Aggravated experimental autoimmune encephalomyelitis in IL-15 knockout mice

IL-15 initially identified as a T proliferating cytokine has several structural and biological similarities with IL-2 and has been associated with a number of autoimmune diseases. Because of the scarcity of information available on the role of IL-15 in MS pathogenesis, we have investigated how the absence of IL-15 affected the development of experimental autoimmune encephalomyelitis, a mouse model of MS. Following immunization of IL-15^?/? and C57BL/6 mice with MOG_35–55, we observed a more severe neurological impairment in the IL-15 knockout mice than in the wild-type group. The enhanced disease severity in IL-15^?/? mice was associated with greater demyelination in the spinal cord, increased immune cell infiltration and inflammation. These events may be related to the higher CD4/CD8 ratio and the almost absent NK cell activity, congenital immune features of IL-15KO mice. Moreover, we found that the fractalkine receptor CX3CR1 was overexpressed in the spinal cord of IL-15^?/? mice, mainly localized on infiltrating CD8⁺ T cells. How these findings are contributing to the aggravated EAE development in IL-15 KO mice remain unclear and need to be further investigated.     

Weight management interventions in adults with a serious mental illness: A meta-analytic review

Persons with a serious mental illness have more physical health problems and shorter life expectancy compared to the general population, in part due to modifiable at-risk health behaviors like obesity. This study provides a systematic review and meta-analysis of the available evidence on the efficacy of weight management interventions when compared to treatment as usual. Fourteen studies were included in the meta-analysis, analyzing data from a total of 1779 participants. Across all studies, an effect in favor of the intervention groups, with a reduction in mean absolute weight of ?2.01 kg, compared to control groups (95% CI: ?2.93 kg to ?1.10 kg, p< 0.001) over a period ranging from 3 months to 12 months. Subgroup meta-analyses indicate programs that incorporate individual sessions and are implemented at the onset of illness may have the greatest impact on weight management for this population. Despite the statistically significant findings of mean weight change in the intervention groups compared to controls, the reported weight loss only equates to a 2% change from the initial body weight. This falls short of the clinically significant target of 5% weight loss in order to reduce related health complications. The current research was not consistent in capturing data on other metrics that could supplement mean weight loss in assessing positive health outcomes. Due the current health epidemic faced by this population, it is imperative for future research to include adequate follow-up periods, provide protocols, and employ better control methods.     

Overcoming resistance to BRAF inhibition in BRAF-mutated metastatic melanoma

Almost 50% of metastatic melanoma patients harbor a BRAF^V600 mutation andthe introduction of BRAF inhibitors has improved their treatment options. BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. However, most patients develop mechanisms of acquired resistance and about 15% of them do not achieve tumor regression at all, due to intrinsic resistance to therapy. Moreover, early adaptive responses limit the initial efficacy of BRAF inhibition, leading mostly to incomplete responses that may favor the selection of a sub-population of resistant clones and the acquisition of alterations that cause tumor regrowth and progressive disease.The purpose of this paper is to review the mechanisms of resistance to therapy with BRAF inhibitors and to discuss the strategies to overcome them based on pre-clinical and clinical evidences.     

Epidemiological characteristics and disease spectrum of emergency patients in two cities in China:Hong Kong and Shenzhen

Dear editor,China is the most populated country and the second economic entity worldwide.Hong Kong and Shenzhen are two adjacent cities in southern China,with similar environmental,cultural,ethnic groups,and economic development.They both have a very interesting turning point in their destiny,leading to a miraculous economic development.However,their government structure and health care system are totally different.[1]This is a vivid example of Deng Xiaoping’s formulation of the principle of“one country,two systems”.     

Atrial natriuretic factor in cardiogenic shock, in hypovolemic shock and in the bradycardia-hypotension syndrome following acute myocardial infarction

The aim of this paper was to study plasma atrial natriuretic factor, renin activity, aldosterone and antidiuretic hormone in low-output heart failure syndromes such as cardiogenic shock, hypovolemic shock and hypotension with bradycardia syndrome. A total of 30 patients were investigated: 10 with cardiogenic shock due to acute myocardial infarction of the anterior wall (systolic and diastolic blood pressure 56.0 +/- 3.7/40.5 +/- 2.0 mmHg; heart rate 119.7 +/- 1.2 beats/min; central venous pressure 16.2 +/- 0.6 cmH2O) (I group), 10 with hypovolemic shock induced by melena in peptic ulcer (systolic and diastolic blood pressure 74.5 +/- 1.5/57.5 +/- 1.7 mmHg; heart rate 111.0 +/- 1.4; central venous pressure 6.3 +/- 0.5 cmH2O) (II group), 10 with hypotension with bradycardia syndrome which occurred in patients during acute myocardial infarction of the inferior wall (systolic and diastolic blood pressure 71.9 +/- 2.0/58.0 +/- 2.6 mmHg; heart rate 52.0 +/- 2.2 beats/min; central venous pressure 4.6 +/- 0.4 cmH2O) (III group). Plasma atrial natriuretic factor values were measured using radioimmunoassay after chromatographic pre-extraction; plasma renin activity, aldosterone and antidiuretic hormone values were calculated using radioimmunoassay. Circulating atrial natriuretic factor was significantly (p less than 0.01) higher in patients with cardiogenic shock (102.4 +/- 7.4 pg/ml) than in healthy volunteers (8.4 +/- 0.3 pg/ml). In the former there was a positive correlation between atrial natriuretic factor and central venous pressure values. Atrial natriuretic factor and central venous pressure values in the IInd and IIIrd groups of patients were in the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)     

