Tapasin gene polymorphism in systemic onset juvenile rheumatoid arthritis: a family-based case-control study

Juvenile rheumatoid arthritis (JRA) comprises a group of chronic systemic inflammatory disorders that primarily affect joints and can cause long-term disability. JRA is likely to be a complex genetic trait, or a series of such traits, with both genetic and environmental factors contributing to the risk for developing the disease and to its progression. The HLA region on the short arm of chromosome 6 has been intensively evaluated for genetic contributors to JRA, and multiple associations, and more recently linkage, has been detected. Other genes involved in innate and acquired immunity also map to near the HLA cluster on 6p, and it is possible that variation within these genes also confers risk for developing JRA. We examined the TPSN gene, which encodes tapasin, an endoplasmic reticulum chaperone that is involved in antigen processing, to elucidate its involvement, if any, in JRA. We employed both a case-control approach and the transmission disequilibrium test, and found linkage and association between the TPSN allele (Arg260) and the systemic onset subtype of JRA. Two independent JRA cohorts were used, one recruited from the Rheumatology Clinic at Cincinnati Children's Hospital Medical Center (82 simplex families) and one collected by the British Paediatric Rheumatology Group in London, England (74 simplex families). The transmission disequilibrium test for these cohorts combined was statistically significant (chi(2) = 4.2, one degree of freedom; P = 0.04). Linkage disequilibrium testing between the HLA alleles that are known to be associated with systemic onset JRA did not reveal linkage disequilibrium with the Arg260 allele, either in the Cincinnati systemic onset JRA cohort or in 113 Caucasian healthy individuals. These results suggest that there is a weak association between systemic onset JRA and the TPSN polymorphism, possibly due to linkage disequilibrium with an as yet unknown susceptibility allele in the centromeric part of chromosome 6

Multiple Myeloma Manifesting as a Fluctuating Sixth Nerve Palsy

We report a case of multiple myeloma that presented as a fluctuating sixth cranial nerve palsy in the absence of widespread signs of systemic disease. A 63-year-old woman presented with horizontal diplopia of two weeks duration that subjectively changed over time. Ocular examination showed a fluctuating sixth nerve palsy. A computed tomography (CT) scan of the brain showed multiple, enhancing, soft tissue, mass-like lesions involving the left cavernous sinus and the apex of both petrous bones. Based on bone marrow biopsy and hematologic findings, she was diagnosed with multiple myeloma. Multiple myeloma may be included in the differential diagnosis of a fluctuating sixth nerve palsy, and although ophthalmic signs are rare and generally occur late in the course of multiple myeloma, they can still be its first signs

Abdominal functional electrical stimulation to improve respiratory function after spinal cord injury: a systematic review and meta-analysis

Objectives: Abdominal functional electrical stimulation (abdominal FES) is the application of a train of electrical pulses to the abdominal muscles, causing them to contract. Abdominal FES has been used as a neuroprosthesis to acutely augment respiratory function and as a rehabilitation tool to achieve a chronic increase in respiratory function after abdominal FES training, primarily focusing on patients with spinal cord injury (SCI). This study aimed to review the evidence surrounding the use of abdominal FES to improve respiratory function in both an acute and chronic manner after SCI. Settings: A systematic search was performed on PubMed, with studies included if they applied abdominal FES to improve respiratory function in patients with SCI. Methods: Fourteen studies met the inclusion criteria (10 acute and 4 chronic). Low participant numbers and heterogeneity across studies reduced the power of the meta-analysis. Despite this, abdominal FES was found to cause a significant acute improvement in cough peak flow, whereas forced exhaled volume in 1 s approached significance. A significant chronic increase in unassisted vital capacity, forced vital capacity and peak expiratory flow was found after abdominal FES training compared with baseline. Conclusions: This systematic review suggests that abdominal FES is an effective technique for improving respiratory function in both an acute and chronic manner after SCI. However, further randomised controlled trials, with larger participant numbers and standardised protocols, are needed to fully establish the clinical efficacy of this technique

Prevalence and factors associated with rotavirus infection among children admitted with acute diarrhea in Uganda

