Future of extracranial-intracranial bypass

Total occlusion of internal carotid artery in the cervical region is an end result of progressive occlusive vascular disease. A small proportion of these patients will have symptoms of cerebral ischemia due to cerebral hypoperfusion in a delayed fashion. Identification of those individuals who are at risk of developing symptoms and prophylactically treating with a revascularization procedure will prevent such catastrophic events. With the co-operative study for bypass not supporting the bypass procedure and trial being questioned for its design and conclusions, a new trial of extracranial-intracranial bypass, The Carotid Occlusion Surgery Study, using the currently available technology will be undertaken to verify that the bypass will decrease the future stroke rate by at least 40% in patients with total carotid occlusion. A subset of patients with skull base pathology including tumors and aneurysms who may have to undergo carotid sacrifice as part of the surgical procedure are at risk of peri-operative and delayed stroke. Identification of these patients at risk by pre-operative tests may allow performance of extracranial-intracranial bypass prior to undertaking complex skull base procedures. The new imaging technology will guide management of these patients at risk and help identify patients who may need a bypass procedure.     

Treatment of social anxiety disorder with citalopram

Selective serotonin reuptake inhibitors (SSRIs) are used as treatment for generalized and specific social phobias (social anxiety disorders). The efficacy of citalopram, an SSRI, for the treatment of social anxiety disorders has not yet been fully evaluated. These cases suggest that citalopram may be an effective treatment for social anxiety disorder (social phobia). These cases are consistent with two other published reports with citalopram from outside the US. Randomized controlled studies are warranted.     

Pneumatic splints: fabrication and use in neurorehabilitation

Asymmetrical tone and weakness in antagonistic muscles often result in misalignment of joint, contractures and deformities. Traditional static splints used to prevent these complications are expensive, have to be custom made and cannot be used when deformities are marked. Authors describe fabrication and use of pneumatic splints, which are economic, safe and easy to apply. These splints have wide application in the management of common medical problems in neurological rehabilitation like hypotension, edema, pain, spasticity and early deformities.     

Effect of chondroitinase ABC on purulent sputum from cystic fibrosis and other patients

Cystic fibrosis (CF) patients develop chronic lung infections associated with airway obstruction by viscous and insoluble mucus secretions. Although mucus glycoproteins (mucins) are thought to be responsible for mucus plugs, other glycoconjugate components of airway secretions have not been systematically evaluated. The aim of the present study was to determine whether chondroitin sulfate proteoglycans (CSPG) contribute to the insolubility of CF sputum. Sputa obtained from 18 CF patients were incubated with chondroitinase ABC (ChABC) or buffer (control) for 18 h at 37 degrees C, and after centrifugation at 12,000 g, the volume of the insoluble pellet and turbidity of the supernatant were determined as measures of solubility. ChABC caused a 70-90% reduction in supernatant turbidity and a 60-70% decrease in pellet volume of the 13 purulent CF sputa, but had much less effect on the five nonpurulent CF sputa tested. Similar results were obtained with two non-CF purulent and two non-CF, nonpurulent sputa. Gel electrophoresis, Western blot, and slot blot immunoassays with antichondroitin sulfate and antimucin antibodies revealed that purulent sputa (CF and non-CF) contained more CSPG and less mucin than nonpurulent sputa. In vitro mixing experiments showed that mucin in nonpurulent sputa was reduced upon incubation with purulent sputa, presumably because of degradation or a loss of immunoreactive mucin epitopes from leukocyte and/or bacterial enzymes present in purulent sputa. Our results suggest that CSPG contribute more significantly than mucins to the insolubility of purulent tracheobronchial secretions from CF patients. Because purulent sputa from non-CF patients showed a similar pattern, our observations with CF sputa may have wider applicability.     

Structure-based approaches to inhibition of erbB receptors with peptide mimetics

The epidermal growth factor (EGF) family of tyrosine kinase receptors (erbB receptors) are expressed at high levels in a wide variety of human cancers and have been associated with various features of advanced disease and poor prognosis. Therapeutic blockade of erbB signaling is a novel approach to the treatment of human tumors that could offer a noncytotoxic alternative to cancer treatment. A number of monoclonal antibodies (MAbs) directed against erbB receptors have been developed and demonstrated promising therapeutic results. We have designed small-molecule peptide mimetics of an anti-erbB rhu MAb 4D5 that can mimic structural and functional properties of the parental antibody. An alternative structure-based strategy of erbB receptor blockade with peptide mimetics by targeting receptor dimerization interfaces is also described.     

