Are differences in interleukin 10 production associated with joint damage?

OBJECTIVE: Constitutive differences between individuals in cytokine production may determine the variation in the course of inflammatory arthritis. METHODS: The association between interleukin 10 (IL-10) production and joint destruction was studied by comparing IL-10 mRNA content in synovial biopsies from seven patients with destructive joint disease and six patients with non-destructive joint disease. The IL-10 mRNA content was 0.4 +/- 0.6 arbitrary units in erosive joints compared with 2.3 +/- 1.2 arbitrary units in non-erosive joints (P: < 0.03, Mann-Whitney U:-test). As this difference suggested that IL-10 production was associated with joint destruction, we tested whether the IL-10 locus determined the extent of joint damage. RESULTS: Innate differences in IL-10 production are locus-dependent. In line with these data, we showed that innate differences in IL-10 protein production were also present as differences in IL-10 mRNA levels. We tested if polymorphisms in the promoter of IL-10 were associated with the extent of joint damage. DISCUSSION: In a cohort study of female rheumatoid arthritis patients followed for 12 yr, the extent of joint destruction differed significantly between patients with different IL-10 genotypes. In patients with the -1082AA genotype who were studied prospectively, the mean increase in radiographic damage score (modified Sharp score of X-rays of hands and feet) during the first 6 yr was 9 +/- 9 per yr vs 19 +/- 16 per yr for patients with the genotype -1082GG (P: < 0.02). In line with these data, cultures of endotoxin-stimulated whole blood from 158 donors showed that the presence of the allele associated with less joint destruction correlated with slightly higher IL-10 production. CONCLUSIONS: Both the immunogenetic and the synovial biopsies suggest that a variation in IL-10 production is associated with joint destruction.     

Are bone defects in rare patients with Glanzmann's thrombasthenia associated with ITGB3 or ITGA2B mutations?

The question as to whether Glanzmann thrombasthenia patients with ITGB3 defects and deficiencies of both αIIbβ3 and αvβ3 show phenotypic differences to those with abnormalities exclusive to αIIbβ3 is unresolved. Studies on β3-deficient mice have shown an increased bone mass. Here we review the literature on bone defects in thrombasthenia patients and report the molecular analysis of a patient associating a lifelong thrombasthenia-like syndrome with skeletal defects. We show that the patient is compound heterozygote for Arg327His and Gly391Arg mutations in αIIb, with one mutation inherited from each parent. Modelling strongly suggested that both mutations act by destabilizing the αIIb beta propeller. So it appears likely that this patient has a combination of co-expressed genetic defects.     

Are bone defects in rare patients with Glanzmann's thrombasthenia associated with ITGB3 or ITGA2B mutations?

The question as to whether Glanzmann thrombasthenia patients with ITGB3 defects and deficiencies of both αIIbβ3 and αvβ3 show phenotypic differences to those with abnormalities exclusive to αIIbβ3 is unresolved. Studies on β3-deficient mice have shown an increased bone mass. Here we review the literature on bone defects in thrombasthenia patients and report the molecular analysis of a patient associating a lifelong thrombasthenia-like syndrome with skeletal defects. We show that the patient is compound heterozygote for Arg327His and Gly391Arg mutations in αIIb, with one mutation inherited from each parent. Modelling strongly suggested that both mutations act by destabilizing the αIIb beta propeller. So it appears likely that this patient has a combination of co-expressed genetic defects.     

Risk factors for retinopathy associated with interferon α-2b and ribavirin combination therapy in patients with chronic hepatitis C

AIM: To elucidate the frequency and risk factors for retinopathy in patients with chronic hepatitis C who are treated by interferon-ribavirin combination therapy. METHODS: We prospectively analyzed 73 patients with histologically confirmed chronic hepatitis C, who underwent combination therapy for 24 wk. Optic fundi were examined before, and 2, 4, 12 and 24 wk after the start of combination therapy. RESULTS: Fourteen patients (19%) developed retinopathy, which was initially diagnosed by the appearance of a cotton wool spot in 12 patients. Retinal hemorrhage was observed in 5 patients. No patient complained of visual disturbance. Retinopathy disappeared in 9 patients (64%) despite the continuation of combination therapy. However, retinopathy persisted in 5 patients with retinal hemorrhage. A comparison of the clinical background between the groups with and without retinopathy showed no significant differences in age, gender, viral genotype, RNA level, white blood cell count, platelet count, prothrombin time, complications by diabetes mellitus or hypertension, or pretreatment arteriosclerotic changes in the optic fundi. However, multiple logistic regression analysis revealed that complication by hypertension was observed with a high frequency in the group with retinopathy (P = 0.004, OR = 245.918, 95% CI = 5.6-10786.2). CONCLUSION: Retinopathy associated with combination therapy of interferon alpha-2b and ribavirin tends to develop in patients with hypertension.     

Hb Chad or α223(B4)GLU→LYSβ2 Observed in Members of a Surinam Family in Association with α-Thalassemia-2 and with HB S

Three different hemoglobinopathies, i.e. Hb S, Hb Chad [α23 (B4)Glu→Lys], and α-thalassemia-2 (?3.7) have been observed in eight members of a family from Surinam. The proposita had all three abnormalities, while her mother and four of her half-brothers had Hb Chad together with an α-thalassemia-2 heterozygosity or homozygosity. Gene mapping and dot-blot analysis of amplified DNA identified a G→A mutation in codon 23 of the α2αl hybrid gene resulting in the Glu→Lys substitution. The quantity of the α-Chad chain averaged 31.5% in its carriers with an additional α-thalassemia-2 heterozygosity [-α^Cnad(?3.7 kb)/ α α], and 43% in the two carriers with an additional α-thalassemia-2 homozygosity [-α^Chad(?3.7 kb)/- α (3.7 kb)]. These quantities are considerably higher than those reported for families from Chad, China, and Japan; the low levels of 14.5-24% Hb Chad in members of previously reported cases suggest a mutation on a chromosome with two α-globin genes [α α^Chad/α α or α^Chadα/ α α].     

Platelet FcγRIIA expression is associated with the α2 integrin C807T gene polymorphism in type 2 diabetes

“Patelet” FcγRIIA is stably overexpressed in type 2 diabetes and may also play a role in collagen-mediated platelet activation. Platelet surface integrin α₂β₁–collagen interaction is an early step associated with platelet adhesion and activation and plays an important role in arterial thrombosis. The objective of this study was to characterize the relationship in diabetes and non-diabetes platelets between FcγRIIA expression and a polymorphism associated with arterial thrombotic events, polymorphism C807T on the gene encoding α₂β₁. Platelet flow cytometry and allele-specific PCR revealed a significant correlation in type 2 diabetes between low platelet FcγRIIA expression and the 807TT genotype that is associated with increased platelet α₂β₁ receptor density. We conclude that uni- or bi-directional modulation of surface expression may exist between the platelet FcγRIIA receptor and a α₂β₁ thrombogenic polymorphism that could play a role in platelet sensitivity to collagen in type 2 diabetes.     

Anti-β<Subscript>2</Subscript>-glycoprotein I in Sjogren’s syndrome is associated with parkinsonism

The nervous system may be involved in up to 30% of patients with Sjogren’s syndrome (SS). We describe three patients with Sjogren’s syndrome and a concomitant parkinsonian syndrome. Elevated titers of anti-β₂-glycoprotein I IgG were found in the serum of all three patients. This autoantibody is strongly associated with anticardiolipin (aCL) antibodies, antiphospholipid syndrome (APS), and thromboembolic phenomena, but its role in the pathogenesis of the parkinsonian disorder in SS is unclear. These patients may present a subtype of SS patients in which the presence of aCL antibodies is associated with central nervous system involvement predominantly in the basal ganglia. Sharon Hassin-Baer and Levy Yair contributed equally to this work.     

