Stroke etiology among Haitians living in Miami

The black Caribbean population continues to grow in the US and little is known about stroke etiologies in that community. We examined stroke subtypes in 175 consecutive Haitian-born patients living in Miami, admitted for acute stroke. Ischemic stroke was diagnosed in 72%. Small vessel occlusion was the most frequent stroke subtype. There was a high prevalence of hypertension, medication noncompliance and intracranial atherosclerosis. Hypertension was the only cardiovascular risk factor significantly associated with small vessel infarction when compared with non-small vessel infarcts.     

Inhibitors of cation-chloride-cotransporters affect hypoxic/hypoglycemic injury in hippocampal slices

Electroneutral cation-chloride cotransporters are abundantly expressed in the brain and are involved in the regulation of the intracellular Cl(-) concentration and thus gamma-aminobutyric acid-dependent inhibition of neuronal excitability. As yet there is little evidence whether or not Na(+)-K(+)-2Cl(-) or K(+)-Cl(-) cotransporters are involved in neuronal hyperexcitability and death in cerebral ischemia. In this study, by measuring propidium iodide staining in organotypic hippocampal slice cultures from young rats and population spike recovery in acutely isolated hippocampal slices from adult rats after a hypoxic/hypoglycemic insult, we were able to assess if cation-chloride cotransport inhibitors reduce neuronal injury. The Na(+)-K(+)-2Cl(-) cotransport inhibitor bumetanide in the range of 1-10 microM reduced neuronal damage in the slice cultures by 25%, but did not affect population spike recovery in acutely isolated slices. In contrast the K(+)-Cl(-) cotransport inhibitor [(dihydroindenyl)oxy] alkanoic acid (DIOA, 100 microM) significantly diminished the restitution of the population spikes from 33% before to 8% after hypoxia/hypoglycemia and increased the damage in the slice cultures by 60%. Consequently, our data suggest that the Na(+)-K(+)-2Cl(-) cotransporter may contribute to neuronal injury and that the activity of the K(+)-Cl(-) cotransporters is an intrinsic protective mechanism of neurons against ischemic damage.     

Brain effects of chronic IBD in areas abnormal in autism and treatment by single neuropeptides secretin and oxytocin

Recent research points to the connection between behavioral and gut disorders. Early adverse events are associated with inflammatory bowel disease (IBD). In animal models, maternal deprivation and social isolation predispose to gastric erosion and brain pathology. This study examined (1) brain effects of chronic gastrointestinal inflammation in a rat model of acquired IBD and (2) whether such changes are resolved by individual secretin (S) or oxytocin (OT) peptide treatment. Neurological manifestations of IBD were mapped by c-fos gene expression in male Sprague-Dawley rats (n=10) with trinitrobenzene sulfonic acid (TNBS)-induced IBD vs controls (n=11). IBD was characterized by moderate/severe infiltration of inflammatory cells 10 d after TNBS infusion. Age-matched pairs were processed for immunocytochemical detection of Fos, expressed when neurons are stimulated. S or OT (100 μg/250 μL saline) or equivolume saline was administered iv by Alzet pump for 20 d after disease onset. Degree of resolution of colitis-induced brain activation was assessed by c-fos expression, and mean numbers of Fos-immunoreactive nuclei for each group were compared using Independent Samples T-test. Chronic IBD activated periventricular gray, hypothalamic/visceral thalamic stress axes and cortical domains, and septal/preoptic/amygdala, brain areas abnormal in autism. Single peptide treatment with S or OT did not alter the effects of inflammation on the brain. Brain areas concomitantly activated by visceral inflammation are those often abnormal in autism, suggesting that IBD could be a model for testing treatments of autism. Other single and combined peptide treatments of IBD should be tested. The clinical implications for treating autism, IBD, and concomitant sickness behaviors with peptide therapy, with or without maternal nurturing as a natural equivalent, are presented.     

