Differential phenotypes of memory CD4 and CD8 T cells in the spleen and peripheral tissues following immunostimulatory therapy

Abstract

Background

Studies assessing immune parameters typically utilize human PBMCs or murine splenocytes to generate data that is interpreted as representative of immune status. Using splenocytes, we have shown memory CD4-T cells that expand following systemic immunostimulatory therapies undergo rapid IFNg-mediated activation induced cell death (AICD) resulting in a net loss of total CD4-T cells which correlates with elevated PD-1 expression. This is in contrast to CD8-T cells which expand with minimal PD-1 upregulation and apoptosis. In this study we expand upon our previous work by evaluating CD4 and CD8-T cell phenotype and distribution in peripheral organs which are more representative of immune responses occurring at metastatic sites following immunotherapy.

Methods

Phenotypic assessment of T cells in both lymphoid (spleen and LN) as well as peripheral organs (liver and lungs) in control and immunotherapy treated mice was performed to survey the impact of location on memory phenotype and activation marker status. Peripheral blood from patients undergoing systemic high dose IL-2 was also assessed for expression of PD-1 and memory phenotype.

Results

Here we reveal that, similar to what occurs in the spleen and lymph nodes, CD4-T cell numbers decreased while CD8-T cells expanded at these peripheral sites. In contrast to having differential expression of PD-1 as occurs in the spleen, both CD4 and CD8-T cells had significantly elevated levels of PD-1 in both the liver and lungs. Further analysis correlated PD-1 expression to CD62L^low (T effector/effector memory,T_E/EM) expression which are more prevalent in CD4-T cells in general as well as CD8-T cells in peripheral organs. Similar elevated PD-1 expression on T_E/EM cells was observed in patients undergoing systemic high-dose IL-2 therapy.

Conclusions

These data highlight PD-1 expressing and/or T_E/EM subsets of T cells in circulation as more representative of cells at immune sites and underscore the importance of valuation both in lymphoid as well as target organs when making determinations about immune status.

Trial registration

ClinicalTrials.gov NCT01416831. Registered August 12, 2011.

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The Why, what, and How of the New FACT standards for immune effector cells

Abstract

Novel cellular therapies outside of traditional hematopoietic stem cell transplantation or hematopoietic progenitor cell (HPC) therapy are currently under evaluation in clinical trials across the United States and around the world. Several cellular products, e.g., CD19-directed Chimeric Antigen Receptor (CAR) T cells, are poised for FDA approval and thus increased use at a wider range of academic centers within the next year, with the likelihood of dissemination to standard oncology practice once safety is confirmed. However, these therapies entail some unique challenges in terms of logistics of delivery and toxicity management. Building on experiences and Standards established for HPC programs, the Foundation for the Accreditation of Cellular Therapy (FACT) has established new Standards specific to the use of Immune Effector Cells (IEC), including gene-modified T cells and natural (NK) cells. These Standards specify the clinical and quality infrastructure to facilitate safe administration of immune effector cells and formalize subsequent monitoring and reporting of patient outcomes to enable continual process improvement. Below we detail why these standards came into being, what they entail, and how a clinical team might access educational materials and implement these Standards. We propose that these Standards will be increasingly useful and relied up on as institutions and clinical service lines seek access to these treatment for their patients. FACT will begin accrediting programs that meet these new Standards for clinical administration of Immune Effector Cells in 2017.

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The Value of Cancer Immunotherapy Summit at the 2016 Society for Immunotherapy of Cancer 31 st anniversary annual meeting

