Transnasal sphenopalatine ganglion block for post-dural puncture headache and associated tinnitus.

Lumbar epidurals are frequently inserted for women in labour as they provide excellent analgesia. One of the more common procedural complications is post-dural puncture headache which can be associated with auditory symptoms such as hearing loss and tinnitus and can be treated with an epidural blood patch. Sphenopalatine ganglion blocks have also been used to treat post-dural puncture headache but have not been previously shown to resolve the associated tinnitus. We report a case where postural neck pain and tinnitus from an accidental dural puncture during lumbar epidural insertion for labour analgesia was treated successfully with a sphenopalatine ganglion block. Further, we explore the literature on the cause of tinnitus in post-dural puncture headache and the possible mechanism by which a sphenopalatine ganglion block relieves both post-dural puncture headache and the associated tinnitus.

Effectiveness of a Tailored Work-Related Support Intervention for Patients Diagnosed with Gastrointestinal Cancer: A Multicenter Randomized Controlled Trial.

Purpose The aim of this research was to study the effectiveness on return to work (RTW) of an early tailored work-related support intervention in patients diagnosed with curative gastrointestinal cancer. Methods A multicenter randomized controlled trial was undertaken, in which patients were assigned randomly to the intervention or the control group (usual care). The intervention encompassed three psychosocial work-related support meetings, starting before treatment. Five self-reported questionnaires were sent over twelve months of follow-up. Primary outcome was days until RTW (fulltime or partial) and secondary outcomes included work status, quality of life, work ability, and work limitations. Descriptive analysis, Kaplan-Meier analysis, relative risk ratio and linear mixed models were applied. Results Participants (N = 88) had a mean age of 55 years; 67% were male and the most common cancer type was colon cancer (66%). Of the participants, 42 were randomized to the intervention group. The median time from sick leave until RTW was 233 days (range 187-279 days) for the control group, versus 190 days (range 139-240 days) for the intervention group (log-rank p = 0.37). The RTW rate at twelve months after baseline was 83.3% for the intervention group and 73.5% for the control group. Work limitations did statistically differ between the groups over time (p = 0.01), but quality of life and work ability did not. Conclusion Patients in the intervention group seem to take fewer days to RTW, albeit not to a statistically significant extent.Trial registration Trial NL4920 (NTR5022) (Dutch Trial Register https://www.trialregister.nl ).

Low-dose corticosteroid and mycophenolate for primary treatment of minimal change disease.

BACKGROUND: Mycophenolate has been shown to be effective in glomerular disease. However, the role of mycophenolate in the first-line treatment of adult-onset idiopathic minimal change disease (MCD) has not been systematically studied in a randomized fashion. AIM: To evaluate the therapeutic efficacy of enteric-coated mycophenolate sodium combined with low-dose corticosteroid as first-line treatment for MCNS. DESIGN: A prospective, open-label, randomized clinical trial. METHODS: Twenty adult patients with biopsy proven MCD were recruited and randomly assigned to receive either enteric-coated Mycophenolate Sodium (EC-MPS) plus low-dose prednisolone (Group 1: Prednisolone 0.25 mg/kg/day, n = 10) or standard-dose prednisolone (Group 2: Prednisolone 1 mg/kg/day, n = 10). RESULTS: After 24 weeks of therapy, eight patients in Group 1 vs. seven of patients in Group 2 achieved complete remission (P = 0.606). Both groups showed a significant reduction of urine protein excretion (P < 0.05) and increased serum albumin (P < 0.001) vs. baseline levels. However, no significant between-group differences were demonstrated. The relapse rate was also similar in both groups. Both treatment regimens were well tolerated but there were more patient reported adverse effects in the standard-dose prednisolone group. CONCLUSION: EC-MPS plus low-dose prednisolone is non-inferior to standard-dose prednisolone therapy in inducing clinical remission and preventing relapse in adult-onset idiopathic MCD and is associated with better tolerability and less adverse effects. This trial is registered with the ClinicalTrials.gov number NCT01185197.

Conserved, unstructured regions in Pseudomonas aeruginosa PilO are important for type IVa pilus function.

