Thermoregulatory pathway underlying the pyrogenic effects of prostaglandin E2 in the lateral parabrachial nucleus of male rats.

It has been shown that prostaglandin (PG) E2 synthesized in the lateral parabrachial nucleus (LPBN) is involved in lipopolysaccharide-induced fever. But the neural mechanisms of how intra-LPBN PGE2 induces fever remain unclear. In this study, we investigated whether the LPBN-preoptic area (POA) pathway, the thermoafferent pathway for feed-forward thermoregulatory responses, mediates fever induced by intra-LPBN PGE2 in male rats. The core temperature (Tcore) was monitored using a temperature radiotelemetry transponder implanted in rat abdomen. We showed that microinjection of PGE2 (0.28 nmol) into the LPBN significantly enhanced the density of c-Fos-positive neurons in the median preoptic area (MnPO). The chemical lesioning of MnPO with ibotenate or selective genetic lesioning or inhibition of the LPBN-MnPO pathway significantly attenuated fever induced by intra-LPBN injection of PGE2. We demonstrated that EP3 receptor was a pivotal receptor for PGE2-induced fever, since microinjection of EP3 receptor agonist sulprostone (0.2 nmol) or EP3 receptor antagonist L-798106 (2 nmol) into the LPBN mimicked or weakened the pyrogenic action of LPBN PGE2, respectively, but this was not the case for EP4 and EP1 receptors. Whole-cell recording from acute LPBN slices revealed that the majority of MnPO-projecting neurons originating from the external lateral (el) and dorsal (d) LPBN were excited and inhibited, respectively, by PGE2 perfusion, initiating heat-gain and heat-loss mechanisms. The amplitude but not the frequency of spontaneous and miniature glutamatergic excitatory postsynaptic currents (sEPSCs and mEPSCs) in MnPO-projecting LPBel neurons increased after perfusion with PGE2; whereas the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) and the A-type potassium (IA) current density did not change. In MnPO-projecting LPBd neurons, neither sEPSCs nor sIPSCs responded to PGE2; however, the IA current density was significantly increased by PGE2 perfusion. These electrophysiological responses and the thermoeffector reactions to intra-LPBN PGE2 injection, including increased brown adipose tissue thermogenesis, shivering, and decreased heat dissipation, were all abolished by L-798106, and mimicked by sulprostone. These results suggest that the pyrogenic effects of intra-LPBN PGE2 are mediated by both the inhibition of the LPBd-POA pathway through the EP3 receptor-mediated activation of IA currents and the activation of the LPBel-POA pathway through the selective enhancement of glutamatergic synaptic transmission via EP3 receptors.

[A case of duodenal ulcer as prominent manifestation of IgG4-related disease].

A case of IgG4-related disease presented with a duodenal ulcer to improve the understan-ding of IgG4-related diseases was reported. A 70-year-old male presented with cutaneous pruritus and abdominal pain for four years and blackened stools for two months. Four years ago, the patient went to hospital for cutaneous pruritus and abdominal pain. Serum IgG4 was 3.09 g/L (reference value 0-1.35 g/L), alanine aminotransferase 554 U/L (reference value 9-40 U/L), aspartate aminotransferase 288 U/L (reference value 5-40 U/L), total bilirubin 54.16 µmol/L (reference value 2-21 µmol/L), and direct bilirubin 29.64 µmol/L (reference value 1.7-8.1 µmol/L) were all elevated. The abdominal CT scan and magnetic resonance cholangiopancreatography indicated pancreatic swelling, common bile duct stenosis, and secondary obstructive dilation of the biliary system. The patient was diagnosed with IgG4-related disease and treated with prednisone at 40 mg daily. As jaundice and abdominal pain improved, prednisone was gradually reduced to medication discontinuation. Two months ago, the patient developed melena, whose blood routine test showed severe anemia, and gastrointestinal bleeding was diagnosed. The patient came to the emergency department of Beijing Hospital with no improvement after treatment in other hospitals. Gastroscopy revealed a 1.5 cm firm duodenal bulb ulcer. After treatment with omeprazole, the fecal occult blood was still positive. The PET-CT examination was performed, and it revealed no abnormality in the metabolic activity of the duodenal wall, and no neoplastic lesions were found. IgG4-related disease was considered, and the patient was admitted to the Department of Rheumatology and Immunology of Beijing Hospital for further diagnosis and treatment. The patient had a right submandibular gland mass resection history and diabetes mellitus. After the patient was admitted to the hospital, the blood test was reevaluated. The serum IgG4 was elevated at 5.44 g/L (reference value 0.03-2.01 g/L). Enhanced CT of the abdomen showed that the pancreas was mild swelling and was abnormally strengthened, with intrahepatic and extrahepatic bile duct dilation and soft tissue around the superior mesenteric vessels. We pathologically reevaluated and stained biopsy specimens of duodenal bulbs for IgG and IgG4. Immunohistochemical staining revealed remarkable infiltration of IgG4-positive plasma cells into duodenal tissue, the number of IgG4-positive cells was 20-30 cells per high-powered field, and the ratio of IgG4/IgG-positive plasma cells was more than 40%. The patient was treated with intravenous methylprednisolone at 40 mg daily dosage and cyclophosphamide, and then the duodenal ulcer was healed. IgG4 related disease is an immune-medicated rare disease characterized by chronic inflammation and fibrosis. It is a systemic disease that affects nearly every anatomic site of the body, usually involving multiple organs and diverse clinical manifestations. The digestive system manifestations of IgG4-related disease are mostly acute pancreatitis and cholangitis and rarely manifest as gastrointestinal ulcers. This case confirms that IgG4-related disease can present as a duodenal ulcer and is one of the rare causes of duodenal ulcers.

