JNJ-10280205 and JNJ-10287069: Novel PDE5 inhibitors as clinical candidates for erectile dysfunction

Phosphodiesterase 5 (PDE5) inhibitors are efficacious in treating patients with erectile dysfunction. New PDE5 inhibitors with different selectivity and pharmacokinetic profiles have been vigorously pursued. Here we report two novel, potent, and selective PDE5 inhibitors, JNJ-10280205 and JNJ-10287069, with Ki values of 0.05 and 0.12 nM, respectively. Both compounds displayed superior selectivity against PDE1-4 and -6 when compared to sildenafil. In the anesthetized dogs, JNJ-10280205 and JNJ-10287069 exhibited similar efficacy as sildenafil in enhancing erectile functions, with no significant effect on cardiovascular parameters. Pharmacokinetic studies showed that JNJ-10287069 had better oral bioavailability than JNJ-10280205 in several animal species. In vitro study suggested that cytochrome P450 (CYP) 3A4 played a major role in the metabolism of both compounds. The compounds inhibited some of the CYP450 enzymes and the human ether-a-go-go (HERG) channel at much higher concentrations than that required to inhibit PDE5, thus, no cross inhibition would be expected at therapeutic doses. Both compounds are suitable clinical candidates.     

Statins for improving renal outcomes: a meta-analysis

Statins frequently are used to prevent cardiovascular events. Several recent studies suggest that statins also may have renal benefits, although this is controversial. This systematic review and meta-analysis were performed to assess the effect of statins on change in kidney function and urinary protein excretion. Medline, EMBASE, the Cochrane Central Register of Controlled Trials, conference proceedings, and the authors' personal files were searched. Published or unpublished randomized, controlled trials or crossover trials of statins that reported assessment of kidney function or proteinuria were included, and studies of individuals with ESRD were excluded. Data were extracted for study design, subject characteristics, type of statin and dose, baseline/change in cholesterol levels, and outcomes (change in measured or estimated GFR [eGFR] and/or urinary protein excretion). Weighted mean differences were calculated for the change in GFR between statin and control groups using a random-effects model. A random-effects model also was used to calculate the standardized mean difference for the change in urinary protein excretion between groups. Twenty-seven eligible studies with 39,704 participants (21 with data for eGFR and 20 for proteinuria or albuminuria) were identified. Overall, the change in the weighted mean differences for eGFR was statistically significant (1.22 ml/min per yr slower in statin recipients; 95% confidence interval [CI] 0.44 to 2.00). In subgroup analysis, the benefit of statin therapy was statistically significant in studies of participants with cardiovascular disease (0.93 ml/min per yr slower than control subjects; 95% CI 0.10 to 1.76) but was NS for studies of participants with diabetic or hypertensive kidney disease or glomerulonephritis. The standardized mean difference for the reduction in albuminuria or proteinuria as a result of statin therapy was statistically significant (0.58 units of SD greater in statin recipients; 95% CI 0.17 to 0.98). Statin therapy seems to reduce proteinuria modestly and results in a small reduction in the rate of kidney function loss, especially in populations with cardiovascular disease.     

Changes in connectivity profiles as a mechanism for strategic control over interfering subliminal information

Human behavior can be influenced by information that is not consciously perceived. Recent behavioral and electrophysiological evidence suggests, however, that the processing of subliminal stimuli is not completely beyond an observer's conscious control. The present study aimed to characterize the cortical network that implements strategic control over interfering subliminal information at multiple stages. Fourteen participants underwent functional magnetic resonance imaging (fMRI) scanning while performing a metacontrast masking paradigm. We systematically varied the amount of conflicting versus non-conflicting trials across experimental blocks, and behavioral performance demonstrated strategic effects whenever a high proportion of subliminal prime stimuli induced response competition. A psychophysiological interaction analysis revealed the pre-supplementary motor area (pre-SMA) to exhibit context-dependent covariation with activation in the lateral occipital complex (LOC) and the putamen. The pre-SMA thereby appears to fulfill a superordinate function in the control of processing subliminal information by simultaneously modulating perceptual analysis and motor selection.     