Pseudomonas aeruginosa uses long, thin fibres called type IV pili (T4P) for adherence to surfaces, biofilm formation, and twitching motility. A conserved subcomplex of PilMNOP is required for extension and retraction of T4P. To better understand its function, we attempted to co-crystallize the soluble periplasmic portions of PilNOP, using reductive surface methylation to promote crystal formation. Only PilOΔ109 crystallized; its structure was determined to 1.7 Å resolution using molecular replacement. This new structure revealed two novel features: a shorter N-terminal α1-helix followed by a longer unstructured loop, and a discontinuous ß-strand in the second αßß motif, mirroring that in the first motif. PISA analysis identified a potential dimer interface with striking similarity to that of the PilO homolog EpsM from the Vibrio cholerae type II secretion system. We identified highly conserved residues within predicted unstructured regions in PilO proteins from various Pseudomonads and performed site-directed mutagenesis to assess their role in T4P function. R169D and I170A substitutions decreased surface piliation and twitching motility without disrupting PilO homodimer formation. These residues could form important protein-protein interactions with PilN or PilP. This work furthers our understanding of residues critical for T4aP function.

Evaluation of P16 expression in canine appendicular osteosarcoma.

BACKGROUND: Osteosarcoma (OSA) is a common malignant bone tumor of large breed dogs that occurs at predictable anatomic sites. At the time of initial diagnosis, most affected dogs have occult pulmonary metastases. Even with aggressive surgical treatment combined with chemotherapy, the majority of dogs diagnosed with OSA live less than 1 year from the time of diagnosis. The ability to identify canine OSA cases most responsive to treatment is needed. In humans, OSA is also an aggressive tumor that is histologically and molecularly similar to canine OSA. The expression of the tumor suppressor gene product P16 by human OSA tissue has been linked to a favorable response to chemotherapy. RESULTS: We identified an antibody that binds canine P16 and developed a canine OSA tissue microarray in order to test the hypothesis that P16 expression by canine OSA tissue is predictive of clinical outcome following amputation and chemotherapy. Although statistical significance was not reached, a trend was identified between the lack of canine OSA P16 expression and a shorter disease free interval. CONCLUSIONS: The identification of a molecular marker for canine OSA is an important goal and the results reported here justify a larger study.

The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist, counteracts hepatocarcinogenesis through cAMP-PKA-EGFR-STAT3 axis.

Epidemiological studies have demonstrated a close association of type 2 diabetes and hepatocellular carcinoma (HCC). Exenatide (Ex-4), a potent diabetes drug targeting glucagon-like peptide-1 receptor (GLP-1R), is protective against non-alcoholic fatty liver disease (NAFLD). However, the Ex-4 function and GLP-1R status have yet been explored in HCC. Herein we investigated the effect of Ex-4 in diethylnitrosamine (DEN)-treated mice consuming control or high-fat high-carbohydrate diet. Administration of Ex-4 significantly improved obesity-induced hyperglycemia and hyperlipidemia and reduced HCC multiplicity in obese DEN-treated mice, in which suppressed proliferation and induced apoptosis were confined to tumor cells. The tumor suppression effects of Ex-4 were associated with high expression of GLP-1R and activation of cyclic AMP (cAMP) and protein kinase A (PKA). Importantly, Ex-4 also downregulated epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3), which lie downstream of cAMP-PKA signaling, resulting in suppression of multiple STAT3-targeted genes including c-Myc, cyclin D1, survivin, Bcl-2 and Bcl-xl. The growth inhibitory effects of Ex-4 were consistent in GLP-1R-abundant hepatoma cell lines and xenograft mouse model, wherein both PKA and EGFR had obligatory roles in mediating Ex-4 functions. In addition, Ex-4 also effectively suppressed inflammatory and fibrotic phenotypes in mice fed with methionine-choline-deficient (MCD) diet and choline-deficient ethionine-supplemented (CDE) diet, respectively. In summary, Ex-4 elicits protective functions against NAFLD and obesity-associated HCC through cAMP-PKA-EGFR-STAT3 signaling, suggesting its administration as a novel approach to reduce HCC risk in diabetic patients.

