Protective role of IL‐22 against Schistosoma mansoni soluble egg antigen‐induced granuloma in Vitro

The role of T helper‐17 (Th17) lymphocytes in the regulation of Schistosoma mansoni soluble egg antigen (SEA)‐induced granuloma is unknown. This study examined the effect of Th17 cytokines (IL‐17 and IL‐22) on granulocyte recruitment and functions during SEA‐induced granuloma formation in vitro in Schistosoma‐infected and noninfected individuals. Granulocytes were isolated from 27 Schistosoma‐infected patients and 13 controls and were used for granuloma induction using SEA‐conjugated polyacrylamide beads in the presence of Th17 cytokines. Granuloma index was assessed, and granulocyte mediators such as tumour necrosis factor (TNF‐α), hydrogen peroxide (H₂O₂) and nitric oxide (NO) were measured in the culture supernatant at the 7th day using enzyme‐linked immunosorbent assay (ELISA). Schistosoma‐infected patients had significant larger SEA‐induced granuloma than controls. IL‐17 (125 pg/mL) induced the optimum size for granuloma within 3‐7 days. However, IL‐22 at different concentrations up to 300 pg/mL had no effect on granuloma formation. Using both cytokines simultaneously, IL‐22 suppressed the effect of IL‐17 and prevented granuloma formation. IL‐17 significantly decreased TNF‐α, H₂O₂ and NO levels in Schistosoma‐infected individuals. In contrast, IL‐22 increased TNF‐α and H₂O₂ levels. In conclusion, IL‐17 accelerates SEA‐induced granuloma formation and inhibits granulocytes functions in Schistosoma‐infected patients, while IL‐22 inhibited the granuloma formation, but enhanced granulocyte functions.     

High titre of antiglutamic acid decarboxylase autoantibody is a strong predictor of the development of thyroid autoimmunity in patients with type 1 diabetes and latent autoimmune diabetes in adults

Objective Type 1 diabetes mellitus (T1DM) is frequently associated with autoimmune thyroid diseases (AITD), but little is known about the risk of AITD in latent autoimmune diabetes in adults (LADA). We evaluated the genetic and immunological factors involved in the development of thyroid autoimmunity in patients with LADA and T1DM. Patients and measurements One hundred and ninety T1DM and 135 LADA patients were recruited in the study. Thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TGAb), glutamic acid decarboxylase antibody (GADA) and thyroid function were measured. The cytotoxic‐lymphocyte‐associated antigen‐4 (CTLA‐4) +49A/G and CT60 polymorphisms and the human leucocyte antigen (HLA)‐DQA1‐DQB1 genotype were determined. Results The prevalence of thyroid antibodies (TGAb and/or TPOAb) and thyroid dysfunction was 27·4% and 9·5% in patients with T1DM, and 21·5% and 11·1% in patients with LADA. Thyroid‐antibody‐positive T1DM patients had higher frequencies of GADA and HLA‐DQA1*03‐DQB1*0401 haplotypes than thyroid‐antibody negatives (P < 0·05). Thyroid‐antibody‐positive LADA patients had higher GADA titre, lower C‐peptide levels and higher frequencies of HLA‐DQA1*03‐DQB1*0401 haplotypes (P < 0·05). The CTLA‐4 +49A/G and CT60 polymorphism was associated with T1DM complicated with thyroid autoimmunity (OR = 2·33 and 2·54). Logistic regression revealed that only high‐titre GADA was associated with development of thyroid autoimmunity in patients with T1DM and LADA (OR = 3·50 and 3·10, respectively), and the presence of thyroid antibody predicted high risk for thyroid dysfunction in patients with T1DM and LADA (OR = 9·25 and 10·70, respectively). Conclusion Regular screening of thyroid antibody and function are recommended, especially in patients with T1DM and LADA with high GADA titre.     

Effect of exercise training on A-FABP, lipocalin-2 and RBP4 levels in obese women