Quality analysis of internet information on epicondylitis radialis humeri

AIM: By means of conventional internet search engines we assessed the World Wide Web for the topic "epicondylitis radialis humeri" and analysed the content of the listed pages for their quality and transparency. METHODS: Three of the most frequently used internet search engines were utilised to search the World Wide Web for the terms "tennis arm", "tennis elbow" and "epicondylitis". The first 50 listed internet addresses per search engine were scrutinised in respect to the authors' source, financier of the web page and whether commercial interests were evident. Furthermore, the medical content concerning radial epicondylitis was analysed using a 10-point score. RESULTS: After elimination of repetitive and not accessible internet pages, as well as web pages only giving links to further web-sites or chat-rooms, we were able to evaluate 137 internet sites. The average content-score of all pages was low with 2.91 +/- 3.27 SD. Web-pages, where authorship could not be identified or where commercial interests were clearly evident, had the lowest content-scores. Sites authored by or associated with orthopaedic surgeons had a significantly higher content-score (6.84 +/- 3.17 SD) in comparison to other initiators of web-pages (p < 0.0001). CONCLUSION: The facts derived from the World Wide Web when searching for information on epicondylitis radialis humeri are mostly of low professional quality and transparency. Orthopaedic surgeons need to point out this problem to patients who additionally inform themselves on the internet. If the desire for browsing the web for further information concerning musculoskeletal pathology exists, orthopaedic surgeons should tell their patients which web sites are suitable.     

Achilles tendon lengthening for ankle equinus deformity in hemophiliacs: 23 patients followed for 1-24 years

BACKGROUND: Bleeding in the calf or ankle joint may lead to ankle equinus deformity, particularly in childhood and during adolescence. We assessed the long-term functional and radiographic results after Achilles tendon lengthening for ankle equinus deformity in hemophiliacs. PATIENTS AND METHODS: Between 1975 and 1986, 30 hemophilic patients with pes equinus were surgically managed by Achilles tendon lengthening. Of these, 23 were followed up prospectively twice a year for an average of 13 (1-24) years. The mean age at operation was 29 (12-46) years. The clinical results were documented according to the score of the Advisory Committee of the World Federation of Hemophilia (WFH), while radio-graphs were evaluated using the Pettersson score. On average, preoperative ankle equinus deformity was 21 (5-55) degrees. Mean range of motion was 21 (5-42) degrees prior to surgery. RESULTS: At the first postoperative examination 1 year after surgery, 21/23 cases were improved, and 9/21 reached dorsiflexion to at least neutral position. At the last follow-up, ankle equinus deformity was 10 (4-20) degrees on average. 20/23 patients still showed significant improvement compared to their condition before surgery. 7 patients still had complete correction of the equinus deformity, while mean range of motion decreased constantly over the observation period. The clinical score was significantly improved 1 year after surgery and diminished only slightly afterwards. Radio-graphic outcome deteriorated, with scores rising from 4.3 (1-10) points preoperatively to 7.3 (3-12) points at last follow-up. INTERPRETATION: Most patients treated for hemophilic pes equinus by Achilles tendon lengthening experienced long-term benefit concerning the equinus deformity, but gradually lost overall movement of the ankle joint. Progression of the ankle arthropathy cannot be hindered.     

First prenatal molecular diagnosis in a family with holocarboxylase synthetase deficiency

OBJECTIVES: We report on the first prenatal molecular diagnosis of holocarboxylase synthetase (HLCS) deficiency in the fourth pregnancy of an at-risk family. This disorder is a rare autosomal recessive inborn error of metabolism, leading to a multiple carboxylase defect (MCD). HLCSD diagnosis was performed postmortem in the proband on DNA from autoptic biological material. Molecular analysis of the proband's entire HLCS gene by direct sequencing identified the R508W amino acid change, at the homozygous status. METHODS: Fetal DNA was isolated from chorionic villus sampling at 11 weeks of gestation. Direct sequencing of exon 6 of the fetal HLCS gene was performed. RESULTS: The R508W mutation was identified in the fetal DNA at the homozygous level. The genetic lesion was confirmed on abortive tissue. CONCLUSION: Molecular diagnosis has several advantages over enzymatic activity assay of carboxylases in chorionic villi or amniocytes. It can be performed earlier, is faster, and the response time is shorter.     

Calls to an inner-city hospital breastfeeding telephone support line.

Support for breastfeeding mothers after they leave the hospital is often inadequate in low-income, inner-city areas where few resources are available. In becoming a Baby-Friendly Hospital, inner-city Boston Medical Center established a breastfeeding telephone support line to overcome this discrepancy. Records of support line calls for the first 5 years of operation were reviewed to record the level of need and determine reasons for use. A total of 1959 calls for 2482 reasons were received between January 1999 and December 2003. The most common reason for calling was "need help obtaining a breast pump" or "need information about breast pumps" (44%; 1096/2482), followed by "breast issue" (7%; 181/2482) and "milk supply question" (7%; 167/2482). The results indicate that inner-city women seek breastfeeding support and demonstrate a substantial need for breast pumps. These findings suggest that the lack of breast pumps may be a barrier to continued breastfeeding for inner-city breastfeeding women.