Proteinuric renal disease in type 2 diabetes—Is remission of proteinuria associated with improved mortality and morbidity?

Aims

Patients with type 2 diabetes and macroalbuminuria are at high risk for end stage renal disease (ESRD), cardiovascular disease and death, but remission of proteinuria may improve prognosis. We examine the effectiveness of currently recommended treatments on inducing remission of proteinuria, and on morbidity and mortality.

Methods

Observational study of 78 patients with type 2 diabetes (46 male) with mean age (SD) of 61.5 (11) years, with a urinary albumin/creatinine ratio (ACR) ≥ 50 mg/mmol. All were treated with agents blocking the renin–angiotensin system. Follow-up was from recognition of ACR ≥ 50 mg/mmol until death or March 2011 (median 6 years). Remission of proteinuria was defined as ≥70% reduction from peak ACR, sustained for ≥1 year.

Results

Only 22 of 78 patients (28%) achieved remission of proteinuria. Thirty-six (46%) had at least one major event (death, dialysis or cardiovascular). Remission of proteinuria was associated with lower incidence of ESRD/death (9% vs 36%; p = 0.02) but cardiovascular events were not reduced (32% vs 30%). A third of patients had no retinopathy when albuminuria was first recognised, suggesting that non-diabetic renal pathologies were prominent. There was a significant interaction between the severity of diabetic retinopathy and remission of proteinuria on the risk of ESRD/death (p = 0.0003).

Conclusions

Remission of proteinuria was achieved in only a third of patients despite efforts to achieve blood pressure targets <130/80 mmHg. Failure to attain remission of proteinuria was associated with increased risk of ESRD or death, a risk compounded by the presence of severe diabetic retinopathy.     

Immunosuppressive treatment in patient with pure red cell aplasia associated with chronic myelomonocytic leukemia: harm or benefit?

Acquired pure red cell aplasia (PRCA) can be primary or secondary to other diseases. PRCA association with chronic myelomonocytic leukemia (CMML) is very rarely reported. Although treatment is directed to underlying cause in secondary PRCA treatment, optimal treatment in patients with CMML and PRCA is unknown, because only four case reports are available. In addition, the effect of hypomethylating agents can be detrimental due to myelosuppression, at least in the early phase of treatment. Bone marrow examination of a 66-year-old woman with severe anemia revealed PRCA and was suspicious for CMML. There was no HLA-matched sibling for bone marrow transplantation. The patient received immunosuppressive therapy with steroids and cyclosporine with temporary response in anemia; however, progressed to acute leukemia over 8 months and died. Immunosuppressive therapy in patients with CMML and PRCA should be cautiously used because it may accelerate acute leukemia transformation.     

Does long-term ventilation with PEEP > or = 10mbar influence graft-function in patients following liver transplantation?

BACKGROUND/AIMS: Long-term positive end-expiratory pressure (PEEP) ventilation, particular with PEEP up to 15 mbar may impair graft-function in liver transplant (LT) patients. The aim of our study was to evaluate the impact of long-term high PEEP (at least 48 hours) on liver graft function. We retrospectively reviewed the records of 50 patients, who required artificial ventilation for at least 1 week with a PEEP level > or = 10mbar due to pulmonary complication caused mainly by sepsis (n = 19), pneumonia (n = 7) and lung edema associated with reperfusion syndrome or primary non-function of the graft (n = 13). Patients who required a PEEP > or = 10mbar within the first two days after transplantation (group A, n = 23) showed significant decrease of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin on day 3 and day 7 after initiation of high PEEP, whereas prothrombin time (PT) significantly increased on day 7. Group B (patients ventilated with PEEP > or = 10mbar after more than 2 days after transplantation, n = 27) showed a significant decrease of bilirubine and a significantly increase of PT on day 7. CONCLUSION: Long-term ventilation with PEEP levels of at least 10mbar does not harm graft function in patients following LT.     