<p>Abstract</p> <p>Background</p> <p>Rotavirus remains the commonest cause of severe dehydrating diarrhea among children worldwide. Children in developing countries die more because of several factors including poorer access to hydration therapy and greater prevalence of malnutrition. Hitherto, the magnitude of rotavirus disease in Uganda has remained unknown. This study was therefore done to determine the prevalence and factors associated with rotavirus infection among children aged 3-59 months admitted with acute diarrhea to paediatric emergency ward of Mulago Hospital, Uganda</p> <p>Methods</p> <p>Three hundred and ninety children, aged between 3-59 months with acute diarrhoea were recruited. The clinical history, socio-demographic characteristics, physical examination findings and laboratory investigations were recorded. Stool samples were tested for rotavirus antigens using the DAKO IDEIA rotavirus EIA detection kit.</p> <p>Results</p> <p>The prevalence of rotavirus infection was 45.4%. On multivariate analysis rotavirus was significantly associated with a higher education (above secondary) level of the mother [OR 1.8; 95% CI 1.1-2.7]; dehydration [OR 1.8; 95% CI 1.1-3.0] and breastfeeding [OR 2.6; 95% CI 1.4-4.0]. Although age was significantly associated with rotavirus on bivariate analysis; this association disappeared on multivariate analysis. No significant association was found between rotavirus infection and nutritional status, HIV status and attendance of day care or school.</p> <p>Conclusions</p> <p>Rotavirus infection is highly prevalent among children with acute diarrhoea admitted to Mulago Hospital in Uganda.</p

A Study of the Δ−\Delta^--component of the wave-function in light nuclei

We have measured cross sections for the $(\pi^+,\pi^\pm p)$ reactions on ${\rm ^3H}$, ${\rm ^4He}$, ${\rm ^6Li}$ and ${\rm ^7Li}$ in quasi-free kinematics at incident pion beam energy 500 MeV. An enhancement of the $(\pi^+,\pi^- p)$ cross section in this kinematics is observed. If this is interpreted as due to quasi-free scattering from pre-existing $\Delta$ components of the nuclear wave function, the extracted probabilities are in agreement with theoretical expectations.Comment: 3 pages, 3 figures, 1 tabl

STAT3 Activation in Skeletal Muscle Links Muscle Wasting and the Acute Phase Response in Cancer Cachexia

Cachexia, or weight loss despite adequate nutrition, significantly impairs quality of life and response to therapy in cancer patients. In cancer patients, skeletal muscle wasting, weight loss and mortality are all positively associated with increased serum cytokines, particularly Interleukin-6 (IL-6), and the presence of the acute phase response. Acute phase proteins, including fibrinogen and serum amyloid A (SAA) are synthesized by hepatocytes in response to IL-6 as part of the innate immune response. To gain insight into the relationships among these observations, we studied mice with moderate and severe Colon-26 (C26)-carcinoma cachexia.Moderate and severe C26 cachexia was associated with high serum IL-6 and IL-6 family cytokines and highly similar patterns of skeletal muscle gene expression. The top canonical pathways up-regulated in both were the complement/coagulation cascade, proteasome, MAPK signaling, and the IL-6 and STAT3 pathways. Cachexia was associated with increased muscle pY705-STAT3 and increased STAT3 localization in myonuclei. STAT3 target genes, including SOCS3 mRNA and acute phase response proteins, were highly induced in cachectic muscle. IL-6 treatment and STAT3 activation both also induced fibrinogen in cultured C2C12 myotubes. Quantitation of muscle versus liver fibrinogen and SAA protein levels indicates that muscle contributes a large fraction of serum acute phase proteins in cancer.These results suggest that the STAT3 transcriptome is a major mechanism for wasting in cancer. Through IL-6/STAT3 activation, skeletal muscle is induced to synthesize acute phase proteins, thus establishing a molecular link between the observations of high IL-6, increased acute phase response proteins and muscle wasting in cancer. These results suggest a mechanism by which STAT3 might causally influence muscle wasting by altering the profile of genes expressed and translated in muscle such that amino acids liberated by increased proteolysis in cachexia are synthesized into acute phase proteins and exported into the blood

Effect of ketamine pretreatment for anaesthesia in patients undergoing percutaneous transluminal balloon angioplasty with continuous remifentanil infusion