Abstract

As healthcare costs continue to rise, there has been great interest in understanding and defining the value of current therapeutic strategies for the treatment of cancer. Cancer immunotherapy has emerged as a clinically beneficial alternative to conventional therapies for a variety of malignancies. Characterized by broad clinical activity, durable response rates, distinct side effects, and unique response kinetics, immune-based agents are vastly different compared with traditional cytotoxic or targeted therapies. To date, however, value assessments in oncology have not focused on the unique aspects of cancer immunotherapy, which has resulted in a lack of understanding of the true value of these therapies. Therefore, the Society for Immunotherapy of Cancer (SITC) convened key stakeholders to address the critical issues that define the value of cancer immunotherapy in National Harbor, Maryland on November 13, 2016. Organized in collaboration with the American Society for Clinical Oncology (ASCO) and with over 1500 registrants, this Value of Cancer Immunotherapy Summit united research scientists, academic physicians, industry professionals, health economists, third-party payers, and patients to discuss critical issues surrounding the value framework for cancer immunotherapy. This half-day summit addressed the current landscape of cancer therapy value models, economic outcomes, the current status of predictive biomarkers, as well as presentations from third-party payers, industry representatives, patient outcome experts, and patient advocacy groups to gain their perspectives on the value of cancer immunotherapy. Here, we summarize the presentations and the dominant themes from this symposium, with the intention of providing insight on future directions and to develop recommendations to better define the value of cancer immunotherapy for patients with cancer.

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Long-term complete remission with Ipilimumab in metastatic castrate-resistant prostate cancer: case report of two patients

Abstract

Background

Prostate cancer is one of the most common cancers in men and the fourth leading cause of cancer mortality worldwide. Although major progress has been achieved in the last years for patients with metastatic castrate-resistant prostate cancer (mCRPC), thanks to next-generation androgen receptor axis targeted drugs, taxanes, and bone-targeted agents, immunotherapy has not been widely approved and used for the treatment of prostate cancer. Two large studies with ipilimumab, an anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) antibody reported improved progression-free survival, but not statistically improved overall survival at the primary analysis (CA184 043 and CA184 095).

Case presentation

Here, we report on two patients who received ipilimumab in these trials and are still in long-term complete remission with a follow-up of 64 and 52 months respectively after the initiation of ipilimumab. Immunohistochemical staining for hMLH1, hMSH2, hMSH6 and PMS2 was performed on archival prostate biopsy samples from one of the two patients; they exhibited normal protein expression. Interestingly for this patient, a high CD3+ and CD8+ T cell infiltration was observed on archival prostate biopsies as well as Treg FoxP3+ T cells.

Conclusion

Ipilimumab produces clinical activity in patients with CRPC, including very long responders with no detectable residual disease.

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Nano-Pulse Stimulation is a physical modality that can trigger immunogenic tumor cell death

Abstract

Background

We have been developing a non-thermal, drug-free tumor therapy called Nano-Pulse Stimulation (NPS) that delivers ultrashort electric pulses to tumor cells which eliminates the tumor and inhibits secondary tumor growth. We hypothesized that the mechanism for inhibiting secondary tumor growth involves stimulating an adaptive immune response via an immunogenic form of apoptosis, commonly known as immunogenic cell death (ICD). ICD is characterized by the emission of danger-associated molecular patterns (DAMPs) that serve to recruit immune cells to the site of the tumor. Here we present evidence that NPS stimulates both caspase 3/7 activation indicative of apoptosis, as well as the emission of three critical DAMPs: ecto-calreticulin (CRT), ATP and HMGB1.

Methods

After treating three separate cancer cell lines (MCA205, McA-RH7777, Jurkat E6-1) with NPS, cells were incubated at 37 °C. Cell-culture supernatants were collected after three-hours to measure for activated caspases 3/7 and after 24 h to measure CRT, ATP and HMGB1 levels. We measured the changes in caspase-3 activation with Caspase-Glo® by Promega, ecto-CRT with anti-CRT antibody and flow cytometry, ATP by luciferase light generation and HMGB1 by ELISA.

Results

The initiation of apoptosis in cultured cells is greatest at 15 kV/cm and requires 50 A/cm². Reducing this current inhibits cell death. Activated caspase-3 increases 8-fold in Jurkat E6-1 cells and 40% in rat hepatocellular carcinoma and mouse fibrosarcoma cells by 3 h post treatment. This increase is non-linear and peaks at 15–20 J/mL for all field strengths. 10 and 30 kV/cm fields exhibited the lowest response and the 12 and 15 kV/cm fields stimulated the largest amount of caspase activation. We measured the three DAMPs 24 h after treatment. The expression of cell surface CRT increased in an energy-dependent manner in the NPS treated samples. Expression levels reached or exceeded the expression levels in the majority of the anthracycline-treated samples at energies between 25 and 50 J/mL. Similar to the caspase response at 3 h, secreted ATP peaked at 15 J/mL and then rapidly declined at 25 J/mL. HMGB1 release increased as treatment energy increased and reached levels comparable to the anthracycline-treated groups between 10 and 25 J/mL.

