Piroxicam and intracavitary platinum-based chemotherapy for the treatment of advanced mesothelioma in pets: preliminary observations

Malignant Mesothelioma is an uncommon and very aggressive tumor that accounts for 1% of all the deaths secondary to malignancy in humans. Interestingly, this neoplasm has been occasionally described in companion animals as well. Aim of this study was the preclinical evaluation of the combination of piroxicam with platinum-based intracavitary chemotherapy in pets. Three companion animals have been treated in a three years period with this combination. Diagnosis was obtained by ultrasonographic exam of the body cavities that evidenced thickening of the mesothelium. A surgical biopsy further substantiated the diagnosis. After drainage of the malignant effusion from the affected cavity, the patients received four cycles of intracavitary CDDP at the dose of 50 mg/m2 every three weeks if dogs or four cycles of intracavitary carboplatin at the dose of 180 mg/m2 (every 3 weeks) if cats, coupled with daily administration of piroxicam at the dose of 0.3 mg/kg. The therapy was able to arrest the effusion in all patients for variable remission times: one dog is still in remission after 3 years, one dog died of progressive disease after 8 months and one cat died due to progressive neoplastic growth after six months, when the patient developed a mesothelial cuirass. The combination showed remarkable efficacy at controlling the malignant effusion secondary to MM in our patients and warrants further investigations

Walk well:a randomised controlled trial of a walking intervention for adults with intellectual disabilities: study protocol

Background - Walking interventions have been shown to have a positive impact on physical activity (PA) levels, health and wellbeing for adult and older adult populations. There has been very little work carried out to explore the effectiveness of walking interventions for adults with intellectual disabilities. This paper will provide details of the Walk Well intervention, designed for adults with intellectual disabilities, and a randomised controlled trial (RCT) to test its effectiveness. Methods/design - This study will adopt a RCT design, with participants allocated to the walking intervention group or a waiting list control group. The intervention consists of three PA consultations (baseline, six weeks and 12 weeks) and an individualised 12 week walking programme. A range of measures will be completed by participants at baseline, post intervention (three months from baseline) and at follow up (three months post intervention and six months from baseline). All outcome measures will be collected by a researcher who will be blinded to the study groups. The primary outcome will be steps walked per day, measured using accelerometers. Secondary outcome measures will include time spent in PA per day (across various intensity levels), time spent in sedentary behaviour per day, quality of life, self-efficacy and anthropometric measures to monitor weight change. Discussion - Since there are currently no published RCTs of walking interventions for adults with intellectual disabilities, this RCT will examine if a walking intervention can successfully increase PA, health and wellbeing of adults with intellectual disabilities

Synaptic and Intrinsic Activation of GABAergic Neurons in the Cardiorespiratory Brainstem Network

GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA). These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca2+ currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a framework for respiratory sinus arrhythmia as there is an increase in heart rate during inspiration that occurs via inhibition of premotor parasympathetic cardioinhibitory neurons in the NA during inspiration

Downregulation of the AU-Rich RNA-Binding Protein ZFP36 in Chronic HBV Patients: Implications for Anti-Inflammatory Therapy

Inflammation caused by chronic hepatitis B virus (HBV) infection is associated with the development of cirrhosis and hepatocellular carcinoma; however, the mechanisms by which HBV infection induces inflammation and inflammatory cytokine production remain largely unknown. We analyzed the gene expression patterns of lymphocytes from chronic HBV-infected patients and found that the expression of ZFP36, an AU-rich element (ARE)-binding protein, was dramatically reduced in CD4+ and CD8+ T lymphocytes from chronic HBV patients. ZFP36 expression was also reduced in CD14+ monocytes and in total PBMCs from chronic HBV patients. To investigate the functional consequences of reduced ZFP36 expression, we knocked down ZFP36 in PBMCs from healthy donors using siRNA. siRNA-mediated silencing of ZFP36 resulted in dramatically increased expression of multiple inflammatory cytokines, most of which were also increased in the plasma of chronic HBV patients. Furthermore, we found that IL-8 and RANTES induced ZFP36 downregulation, and this effect was mediated through protein kinase C. Importantly, we found that HBsAg stimulated PBMCs to express IL-8 and RANTES, resulting in decreased ZFP36 expression. Our results suggest that an inflammatory feedback loop involving HBsAg, ZFP36, and inflammatory cytokines may play a critical role in the pathogenesis of chronic HBV and further indicate that ZFP36 may be an important target for anti-inflammatory therapy during chronic HBV infection

Diagnosis and management of adhesive capsulitis

Adhesive capsulitis is a musculoskeletal condition that has a disabling capability. This review discusses the diagnosis and both operative and nonoperative management of this shoulder condition that causes significant morbidity. Issues related to medications, rehabilitation, and post surgical considerations are discussed