Objective Lipocalin family proteins, including adipocyte fatty acid‐binding protein (A‐FABP), lipocalin‐2 and retinol‐binding protein 4 (RBP4), have recently been identified as novel adipokines associated with obesity, type 2 diabetes and the metabolic syndrome. We have evaluated the effect of exercise training on lipocalin family proteins and inflammatory markers. Study subjects Thirty obese Korean women and 15 age‐matched nonobese control subjects were studied. Design Concentrations of the lipocalin family proteins were compared between obese and nonobese women and were evaluated before and 3 months after an exercise programme consisting of aerobic exercise (45 min/session, 300 kcal/day) and muscle strength training (20 min/session, 100 kcal/day) five times a week. Results Obese women exhibited higher A‐FABP levels compared to nonobese women (21·4 ± 6·4 µg/l vs. 13·6 ± 4·4 µg/l, P < 0·001). However, neither lipocalin‐2 nor RBP4 levels were significantly different between the two groups, although the difference in lipocalin‐2 was marginally significant (P = 0·054). Circulating A‐FABP levels were significantly associated with body mass index (BMI), waist circumference, triglyceride, alanine aminotransferase (ALT), lipocalin‐2 and high‐sensitivity C‐reactive protein (hsCRP) levels. After 3 months of the exercise training programme, serum A‐FABP levels decreased significantly from 21·4 ± 6·4 µg/l to 19·3 ± 6·8 µg/l (P = 0·038), along with a reduction in weight, BMI, waist circumference, fasting glucose and total cholesterol levels. There was no significant change in the lipocalin‐2 and RBP4 levels, although IL‐6 levels increased after the exercise programme. Conclusion Exercise training with weight loss induced a significant reduction in circulating A‐FABP levels in obese Korean women.     

Precise pH measuring of platelet concentrates containing additive solution--the impact of the temperature

Background and Objectives Blood gas analysers measuring pH at 37°C (pH37) are widely used for pH determination of platelet (PLT) concentrates (PCs). For reporting pH at 22°C (pH22), converting of pH37 using the correct conversion factor is mandatory. For PCs stored in PLT additive solution (PAS), such conversion factors are not yet widely available. We studied pH in samples of PCs with different PAS/plasma ratios during warming from 22 to 37°C. Materials and Methods We measured pH in 39 samples containing modified PAS‐III (PAS‐IIIM) with a plasma carryover of 20%, 30% or 40% or no PAS‐IIIM. Differences between pH22 and pH37 (dpH) were compared within and between study groups. Correlation between pH22 and dpH was tested. Additional measurements in 33 samples with three different PLT counts were performed to study the influence of PLT count on dpH. Results pH22 and pH37 within each group and dpH or dpH/dT between study groups differed significantly. The dpH was 0·135 ± 0·040, 0·021 ± 0·009, 0·033 ± 0·011 and 0·048 ± 0·017 for samples containing 100%, 20%, 30% or 40% plasma, respectively. Correlation between dpH and pH22 was strong in 100% (r = 0·696, P < 0·001), weaker in 30% and 40% (r = 0·367, P = 0·022 and r = 0·345, P = 0·032, respectively) and not existing in 20% plasma (r = 0·153, P = 0·354). PLT count did not influence the dpH significantly. Conclusion The dpH is dependent on different PAS‐IIIM/plasma ratios and pH range. For precise reporting of pH22, the respective dpH must be used if converting is necessary. Preferably, the pH should be reported at 37°C or measured directly at 22°C.     

Codelivery of DNA vaccination encoding LeIF gene and IL‐12 increases protection against Leishmania major infection in BALB/c mice

Previous studies have shown that Leishmania elongation initiation factor (LeIF) antigen causes a partial immunity against leishmaniasis. The antigen develops type I immunity by overexpression of inflammatory cytokines such as interleukin‐12 (IL‐12), IFN‐γ and TNF‐α. Therefore, We evaluated immune responses induced by the LeIF gene against Leishmania major infection. Immunization with LeIF gene alone or with IL‐12 induced Th1 response and produced higher IFN‐γ and lower IL‐4 levels by splenocytes than control groups (P < 0·05) and also ratios of IFN‐γ/IL‐4 were 11·68 to 18·53 times more in immunized groups than control groups after challenge. In addition, analysis of humoral immune response revealed that immunized mice had more IgG2a levels than both control groups (P < 0·05). On the other hand, lesion size was less for immunized animals than control groups from 4th week after challenge (P < 0·05). The percentage reduction in lesion size was 29·30% for LeIF and 51·98% for LeIF + IL‐12 than PBS at 12th week post‐infection. Spleen parasite burden decreased in all immunized groups in comparison with control groups (P < 0·05). The results indicated that LeIF gene induced partial immunity against L. major infection in BALB/c mice. However, LeIF plus IL‐12 group showed more potent immunity with smaller lesions than other groups.     

Shear wave elastography in the diagnosis of thyroid nodules: feasibility in the case of coexistent chronic autoimmune Hashimoto's thyroiditis

Objective ShearWave? Elastography (SWE) is real‐time, quantitative and user‐independent technique, recently introduced in the diagnostic work‐up of thyroid nodules. Hashimoto’s thyroiditis (HT), characterized by variable degrees of lymphocytic infiltration and fibrosis, might affect shear wave propagation. The aim of this study was to assess the feasibility of SWE in cytologically benign thyroid nodules within both Hashimoto’s and nonautoimmune thyroid glands. The effect of autoimmunity on the gland stiffness was also evaluated. Design longitudinal study in a single centre. Patients SWE was performed in 75 patients with a benign thyroid nodule at cytology: 33 with Hashimoto’s thyroiditis (HT group) and 42 with uni‐ or multi‐nodular goitre, negative for thyroid autoimmunity (non‐HT group). Results The elasticity index (EI) of the extra‐nodular tissue was greater, though not statistically significant, in the HT than in the non‐HT group (24·0 ± 10·5 kPa vs 20·8 ± 10·4 kPa; P = 0·206). However, the EI of extra‐nodular tissue was related to the TPOAb titre in the HT group (P = 0·02) and was significantly higher in patients with HT receiving L‐thyroxine than in the euthyroid subjects (P = 0·02). The EI of thyroid nodules was similar in HT and non‐HT groups. In both groups, the stiffness of nodules was significantly higher than that of the embedding tissue. Conclusions Our data indicate that SWE correctly defines the elasticity of thyroid nodules independently from the coexistence of autoimmune thyroiditis, always being able to differentiate nodular tissue from the surrounding parenchyma. In HT, the stiffness of extra‐nodular tissue increases in relation to both the thyroid antibody titre and the degree of impairment of thyroid function.     

Tumour Necrosis Factor‐alpha (TNF‐α) and its soluble receptor type 1 (sTNFR I) in human active and healed leishmaniases

The role of tumour necrosis factor‐alpha (TNF‐α) is not fully understood in human leishmaniasis. We analysed the alterations in the levels of TNF‐α, soluble TNF receptor type 1 (sTNFR I), IL‐17 and IL‐22 productions in active and healed leishmaniases. Blood samples were collected from volunteers with active cutaneous leishmaniasis (ACL), the same subjects after lesion healing (healed CL = HCL), volunteers with active visceral leishmaniasis (AVL), healed VL (HVL) and healthy controls. Levels of cytokines were titrated on Leishmania Ag‐stimulated PBMC culture. The mean level of TNF‐α production from stimulated cells was significantly higher in ACL than controls (P < 0·001) and significantly reduced after treatment in HCL volunteers (P < 0·05). The mean level of sTNFR I production was significantly higher in ACL than controls (P < 0·001) and significantly reduced after treatment in HCL volunteers (P < 0·05). The mean level of IL‐22 production in AVL was significantly higher than controls (P < 0·05) and was significantly lower in HVL compared with AVL (P < 0·001) and controls (P < 0·05). The levels of TNF‐α (P = 0·0025) and sTNFR I (P < 0·01) productions from PBMCs showed significant decreasing trend after treatment in each CL volunteer. Reduction in TNF‐α is associated with clinical response to treatment and healing of CL lesions due to L. major.     

Single‐agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences

We present data from a phase II study investigating a novel treatment strategy for relapsed/refractory mantle cell lymphoma (MCL). Twenty‐six patients received lenalidomide 25 mg/d (days 1–21 of a 28‐d cycle) for up to 6 cycles followed by low‐dose maintenance lenalidomide (15 mg) in responding patients. Eight patients achieved complete or partial response to give an overall response rate of 31% with median response duration of 22·2 months [95% confidence interval (CI) 0·0–53·6] and median progression‐free survival (PFS) of 3·9 months (95% CI 0·0–11·1). An additional six patients (23%) achieved stable disease. Eleven patients received maintenance with median PFS of 14·6 months (95% CI 7·3–21·9). Correlative studies showed that peripheral T and Natural Killer (NK) cells increased in responding patients by 40–60% over the first 6 cycles with an initial dip in NK cells suggestive of tumour infiltration. Peripheral regulatory T cells were increased in MCL patients (P = 0·001) and expanded further following lenalidomide. Sequential plasma analysis showed increased IL12 p40 and IL7 alongside decreased MMP9, IL10, and adiponectin. Finally, a significant correlation (P = 0·02) between gender and response suggested that female MCL patients were more sensitive to lenalidomide than males. In summary, we confirm the activity, safety and immunomodulatory properties of lenalidomide in MCL and highlight its potential as a low‐dose maintenance agent.     

Changes and relationships of IGFS and IGFBPS and cytokines in coeliac disease at diagnosis and on gluten-free diet

