Hemispheric lateralization of the corticostriatal glutamatergic system in the rat

Little is known about hemispheric lateralization of subcortical structures. Here, we show a higher expression of the subunit NR2A of the NMDA receptor mRNA in the striatum and of vGluT1 mRNA in the cingulate cortex, in the left hemisphere compared to the right one. This suggests a lateralization of the glutamatergic cortico-subcortical system, at the level of postsynaptic receptors as well as at the level of corticostriatal projections. Such lateralization could play a role in asymmetric diseases like Parkinson's disease.

Analysis of key molecules of the innate immune system in mammary epithelial cells isolated from marker-assisted and conventionally selected cattle

Mastitis is the most prevalent infectious disease in dairy herds. Breeding programs considering mastitis susceptibility were adopted as approaches to improve udder health status. In recent decades, conventional selection criteria based on phenotypic characteristics such as somatic cell score in milk have been widely used to select animals. Recently, approaches to incorporate molecular information have become feasible because of the detection of quantitative trait loci (QTL) affecting mastitis resistance. The aims of the study were to explore molecular mechanisms underlying mastitis resistance and the genetic mechanisms underlying a QTL on Bos taurus chromosome 18 found to influence udder health. Primary cell cultures of mammary epithelial cells from heifers that were selected for high or low susceptibility to mastitis were established. Selection based on estimated pedigree breeding value or on the basis of marker-assisted selection using QTL information was implemented. The mRNA expression of 10 key molecules of the innate immune system was measured using quantitative real-time PCR after 1, 6, and 24 h of challenge with heat-inactivated mastitis pathogens (Escherichia coli and Staphylococcus aureus) and expression levels in the high and low susceptibility groups were compared according to selection criteria. In the marker-assisted selection groups, mRNA expression in cells isolated from less-susceptible animals was significantly elevated for toll-like receptor 2, tumor necrosis factor-alpha, IL-1beta, IL-6, IL-8, RANTES (regulated upon activation, normal t-cell expressed and secreted), complement factor C3, and lactoferrin. In the estimated pedigree breeding value groups, mRNA expression was significantly elevated only for V-rel reticuloendotheliosis viral oncogene homolog A, IL-1 beta, and RANTES. These observations provide first insights into genetically determined divergent reactions to pathogens in the bovine mammary gland and indicate that the application of QTL information could be a successful tool for the selection of animals resistant to mastitis.

Does single use of an autologous transfusion system in TKA reduce the need for allogenic blood?: a prospective randomized trial

BACKGROUND Mechanical autotransfusion systems for washed shed blood (WSB) were introduced to reduce the need for postoperative allogenic blood transfusions (ABTs). Although some authors have postulated decreased requirements for ABT by using autologous retransfusion devices, other trials, mostly evaluating retransfusion devices for unwashed shed blood (USB), verified a small or no benefit in reducing the need for postoperative ABT. Because of these contradictory findings it is still unclear whether autologous retransfusion systems for WSB can reduce transfusion requirements. QUESTIONS/PURPOSES We therefore asked whether one such autologous transfusion system for WSB can reduce the requirements for postoperative ABT. METHODS In a prospective, randomized, controlled study, we enrolled 151 patients undergoing TKA. In Group A (n=76 patients), the autotransfusion system was used for a total of 6 hours (intraoperatively and postoperatively) and the WSB was retransfused after processing. In Control Group B (n=75 patients), a regular drain without suction was used. We used signs of anemia and/or a hemoglobin value less than 8 g/dL as indications for transfusion. If necessary, we administered one or two units of allogenic blood. RESULTS Twenty-three patients (33%) in Group A, who received an average of 283 mL (range, 160-406 mL) of salvaged blood, needed a mean of 2.1 units of allogenic blood, compared with 23 patients (33%) in Control Group B who needed a mean of 2.1 units of allogenic blood. CONCLUSIONS We found the use of an autotransfusion system did not reduce the rate of postoperative ABTs. LEVEL OF EVIDENCE Level II, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Dysfunctions of the motor system in schizophrenia

Objective: Schizophrenia patients suffer from a variety of motor symptoms, including parkinsonism, catatonia, neurological soft signs, abnormal involuntary movements and psychomotor slowing. Methods: Literature review of prevalence rates and presentation of own results. Results: Parkinsonism and abnormal involuntary movements are intrinsic to schizophrenia, but may also be evoked by antipsychotic treatment. Reduced motor activity is associated with negative symptoms, catatonia and psychomotor slowing. Furthermore, 40 % of schizophrenia patients are impaired in gesture performance, which is related to executive and basic motor function. Mild motor disturbances are found in the majority of patients, while severe dysfunctions are limited to a minority. Our neuroimaging studies suggest that hypokinesia is caused by defective cortico-subcortical motor loops in schizophrenia. Taken together, a dimensional approach to schizophrenia motor symptoms seems promising. A purely descriptive assessment of motor signs is preferred over theoryladen categorization. Using objective motor parameters allows finding neural correlates of abnormal motor behaviour. Conclusion: The motor dimension of schizophrenia is linked to distinct disturbances in the cerebral motor system. Targeted modification of the defective motor system might become a relevant treatment option in patients suffering from schizophrenia with predominant motor features.

Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease

OBJECTIVE: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up. DESIGN: We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis. RESULTS: Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (pFDR=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-κB regulator CYLD. This resulted in IκB-α degradation and NF-κB activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly. CONCLUSIONS: Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors.

Reassembling a system from the sensor to cerebral representation: the olfactory system in vitro.

An odorant's code is represented by activity in a dispersed ensemble of olfactory sensory neurons in the nose, activation of a specific combination of groups of mitral cells in the olfactory bulb and is considered to be mapped at divergent locations in the olfactory cortex. We present here an in vitro model of the mammalian olfactory system developed to gain easy access to all stations of the olfactory pathway. Mouse olfactory epithelial explants are cocultured with a brain slice that includes the olfactory bulb and olfactory cortex areas and maintains the central olfactory pathway intact and functional. Organotypicity of bulb and cortex is preserved and mitral cell axons can be traced to their target areas. Calcium imaging shows propagation of mitral cell activity to the piriform cortex. Long term coculturing with postnatal olfactory epithelial explants restores the peripheral olfactory pathway. Olfactory receptor neurons renew and progressively acquire a mature phenotype. Axons of olfactory receptor neurons grow out of the explant and rewire into the olfactory bulb. The extent of reinnervation exhibits features of a postlesion recovery. Functional imaging confirms the recovery of part of the peripheral olfactory pathway and shows that activity elicited in olfactory receptor neurons or the olfactory nerves is synaptically propagated into olfactory cortex areas. This model is the first attempt to reassemble a sensory system in culture, from the peripheral sensor to the site of cortical representation. It will increase our knowledge on how neuronal circuits in the central olfactory areas integrate sensory input and counterbalance damage.

No evidence for a local renin-angiotensin system in liver mitochondria

The circulating, endocrine renin-angiotensin system (RAS) is important to circulatory homeostasis, while ubiquitous tissue and cellular RAS play diverse roles, including metabolic regulation. Indeed, inhibition of RAS is associated with improved cellular oxidative capacity. Recently it has been suggested that an intra-mitochondrial RAS directly impacts on metabolism. Here we sought to rigorously explore this hypothesis. Radiolabelled ligand-binding and unbiased proteomic approaches were applied to purified mitochondrial sub-fractions from rat liver, and the impact of AngII on mitochondrial function assessed. Whilst high-affinity AngII binding sites were found in the mitochondria-associated membrane (MAM) fraction, no RAS components could be detected in purified mitochondria. Moreover, AngII had no effect on the function of isolated mitochondria at physiologically relevant concentrations. We thus found no evidence of endogenous mitochondrial AngII production, and conclude that the effects of AngII on cellular energy metabolism are not mediated through its direct binding to mitochondrial targets.