Structural Brain Network Reorganization in Patients with Neuropsychiatric Systemic Lupus Erythematosus.

BACKGROUND AND PURPOSE: Patients with neuropsychiatric systemic lupus erythematosus have worse outcomes compared with those with systemic lupus erythematosus. A better understanding of the mechanisms of neuropsychiatric systemic lupus erythematosus could potentially improve diagnosis and management. The goal of this study was to investigate the differences in the structural brain network of patients with neuropsychiatric systemic lupus erythematosus compared with patients with systemic lupus erythematosus by using brain connectivity analysis. MATERIALS AND METHODS: We recruited 20 subjects for each patient cohort and age-matched healthy controls. The topology and efficiency of the network and the characteristics of various brain hubs were investigated by using brain connectivity analysis of diffusion MR imaging data. RESULTS: There were more extensive reorganizations in the structural brain network of patients with neuropsychiatric systemic lupus erythematosus than in patients with systemic lupus erythematosus. For example, the network of the former had significantly decreased clustering coefficient and local efficiency. They also had significantly lower nodal efficiency in the superior temporal gyrus (P = .046) and middle temporal gyrus (P = .041). CONCLUSIONS: Our results hint at a plausible relationship between the neuropsychiatric symptoms and reorganization of the structural brain network of patients with systemic lupus erythematosus. Brain connectivity analysis may be a potential tool to subtype these patients.

Pharmacological characterization of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2, 3-dihydro-1H-inden-2-yl]-2-propanesulfonamide: a novel, clinical AMPA receptor positive allosteric modulator.

BACKGROUND AND PURPOSE: AMPA receptor positive allosteric modulators represent a potential therapeutic strategy to improve cognition in people with schizophrenia. These studies collectively constitute the preclinical pharmacology data package used to build confidence in the pharmacology of this molecule and enable a clinical trial application. EXPERIMENTAL APPROACH: [N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro 1H-inden-2-yl]-2-propanesulfonamide] (UoS12258) was profiled in a number of in vitro and in vivo studies to highlight its suitability as a novel therapeutic agent. KEY RESULTS: We demonstrated that UoS12258 is a selective, positive allosteric modulator of the AMPA receptor. At rat native hetero-oligomeric AMPA receptors, UoS12258 displayed a minimum effective concentration of approximately 10 nM in vitro and enhanced AMPA receptor-mediated synaptic transmission at an estimated free brain concentration of approximately 15 nM in vivo. UoS12258 reversed a delay-induced deficit in novel object recognition in rats after both acute and sub-chronic dosing. Sub-chronic dosing reduced the minimum effective dose from 0.3 to 0.03 mg·kg-1 . UoS12258 was also effective at improving performance in two other cognition models, passive avoidance in scopolamine-impaired rats and water maze learning and retention in aged rats. In side-effect profiling studies, UoS12258 did not produce significant changes in the maximal electroshock threshold test at doses below 10 mg·kg-1 . CONCLUSION AND IMPLICATIONS: We conclude that UoS12258 is a potent and selective AMPA receptor modulator exhibiting cognition enhancing properties in several rat behavioural models superior to other molecules that have previously entered clinical evaluation.

Epigenetic silencing of GDF1 disrupts SMAD signaling to reinforce gastric cancer development.

