Cardiopulmonary,biomarkers, and vascular responses to acute hypoxia following cardiac transplantation

Previous studies have suggested good adaptation of cardiac transplant (CTx) recipients to exposure to a high altitude. No studies have investigated the cardiopulmonary and biomarker responses to acute hypoxic challenges following CTx. Thirty‐six CTx recipients and 17 age‐matched healthy controls (HC) were recruited. Sixteen (16) patients (42%) had cardiac allograft vasculopathy (CAV). Cardiopulmonary responses to maximal and submaximal exercise at 21% O₂, 20‐minutes hypoxia (11.5% O₂), and following a 10‐minute exposure to 11.5% O₂ using 30% of peak power output were completed. Vascular endothelial growth factor (VEGF), interleukin‐6 (IL‐6), suppression of tumorigenicity 2 (ST2) were measured at baseline and at peak stress. Endothelial peripheral function was assessed using near‐infrared spectroscopy. Compared with HC, CTx presented a lesser O₂ desaturation both at rest (?19.4 ± 6.8 [CTx] vs ?24.2 ± 6.0% O₂ [HC], P < 0.05) and following exercise (?23.2 ± 4.9 [CTx] vs ?26.2 ± 4.7% O₂ [HC], P < 0.05). CTx patients exhibited a significant decrease in peak oxygen uptake. IL‐6 and VEGF levels were significantly higher in CTx recipients in basal conditions but did not change in response to acute stress. CTx patients exhibit a favorable ventilatory and overall response to hypoxic stress. These data provide further insights on the good adaptability of CTx to exposure to high altitude.     

Interferon-gamma potentiates the antitumor effect of cyclosporine-induced autoimmunity.

Graft-versus-host-disease (GVHD), which results after allogeneic bone marrow transplantation (BMT), is associated with reduced leukemic relapse. This may be mediated by an immunologic attack with subsequent destruction of residual tumor cells. On the other hand, GVHD does not normally occur after autologous BMT (ABMT), which has an inherently high relapse rate. However, an autoimmune syndrome (AIS) similar to GVHD can be induced after autologous/syngeneic BMT by administration of cyclosporine-A (CsA), resulting in the production of major histocompatibility complex (MHC) class II or Ia autoreactive cytolytic effector cells. Since many hematopoietic malignancies express variable levels of class II molecules, we hypothesized that the adjuvant use of interferon-gamma (IFN-gamma) with CsA-induced autoimmunity after autologous/syngeneic BMT may upregulate class II antigens on residual tumor cells and make them more susceptible to attack by the Ia-reactive cells of CsA-induced AIS. The present studies demonstrated that the CsA-induced autoimmune syndrome mediated an anti-tumor effect, although this effect was dependent on challenge with a minimal number of tumor cells. Further studies clearly demonstrated that the antitumor effect could be markedly enhanced by administration of IFN-gamma which increased the susceptibility of the tumor to recognition and lysis by the CsA induced autoimmune effector cells. The induction of MHC class II-restricted AIS similar to GVHD by administration of CsA together with the ability to manipulate the surface phenotype of residual tumor cells may lead to decreased relapse rates in the ABMT setting.     

Lack of mGluR6‐related cascade elements leads to retrograde trans‐synaptic effects on rod photoreceptor synapses via matrix‐associated proteins

Heterotrimeric G‐proteins couple metabotropic receptors to downstream effectors. In retinal ON bipolar cells, G_o couples the metabotropic receptor mGluR6 to the TRPM1 channel and closes it in the dark, thus hyperpolarizing the cell. Light, via GTPase‐activating proteins, deactivates G_o, opens TRPM1 and depolarizes the cell. G_o comprises Gα_o1, Gβ3 and Gγ13; all are necessary for efficient coupling. In addition, Gβ3 contributes to trafficking of certain cascade proteins and to maintaining the synaptic structure. The goal of this study was to determine the role of Gα_o1 in maintaining the cascade and synaptic integrity. Using mice lacking Gα_o1, we quantified the immunostaining of certain mGluR6‐related components. Deleting Gα_o1 greatly reduced staining for Gβ3, Gγ13, Gβ5, RGS11, RGS7 and R9AP. Deletion of Gα_o1 did not affect mGluR6, TRPM1 or PCP2. In addition, deleting Gα_o1 reduced the number of rod bipolar dendrites that invaginate the rod terminal, similar to the effect seen in the absence of mGluR6, Gβ3 or the matrix‐associated proteins, pikachurin, dystroglycan and dystrophin, which are localized presynaptically to the rod bipolar cell. We therefore tested mice lacking mGluR6, Gα_o1 and Gβ3 for expression of these matrix‐associated proteins. In all three genotypes, staining intensity for these proteins was lower than in wild type, suggesting a retrograde trans‐synaptic effect. We propose that the mGluR6 macromolecular complex is connected to the presynaptic rod terminal via a protein chain that includes the matrix‐associated proteins. When a component of the macromolecular chain is missing, the chain may fall apart and loosen the dendritic tip adherence within the invagination.     

Tele-rehabilitation service delivery journey from prototype to robust in-home use

Purpose: The purpose of this study is to present a retrospective study on clients with Acquired Brain Injury (ABI) enrolled in a tele-motion-rehabilitation service program for two or more months.