Conclusion

Nano-Pulse Stimulation treatment at specific energies was able to trigger the emission of three key DAMPs at levels comparable to Doxorubicin and Mitoxantrone, two known inducers of immunogenic cell death (ICD). Therefore NPS is a physical modality that can trigger immunogenic cell death in tumor cells.

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A systems biology approach to investigating the influence of exercise and fitness on the composition of leukocytes in peripheral blood

Abstract

Background

Exercise immunology has become a growing field in the past 20 years, with an emphasis on understanding how different forms of exercise affect immune function. Mechanistic studies are beginning to shed light on how exercise may impair the development of cancer or be used to augment cancer treatment. The beneficial effects of exercise on the immune system may be exploited to improve patient responses to cancer immunotherapy.

Methods

We investigated the effects of acute exercise on the composition of peripheral blood leukocytes over time in a male population of varying fitness. Subjects performed a brief maximal intensity cycling regimen and a longer less intense cycling regimen at separate visits. Leukocytes were measured by multi-parameter flow cytometry of more than 50 immunophenotypes for each collection sample.

Results

We found a differential induction of leukocytosis dependent on exercise intensity and duration. Cytotoxic natural killer cells demonstrated the greatest increase (average of 5.6 fold) immediately post-maximal exercise whereas CD15⁺ granulocytes demonstrated the largest increase at 3 h post-maximal exercise (1.6 fold). The longer, less intense endurance exercise resulted in an attenuated leukocytosis. Induction of leukocytosis did not differ in our limited study of active (n = 10) and sedentary (n = 5) subjects to exercise although we found that in baseline samples, sedentary individuals had elevated percentages of CD45RO⁺ memory CD4⁺ T cells and elevated proportions of CD4⁺ T cells expressing the negative immune regulator programmed death-1 (PD-1). Finally, we identified several leukocytes whose presence correlated with obesity related fitness parameters.

Conclusions

Our data suggests that leukocytes subsets are differentially mobilized into the peripheral blood and dependent on the intensity and duration of exercise. Pre-existing compositional differences of leukocytes were associated with various fitness parameters.

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Vaccination with inhibin-α provides effective immunotherapy against testicular stromal cell tumors

Abstract

Background

Testicular cancer is the most common male neoplasm occurring in men between the ages of 20 and 34. Although germ-line testicular tumors respond favorably to current standard of care, testicular stromal cell (TSC) tumors derived from Sertoli cells or Leydig cells often fail to respond to chemotherapy or radiation therapy and have a 5-year overall survival significantly lower than the more common and more treatable germ line testicular tumors.

Methods

To improve outcomes for TSC cancer, we have developed a therapeutic vaccine targeting inhibin-α, a protein produced by normal Sertoli and Leydig cells of the testes and expressed in the majority of TSC tumors.

Results

We found that vaccination against recombinant mouse inhibin-α provides protection and therapy against transplantable I-10 mouse TSC tumors in male BALB/c mice. Similarly, we found that vaccination with the immunodominant p215-234 peptide of inhibin-α (Inα 215-234) inhibits the growth of autochthonous TSC tumors occurring in male SJL.AMH-SV40Tag transgenic mice. The tumor immunity and enhanced overall survival induced by inhibin-α vaccination may be passively transferred into naive male BALB/c recipients with either CD4+ T cells, B220+ B cells, or sera from inhibin-α primed mice.

Conclusions

Considering the lack of any alternative effective treatment for chemo- and radiation-resistant TSC tumors, our results provide for the first time a rational basis for immune-mediated control of these aggressive and lethal variants of testicular cancer.

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Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies

Abstract

Background

Imatinib mesylate can induce rapid tumor regression, increase tumor antigen presentation, and inhibit tumor immunosuppressive mechanisms. CTLA-4 blockade and imatinib synergize in mouse models to reduce tumor volume via intratumoral accumulation of CD8+ T cells. We hypothesized that imatinib combined with ipilimumab would be tolerable and may synergize in patients with advanced cancer.

Methods

Primary objective of the dose-escalation study (3 + 3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose. Secondary objectives included evaluation of antitumor activity of the combination based on KIT mutation status and the capacity of tumor-associated immune biomarkers to predict response.

Results

The primary objective to establish the maximum tolerated dose (MTD) was achieved, and the recommended phase II doses are ipilimumab at 3 mg/kg every 3 weeks and imatinib 400 mg twice daily. Of the 35 patients treated in the escalation and GIST expansion, none experienced dose-limiting toxicities. The most common grade 1/2–related adverse events (AEs) were fatigue (66%), nausea (57%), anorexia, vomiting (each 31%), edema (29%), and anemia, diarrhea, and rash (each 23%). Grade 3 AEs occurred in 6 patients (17%) and included fatigue, anemia, fever, rash, and vomiting. There were no grade 4 AEs. In general, the combination was well tolerated. Among all patients, 2 responses were seen: 1 partial response (GIST) and 1 partial response (melanoma). Stable disease was seen in 6 patients lasting an average of 6 months. The melanoma responder was KIT mutated and the GIST responder was wild-type.

Conclusions

Our findings suggest that this combination of a targeted agent with checkpoint blockade is safe across multiple tumor types. Low activity with no clear signal for synergy was observed in escalation or GIST expansion cohorts. Assessment of antitumor activity of this combination in the KIT-mutant melanoma population is being evaluated.

Trial registration

Clinicaltrials.gov NCT01738139, registered 28 November 2012.

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Response after treatment with pembrolizumab in a patient with myelophthisis due to melanoma: the role of checkpoint inhibition in the bone

Abstract

Background

Myelophthisis due to melanoma is a rare phenomenon. Treatment strategies for patients with this serious complication of malignancy have not been well documented, and none have previously reported efficacy of immune checkpoint inhibition. Since bone metastases are not measurable lesions per standard response criteria, the efficacy of immune checkpoint inhibition in the bones is also not well described.

Case presentation

We describe a patient with widespread melanoma metastases involving the bone marrow causing myelophthisis and pancytopenia who responded to immune checkpoint inhibition with the anti-programmed cell death-1 (PD-1) inhibitor pembrolizumab.

Conclusions

This is the first report to our knowledge of disease response to immune checkpoint inhibition in a patient with myelophthisis. Clinical trials have recently emerged describing the efficacy of PD-1 inhibition for disorders regularly involving the bone marrow, such as hematologic malignancies, suggesting the importance of better understanding the bone marrow as an immunologically active compartment. Clinicians should be aware that immune checkpoint inhibition alone may be effective in treating malignancy involving the bone marrow, even in cases of extensive involvement resulting in pancytopenia due to myelophthisis from a solid tumor as our case suggests.

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Neuroprotective effect of three caffeic acid derivatives via ameliorate oxidative stress and enhance PKA/CREB signaling pathway

Publication date: 15 June 2017
Source:Behavioural Brain Research SreeTestContent1, Volume 328
Author(s): Wei Fu, Hongyan Wang, Xiuhua Ren, Hengyi Yu, Yongfang Lei, Qian Chen
This study was conducted to elucidate the neuroprotective effect of caffeic acid phenethyl ester (CAPE), (R)-2-Hydroxy-3-(3,4-dihydroxyphenyl) propionic acid (Danshensu) and Curcumin, three caffeic acid derivatives which are contained in fruits, grains and certain dietary supplements.Our results showed that these compounds significantly attenuated H2O2-induced toxicity in PC12 cells in a dose-dependent manner. Furthermore, these compounds significantly improved the behavioral performance of d-gal-treated mice in both step-down avoidance test and Morris water maze test. Biochemical examination and western blot analysis showed that these compounds could ameliorate oxidative stress and facilitate activation of the protein kinase A (PKA)-cyclic AMP response element-binding protein (CREB) pathway.Its beneficial effects may partly relate to enhancing the activity of endogenous antioxidant enzymes and modulating the PKA/CREB signaling pathway. Furthermore, our results also indicated that the presence of 3, 4-dihydroxyphenyl groups in A ring may enhance their neuroprotective activity.



