Liposomes for HIV prophylaxis

There are approximately 33.4 million adults living with HIV worldwide of which an estimated 15.7 million are women. Although there has been enormous progress in the therapy of HIV/AIDS, treatment is not curative. Prevention is therefore of paramount importance, but vaccine-based and microbicidal approaches are still in their infancy. Since women acquire the virus largely through sexual intercourse, we developed liposomal systems potentially suitable for intra-vaginal use to prevent HIV-1 infection. We formulated liposomes from a range of naturally-occurring and synthetic lipids with varying physicochemical properties, and tested their ability to inhibit infection of transformed cells that express receptors specific to the virus. We identified formulations with the most favorable balance between decreasing HIV infection and causing cytotoxicity (i.e. therapeutic index). The therapeutic index improved with increasing cardiolipin content, and degree of unsaturation. Tissue reaction to these formulations was benign after intra-vaginal instillation in an in vivo female mouse model. These results support the potential use of cardiolipin-based liposomes enriched with synthetic lipids as microbicides for the prevention of HIV infection in women.     

Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

Tissue-type plasminogen activator (tPA) is a major protease of the central nervous system. Most studies to date have used in situ- or gel-based zymographic assays to monitor in vivo changes in neural tPA activity. In this study, we demonstrate that the amidolytic assay can be adapted to accurately detect changes in net tPA activity in mouse brain tissues. Using the amidolytic assay, we examined differences in net tPA activity in the cerebral cortex, sub-cortical structures and cerebellum in wildtype (WT) and tPA(-/-) mice, and in transgenic mice selectively overexpressing tPA in neurons. In addition, we assessed changes in endogenous net tPA activity in WT mice following morphine administration, epileptic seizures, traumatic brain injury and ischaemic stroke-neurological settings in which tPA has a known functional role. Under these conditions, acute and compartment-specific regulation of tPA activity was observed. tPA also participates in various forms of chronic neurodegeneration. Accordingly, we assessed tPA activity levels in mouse models of Alzheimer's disease (AD) and spinocerebellar ataxia type-1 (SCA1). Decreased tPA activity was detected in the cortex and subcortex of AD mice, whereas increased tPA activity was found in the cerebellum of SCA1 mice. These findings extend the existing hypotheses that low tPA activity promotes AD, whereas increased tPA activity contributes to cerebellar degeneration. Collectively, our results exemplify the utility of the amidolytic assay and emphasise tPA as a complex mediator of brain function and dysfunction. On the basis of this evidence, we propose that alterations in tPA activity levels could be used as a biomarker for perturbations in brain homeostasis.     

An Improved Method of Assessing Esophageal Emptying Using the Timed Barium Study Following Surgical Myotomy for Achalasia

Introduction  The timed barium study (TBS) is used to assess esophageal emptying in patients with achalasia. Improvement in emptying correlates with outcome after endoscopic therapy, but the results of the TBS have been variable after myotomy. Our aim was to evaluate a new method for assessing improvement in emptying after myotomy. Methods  A TBS was performed before and 3–6 months after myotomy in 30 patients. Emptying was assessed by measuring the percent difference in area of the barium column on films obtained 1 and 5 min after ingesting 150 ml of barium. Initial esophageal clearance was also assessed by comparing the area of the barium column on 1-min images obtained before and after therapy. Both measures were compared to clinical outcome. Results  After myotomy, 21 patients (70%) had no symptoms, four (13%) had mild, and five (17%) had moderate/severe symptoms. Using the standard method, esophageal emptying before and after surgery were not significantly different (25% vs. 37%; p = 0.22) and did not correlate with clinical outcome. In contrast, initial esophageal clearance improved significantly (median 81%) and correlated with clinical outcome. Conclusion  Esophageal emptying measured by the standard method is not useful to assess outcome after myotomy. However, initial esophageal clearance correlates well with clinical outcome. Previous presentations: 49th SSAT Annual Meeting at Digestive Disease Week, San Diego, 2008 and 23rd Annual SSAT Residents and Fellows Research Conference, San Diego, 2008     

Cotard's syndrome. Different treatment strategies according to subclassification

After performing an exploratory factor analysis, Berrios & Luque (1995) identified three subcategories in the Cotard's syndrome: Cotard type I, Cotard type II and Cotard type psychotic depression. The article, which is based on two case studies and an examination of the relevant literature since 1995, explores whether there are different treatment strategies for Cotard type I and the Cotard type psychotic depression. For the Cotard type psychotic depression, electroconvulsive therapy proves to be an effective method of treatment. For Cotard type I, antipsychotic therapy seems to be sufficient.