Accumulating evidence reveals the effectiveness of epigenetic therapy in gastric cancer. However, the molecular mechanisms and targets underlying such therapeutic responses remain elusive. Herein, we report an aberrant yet therapeutically rectifiable epigenetic signaling in gastric carcinogenesis. Administration of DNA-demethylating drug 5-aza-2'-deoxycytidine (5-aza-dC) reduced gastric cancer incidence by ~74% (P < 0.05) in N-nitroso-N-methylurea-treated mice. Through genome-wide methylation scanning, novel promoter hypermethylation-silenced and drug-targeted genes were identified in the resected murine stomach tumors and tissues. We uncovered that growth/differentiation factor 1 (Gdf1), a member of the transforming growth factor-ß superfamily, was silenced by promoter hypermethylation in control tumor-bearing mice, but became reactivated in 5-aza-dC-treated mice (P < 0.05). In parallel, the downregulated SMAD2/3 phosphorylation in gastric cancer was revived by 5-aza-dC in vivo. Such hypermethylation-dependent silencing and 5-aza-dC-mediated reactivation of GDF1-SMAD2/3 activity was conserved in human gastric cancer cells (P < 0.05). Subsequent functional characterization further revealed the antiproliferative activity of GDF1, which was exerted through activation of SMAD2/3/4-mediated signaling, transcriptional controls on p15, p21 and c-Myc cell-cycle regulators and phosphorylation of retinoblastoma protein. Clinically, hypermethylation and loss of GDF1 was significantly associated with reduced phosphorylated-SMAD2/3 and poor survival in stomach cancer patients (P < 0.05). Taken together, we demonstrated a causal relationship between DNA methylation and a tumor-suppressive pathway in gastric cancer. Epigenetic silencing of GDF1 abrogates the growth-inhibitory SMAD signaling and renders proliferation advantage to gastric epithelial cells during carcinogenesis. This study lends support to epigenetic therapy for gastric cancer chemoprevention and identifies a potential biomarker for prognosis.

Systemic lupus erythematosus patients with past neuropsychiatric involvement are associated with worse cognitive impairment: a longitudinal study.

Longitudinal studies on cognitive impairment in patients with past history of neuropsychiatric lupus (NPSLE) are scant. In this study, NPSLE patients and matched disease and healthy controls were examined with a full battery of neuropsychological tests that covered eight cognitive domains at two time-points 12 months apart. Confounders, including depressive and anxiety symptoms, were measured by the Hospital Anxiety and Depression Scale. Eighteen NPSLE, 18 patients with systemic lupus erythematosus (SLE) who had no previous cerebral involvement (non-NPSLE) and 16 healthy subjects were recruited. NPSLE patients consistently reported more cognitive and anxiety symptoms than non-NPSLE patients over both time-points. NPSLE patients had significantly worse memory, simple and complex attention compared to non-NPSLE patients, among which memory remained significantly impaired after adjustment for confounders. NPSLE patients demonstrated a trend of higher raw scores of some neurocognitive tests upon re-evaluation over 12 months, but NPSLE patients did not demonstrate any practice effect. In conclusion, NPSLE patients had significantly worse and persistently impaired memory and learning deficits compared to non-NPSLE patients over the 12-month re-assessment period.

Symptoms of attention deficit hyperactivity disorder in patients with systemic lupus erythematosus.

OBJECTIVES: Cognitive function and mood disturbance are common in patients with systemic lupus erythematosus (SLE). This study aims to examine whether SLE patients have more features of adult attention deficit hyperactivity disorder (ADHD) and their relation to anxiety and depressive symptoms. METHODS: Symptoms and clinically significant items of the inattention and hyperactivity/impulsivity domains of ADHD were examined in Part A and Part B by the screening instrument of the ADHD Self-Reported Scale (ASRS), respectively. Anxiety and depressive symptoms were measured by HADS-A and HADS-D, respectively. RESULTS: There were no differences in symptom scores of inattention and hyperactivity/impulsivity between inactive SLE patients (n = 117) and age- and sex-matched controls (n = 64). However, SLE patients had more clinically significant items in the inattention domain compared with controls (p = 0.006), particularly among those who had previous cerebral involvement (p = 0.004). Patients who had psychiatric diseases had more clinically significant items in the hyperactivity/impulsivity domain (p = 0.006). Possible ADHD was found in 7.7% of SLE and 6.3% of healthy individuals (p = 1.00) by the screening tool. Patients with higher inattention symptom scores were more likely to be unemployed but not for duration of education and smoking habit. Anxiety and depressive symptoms correlated with ADHD symptoms. HADS-A was an independent predictive factor for clinically significant symptoms of inattention (p < 0.001) and hyperactivity/impulsivity (p = 0.04) by logistic regression. CONCLUSION: Inactive SLE patients, particularly those who had previous cerebral lupus, had more clinically significant symptoms of inattention but not hyperactivity/impulsivity reflecting underlying cognitive impairment. Anxiety and depressive symptoms were common confounders for ADHD-like symptoms.