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Time-source of neural plasticity in complex bimanual coordinative tasks: Juggling

Publication date: 15 June 2017
Source:Behavioural Brain Research SreeTestContent1, Volume 328
Author(s): Marika Berchicci, Federico Quinzi, Andrea Dainese, Francesco Di Russo
Brain plasticity is especially stimulated by complex bimanual tasks, because, as for juggling, they require simultaneous control of multiple movements, high level of bimanual coordination, balance and sustained swapping attention to multiple objects interacting with both hands. Neuroimaging studies on jugglers showed changes in white and grey matter after juggling training, while the very few electroencephalographic (EEG) studies showed changes in the frequency domain. However, no study has focused on the fine temporal brain activations during a bimanual coordinative task in ecological settings. We aimed at understanding the neural correlates of juggling tasks comparing expert jugglers to non-jugglers. Both groups performed two juggling tasks with increasing difficulty (1-ball fountain and 2-ball shower in non-jugglers, 2- and 3-ball shower in expert jugglers), while the EEG was recorded. This design allowed to compare brain activities related to increasing task difficulty within the same group, and the two groups on the same task. The movement-related cortical potentials (MRCPs) for each task were segmented into epochs lasting 4.5s (−1.5/+3.0s). Results showed enhanced prefrontal recruitment with increasing task difficulty in both groups, even before movement onset. Comparing the groups on the same task, non-jugglers showed enhanced activation of prefrontal regions before and during the task execution, whereas jugglers showed enhanced activity in motor-related regions. The results provide a clear indication of practice-induced brain efficiency during the performance of complex bimanual coordinative skills.



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A Novel TP53 Mutation Associated with TWIST1 and SIP1 Expression in an Aggressive Adrenocortical Carcinoma

Abstract

Adrenocortical carcinomas (ACC) are very rare tumors related to TP53 mutations mostly in childhood onset cases. Epithelial-mesenchymal transition (EMT) transcription factors TWIST1 and Smad interacting protein 1 (SIP1) are related to poorer outcomes in other malignancies, but their role in ACC is unknown. We describe a case of an advanced metastatic ACC (Weiss-score of 9) in a patient at age 76. After primary tumor resection, mitotane therapy was started as palliation to low-volume liver metastasis. After a 2-year period of stable disease, the patient died due to brain metastasis. Somatic gene sequencing revealed a novel TP53 mutation in DNA extracted from paraffin-embedded tissue, a deletion of 8bp in exon 8 (c.811_818del8; GAGGTGCG/−) in homo or hemizygosis causing a subsequent frameshift and premature stop codon at position 302. Immunohistochemistry of P53 and p-Ser-15 P53 showed absent tumoral staining. In addition, immunohistochemical analysis showed an increased expression of the mesenchymal markers vimentin and fibronectin. At last, EMT transcription factors TWIST1 and SIP1 were also overexpressed in tumoral cells. This case report describes an aggressive ACC with not only a novel somatic mutation, but also a novel International Agency for Research on Cancer database 8 base-pair deletion in TP53 exon 8. In addition, the expression of EMT inducers TWIST1 and SIP1 have been reported for the first time in an ACC case. Further investigation is needed to clarify the biologic significance of this new TP53 mutation and its role in the EMT process.

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Pathogenesis of Immune Thrombocytopenia

Publication date: Available online 17 April 2017
Source:Autoimmunity Reviews
Author(s): Sylvain Audia, Matthieu Mahévas, Maxime Samson, Bertrand Godeau, Bernard Bonnotte
Immune thrombocytopenia (ITP) is a rare autoimmune disease due to an abnormal T cell response, notably supported by splenic T follicular helper cells, that stimulates the proliferation and differentiation of autoreactive B cells. The antiplatelet autoantibodies they produce facilitate platelet phagocytosis by macrophages, essentially in the spleen. Macrophages contribute to the perpetuation of the auto-immune response as the main antigen-presenting cell during ITP. CD8⁺ T cells also participate to thrombocytopenia by increasing platelet apoptosis. Besides this peripheral platelet destruction, inappropriate bone marrow production also exacerbates thrombocytopenia, due to an immune response against megakaryocytes. Moreover, the level of circulating thrombopoietin, the main growth factor of megakaryocytes, is low during ITP. In this review, the major mechanisms leading to thrombocytopenia, the role of the different immune cells and the different targets of treatments are described.



