symptom of the overactive bladder syndrome

Purpose

Overactive bladder (OAB) is a common condition that is associated with a negative impact on quality of life. Urgency is the essential symptom when making a diagnosis, and its effective treatment is a principal aim in OAB management. However, urgency has often been relatively neglected as an outcome measure in clinical trials. The aim of this review is, first, to describe the background to urgency in OAB; second, to determine whether results provided by several tools used to measure urgency in clinical trials could be cross-related to each other in a meaningful way.

Methods

The wording of various tools used to measure urgency in OAB was compared against the definition of urgency proposed by the International Continence Society (ICS). Urgency data were evaluated from two randomised, double-blinded, placebo-controlled trials with solifenacin in which seven tools were used to measure urgency as a primary or secondary outcome. In particular, subanalyses were available from these tools, which measured urgency equating to the ICS definition, excluding data points that could be interpreted as normal/strong desire to void.

Results

Baseline scores for ICS-defined urgency differed between the tools, which might reflect imprecision in their wording and consequent overlap between urgency and normal/strong desire to void. All the tools detected broadly similar mean percentage reductions in the number of urgency episodes from baseline to the endpoint of the studies.

Conclusions

Urgency should be the primary or co-primary endpoint for future studies of OAB and detrusor overactivity. Greater clarity is needed in the development of instruments for measuring urgency, so that they do not confuse urgency with normal bladder sensations; more education and guidance are needed on how urgency is defined.     

Expression of brain-derived neurotrophic factor in rapid ejaculator rats: A further study

Limited evidence has indicated that brain-derived neurotrophic factor (BDNF) may be involved in the neurobiology of premature ejaculation (PE). This study aimed to investigate BDNF levels in the central and peripheral nervous systems of a rapid ejaculation model. Eighteen male rats were selected and classified as ‘sluggish’, ‘normal’ and ‘rapid’ ejaculators on the basis of ejaculation frequency during copulatory behavioural tests. BDNF levels in specific brain regions, spinal cord and serum were determined by enzyme-linked immunosorbent assay (ELISA). Consistent with the results in PE patients, the concentration of serum BDNF decreased significantly from the sluggish rats to normal and rapid rats. Besides, in both brain regions and spinal cord, the sluggish group had the highest BDNF levels, while the rapid group had the lowest BDNF levels. Regression analyses of the expression of BDNF presented positive correlations between serum and brain (r = 0.958, p < .001), and between serum and spinal cord (r = 0.967, p < .001) respectively. Our findings suggested insufficient BDNF in the nervous system and serum may lead to rapid ejaculation. The current study adds to the evidence that BDNF is involved in the regulation of ejaculation.     

Urinary phthalate metabolites and semen quality: a review of a potential biomarker of susceptibility

Phthalates are a class of chemicals with widespread general population exposure. Some phthalates are reproductive and developmental toxicants in laboratory animals. Advances in the field of phthalate research in humans are dependent on the development and implementation of biomarkers to assess exposure and outcome, as well as potential markers that may be indicative of increased susceptibility. Recently, we incorporated a novel biomarker of potential 'susceptibility' into our study on the relationship of phthalates with semen quality and sperm DNA damage among men recruited from an infertility clinic. We measured urinary concentrations of three di(2-ethylhexyl) phthalate (DEHP) metabolites, mono(2-ethylhexyl) phthalate (MEHP) and two oxidative metabolites, mono-(2-ethyl-5-hydroxylhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP). We calculated the percent of DEHP excreted as the hydrolytic monoester (i.e., MEHP). We referred to this as %MEHP and considered it a phenotypic marker of the proportion of DEHP excreted in the urine as MEHP. In our sperm DNA study, we found novel results for the DEHP metabolites. Although MEHP was positively correlated with the oxidative metabolites, the association of sperm DNA damage with MEHP, as compared to MEHHP and MEOHP, were in opposite directions. We hypothesized that MEHP is the bioactive toxicant and further metabolism to MEHHP/MEOHP may lower internal burden of MEHP and thus be protective from sperm DNA damage. An alternative explanation may include that the relative percentage of DEHP excreted as MEHP was a surrogate for the function of phase I enzymes. Men with high %MEHP may have higher levels of sperm DNA damage because of poor metabolism (detoxification) of other genotoxic chemicals. Our hypothesis that %MEHP may represent a phenotypic marker of metabolism is novel but requires further exploration to confirm.     

Solifenacin for overactive bladder: a systematic review and meta-analysis

This study aims to evaluate the efficacy and safety of solifenacin for treating overactive bladder. Randomized controlled trials (RCTs) were identified and extracted from MEDLINE, Embase, and CENTRAL. The quality of the included RCTs was assessed using the Jadad score, and heterogeneity was analyzed using the chi-squared test. The data of the included RCTs were collected, extracted, and assessed by our protocol. A total of nine RCTs were identified from the search strategy. Compared with the placebo and tolterodine treatments, both short-term (mostly 12-week) trials indicated that solifenacin significantly reduced urgency episodes, micturitions, and incontinence episodes per 24 h. Compared with the solifenacin (5 mg) group, the solifenacin (10 mg) group was significantly better in terms of the number of micturitions per 24 h. With regard to adverse effects, the patients treated with solifenacin had significantly higher rates of constipation and blurred vision than patients treated with tolterodine. The solifenacin therapy was not inferior to tolterodine in terms of efficacy profiles and had a similar incidence of overall adverse events compared with tolterodine treatment. Solifenacin (5 mg) is thus a recommended dose because of its reported balance between efficacy and acceptable tolerability.     

脑源性神经营养因子在卵母细胞成熟过程中的表达与作用

卵泡发育及卵母细胞成熟是一个非常复杂的过程,是一种多种因子相互作用、相互协调的结果.近年来研究脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)不仅广泛分布于神经系统,对神经元的分裂和发育发挥重要作用,而且在生殖系统也有表达.并认为BDNF能够通过某种旁分泌或自分泌的方式促进卵母细胞成熟,尤其是胞浆成熟,从而促进移植前胚胎的发育.但其具体作用机制还不甚清楚,有待于进一步研究.     

Urinary nerve growth factor: a biomarker of detrusor overactivity? A systematic review

Nerve growth factor (NGF) is a signalling protein that interacts with specific receptors in autocrine, paracrine and endocrine modes. It is produced by bladder smooth muscle and urothelium. Patients with overactive bladder and detrusor overactivity (DO) have been found to have increased urinary NGF levels in several small studies. The objective of the review was to assess the accuracy of NGF as a biomarker in the diagnosis of DO by a systematic review of the literature. A systematic search of MEDLINE, Embase, CINAHL, MEDION and LILACS databases was conducted (inception till December 2012). Selection criteria included studies where NGF (as a biomarker for DO) and urodynamics were performed in humans with symptoms of overactive bladder. Two reviewers independently selected articles and extracted data on study characteristics, quality and results. All the eight included studies were of case-control design. A meta-analysis was not performed as there were variations in the quality, methods of performing the NGF assay, different NGF cut-offs used and the format of reporting findings. Two studies used a cut-off of 0.05 for NGF levels. Six studies observed a trend towards higher NGF levels in patients with DO. There was a trend towards higher NGF in patients with DO. However, the data are imprecise and hence cannot be recommended for use in current clinical practice.