Does antidepressant therapy improve cognition in elderly depressed patients?

OBJECTIVES: To analyze the effects of antidepressants on cognitive functioning in elderly depression. METHODS: Data were pooled for elderly participants with major depression from two double-blind 12-week studies (n = 444) comparing sertraline to fluoxetine and to nortriptyline. A cognitive battery was performed pre-treatment and post-treatment that included the Shopping List Task (SLT), which quantifies short-term and long-term memory storage and retrieval, and the Digit Symbol Substitution Test (DSST), which measures visual tracking, motor performance, and coding. RESULTS: Older age, male gender, higher systolic blood pressure, and higher illness severity were associated with lower performance on specific cognitive measures at baseline. For the entire group, improved depression and a lower anticholinergic side effect (dry mouth and constipation) severity were associated with statistically significant improvement in the SLT and DSST. The correlations between improvements in depression and improvement in tested cognitive function were highest for sertraline followed by nortriptyline and then fluoxetine. CONCLUSIONS: Acute improvement in depression is associated with cognitive improvement as measured by the SLT and DSST. Prospective studies are warranted to study the effects of potential differences among antidepressant therapies on long-term cognitive outcomes in geriatric depression.     

Does increased platelet release of Abeta peptide contribute to brain abnormalities in individuals with depression?

Increased platelet activation with release of procoagulant factors from their alpha granules has been demonstrated in individuals with major depression. Platelet activation has also been shown to be associated with release of beta-amyloid peptides, which have been implicated in Alzheimer's disease. Thus, we are hypothesizing that sustained elevations of Abeta peptides might occur in individuals with recurrent depression. We further hypothesize that such elevations contribute to brain abnormalities in depressed individuals through the formation of neurotoxic oligomeric forms of Abeta peptides and amyloid deposition. We also propose that increased amyloid Abeta peptides from platelet activation may be a mechanism underlying the increased risk for cognitive impairment in nondepressed patients who have other reasons for such activation. If true, our hypothesis would imply that platelet inhibitors may have a role in preventing or delaying the neuronal consequences of disorders characterized by activated platelets.     

The designed angiostatic peptide anginex synergistically improves chemotherapy and antiangiogenesis therapy with angiostatin

Recently, we demonstrated that the designed peptide anginex displays potent antiangiogenic activity. The aim of the present study was to investigate anginex treatment as a single-agent therapy and to test its ability to improve conventional chemotherapy and antiangiogenesis therapy. In a human ovarian carcinoma mouse model, anginex inhibited tumor growth by 70%. When anginex was combined with a suboptimal dose of carboplatin, tumors regressed to an impalpable state. Anginex plus angiostatin worked synergistically to inhibit tumor growth. Assessment of microvessel density suggested that the antitumor activity of anginex is mediated by angiogenesis inhibition. In any of the experiments, no sign of anginex-induced toxicity was observed.     

Expression of the zinc transporter ZnT4 is decreased in the progression from early prostate disease to invasive prostate cancer

We have utilized oligonucleotide microarrays to identify novel genes of potential clinical and biological importance in prostate cancer. RNA from 74 prostate cancers and 164 normal body samples representing 40 different tissues were analysed using a customized Affymetrix GeneChip oligonucleotide microarray representative of over 90% of the expressed human genome. The gene for the zinc transporter ZnT4 was one of several genes that displayed significantly higher expression in prostate cancer compared to normal tissues from other organs. A polyclonal antipeptide antibody was used to demonstrate ZnT4 expression in the epithelium of all 165 elements of benign and 326 elements of localized prostate cancers examined and in nine of 10 advanced prostate cancer specimens by immunohistochemistry. Interestingly, decreased intensity of ZnT4 immunoreactivity occurred in the progression from benign to invasive localized prostate cancer and to metastatic disease. Immunofluorescence analysis and surface biotinylation studies of cells expressing ZnT4 localised the protein to intracellular vesicles and to the plasma membrane. These findings are consistent with a role for ZnT4 in vesicular transport of zinc to the cell membrane and potentially in efflux of zinc in the prostate.