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The theory of planned behaviour explains intentions to use antiresorptive medication after a fragility fracture

Abstract

Our objective was to ascertain whether the Theory of Planned Behaviour (TPB) explains patient intentions to use antiresorptive medication after a fracture. A qualitative study was conducted with English-speaking members of the Canadian Osteoporosis Patient Network (COPN) who had sustained a fragility fracture at 50+ years of age and were not taking antiresorptive medication at the time of that fracture. Questions during a 1-h telephone interview were guided by the domains of the TPB: they addressed the antecedent constructs regarding antiresorptive medication (attitudes, subjective norms, and perceived behavioural control) as well as intentions regarding antiresorptive medication use. We created a coding template a priori based on the TPB domains and applied this template to the interview data. Twenty-six eligible participants (24 females, 2 males) aged 51–89 completed an interview. The TPB appeared to be predictive of intentions in 19 (73%) participants. In the majority of participants where the TPB did not appear to be predictive (57%), a positive attitude toward antiresorptive medication was the most important antecedent variable in determining intentions. The TPB appeared to be predictive of intentions to use antiresorptive medication among individuals who had experienced a fragility fracture. Attitudes towards medication were especially important.

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Incidence of autoimmune diseases in patients with scabies: a nationwide population-based study in Taiwan

Abstract

Scabies is a commonly occurring infectious immune-mediated inflammatory skin disease. Immune-mediated inflammatory processes are also observed in autoimmune diseases. There have been very few previous studies; however, that have investigated the possible association between scabies and autoimmune diseases. To address this research gap, we conducted a nationwide population-based cohort study that included a total of 4481 scabies patients and 16,559 control subjects matched by gender, age, insured region, urbanization and income. We tracked both cohorts for a 7-year period to identify the incidence of autoimmune diseases in both groups during that follow-up period. Relatedly, a Cox regression analysis was performed to calculate and compare the hazard ratio (HR) for autoimmune diseases of both groups. An overall increased risk for 19 autoimmune diseases was observed in the scabies patients, with an adjusted HR (aHR) of 1.14 (95% CI 1.04–1.25). Compared with the control group, the scabies patients exhibited increased risks of hypersensitivity vasculitis (aHR 5.44, 95% CI 1.64–18.07), dermatomyositis (aHR 4.91, 95% CI 1.80–13.38), polyarteritis nodosa (aHR 2.89, 95% CI 1.46–5.73), systemic lupus erythematosus (aHR 2.73, 95% CI 1.33–5.64), psoriasis (aHR 2.31, 95% CI 1.85–2.88), myasthenia gravis (aHR 2.01, 95% CI 1.31–3.12), type 1 diabetes mellitus (aHR 1.93, 95% CI 1.53–2.44), pernicious anemia (aHR 1.92, 95% CI 1.42–2.61), and rheumatoid arthritis (aHR 1.43, 95% CI 1.12–1.83). In conclusion, the associations between scabies and a variety of autoimmune diseases may exist. Further studies are needed to clarify the shared etiologies and relationships between scabies and autoimmune diseases.

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Vitamin D supplementation for the management of knee osteoarthritis: a systematic review of randomized controlled trials

Abstract

Conflicting evidence exists concerning the supplementation of vitamin D in knee osteoarthritis condition. This systematic literature review was done to explore the effects of vitamin D supplementation in the management of knee osteoarthritis. Electronic literature search was done in databases like PubMed^®, Embase^®, and Cochrane CENTRAL from inception to 6th July 2016. The quality of included Randomized Controlled Trials (RCTs) was assessed using Cochrane risk of bias tool. We considered change in Western Ontario and McMaster Universities (WOMAC) index, Visual Analog Scale (VAS) and Functional Pain Score (FPS) as the primary outcome measure. Change in tibial cartilage thickness, joint space width and safety profile was considered as secondary outcomes. Participants were randomized either to treatment or placebo group. Participants received cholecalciferol as an intervention through oral route in the dose range of 800–60,000 IU except in the one study where participants received ergocalciferol. All included RCTs showed a significant increase in serum vitamin D level in the treatment group compared to the placebo group at the end point. No significant reduction in pain and function was reported on WOMAC scale except in one study. No significant difference was reported for WOMAC stiffness in any study. VAS was assessed in three studies in which two showed statistically significant improvement in knee pain. Three of the RCTs reported safety data with one incidence of calculus ureteric and hip fracture found to be related to the drug. The study found evidence from RCTs to be insufficient to support the use of vitamin D supplementation for patients with knee osteoarthritis.