A common haplotype of the C-C chemokine receptor 2 gene and HLA-DRB1*0301 are independent genetic risk factors for Löfgren's syndrome

Aim. Sarcoidosis is a heterogeneous disorder with a strong genetic influence. Genetic factors are also thought to influence disease severity and outcome. We sought to determine whether polymorphisms within CCR2 gene predispose to Löfgren’s syndrome – a clinically and genetically distinct sarcoidosis phenotype – and, importantly, whether this association is independent of the known association with the HLA‐DRB1*0301 allele. Methods. We investigated 5 CCR2 variants and HLA‐DRB1*0301 by sequence‐specific primer (SSP) polymerase chain reaction (PCR) in 176 Spanish (76 Löfgren’s syndrome, 100 controls) and 387 Swedish subjects (126 Löfgren’s syndrome, 77 non‐Löfgren sarcoidosis, 184 controls). Results. One of the deduced haplotypes (CCR2 haplotype 2) was associated with Löfgren’s syndrome in both Spanish (OR: 2.03, uncorrected P = 0.02; permuted P = 0.041 vs. controls) and Swedish patients (OR: 3.02, uncorrected P = 0.0007; permuted P = 0.0027 vs. non‐Löfgren sarcoidosis; OR: 2.46, uncorrected P = 0.0005; permuted P = 0.0031 vs. controls). HLA‐DRB1*0301 allele frequency was also increased in Spanish (OR: 3.52, P = 0.0004 vs. controls) and Swedish patients with Löfgren’s syndrome (OR: 10.98, P < 0.0001 vs. non‐Löfgren sarcoidosis, OR: 7.71, P < 0.0001 vs. controls). Finally, multivariate analysis revealed that the CCR2 association was independent of HLA‐DRB1*0301 in both Spanish (P = 0.02 vs. controls) and Swedish cohorts (P = 0.002 vs. non‐Löfgren sarcoidosis, P = 0.001 vs. controls). Conclusions. This study confirms that CCR2 haplotype 2 and HLA‐DRB1*0301 are independent genetic risk factors for Löfgren’s syndrome.     

IL-5 promotes induction of antigen-specific CD4+CD25+ T regulatory cells that suppress autoimmunity

Immune responses to foreign and self-Ags can be controlled by regulatory T cells (Tregs) expressing CD4 and IL-2Rα chain (CD25). Defects in Tregs lead to autoimmunity, whereas induction of Ag-specific CD4+CD25+ Tregs restores tolerance. Ag-specific CD4+CD25+ FOXP3+Tregs activated by the T helper type 2 (Th2) cytokine, IL-4, and specific alloantigen promote allograft tolerance. These Tregs expressed the specific IL-5Rα and in the presence of IL-5 proliferate to specific but not third-party Ag. These findings suggest that recombinant IL-5 (rIL-5) therapy may promote Ag-specific Tregs to mediate tolerance. This study showed normal CD4+CD25+ Tregs cultured with IL-4 and an autoantigen expressed Il-5rα. Treatment of experimental autoimmune neuritis with rIL-5 markedly reduced clinical paralysis, weight loss, demyelination, and infiltration of CD4+ (Th1 and Th17) CD8+ T cells and macrophages in nerves. Clinical improvement was associated with expansion of CD4+CD25+FOXP3+ Tregs that expressed Il-5rα and proliferated only to specific autoantigen that was enhanced by rIL-5. Depletion of CD25+ Tregs or blocking of IL-4 abolished the benefits of rIL-5. Thus, rIL-5 promoted Ag-specific Tregs, activated by autoantigen and IL-4, to control autoimmunity. These findings may explain how Th2 responses, especially to parasitic infestation, induce immune tolerance. rIL-5 therapy may be able to induce Ag-specific tolerance in autoimmunity.     

New insights on COPD imaging via CT and MRI

Multidetector-row computed tomography (MDCT) can be used to quantify morphological features and investigate structure/function relationship in COPD. This approach allows a phenotypical definition of COPD patients, and might improve our understanding of disease pathogenesis and suggest new therapeutical options. In recent years, magnetic resonance imaging (MRI) has also become potentially suitable for the assessment of ventilation, perfusion and respiratory mechanics. This review focuses on the established clinical applications of CT, and novel CT and MRI techniques, which may prove valuable in evaluating the structural and functional damage in COPD.     

A biochemical defect in the repair of alkylated DNA in cells from an immunodeficient patient (46BR)

The fibroblast cell strain 46BR, derived from an immunodeficientindividual, is hypersensitive to the lethal effects of a varietyof DNA-damaging agents, this effect being particularly markedfor monofunctional methylating agents. After u.v. irradiation46BR cells show normal unscheduled DNA synthesis, daughter strandrepair, and recovery of DNA and RNA synthesis. The inhibitionof DNA replicative synthesis by u.v. is slightly less than thatof normal cells. After gamma-irradiation the rejoining of strandbreaks is normal as are the kinetics of replicative DNA synthesis.Following treatment with dimethylsulphate, replicative DNA synthesisis affected in a similar way to normal cells, unscheduled DNAsyntheis may be increased relative to normal cells, but morestrand breaks persist in 46BR than in normal cells. In addition46BR cells are hypersensitive to the toxic effects of 3-aminobenz-amide,an inhibitor of ADP-ribosyl transferase. This enzyme is involvedin the ligation step of repair of alkylation damage. A hypothesisis presented suggesting that 46BR may be defective in DNA ligaseI.