Methods: Data from 82 clients (46 males; 74 with ABI), aged 22–85 years, are reported. The Kinect-based CogniMotion System (ReAbility Online, Gertner Institute, Tel Hashomer, Israel) provided services that included 30-min biweekly sessions. Participants were evaluated prior to and 2 months following the commencement of service with clinical assessments that measured movements and function of the weaker upper extremity and cognitive abilities.

Results: Clients enrolled in the service had intact or mild cognitive impairment, mild-moderate motor impairment but little use of their weak upper extremity for daily activities. They were satisfied with the service and reported high levels of system usability. Post-intervention clinical assessments were performed on about half of the participants after 2 months; significant improvements in active movements of the weak upper extremity, shoulder flexion range of motion and in the Trail Making Test were found (p?Conclusions: The service appears to be feasible for people with ABI and effective in important clinical outcomes related to improvements in upper extremity function.

• Implications for Rehabilitation

• Tele-rehabilitation provided with Microsoft Kinect 3D sensor virtual reality tracking system is feasible for people with Acquired Brain Injury.

• People with Acquired Brain Injury in the chronic stage were satisfied with the tele-rehabilitation service and perceived it as beneficial to improve their motor and cognitive abilities

• The CogniMotion System service appears to be effective in important clinical outcomes related to improvements in upper extremity function.

     

Inconsistent effects of photoperiod manipulations in tests for affective-like changes in mice: implications for the selection of appropriate model animals

Deficiencies in appropriate animal models are a significant factor hindering the research of affective disorders. Significant data suggest that systems related to circadian rhythms are strongly linked to affective changes, but study with animal models in this context had unclear and inconsistent results. Circadian physiology is significantly different in diurnal and nocturnal animals and a recent project showed that in diurnal rodents, short photoperiods induce depression and anxiety-like phenotypes. This study was designed to evaluate the possibility that using a similar methodology would also result in behavioral changes in nocturnal mice. Mice from two strains were maintained in either short photoperiod, neutral photoperiod or long photoperiod for 3 weeks and tested for depression or anxiety-related behaviors, as done earlier with the diurnal rodents. Tests included activity levels, sweet solution preference, elevated plus-maze, resident-intruder aggression, and forced swim test. Tests were conducted either during the light phase or during the dark phase of the mice. In contrast to the clear phenotype in diurnal rodents, the effects of photoperiod manipulations in nocturnal mice were inconsistent. These results suggest that diurnal rodents may be advantageous compared with nocturnal species for studies exploring the relationship between circadian rhythms and affective disorders.     

Bladder Tumor Infiltrating Mature Dendritic Cells and Macrophages as Predictors of Response to Bacillus Calmette-Guérin Immunotherapy

Background

The clinical significance of tumor-infiltrating dendritic cells (TIDCs) and tumor-associated macrophages (TAMs) as markers of immune response has been reported for many cancers.

Objective

To measure tumor infiltration by CD83⁺ dendritic cells (DCs) and CD68⁺ macrophages in non–muscle-invasive urothelial cancer (NMIUC) prior to bacillus Calmette-Guérin (BCG) immunotherapy and to evaluate their significance in the response to immunotherapy.

Design, setting, and participants

Patients with NMIUC at high risk of recurrence and progression were recruited for a study on markers of the response to BCG.

Intervention

Patients were treated by transurethral resection followed by maintenance BCG.

Measurements

Immunohistochemical staining with anti-CD83 and anti-CD68 monoclonal antibodies on 53 and 46 NMIUC tumors, respectively, prior to BCG treatment. A scoring index was calculated based on the average density of positive cells within the papillary axis, the stroma, lymphoid aggregates, and infiltration into tumors.

Results and limitations

CD83⁺ TIDCs were observed mostly within lymphoid aggregates. Multivariate Cox regression analysis showed that maintenance BCG (more than one maintenance cycle) was highly effective in patients with a low level of CD83⁺ TIDCs at time of resection (hazard ratio [HR]: 0.035; p = 0.002) but showed reduced efficacy in patients with a high level of CD83⁺ TIDCs (HR: 0.87; p = 0.810). A high level of infiltration by CD83⁺ TIDCs slightly decreased the risk of recurrence in patients treated with one or no maintenance BCG cycle (HR: 0.4; p = 0.117). In the same population, a strong infiltration of CD68⁺ TAMs was associated with an increased risk of recurrence (HR: 3.8; p = 0.013).

Conclusions

These results suggest that patients with a high level of infiltration by CD83⁺ TIDCs or CD68⁺ TAMs do not respond as well to BCG immunotherapy. If confirmed in larger cohorts, the pretreatment level of infiltration by these cells may be useful to influence the choice of treatment strategy.     

Single dose of methylphenidate improves cognitive performance in multiple sclerosis patients with impaired attention process

BACKGROUND AND PURPOSE: Attention is one of the major cognitive domains adversely affected in multiple sclerosis (MS). The aim of the current study was to determine the effect of a single dose of methylphenidate on cognitive performance of MS patients with significant attention deficit. METHODS: In a double-blind placebo-controlled study design, 26 MS patients with impaired attention were randomly assigned to receive a single dose of 10 mg methylphenidate or placebo. Attention was assessed using the paced auditory serial addition test for 3 and 2 s (PASAT3' and PASAT2') at baseline and 1 h after drug/placebo administration. RESULTS: Methylphenidate significantly improved performance of both PASAT3' and PASAT2' tests by 22.8% and 25.6% respectively (p<0.001), while no significant changes were observed in placebo treated patients. CONCLUSION: Administration of a single dose of methylphenidate significantly improved attention in MS patients with considerable attention deficit.