Recharge Areas and Geochemical Evolution of Groundwater in an Alluvial Aquifer System in the Sultanate of Oman

A regional hydrogeochemical model was developed to evaluate the geochemical evolution of different groundwaters in an alluvial aquifer system in the Interior of Oman. In combination with environmental isotopes the model is able to extract qualitative and quantitative information about recharge, groundwater flow paths and hydraulic connections between different aquifers. The main source of water to the alluvial aquifer along the flow paths ofWadi Abyadh andWadi M’uaydin in the piedmont is groundwater from the high-altitude areas of the Jabal Akhdar and local infiltration along the wadi channels. In contrast, the piedmont alluvial aquifer alongWadi Halfayn is primarily replenished by lateral recharge from the ophiolite foothills to the east besides smaller contributions from the Jabal Akhdar and local infiltration. Further down gradient in the Southern Alluvial Plain aquifer a significant source of recharge is direct infiltration of rain and surface runoff, originating from a moisture source that approaches Oman from the south. The model shows that the main geochemical evolution of the alluvial groundwaters occurs along the flow path from the piedmont to the Southern Alluvial Plain, where dedolomitization is responsible for the observed changes in the chemical and carbon isotope composition in these waters.

Incidence and Imaging Outcomes of Acute Scaffold Disruption and Late Structural Discontinuity After Implantation of the Absorb Everolimus-Eluting Fully Bioresorbable Vascular Scaffold: Optical Coherence Tomography Assessment in the ABSORB Cohort B Trial (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions).

OBJECTIVES This study sought to describe the frequency and clinical impact of acute scaffold disruption and late strut discontinuity of the second-generation Absorb bioresorbable polymeric vascular scaffolds (Absorb BVS, Abbott Vascular, Santa Clara, California) in the ABSORB (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) cohort B study by optical coherence tomography (OCT) post-procedure and at 6, 12, 24, and 36 months. BACKGROUND Fully bioresorbable scaffolds are a novel approach to treatment for coronary narrowing that provides transient vessel support with drug delivery capability without the long-term limitations of metallic drug-eluting stents. However, a potential drawback of the bioresorbable scaffold is the potential for disruption of the strut network when overexpanded. Conversely, the structural discontinuity of the polymeric struts at a late stage is a biologically programmed fate of the scaffold during the course of bioresorption. METHODS The ABSORB cohort B trial is a multicenter single-arm trial assessing the safety and performance of the Absorb BVS in the treatment of 101 patients with de novo native coronary artery lesions. The current analysis included 51 patients with 143 OCT pullbacks who underwent OCT at baseline and follow-up. The presence of acute disruption or late discontinuities was diagnosed by the presence on OCT of stacked, overhung struts or isolated intraluminal struts disconnected from the expected circularity of the device. RESULTS Of 51 patients with OCT imaging post-procedure, acute scaffold disruption was observed in 2 patients (3.9%), which could be related to overexpansion of the scaffold at the time of implantation. One patient had a target lesion revascularization that was presumably related to the disruption. Of 49 patients without acute disruption, late discontinuities were observed in 21 patients. There were no major adverse cardiac events associated with this finding except for 1 patient who had a non-ischemia-driven target lesion revascularization. CONCLUSIONS Acute scaffold disruption is a rare iatrogenic phenomenon that has been anecdotally associated with anginal symptoms, whereas late strut discontinuity is observed in approximately 40% of patients and could be viewed as a serendipitous OCT finding of a normal bioresorption process without clinical implications. (ABSORB Clinical Investigation, Cohort B [ABSORB B]; NCT00856856).

Geomorphology and evolution of the late Pleistocene to Holocene fluvial system in the south-eastern Llanos de Moxos, Bolivian Amazon

In the Bolivian Amazon several paleochannel generations are preserved. Their wide spectrum of morphologies clearly provides crucial information on the type and magnitude of geomorphic and hydrological changes within the drainage network of the Andean foreland. Therefore, in this study we mapped geomorphological characteristics of paleochannels, and applied radiocarbon and optically stimulated luminescence dating. Seven paleochannel generations are identified. Significant changes in sinuosity, channel widths and river pattern are observed for the successive paleochannel generations. Our results clearly reflect at least three different geomorphic and hydrological periods in the evolution of the fluvial system since the late Pleistocene. Changes in discharge and sediment load may be controlled by combinations of two interrelated mechanisms: (i) spatial changes and re-organizations of the drainage network in the upper catchment, and/or (ii) climate changes with their associated local to catchment-scale modifications in vegetation cover, and changes in discharge, inundation frequencies and magnitudes, which have likely affected the evolution of the fluvial system in the Llanos de Moxos. In summary, our study has revealed the enormous potential which geomorphic mapping and analysis combined with luminescence based chronologies hold for the reconstruction of the late Pleistocene to recent fluvial system in a large portion of Amazonia.