Organ- and treatment-specific local response rates to systemic and local treatment modalities in stage IV melanoma

BACKGROUND: Metastatic melanoma shows different local response rates in organs to systemic or local treatment modalities. Whereas skin, soft tissue, lymph node and lung metastases seem to have better local response rates, the local response of metastases localized in the liver, brain and bone seems to be low. OBJECTIVES: The organ-specific response rate, local response rate of each therapeutic measure and survival of 68 patients with stage IV disease were evaluated. METHODS: Four hundred and ten treatment periods (1-18 per patient) in 17 different organs of 43 men and 25 women (mean age 55 years, range 19-79) with measurable, widespread, surgically incurable disease were analysed. Chemotherapy was given in 405 of 410 treatment periods with dacarbazine, fotemustine, vindesine, carboplatin and temozolomide in different schedules. Local treatment modalities comprising radiotherapy, gamma knife radiosurgery and local hyperthermia were given in 71 of 410 treatment periods. RESULTS: Local response (complete or partial local remission) was achieved in 52 treatment periods (12.7%). When local treatment modalities, either combined with systemic therapy or not, were compared with systemic therapeutic modalities alone, a local response of 24% was achieved with local measures, compared with 10% in systemic treatment only (P = 0.003). When a spontaneous remission rate of less than 5% is considered, however, local as well as systemic treatments had a significant effect (P < 0.001). Organ-specific response rates to local therapies showed no statistically significant differences between the various organs involved. When systemic treatments without local measures were taken into account, lung metastases, cutaneous/subcutaneous metastases and adrenal metastases performed significantly better than liver metastases. When different treatment modalities were considered, there was no significant difference between the three local measures applied (radiotherapy, gamma knife radiosurgery and hyperthermia). Among the systemic therapies, dacarbazine high dose and carboplatin monochemotherapy were superior to combined regimens using fotemustine. A local response, irrespective of the mode of therapy, was significantly associated with longer survival (median 16 months) compared with no local response or local progressive disease (median 7 months; P < 0.0001). When the first treatment period of each patient was considered, local response was no longer a significant predictor. CONCLUSIONS: The study shows that local therapeutic measures are superior in inducing a local response than systemic therapies alone. Induction of remission may be associated with longer survival. Chemotherapy, despite limited local response rates, is still statistically superior to an estimated spontaneous remission rate.     

Computation of tactile object properties requires the integrity of praxic skills

We describe a series of experiments to examine the tactile identification of objects over the course of neurological recovery in a patient with an intracerebral haemorrhage involving the left inferior and superior parietal lobe. Tactile agnosia in this case involved the ipsilesional as well as the contralesional hand, allowing us to observe the effects of dominant parietal lobe damage without the confounding effects of hemiparesis. The findings demonstrate that both apraxia and tactile apperceptive agnosia may result from a unilateral lesion involving the left parietal lobe. The findings further suggest that the computation of macro-geometrical and micro-geometrical tactile object properties is dissociable. Macro-geometrical tactile analysis depends on intact programming of exploratory hand movements, while the role of such movements in micro-geometrical analysis is less clear.     

Homodimerization and internalization of galanin type 1 receptor in living CHO cells

Galanin is a 29- to 30-aa-long neuropeptide affecting feeding, cognitive, and sexual behavior. It exerts its effects through galanin receptors 1, 2 and 3, which are all seven transmembrane domain G-protein coupled receptors (GPCRs). The GPCRs have been shown to function as monomers, homodimers, heterodimers and oligomers. In this study, we examined the extent of galanin receptor 1 (GalR1) dimerization and internalization in living CHO cells using fluorescence resonance energy transfer (FRET) and time lapse confocal imaging. Ratio imaging analysis and emission spectral analysis revealed substantial homodimerization of GalR1. In addition, internalization of GalR1 after 1h of agonist stimulation with the GalR1 agonist galanin (1-29) was observed with time lapse fluorescence imaging, whereas stimulation with the GalR2 specific agonist galanin (2-11) did not lead to internalization. Treatment of GalR1 transfected cells with the non-selective adenylyl cyclase activator forskolin influenced the rate of internalization when administered together with galanin (1-29). These results indicate that GalR1 can act as a dimer on the cell surface and that receptor desensitization and internalization was observed after stimulation with the agonist galanin (1-29). Western blots further confirm the FRET data that GalR1-XFP dimerizes and can be detected in the cell as a monomer or dimer using antibodies to XFP. Internalization and dimerization of GalR1 is shown, contributing to the regulation of galanergic signaling.     