Screening and identification of biomarkers for systemic sclerosis via microarray technology.

Systemic sclerosis (SSc) is a complex autoimmune disease. The pathogenesis of SSc is currently unclear, although like other rheumatic diseases its pathogenesis is complicated. However, the ongoing development of bioinformatics technology has enabled new approaches to research this disease using microarray technology to screen and identify differentially expressed genes (DEGs) in the skin of patients with SSc compared with individuals with healthy skin. Publicly available data were downloaded from the Gene Expression Omnibus (GEO) database and intra­group data repeatability tests were conducted using Pearson's correlation test and principal component analysis. DEGs were identified using an online tool, GEO2R. Functional annotation of DEGs was performed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Finally, the construction and analysis of the protein­protein interaction (PPI) network and identification and analysis of hub genes was carried out. A total of 106 DEGs were detected by the screening of SSc and healthy skin samples. A total of 10 genes [interleukin­6, bone morphogenetic protein 4, calumenin (CALU), clusterin, cysteine rich angiogenic inducer 61, serine protease 23, secretogranin II, suppressor of cytokine signaling 3, Toll­like receptor 4 (TLR4), tenascin C] were identified as hub genes with degrees ≥10, and which could sensitively and specifically predict SSc based on receiver operator characteristic curve analysis. GO and KEGG analysis showed that variations in hub genes were mainly enriched in positive regulation of nitric oxide biosynthetic processes, negative regulation of apoptotic processes, extracellular regions, extracellular spaces, cytokine activity, chemo­attractant activity, and the phosphoinositide 3 kinase­protein kinase B signaling pathway. In summary, bioinformatics techniques proved useful for the screening and identification of biomarkers of disease. A total of 106 DEGs and 10 hub genes were linked to SSc, in particular the TLR4 and CALU genes.

Dietary intake and risk of rheumatoid arthritis-a cross section multicenter study.

Environmental factors play an important role in the development of rheumatoid arthritis (RA). Among these factors, smoking is generally considered to be an established risk factor for RA. Data regarding the impact of diet on risk of RA development is limited. This study assessed the impact of dietary patterns on RA susceptibility in Chinese populations. This was a large scale, case-control study composed of 968 patients with RA and 1037 matched healthy controls. Subjects were recruited from 18 teaching hospitals. Socio-demographic characteristics and dietary intakes 5 years prior to the onset of RA were reported by a self-administered questionnaire. Differences in quantity of consumption between cases and controls were analyzed by Student's t test. Multiple logistic regression analysis was applied to identify independent dietary risk factor(s) responsible for RA susceptibility. Compared to healthy individuals, RA patients had decreased consumption of mushrooms (P = 0.000), beans (P = 0.006), citrus (P = 0.000), poultry (P = 0.000), fish (P = 0.000), edible viscera (P = 0.018), and dairy products (P = 0.005). Multivariate analyses revealed that several dietary items may have protective effects on RA development, such as mushrooms (aOR = 0.669; 95%CI = 0.518-0.864, P = 0.002), citrus fruits (aOR = 0.990; 95%CI = 0.981-0.999, P = 0.04), and dairy products (aOR = 0.921; 95%CI 0.867-0.977, P = 0.006). Several dietary factors had independent effects on RA susceptibility. Dietary interventions may reduce the risk of RA.

Effect of colchicine in prevention of pericardial effusion and atrial fibrillation: a meta-analysis.

Randomized, controlled trials (RCTs) have assessed the effect of colchicine therapy in prevention of pericardial effusion (PE) and atrial fibrillation (AF). However, the effects are still inconclusive. PubMed, Cochrane Library, Google Scholar, and EMBASE database were searched. Primary outcome was the risk of PE and AF. Ten RCTs with 1981 patients and a mean follow-up of 12.6 months were included. Colchicine therapy was not associated with a significantly lower risk of post-operative PE (RR, 0.89; 95 % CI 0.70-1.13; p = 0.33, I (2) = 72.8 %) and AF (RR, 0.77; 95 % CI 0.52-1.13; p = 0.18, I (2) = 47.3 %). However, rates of pericarditis recurrence, symptoms persistence, and pericarditis-related hospitalization were significantly decreased with colchicine treatment. In addition, cardiac tamponade occurrence was similar between groups, and adverse events were significantly higher in the colchicine group. Colchicine may not significantly decrease the post-operative risk of PE and AF. However, only limited studies about patients undergoing cardiac surgery provide data about PE and AF.