BACKGROUND: An appropriate level of sedation and pharmacological assist are essential during percutaneous transluminal balloon angioplasty (PTA). Ketamine provides good analgesia while preserving airway patency, ventilation, and cardiovascular stability with an opioid sparing effect suggesting that it would be ideal in combination with remifentanil and midazolam in spontaneously breathing patients. We evaluated the effect of a small dose of ketamine added to midazolam and remifentanil on analgesia/sedation for PTA procedures. METHODS: Sixty-four patients receiving PTA were enrolled. The Control group received midazolam 1.0 mg i.v. and continuous infusion of remifentanil 0.05 µg/kg/min. The Ketamine group received, in addition, an intravenous bolus of 0.5 mg/kg ketamine. Patients' haemodynamic data were monitored before remifentanil infusion, 5 min after remifentanil infusion, at 1, 3, 5, 30 min after incision, and at admission to the recovery room. Verbal numerical rating scales (VNRS) and sedation [OAA/S (Observer's Assessment of Alertness/Sedation)] scores were also recorded. RESULTS: The VNRS values at 1, 3, and 5 min after incision and OAA/S scores at 5 min after remifentanil infusion, and 1, 3, and 5 min after incision were lower in the Ketamine group than in the Control group. In the Control group, the VNRS value at 1 min after incision significantly increased and OAA/S values at 3, 5, and 30 min after incision significantly decreased compared to baseline values, while there were no significant changes in the ketamine group. CONCLUSIONS: A small dose of ketamine as an adjunct sedative to the combination of midazolam and remifentanil produced a better quality of sedation and analgesia than without ketamine and provided stable respiration without cardiopulmonary deterioration.ope

Recent trends in breast cancer incidence in US white women by county-level urban/rural and poverty status

<p>Abstract</p> <p>Background</p> <p>Unprecedented declines in invasive breast cancer rates occurred in the United States between 2001 and 2004, particularly for estrogen receptor-positive tumors among non-Hispanic white women over 50 years. To understand the broader public health import of these reductions among previously unstudied populations, we utilized the largest available US cancer registry resource to describe age-adjusted invasive and <it>in situ </it>breast cancer incidence trends for non-Hispanic white women aged 50 to 74 years overall and by county-level rural/urban and poverty status.</p> <p>Methods</p> <p>We obtained invasive and <it>in situ </it>breast cancer incidence data for the years 1997 to 2004 from 29 population-based cancer registries participating in the North American Association of Central Cancer Registries resource. Annual age-adjusted rates were examined overall and by rural/urban and poverty of patients' counties of residence at diagnosis. Joinpoint regression was used to assess trends by annual quarter of diagnosis.</p> <p>Results</p> <p>Between 2001 and 2004, overall invasive breast cancer incidence fell 13.2%, with greater reductions among women living in urban (-13.8%) versus rural (-7.5%) and low- (-13.0%) or middle- (-13.8%) versus high- (-9.6%) poverty counties. Most incidence rates peaked around 1999 then declined after second quarter 2002, although in rural counties, rates decreased monotonically after 1999. Similar but more attenuated patterns were seen for <it>in situ </it>cancers.</p> <p>Conclusion</p> <p>Breast cancer rates fell more substantially in urban and low-poverty, affluent counties than in rural or high-poverty counties. These patterns likely reflect a major influence of reductions in hormone therapy use after July 2002 but cannot exclude possible effects due to screening patterns, particularly among rural populations where hormone therapy use was probably less prevalent.</p

Rituximab retherapy in patients with relapsed aggressive B cell and mantle cell lymphoma

Neither effective salvage regimens nor the outcome and response to retherapy with rituximab containing chemotherapy have been defined for rituximab pre-treated patients with relapsing aggressive lymphoma. We report here a single-centre retrospective outcome analysis of second-line immunochemotherapy with rituximab. In 28 patients with relapsed or refractory diffuse large B cell lymphomas, first-line immunochemotherapy had induced objective responses in 18 patients. Nine of 28 patients responded to rituximab containing salvage therapy, leading to a median overall survival of 243 days after start of second immunochemotherapy. Long-term disease free survivors (1,260 and 949 days) were restricted to the group of twelve patients that had received allogeneic stem cell transplantation as consolidation therapy. In 21 patients with relapsed mantle cell lymphomas (MCL), 19 patients had reached remissions with first-line therapy. Of those, 16 patients experienced responses to salvage therapy with a median overall survival of 226 days. Noteworthy, none of patients with initial non-responding disease reached a remission with second immunochemotherapy. Seven patients with MCL stayed free from progression after high-dose therapy with autologous or allogeneic stem cell transplantation in two and five cases, respectively. In summary, responses to repeated immunotherapy with rituximab were observed in approximately one third and two thirds of initially responding patients with aggressive B cell lymphoma and mantle cell lymphoma, respectively, but not in primarily refractory disease. Lasting remissions were achieved only by high-dose chemotherapy with stem cell transplantation

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse