High efficacy of integrated preventive measures against zoonotic cutaneous leishmaniasis in northern Afghanistan, as revealed by Quantified Infection Rates

Following an outbreak of more than 200 cases of zoonotic cutaneous leishmaniasis (ZCL) during 2004 and 2005 among International Security Assistance Force (ISAF) troops stationed in the Mazar-e Sharif (MeS) airport area, epidemiological investigations indicated the presence of a local high-density ZCL focus. Based on ZCL's specific transmission modes, density and seasonality, integrated preventive measures were continuously implemented from February 2006 at a German military camp constructed at MeS. Preventive techniques included such synergistic measures as skin repellents and insecticide-impregnated clothing, bednets and curtains, sand fly and rodent monitoring and control, extended habitat sanitation, and health education, all designed to achieve maximum protection against ZCL. Habitat alteration included: (a) erection of a 3.0 m high stone wall around the entire camp area; (b) removal of ≥30 cm of the upper earth layer throughout the site; (c) soil compaction and stone paving to a depth of ≥30 cm plus compaction of the surrounding area to a distance of 100 m outside the camp wall; and (d) regular eradication of vegetation. Aggressive implementation of these measures led to a 166-fold and 546-fold reduction in sand fly numbers and complete eradication of the local rodent reservoir, Rhombomys opimus, inside the camp during 2006 and 2007, respectively. ZCL attack rates decreased significantly (p < 0.0001), from 17.5% (14 cases/80 persons) for the 2005 German assessment teams to 0.087% (1 case/1150 persons) for the 2006 contingent, and 0% (0 cases) (p < 0.0001) for the 2007 contingent, with Quantified Infection Rates (QIRs) of 0.058, 0.0000055, and 0.0, respectively. Using QIR values, the protective factor of the integrated preventive measures was shown to be ≥10,545 times higher in the 2006 and 2007 contingents, compared with the 2005 assessment teams. Results show that the continuously implemented, integrated preventive techniques used in this study gave excellent and long-lasting protection against zoonotic cutaneous leishmaniasis under field conditions.     

Variable extent of clopidogrel responsiveness in patients after coronary stenting

Clopidogrel is an effective and specific inhibitor of ADP-induced platelet aggregation. After metabolic activation, the active clopidogrel metabolite irreversibly impairs the human platelet P2Y12 ADP receptor. Gialpha-protein activation and inhibition of vasodilator-stimulated phosphoprotein (VASP) phosphorylation are two key elements of the P2Y12 receptor pathway suitable for quantitation of clopidogrel effects. So far, only limited data exist about a diminished responsiveness to clopidogrel and underlying possible mechanisms. We investigated clopidogrel effects in 57 patients after percutaneous coronary intervention and stent implantation by flow cytometry for the analysis of intracellular VASP phosphorylation. Patients were treated with a 300 mg clopidogrel loading dose, followed by 75 mg/day clopidogrel in combination with 100 mg/day aspirin. Samples were drawn after a median of 5 days of clopidogrel treatment. Considerable differences in the responsiveness to clopidogrel could be observed and it was shown that 17.5% (10/57) of the patients revealed an inadequate responsiveness to clopidogrel despite continuation of clopidogrel intake. Comparable amounts of Gialpha and VASP were found in two clopidogrel low-responding patients as well as in two responding patients. To exclude a molecular defect of P2Y12 ADP receptor, the P2Y12 receptor gene of eight clopidogrel treated patients (seven patients with inadequate responsiveness, one responder) was sequenced. We only found a single silent mutation in exon 2 at position 1828 (GA). We suggest that individual differences in clopidogrel metabolization could cause relevant variations in clopidogrel responsiveness despite the use of a 300 mg clopidogrel loading dose.     

Restriction-mediated differential display (RMDD) identifies pip92 as a pro-apoptotic gene product induced during focal cerebral ischemia.

Studies of gene expression changes after cerebral ischemia can provide novel insight into ischemic pathophysiology. Here we describe application of restriction-mediated differential display to screening for differentially expressed genes after focal cerebral ischemia. This method combines the nonredundant generation of biotin-labeled fragment sets with the excellent resolution of direct blotting electrophoresis, reliable fragment recovery, and a novel clone selection strategy. Using the filament model in mouse with 90 minutes MCA occlusion followed by 2, 6, and 20 hours reperfusion, we have compared gene expression in sham-operated animals to both the ipsi- and contralateral forebrain hemisphere of ischemic mice. Our screening method has resulted in the identification of 70 genes differentially regulated after transient middle cerebral artery occlusion (MCAO), several of which represent unknown clones. We have identified many of the previously published regulated genes, lending high credibility to our method. Surprisingly, we detected a high degree of correspondent regulation of genes in the nonischemic hemisphere. A high percentage of genes coding for proteins in the respiratory chain was found to be up-regulated after ischemia, potentially representing a new mechanism involved in counteracting energy failure or radical generation in cerebral ischemia. One particularly interesting gene, whose upregulation by ischemia has not been described before, is pip92; this gene shows a rapid and long-lasting induction after cerebral ischemia. Here we demonstrate that pip92 induces cell death in primary neurons and displays several hallmarks of pro-apoptotic activity upon overexpression, supporting the notion that we have identified a novel pathophysiological player in cerebral ischemia. In summary, restriction-mediated differential display has proven its suitability for screening complex samples such as brain to reliably identify regulated genes, which can uncover novel pathophysiological mechanisms.     