Serum immunoglobulin G level in patients with lupus nephritis and the effect of treatment with corticosteroids and mycophenolate mofetil.

BACKGROUND: Reduced serum IgG level is associated with increased risk of infection. We investigated the circulating IgG level and its determining factors in active lupus nephritis patients treated with corticosteroids and mycophenolate mofetil (MMF). METHODS: This was a retrospective study on the longitudinal IgG profile in Class III/IV ± V lupus nephritis patients treated with prednisolone and MMF. RESULTS: 46 patients were included. At baseline, 34 (73.9%) patients (Group I) had normal or elevated IgG (1444.0 ± 600.5 mg/dL) while 12 (26.1%) (Group II) had IgG levels (567.8 ± 160.9 mg/dL) below the lower limit of normal. IgG levels at baseline, three, six and 12 months after treatment were 1215.4 ± 649.7 mg/dL, 843.9 ± 347.6 mg/dL, 914.5 ± 362.4 mg/dL and 1034.6 ± 452.5 mg/dL respectively. Treatment with prednisolone and MMF led to a significant drop in IgG after two weeks, reaching a nadir at eight weeks, followed by gradual normalization. Similar changes in IgG were observed in Group I patients but there was non-significant change in Group II within the first 24 weeks. Eighteen (39.1%) patients had low IgG by six months, and only one patient had IgG <300 mg/dL, at both three and six months. IgG level was negatively associated with proteinuria at six months (r = -0.711, p = 0.010). Five of 18 patients with low IgG had infections within the first year, while IgG levels below the lower limit of normal did not increase infection risk (relative risk 1.863; 95% confidence interval 0.466 to 6.818, p = 0.280). CONCLUSION: Reduced IgG occurred in 26% of active lupus nephritis patients and the IgG levels are significantly influenced by the severity of proteinuria. Treatment with prednisolone and MMF does not result in clinically important suppression of IgG.

Sunitinib-induced hyperammonaemia in a patient with pancreatic neuroendocrine tumour.

WHAT IS KNOWN AND OBJECTIVE: Sunitinib can improve progression-free survival and overall survival in patients with advanced pancreatic neuroendocrine tumor (PNET). From clinical trial, most commonly reported adverse events of sunitinib were neutropenia (12%), diarrhea (10%), asthenia (7%), erythrodysesthesia (7%), hypertension (7%) and thrombocytopenia (6%). CASE SUMMARY: We report a patient with PNET with liver metastases who developed hyperammonemia with a low dosage of sunitinib probably contributed by the presence of liver metastases. WHAT IS NEW AND CONCLUSIONS: We would like to draw attention to the potential risk of sunitinib induced hyperammonemic encephalopathy even with a low dosage of sunitinib. The absence of sunitinib-induced hyperammonemia during its initial course does not rule out this possibility if there is increased in liver metastases. We suggest checking the ammonia level if patient on sunitinib presented with altered sensorium even if the liver function is normal.

microRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis.