Facilitated percutaneous coronary intervention (PCI) in patients with acute ST-elevation myocardial infarction: comparison of prehospital tirofiban versus fibrinolysis before direct PCI

AIMS: Early start of treatment including coronary revascularization has been recognized as crucial variable in the outcome of acute ST-segment elevation myocardial infarction (STEMI). The lack of availability and the realisation that an optimum reperfusion strategy will need to incorporate mechanical reperfusion as part of that strategy has led to a great deal of interest in pharmacologic reperfusion combined with mechanical reperfusion or facilitated PCI. It is not clear whether GPIIb/IIIa-blockade or fibrinolysis better facilitates PCI. METHODS: We identified 138 patients who have been primarily treated by our mobile emergency care mobile from July 2001 until February 2003 with tirofiban or fibrinolysis. Seventy-nine patients had ST-elevation myocardial infarction (STEMI) and available angiograms within 24 h. RESULTS: Forty-four patients had tirofiban (TIRO; 60.6 S.D. 11.4 years, 64% male) and 35 patients underwent fibrinolysis (FIB; 31.4% tenecteplase, 54.3% reteplase, 11.4% alteplase, 2.9% streptokinase; 58.8 S.D. 12.2 years, 80% male). Data were analyzed with respect to TIMI-flow and corrected frame count (cTFC) before and after PCI, bleeding complications at 30 days and long-term follow up for major adverse events (median 288 days; MACE: Death, hospitalized re-infarction, intracranial hemorrhage). Catheter films were re-analyzed by an investigator blinded to the prehospital therapy. Time from onset of symptoms to first medical contact was 1.98 h in TIRO compared to 0.5 h in FIB (p<0.001) and time from first prehospital medical contact to catheter was 1.46 h in the TIRO compared to 2.85 h in the FIB group (p<0.001). TIMI 3-flow before PCI was observed in 20.5% of TIRO and 62.9% in FIB (p<0.001). After PCI TIMI 3-flow was achieved in 90.5% and 90.0%, respectively (p=n.s.). Final cTFC was 24 in TIRO and 29 in FIB (p=n.s.). Visible thrombi were detected in 30.2% in TIRO and 23.5% in FIB (p=n.s.). Major bleeding occurred in one TIRO patient (fatal lung bleeding after ultima ratio abciximab on top of tirofiban), 2 patients (4.5%) received transfusions. In FIB 2 intracerebral hemorrhages, 5 transfusions (14.3%) and 3 pulmonary bleedings during mandatory ventilation were observed. After 30 days 4.5% in TIRO and 22.9% in FIB had MACE (p=0.015). During long-term follow up the primary endpoint was observed in 4.5% of TIRO and 28.6% (p=0.003) of FIB. Two patients died in TIRO and 9 patients in FIB. CONCLUSIONS: We conclude that (1) prehospital start of tirofiban for facilitated PCI is safe and effective if administered by experienced emergency physicians; (2) routine fibrinolysis should be limited to areas where catheter based therapy is not available within 90 min and (3) fibrinolysis should be given for facilitated PCI in randomized trials only at the moment.     

Analyses of minimal residual disease based on Flt3 mutations in allogeneic peripheral blood stem cell transplantation

Purpose Activating Flt3 mutations are observed in about 30% of patients with acute myeloid leukaemia (AML) and individual Flt3 mutations are applicable for minimal residual disease (MRD) analyses.Methods We investigated the MRD status in four AML patients carrying different Flt3 mutations (three patients with Flt3 length mutations of the juxtamembrane domain, one patient carrying a mutation of the Flt3 tyrosine kinase domain, i.e. Flt3-TKD mutation) who underwent allogeneic peripheral blood stem cell transplantation (PBSCT). Residual leukaemia cells were retrospectively determined by real-time PCR at different time points.Results We can demonstrate a good correlation between the course of MRD status and clinical events in all four investigated patients.Conclusion These examples demonstrate the potential impact of Flt3 based MRD status not only after but also prior to allogeneic PBSCT.