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Hearing diversity in moths confronting a neotropical bat assemblage

Abstract

The tympanal ear is an evolutionary acquisition which helps moths survive predation from bats. The greater diversity of bats and echolocation strategies in the Neotropics compared with temperate zones would be expected to impose different sensory requirements on the neotropical moths. However, even given some variability among moth assemblages, the frequencies of best hearing of moths from different climate zones studied to date have been roughly the same: between 20 and 60 kHz. We have analyzed the auditory characteristics of tympanate moths from Cuba, a neotropical island with high levels of bat diversity and a high incidence of echolocation frequencies above those commonly at the upper limit of moths' hearing sensitivity. Moths of the superfamilies Noctuoidea, Geometroidea and Pyraloidea were examined. Audiograms were determined by non-invasively measuring distortion-product otoacoustic emissions. We also quantified the frequency spectrum of the echolocation sounds to which this moth community is exposed. The hearing ranges of moths in our study showed best frequencies between 36 and 94 kHz. High sensitivity to frequencies above 50 kHz suggests that the auditory sensitivity of moths is suited to the sounds used by sympatric echolocating bat fauna. Biodiversity characterizes predators and prey in the Neotropics, but the bat–moth acoustic interaction keeps spectrally matched.

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Longitudinal MRI evaluation of neuroprotective effects of pharmacologically induced hypothermia in experimental ischemic stroke

Publication date: July 2017
Source:Magnetic Resonance Imaging, Volume 40
Author(s): Silun Wang, Xiaohuan Gu, Ramesh Paudyal, Ling Wei, Thomas A. Dix, Shan P. Yu, Xiaodong Zhang
Pharmacologically induced hypothermia (PIH) shows promising neuroprotective effects after stroke insult. However, the dynamic evolution of stroke infarct during the hypothermic therapy has not been understood very well. In the present study, MRI was utilized to longitudinally characterize the infarct evolution in a mouse model of ischemic stroke treated by PIH using the neurotensin agonist HPI201. Adult male C57BL/6 mice underwent permanent occlusion of the right middle cerebra artery (MCA). Each animal received a vehicle or HPI201 intraperitoneal injection. The temporal changes of stroke lesion were examined using T2-weighted imaging and diffusion-weighted imaging (DWI) in the acute phase (1−3h) and 24h post stroke. Significantly reduced infarct and edema volumes were observed in PIH treated stroke mice, in agreement with TTC staining findings. Also, the TUNEL staining results indicated apoptotic cells were widely distributed among the ischemic cortex in control group but limited in PIH treated mice. Dramatically reduced growth rate of infarction was seen in PIH treated stroke mice. These results demonstrate HPI201 has strong neuroprotection effects during acute stroke. In particular, MRI with the numerical modelling of temporal infarct evolution could provide a unique means to examine and predict the dynamic response of the PIH treatment on infarct evolution.



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Reply to the letter to the editor on “No modulatory effects by tSMS when delivered during a cognitive task”

Publication date: Available online 17 April 2017
Source:Brain Stimulation
Author(s): Marco Kufner, Sabrina Brückner, Thomas Kammer




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Subthalamic nucleus deep brain stimulation for the treatment of secondary dystonia: A case series and review of literature

Publication date: Available online 18 April 2017
Source:Brain Stimulation
Author(s): Jason Margolesky, Nathan Schoen, Walter Jermakowicz, Samir Sur, Iahn Cajigas, Carlos Singer, Jonathan Jagid, Corneliu Luca




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