Using microRNA (miRNA) expression array, we identified that miR-7 was deregulated in colorectal cancer (CRC). We studied the biological role and molecular target of miR-7 in CRC. miR-7 was downregulated in six out of seven colon cancer cell lines. Ectopic expression of miR-7 suppressed colon cancer cell proliferation (P<0.05), induced apoptosis (P<0.05) and caused cell-cycle arrest in G1 phase (P<0.05). The tumor suppressive function of miR-7 was further confirmed in nude mice (P<0.05). The 3'-untranslated region (3'UTR) of Yin Yang 1 (YY1) mRNA contains an evolutionarily conserved miR-7 binding site using in silico searches, luciferase reporter assay and western blot analysis confirmed that miR-7 directly bound to YY1 3'UTR to negatively regulate the protein expression of YY1 in colon cancer cell lines HCT116 and LOVO. Intriguingly, knock-down of YY1 in three colon cancer cell lines (HCT116, LOVO and DLD1) consistently suppressed cell proliferation (P<0.01) and induced apoptosis (P<0.01), indicating the opposite functions of miR-7 and YY1 in CRC. Consistent with these data, ectopic expression of YY1 promoted cell growth by increasing proliferation (P<0.01) and suppressing apoptosis (P<0.001). The tumorigenic ability of YY1 was further confirmed in vivo in xenograft-nude mouse model (P<0.01). In addition, pathway analyses revealed that the oncogenic effect by YY1 was associated with inhibiting p53 and modulating its downstream effectors p15, caspase cascades and C-Jun, and activating Wnt signaling pathway through activating ß-catenin, anti-apoptotic survivin and fibroblast growth factor 4. Furthermore, multivariate analysis revealed that patients with YY1 protein high expression had a significant decrease in overall survival, and Kaplan-Meier survival curves showed that these patients had significantly shorter survival than others (P<0.0001). In conclusion, MiR-7 is a novel miRNA with tumor suppressive function in colon cancer by targeting oncogenic YY1. YY1 promotes colon cancer growth through inhibiting p53 and promoting Wnt signaling pathways and serves as an independent prognostic biomarker for CRC patients.

Heterologous expression and structural characterisation of a pyrazinone natural product assembly line.

Through a number of strategies nonribosomal peptide assembly lines give rise to a metabolic diversity not possible by ribosomal synthesis. One distinction within nonribosomal assembly is that products are elaborated on an enzyme-tethered substrate, and their release is enzyme catalysed. Reductive release by NAD(P)H-dependent catalysts is one observed nonribosomal termination and release strategy. Here we probed the selectivity of a terminal reductase domain by using a full-length heterologously expressed nonribosomal peptide synthetase for the dipeptide aureusimine and were able to generate 17 new analogues. Further, we generated an X-ray structure of aureusimine terminal reductase to gain insight into the structural details associated with this enzymatic domain.

Lentiviral latency in peripheral CD4+ T cells isolated from feline immunodeficiency virus-infected cats during the asymptomatic phase is not associated with hypermethylation of the proviral promoter.

Lentiviral latency remains a principal obstacle to curative AIDS therapy. Transcriptional repression and latency permits lentiviruses to evade host immune responses and antiretroviral drugs. We have established a model of peripheral CD4+ T cell lentiviral latency in cats experimentally infected with feline immunodeficiency virus (FIV). Multiple mechanisms of lentiviral transcriptional repression have been proposed including epigenetic mechanisms resulting in promoter hypermethylation and/or chromatin condensation. Methylation of promoter-associated cytosines in the cytosine-guanine dinucleotide (CpG) has been associated with transcriptional repression in both eukaryotic promoters and integrated retroviral genomes. Using methylcytosine mapping, we examined the CpG methylation patterns in both the 5' and 3' long terminal repeats (LTR) of the FIV provirus in peripheral blood mononuclear cells, monocytes and CD4+ T cells isolated during the acute and asymptomatic phases of infection. Here we report no evidence that proviral promoter hypermethylation is associated with lentiviral latency in peripheral CD4+ T cells and monocytes obtained from experimentally FIV-infected cats.

Prognostic role of coronary calcification in patients with rheumatoid arthritis and systemic lupus erythematosus.

OBJECTIVES: To study the predictive value of coronary calcification score (CCS) for future cardiovascular (CVS) events as detected by multi-detector computed tomography (MDCT) in patients with rheumatoid arthritis(RA) and systemic lupus erythematosus (SLE). METHODS: A total of 152 patients with RA and SLE, and 106 healthy controls underwent MDCT to measure CCS. All patients were prospectively followed up for major CVS events. RESULTS: Compared with controls, patients with RA and SLE had a significantly higher mean CCS (42.2±154.3 vs. 1.4±13.0, p<0.01) and prevalence of CCS 1-10, CCS 11-100 and CCS>100 (all p<0.05). After a mean period of 4.3±0.6 years, major CVS events occurred in 10 patients with RA and SLE. In patients with RA and SLE, a higher major CVS events rate occurred in patients with CCS 1-10 (5.0%), CCS 11-100 (14.3%) and CCS >100 (40.0%) than those with CCS=0 (1.0%, p<0.01). Multivariate Cox regression analysis revealed that hypercholesterolemia (hazard ratio (HR) 11.2, confidence interval (CI 1.4-89.3, p=0.02) and CCS>100 (HR 11.1, CI 1.31-95.0, p=0.03) were independent predictors of combined events. CONCLUSIONS: Coronary calcification detected by MDCT independently predicts CVS events in patients with RA and SLE. Risk stratification by assessment of CCS may have an important role in patients with systemic inflammatory disease.