[The role of promoter CpG islands methylation of leptin gene in osteoarthritis].

OBJECTIVE: To investigate the effects of 5-Aza-CdR (methylation transferase inhibitor)on the expression levels of leptin gene in chondrocytes and methylation states of leptin promoter region between osteoarthritis (OA) group and control. METHODS: The chondrocytes in osteoarthritis group were treated with 5-Aza-CdR with different doses and time-points, and the expression level of leptin was detected by real-time polymerase chain reaction for picking up the optimum dose and time-point. Next, the chondrocytes in 5 osteoarthritis patients and 5 control patients (amputation due to severe trauma) were treated with 5-Aza-CdR. Lastly, leptin mRNA expression levels in the four groups osteoarthritis and control chondrocytes treated with/without 5-Aza-CdR were measured by real-time PCR and the methylation state of promoter region (-280 - +79) was detected by epitope quantitative DNA methylation analysis. RESULTS: (1) After treating the chondrocytes in OA groups with 10 µmol/L 5-Aza-CdR for 72 h, the mRNA expression levels of leptin were increased significantly. (2) The mRNA expression levels of leptin were significantly different among the four groups (P < 0.05), and the chondrocytes in osteoarthritis groups treated with 5-Aza-CdR showed a marked induction of leptin mRNA expression. (3) Analysis of quantitative methylation data using an unsupervised hierarchical clustering algorithm, showed that methylation patterns of leptin promoter was different between control and osteoarthritis chondrocyte treated with/without 5-Aza-CdR. CONCLUSION: Demethylation of leptin promoter might up-regulate leptin gene expression level and it might contribute to osteoarthritis.

[Immunological characteristics of 1291 cases of severe acute respiratory syndrome in Beijing].

OBJECTIVE: To investigate the immunological characteristics of the cases of severe acute respiratory syndrome (SARS) in Beijing City. METHODS: Clinical data of 1291 patients with SARS from March to July 2003 in Beijing City were retrospectively analyzed. RESULTS: In patients with SARS, the absolute numbers of white blood cells, lymphocytes and CD(3), CD(4) and CD(8) lymphocyte subsets decreased during the early period of the disease, being manifested in 56.91%, 88.26%, 47.96%, 45.56% and 41.10% of the patients, respectively. During the first 3 days the median numbers of CD(3), CD(4) and CD(8) were 425 x 10(6)/L, 223 x 10(6)/L, 170 x 10(6)/L, respectively, being the lowest values in the course of the disease. During the second week the corresponding numbers were 536 x 10(6)/L, 267 x 10(6)/L, 224 x 10(6)/L, respectively; they returned to normal by the fourth week (P < 0.05), showing a trend of gradual increase during the disease progression. Comparison of different time points of the same cases also showed that CD(3), CD(4) and CD(8) were lowest in the first 1 - 3 days. The median number of CD(3) was higher (954 x 10(6)/L) during week 3, and there was no significant difference among other 3 weeks (P > 0.05). In the early period of the disease the CRP increased but ESR, C(3) and C(4) were still in normal ranges. CONCLUSIONS: In the early period of SARS, the WBC, lymphocytes, CD(3), CD(4) and CD(8) lymphocyte subsets decreased remarkably, and they tended to increase as the disease progressed. Simultaneous decreases in CD(3), CD(4) and CD(8) during the first week is a characteristic immunological change, which may facilitate the early diagnosis of SARS.

[The inhibitory effect of hyporesponsive peptide on human leukocyte antigen-DRbeta1 specific T cell activation].

OBJECTIVE: To evaluate the inhibitory effect of human leukocyte antigen (HLA)-DRbeta1 specific collagen II (CII) peptides with substitutions of TCR binding residues on T cell activation, and explore a new therapeutic strategy for T cell mediated autoimmune diseases by interfering with antigen recognition of T Cell receptor (TCR). METHODS: Non-TCR binding peptides were designed by computer modeling based on interaction of HLA DR1. The modified CII263-272. Intracellular transfer of the modified CII peptide and its binding to HLA DR1 were studied using confocal microscopy and fluorescence-activated cell sorter (FACS). The effects of altered peptides on T cell activation were evaluated using an antigen presenting system consisting of HLA-DR1 transgenic APC and CII specific T cells. RESULTS: Computer modeling showed the side chains of 263 (F), 266 (E) fit in the peptide binding groove, and form hydrogen bond with alpha1, beta1 chain of HLA-DR1. The side chains of TCR specific 267 (Q) and 270 (K) protruded out of the groove, which might be TCR recognizing residues. The modified CII peptides with intact HLA-DR1 binding residues were bound to intracellular HLA-DR1 and expressed on cell surface. The modified peptides with single residue substitution of 267-270 and consecutive substitution of 268-270 showed a hyporesponsive T cell activation. Altered peptides 270A, sub268-270 could significantly suppress the T cell activation induced by CII263-272. CONCLUSION: The altered peptides with substitution of TCR binding residues are hyporesponsive in T cell activation, and may competitively inhibit the T cell activation in T cell mediated autoimmune diseases.