The effect of age on the response to the pneumococcal polysaccharide vaccine

<p>Abstract</p> <p>Background</p> <p><it>Streptococcus pneumoniae </it>is a leading cause of morbidity and mortality in the elderly. To prevent invasive pneumococcal diseases, the 23-valent pneumococcal polysaccharide vaccine (PPV) is recommended in subjects over 65 years of age. Although it has been reported to provide approximately 50-80% protection against invasive disease in the general elderly population, there is still controversy as to the effectiveness of the PPV in the elderly.</p> <p>Methods</p> <p>To evaluate the immune response to the pneumococcal polysaccharide vaccine in the elderly, samples from young adults and elderly were obtained before and one month after vaccination. The quantitative and qualitative response to the vaccine were measured by the ELISA and opsonophagocytic killing assay for eight vaccine type serotypes (4, 6B, 9V, 14, 18C, 19A, 19F, 23F) and one vaccine-related serotype (6A).</p> <p>Results</p> <p>The response to the pneumococcal polysaccharide vaccine showed a similar response between adults and elderly when evaluated by the ELISA, however the functional activity of the antibodies elicited after vaccination were lower in the elderly group for more than half of the serotypes evaluated. In comparison of the antibody needed for 1:8 opsonic titer, more antibodies were needed in the elderly for serotypes Pn 4, 19F, 23F and 6A, suggesting the functional activity of antibody detected by the ELISA was lower in the elderly compared with the adult group for these serotypes. As for subjects with an opsonic titer <8 after vaccination, only one subject each for serotypes Pn 4, 9V and 6A were found in the adult group. However, up to 10 (30.3%) of the subjects did not show opsonic activity after vaccination in the elderly group for serotypes Pn 4, 9V, 14, 19A and 6A.</p> <p>Conclusions</p> <p>Although the amount of antibodies elicited were similar between the two age groups, distinct differences in function were noted. This report highlights the importance of a quantitative and qualitative evaluation of the immunogenic response to the PPV in the elderly age group.</p> <p>Trial registration</p> <p>This trial is registered with Clinical trials.gov. Registration number NCT00964769</p

Adverse Drug Reactions in Hospital In-Patients: A Prospective Analysis of 3695 Patient-Episodes

Adverse drug reactions (ADRs) are a major cause of hospital admissions, but recent data on the incidence and clinical characteristics of ADRs which occur following hospital admission, are lacking. Patients admitted to twelve wards over a six-month period in 2005 were assessed for ADRs throughout their admission. Suspected ADRs were recorded and analysed for causality, severity and avoidability and whether they increased the length of stay. Multivariable analysis was undertaken to identify the risk factors for ADRs. The 5% significance level was used when assessing factors for inclusion in multivariable models. Out of the 3695 patient episodes assessed for ADRs, 545 (14.7%, 95% CI 13.6–15.9%) experienced one or more ADRs. Half of ADRs were definitely or possibly avoidable. The patients experiencing ADRs were more likely to be older, female, taking a larger number of medicines, and had a longer length of stay than those without ADRs. However, the only significant predictor of ADRs, from the multivariable analysis of a representative sample of patients, was the number of medicines taken by the patient with each additional medication multiplying the hazard of an ADR episode by 1.14 (95% CI 1.09, 1.20). ADRs directly increased length of stay in 147 (26.8%) patients. The drugs most frequently associated with ADRs were diuretics, opioid analgesics, and anticoagulants. In conclusion, approximately one in seven hospital in-patients experience an ADR, which is a significant cause of morbidity, increasing the length of stay of patients by an average of 0.25 days/patient admission episode. The overall burden of ADRs on hospitals is high, and effective intervention strategies are urgently needed to reduce this burden

An Off-Target Nucleostemin RNAi Inhibits Growth in Human Glioblastoma-Derived Cancer Stem Cells

Glioblastomas (GBM) may contain a variable proportion of active cancer stem cells (CSCs) capable of self-renewal, of aggregating into CD133+ neurospheres, and to develop intracranial tumors that phenocopy the original ones. We hypothesized that nucleostemin may contribute to cancer stem cell biology as these cells share characteristics with normal stem cells. Here we report that nucleostemin is expressed in GBM-CSCs isolated from patient samples, and that its expression, conversely to what it has been described for ordinary stem cells, does not disappear when cells are differentiated. The significance of nucleostemin expression in CSCs was addressed by targeting the corresponding mRNA using lentivirally transduced short hairpin RNA (shRNA). In doing so, we found an off-target nucleostemin RNAi (shRNA22) that abolishes proliferation and induces apoptosis in GBM-CSCs. Furthermore, in the presence of shRNA22, GBM-CSCs failed to form neurospheres in vitro or grow on soft agar. When these cells are xenotransplanted into the brains of nude rats, tumor development is significantly delayed. Attempts were made to identify the primary target/s of shRNA22, suggesting a transcription factor involved in one of the MAP-kinases signaling-pathways or multiple targets. The use of this shRNA may contribute to develop new therapeutic approaches for this incurable type of brain tumor