A Phase II study of bosentan, a dual endothelin receptor antagonist, as monotherapy in patients with stage IV metastatic melanoma

There is no effective systemic therapy for disseminated metastatic melanoma. Data suggest that endothelin may play a role in pathophysiology of melanoma and that the dual endothelin receptor antagonist bosentan may have anti-tumor activity. This multicenter, open-label, single-arm, prospective, proof-of-concept study assessed the effects of bosentan monotherapy (500 mg oral tablets, bid) on tumor response in patients with stage IV metastatic melanoma. Patients were treated until disease progression, death or serious adverse event leading to premature study drug discontinuation. Tumor response was assessed at 6-weekly intervals using the Response Evaluation Criteria in Solid Tumors (RECIST). Among the 35 patients included in this study with stage IV metastatic melanoma, 21 (60%) were stage M1C, 10 (29%) stage M1B and 4 (11%) stage M1A (American Joint Committee on Cancer [AJCC] classification). Nine patients (26%) had received prior therapy for stage IV melanoma. Disease stabilization was observed in 6 of the 32 patients analyzed per protocol at week 6 with confirmatory evaluation at week 12, 5 of whom were still stable at > or =24 weeks. Of the 6 patients with disease stabilization, 2 were stage M1A, 1 was stage M1B and the remaining 3 were stage M1C. Partial or complete response was not observed. Progressive disease was observed in 17 (49%) patients at week 12 and in 25 (71%) patients at the end of the study (data base closure). The most frequent adverse events were typical for the underlying disease or known to be associated with bosentan: headache (43%), fatigue (34%), nausea (31%), back pain (23%) and abnormal hepatic function (23%). Bosentan might have benefit in disease stabilization in certain patients with metastatic melanoma and deserves further investigation in combination with other anticancer drugs.     

Improving venous ulcer healing: designing and reporting randomised controlled trials

The randomised controlled trial (RCT) is often considered the gold standard for judging the benefits of treatments. The application of randomised controlled clinical trials to treatments of venous ulcer healing has lagged behind that of other areas of medicine. To interpret the results of an RCT, readers must understand a variety of aspects of their design, analysis and interpretation. Venous ulcer disease has a high prevalence and has a significant socioeconomic impact in most parts of the world. The management of venous ulcers causes a considerable strain on the health system and is likely to worsen in future. The multi‐layer high compression system is described as the current gold standard for treating venous ulcers. A recent meta‐analysis of bandaging systems found that multi‐layer compression bandages appeared to be superior to single‐layer bandages in promoting venous ulcer healing. However, it was noted that many of the studies had small sample sizes and the quality of research in the area was poor. The consolidating standards of reporting trials (CONSORT) statement can help clinicians to discern high‐quality studies from ones of poorer quality. This paper discusses how CONSORT can help clinicians and researchers to design and report quality studies to contribute to evidence‐based venous ulcer healing.     

Age-related reductions in the estimated numbers of motor units are minimal in the human soleus

The documented impact of contractile level on decomposition-enhanced spike-triggered averaging motor unit number estimates (MUNEs) in young adults demonstrates the importance of selecting an objective contraction intensity that yields the most representative MUNE for a given muscle. Whether the same contraction intensity would be ideal in an altered system (e.g., by aging or disease) has yet to be examined. Thus, the main purpose of this study was to compare the effects of contraction intensity on MUNEs from the soleus muscle in young ( approximately 27 years) and old ( approximately 75 years) men. Using decomposition-enhanced spike-triggered averaging, surface and intramuscular electromyographic signals were collected from the soleus during a range of submaximal isometric plantar-flexion contractions (threshold, 10%, 20%, and 30% of maximum voluntary contraction; MVC). Five MUNEs were calculated, one for each of the four contraction intensities and an ensemble MUNE was derived from all MUs collected. Although MUNE decreased similarly with increased effort in both groups, MUNEs were not significantly reduced in the old men compared to the young men. Consequently, the ensemble MUNE was extrapolated to an intensity of approximately 15% MVC in both young and old. The results suggest that, in the soleus, the use of the same contraction intensity across age groups is a valid comparison.     

Respiratory and olfactory cytotoxicity of inhaled 2,3-pentanedione in sprague-dawley rats

Flavorings-related lung disease is a potentially disabling disease of food industry workers associated with exposure to the α-diketone butter flavoring, diacetyl (2,3-butanedione). To investigate the hypothesis that another α-diketone flavoring, 2,3-pentanedione, would cause airway damage, rats that inhaled air, 2,3-pentanedione (112, 241, 318, or 354 ppm), or diacetyl (240 ppm) for 6 hours were sacrificed the following day. Rats inhaling 2,3-pentanedione developed necrotizing rhinitis, tracheitis, and bronchitis comparable to diacetyl-induced injury. To investigate delayed toxicity, additional rats inhaled 318 (range, 317.9-318.9) ppm 2,3-pentanedione for 6 hours and were sacrificed 0 to 2, 12 to 14, or 18 to 20 hours after exposure. Respiratory epithelial injury in the upper nose involved both apoptosis and necrosis, which progressed through 12 to 14 hours after exposure. Olfactory neuroepithelial injury included loss of olfactory neurons that showed reduced expression of the 2,3-pentanedione-metabolizing enzyme, dicarbonyl/L-xylulose reductase, relative to sustentacular cells. Caspase 3 activation occasionally involved olfactory nerve bundles that synapse in the olfactory bulb (OB). An additional group of rats inhaling 270 ppm 2,3-pentanedione for 6 hours 41 minutes showed increased expression of IL-6 and nitric oxide synthase-2 and decreased expression of vascular endothelial growth factor A in the OB, striatum, hippocampus, and cerebellum using real-time PCR. Claudin-1 expression increased in the OB and striatum. We conclude that 2,3-pentanedione is a respiratory hazard that can also alter gene expression in the brain.     

Epilepsy in the Twitter era: a need to re-tweet the way we think about seizures

Seizures have long been associated with misconceptions and stigma. Exponential growth in Internet use has seen the rapid expansion of social media, such as Twitter, for health promotion. In view of the popularity of Twitter, we sought to explore how seizures are being portrayed on this social networking website and to consider its potential for information dissemination. A 48-hour Twitter search was used as a preliminary data set to determine an appropriate classification scheme of "seizure"-related posts ("tweets"). Analysis was then conducted using "seizure" tweets from a 7-consecutive day sample period. Tweets were analyzed and coded by two independent reviewers. Predominant categories were Metaphorical (32%), Personal Accounts (31%), Informative (12%), and Ridicule/Joke (9%). This study supports the notion that stigmatization associated with seizures continues to flourish, as 41% of "seizure" tweets were derogatory in nature. Although Twitter could be used to disseminate accurate information on seizures and epilepsy, this study suggests that it is currently propagating negative attitudes toward seizures with potential for fueling stigma. In recent years there have been significant advancements in technology offering many new methods of sharing information. Social networking sites allow real-time communication while providing the opportunity for exchange of information and opinions. Twitter, a website launched in 2006, allows users to communicate through "tweets" limited to 140 characters. Twitter's popularity has drastically increased since its inception, with approximately 110 million tweets per day from 200 million users worldwide, as of January 2011 (http://blogs.forbes.com/oliverchiang/2011/01/19/twitter-hits-nearly-200m-users-110m-tweets-per-day-focuses-on-global-expansion/). Such social media facilitate communication about an array of health-related topics including seizures and epilepsy.