Association of CD247 with systemic lupus erythematosus in Asian populations.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. METHODS: In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. RESULTS: The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10(-7); rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production. CONCLUSION: A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.

Evaluation of performance of measurement of faecal α(1)-antitrypsin clearance and technetium-99m human serum albumin scintigraphy in protein-losing enteropathy.

BACKGROUND AND AIM: Our study aimed to compare the performance of faecal α(1)-antitrypsin clearance (AATC) and radiolabelled human serum albumin (HSA) scintigraphy in protein-losing enteropathy (PLE). METHODS: Patients studied by both AATC and technetium-99m ((99m)Tc)-labelled HSA scintigraphy were recruited and categorized into PLE and non-PLE groups based on clinical and laboratory findings. The performance of AATC and (99m)Tc-labelled HSA scintigraphy was evaluated using clinical diagnosis of PLE as a gold standard. RESULTS: 29 patients were recruited and 13 patients were considered to have definite PLE (PLE group). In the PLE group, all patients had a positive HSA scinigraphy and 10 (77%) had demonstrable positive tracing in the early phase. Conversely, only 6 of them (46%) had elevated AATC level (>13 m/day). Results of (99m)Tc-labelled HSA scan (but not AATC) showed significant agreement with the clinical diagnosis (κ 0.35, p = 0.013). (99m)Tc-labelled HSA scintigraphy carried higher sensitivity (100 vs. 46%) and negative predictive value (100 vs. 63%) compared to AATC in diagnosing PLE. The correlation between the results of these two investigations was only modest (κ 0.27, p = 0.04). The area under the receiver operating characteristic curve of AATC level showed no optimal diagnostic cut-off for PLE. CONCLUSION: (99m)Tc-labelled HSA scintigraphy was superior to AATC in diagnosing PLE.

In vitro and in vivo characterization of the novel GABAB receptor positive allosteric modulator, 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (CMPPE).

There is preclinical evidence supporting the finding that the GABA(B) receptor orthosteric agonist, baclofen, has significant effects on eating behavior suggesting the potential therapeutic application of this compound for the treatment of eating related disorders. However, the wide clinical use of baclofen might be limited by the appearance of sedative and motor impairment effects. The identification of positive allosteric modulators (PAMs) of GABA(B) receptors represents a novel therapeutic approach to reduce the centrally-mediated adverse effects typical of the GABA(B) receptor orthosteric agonist. In the present work, we report the in vitro profile of a novel chemical structure, 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (CMPPE) identified by screening the GSK compound collection. CMPPE potentiates GABA-stimulated [(35)S]GTPγS binding to membranes of human recombinant cell line and of rat brain cortex. GABA concentration-response curves (CRC) in the presence of fixed concentrations of CMPPE, in rat native tissue, revealed an increase of both the potency and maximal efficacy of GABA. A similar modulatory effect was observed in GABA(B) receptor-mediated activation of inwardly rectifying potassium channels in hippocampal neurons. CMPPE (30-100 mg/kg) and GS39783 (100 mg/kg) significantly decreased food consumption in rat without impairment on the animal locomotor activity. On the contrary, baclofen (2.5 mg/kg) decreased both food intake and motor performance. All together these findings confirm the role of GABA(B) system in controlling animal food intake and for the first time demonstrate that GABA(B) receptor PAMs may represent a novel pharmacological approach to treat eating disorders without unwanted sedative effects.