Oxidative Stress,Inflammation and Neutrophil Superoxide Release in Patients with Crohn’s Disease: Distinction Between Active and Non-active Disease

Increased oxidative stress has been previously demonstrated in patients with Crohn's disease (CD). However, to date, this parameter has not been assessed in a comparative study of patients in prolonged remission and those with the active disease. We report here our study of lipid peroxidation, antioxidant and inflammation status in serum derived from 16 active CD patients, 27 clinically stable patients, and 15 healthy controls. Results The extent of lipid peroxidation was higher in CD patients than in the healthy controls, while the levels of lipid peroxides (PD) and of thiobarbituric acid-reactive substances (TBARS) were significantly (P < 0.01) higher in serum obtained from patients with active CD (22 and 30%, respectively) than in that obtained from patients in remission. An analysis of the antioxidant status revealed that the beta-carotene levels in sera derived from all CD patients - patients with active or stable CD (49.4 +/- 15 and 95.6 +/- 25 mg% beta-carotene, respectively) - were higher than that in the controls (145 +/- 40 mg%). Serum activity of glutathione peroxidase (GSH-Px) was significantly (P < 0.001) higher (by 31%) in the patients with active CD than in the control group. There was no significant difference in GSH-Px activity between patients in remission and the controls. In terms of the inflammatory status, we found significantly (P < 0.01) higher levels of C-reactive proteins (CRP) and of tumor necrosis factor alpha (TNFalpha) in patients with active CD than in CD patients in remission. There was a significant correlation between those parameters and the extent of lipid oxidation. Neutrophils, which are a potential source of oxygen-free radicals, were activated by incubation with phorbol myristate acetate (PMA). Superoxide and lysozyme release were significantly reduced in neutrophils derived from patients with active CD (by 25 and 28%, respectively) in comparison to the control group. However, stimulated neutrophils from stable patients demonstrated only a minimally non-significant lower release of superoxide and lysozyme compared to the controls. Conclusion The results obtained in this study demonstrate an enhanced inflammatory and oxidative stress and a decreased antioxidant status in patients with active CD. As the patients improved and became clinically stable, the oxidative parameters decreased, approaching normal values. As neutrophil activation was also lower in patients with active disease, neutrophil activation may represent a possible defense mechanism of the body against tissue injury.     

Hb Ramona or α224(B5)TYR->CYSβ2

Hb Ramona was accidentally detected in a pregnant female of part Spanish descent who was tested during a prenatal physical examination program for the possible presence of a hemoglobin (Hb) variant. Her hematological values were normal: Hb 12.3 g/dl; PCV 0.418 l/l; RBC 4.34 × 10¹²/l; MCV 96.3 fl; MCH 28.3 pg; MCHC 29.4 g/dl. The variant was detected by isoelectrofocusing (IEF) (1); its mobility was slightly faster than that of Hb A. It could not be separated from Hb A by cation exchange high performance liquid chromatography (HPLC) (2,3), nor did a variant α or β chain separate from the corresponding normal chains by reversed phase HPLC (4,5).     

Lymphadenitis caused by infection with an isoniazid- and rifampin-resistant strain of Mycobacterium bovis BCG in an infant with IFN-γ/IL-12 pathway defect

We report a rare case in a female infant (age, 3.5 months) with primaryimmunodeficiency (IFN-γ/IL-12 pathway defect) who presented with suppurativelymphadenitis after Mycobacterium bovis BCG vaccination. The strainof M. bovis BCG identified was found to be resistant to isoniazidand rifampin. The patient was treated with a special pharmacological regimeninvolving isoniazid (in a limited, strategic manner), ethambutol, streptomycin, andIFN-γ, after which there was complete resolution of the lesions.