Spatiotemporal distribution pattern of white matter lesion volumes and their association with regional grey matter volume reductions in relapsing‐remitting multiple sclerosis

The association of white matter (WM) lesions and grey matter (GM) atrophy is a feature in relapsing‐remitting multiple sclerosis (RRMS). The spatiotemporal distribution pattern of WM lesions, their relations to regional GM changes and the underlying dynamics are unclear. Here we combined parametric and non‐parametric voxel‐based morphometry (VBM) to clarify these issues. MRI data from RRMS patients with progressive (PLV, n = 45) and non‐progressive WM lesion volumes (NPLV, n = 44) followed up for 12 months were analysed. Cross‐sectionally, the spatial WM lesion distribution was compared using lesion probability maps (LPMs). Longitudinally, WM lesions and GM volumes were studied using FSL‐VBM and SPM5‐VBM, respectively. WM lesions clustered around the lateral ventricles and in the centrum semiovale with a more widespread pattern in the PLV than in the NPLV group. The maximum local probabilities were similar in both groups and higher for T2 lesions (PLV: 27%, NPLV: 25%) than for T1 lesions (PLV: 15%, NPLV 14%). Significant WM lesion changes accompanied by cortical GM volume reductions occured in the corpus callosum and optic radiations (P = 0.01 corrected), and more liberally tested (uncorrected P < 0.01) in the inferior fronto‐occipital and longitudinal fasciculi, and corona radiata in the PLV group. Not any WM or GM changes were found in the NPLV group. In the PLV group, WM lesion distribution and development in fibres, was associated with regional GM volume loss. The different spatiotemporal distribution patterns of patients with progressive compared to patients with non‐progressive WM lesions suggest differences in the dynamics of pathogenesis. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Structural neural correlates of impairments in social cognition in first episode psychosis

Several studies have demonstrated that patients with schizophrenia show impairments in social cognition and current evidence indicate that this deficit is associated with abnormal activity in specific brain regions. In addition to functional imaging studies, we believe that the identification of structural correlates of social cognitive processes may help to better understand the neural underpinnings of these specific skills. The main objective of this study was to investigate the relationship between gray matter density and social cognitive deficits in first episode of schizophrenia spectrum psychosis, using a comprehensive assessment that we previously demonstrated to be a highly sensitive measure of social cognitive deficits in this population. Thirty-eight patients with a first episode of psychosis participated in this study, and the Four Factor Test of Social Intelligence was used as a measure of social cognition. Social cognitive impairments in first episode psychosis were significantly correlated with reduced gray-matter density in the left middle frontal gyrus other regions within the mirror neuron system network (MSN), namely the right supplementary motor cortex, the left superior temporal gyrus and the left inferior parietal lobule. We concluded that structural abnormalities within the MSN may account for the social cognitive deficits present in some psychiatric disorders, such as schizophrenia.     

Joint Congress of European Neurology 31 May–3 June 2014 Istanbul,Turkey

Neuromyelitis optica (NMO, Devic’s syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.     

Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials

Immunotherapeutic approaches are currently in the spotlight for their potential as disease-modifying treatments for neurodegenerative disorders. The discovery that α-synuclein (α-syn) can transmit from cell to cell in a prion-like fashion suggests that immunization might be a viable option for the treatment of synucleinopathies. This possibility has been bolstered by the development of next-generation active vaccination technology with short peptides-AFFITOPEs^® (AFF)- that do not elicit an α-syn-specific T cell response. This approach allows for the production of long term, sustained, more specific, non-cross reacting antibodies suitable for the treatment of synucleinopathies, such as Parkinson’s disease (PD). In this context, we screened a large library of peptides that mimic the C-terminus region of α-syn and discovered a novel set of AFF that identified α-syn oligomers. Next, the peptide that elicited the most specific response against α-syn (AFF 1) was selected for immunizing two different transgenic (tg) mouse models of PD and Dementia with Lewy bodies, the PDGF- and the mThy1-α-syn tg mice. Vaccination with AFF 1 resulted in high antibody titers in CSF and plasma, which crossed into the CNS and recognized α-syn aggregates. Active vaccination with AFF 1 resulted in decreased accumulation of α-syn oligomers in axons and synapses, accompanied by reduced degeneration of TH fibers in the caudo-putamen nucleus and by improvements in motor and memory deficits in both in vivo models. Clearance of α-syn involved activation of microglia and increased anti-inflammatory cytokine expression, further supporting the efficacy of this novel active vaccination approach for synucleinopathies.     

Psychiatric comorbidity in cardiovascular inpatients: costs, net gain, and length of hospitalization

Objective

Although psychiatric comorbidity often goes undetected and untreated in cardiovascular patients, it is not clear whether the costs for a special treatment of psychiatric comorbidity are appropriately reflected in the reimbursement system. To investigate the economic impact of psychiatric comorbidity, we compared costs, returns, net gain, and duration of hospitalization in cardiovascular inpatients with and without psychiatric comorbidity.

Methods

For a period of 2 years, we analyzed costs, net gain, and other outcome variables according to the diagnosis-related group (DRG) system for cardiovascular inpatients of a German university department (n=940). Psychiatric disorders were diagnosed by the treating physicians based on clinical criteria and results from the Patient Health Questionnaire (PHQ). With respect to the outcome variables, we compared patients with and without a psychiatric disorder, controlling for sociodemographic characteristics.

Results

The average total costs of hospitalization (mean±S.E.) for cardiovascular patients without psychiatric comorbidity and for patients with psychiatric comorbidity differed significantly (€5142±210 vs. €7663±571; d=0.39). The increased costs for patients with psychiatric comorbidity were related to elevated returns, but the net gain for patients without psychiatric comorbidity was €277±119. In contrast, the treatment of internal medicine patients with psychiatric disorders resulted in a net loss of −€624±324 (overall group difference, d=−0.25).

Conclusion

Psychiatric comorbidity in cardiovascular inpatients leads to higher costs that are not reflected in the current reimbursement system in Germany. The inappropriate reimbursement of psychiatric comorbidity in cardiovascular inpatients may result in a serious undertreatment of these patients.