Objective To evaluate changes and relationships of IGFs and IGFBPs, serum interleukin 6 (IL‐6) and tumour necrosis factor (TNF)‐α, and auxological parameters at diagnosis of coeliac disease (CD) and at 6 months and 12 months after starting a gluten‐free diet (GFD), compared with a control population. Patients Twenty patients were enrolled at diagnosis (9 male, 11 female; age 9·6 ± 0·8 years). A healthy population of 18 subjects (5 male, 13 female; age 11·3 ± 0·6 years) comparable for age, sex and pubertal status served as controls at baseline. Measurements Blood samples were taken at diagnosis, and at 6 months and 12 months after starting the GFD. Serum IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2, IGFBP‐3, IL‐6 and TNF‐α were measured using commercial kits. Height (Ht) standard deviation score (SDS), body mass index (BMI) SDS and Ht velocity SDS were evaluated at diagnosis and at 6 months and 12 months after starting GFD. Results In CD patients, both Ht SDS and BMI SDS increased during the first year of treatment, and Ht velocity SDS increased during the second 6 months of follow‐up (P < 0·05). At diagnosis, IGF‐I, IGF‐II and IGFBP‐3 were lower compared with controls, IGFBP‐1 was similar, IGFBP‐2, IL‐6 and TNF‐α were higher (P < 0·05). When on GFD, all peptides normalized and IGFBP‐1 decreased. The IGF‐I/IGFBP‐2 and IGF‐I/IGFBP‐3 molar ratios were significantly reduced at diagnosis compared with those of controls, but were increased for both groups when on GFD. Although there was no apparent abnormality at diagnosis, the IGF‐II/IGFBP‐2 molar ratio increased significantly on GFD. Ht velocity SDS was positively correlated with IGFBP‐3 (P < 0·05) and with the IGF‐I/IGFBP‐2 molar ratio (P < 0·05). Serum IL‐6 was negatively correlated with IGF‐I and positively with IGFBP‐1 (P < 0·05). Conclusions The data obtained from this study confirm changes in the IGF and cytokine systems at diagnosis of CD which tend to normalize on the gluten‐free diet. The two systems show relationships with each other and with linear growth.     

The degree of external genitalia virilization in girls with 21-hydroxylase deficiency appears to be influenced by the CAG repeats in the androgen receptor gene

Background Women with 21‐hydroxylase deficiency present much variability in external genitalia virilization, even among those with similar impairments of 21‐hydroxylase (21OH) activity. Objective To evaluate if the number of CAG (nCAG) repeats of the androgen receptor gene influences the degree of external genitalia virilization in women with CYP21A2 mutations, grouped according to impairment of 21OH activity. Patients The nCAG was determined in 106 congenital adrenal hyperplasia (CAH) patients and in 302 controls. The patients were divided, according to their CYP21A2 genotypes, into Groups A and B, which confer total and severe impairment of 21OH activity, respectively. Methods The inactivation pattern of the X‐chromosome was studied through genomic DNA digestion with Hpa II. The CAG repeat region was amplified by polymerase chain reaction (PCR) and analysed by GeneScan. Results The nCAG and the frequency of severe skewed X‐inactivation did not differ between normal women and patients. The nCAG median in genotype A was 20·7 (IQR 2·3) for Prader I + II, 22·5 (3·6) for Prader III and 21 (2·9) for Prader IV + V (P < 0·05 for Prader III and Prader IV + V). The nCAG median in genotype B was 21·3 (1·1) for Prader I + II, 20·5 (2·9) for Prader III and 22 (2·8) for Prader IV + V (P > 0·05). A significant difference was found regarding the nCAG median in patients presenting Prader III from genotypes A and B. Conclusions We observed great variability in the degree of external genitalia virilization in both CYP21A2 genotypes, and we showed that the CAG repeats of the androgen receptor gene influences this phenotypic variability.     

Complement and cytokine response in acute Thrombotic Thrombocytopenic Purpura

Complement dysregulation is key in the pathogenesis of atypical Haemolytic Uraemic Syndrome (aHUS), but no clear role for complement has been identified in Thrombotic Thrombocytopenic Purpura (TTP). We aimed to assess complement activation and cytokine response in acute antibody‐mediated TTP. Complement C3a and C5a and cytokines (interleukin (IL)‐2, IL‐4, IL‐6, IL‐10, tumour necrosis factor, interferon‐γ and IL‐17a) were measured in 20 acute TTP patients and 49 remission cases. Anti‐ADAMTS13 immunoglobulin G (IgG) subtypes were measured in acute patients in order to study the association with complement activation. In acute TTP, median C3a and C5a were significantly elevated compared to remission, C3a 63·9 ng/ml vs. 38·2 ng/ml (P < 0·001) and C5a 16·4 ng/ml vs. 9·29 ng/ml (P < 0·001), respectively. Median IL‐6 and IL‐10 levels were significantly higher in the acute vs. remission groups, IL‐6: 8 pg/ml vs. 2 pg/ml (P = 0·003), IL‐10: 6 pg/ml vs. 2 pg/ml (P < 0·001). C3a levels correlated with both anti‐ADAMTS13 IgG (r_s = 0·604, P = 0·017) and IL‐10 (r_s = 0·692, P = 0·006). No anti‐ADAMTS13 IgG subtype was associated with higher complement activation, but patients with the highest C3a levels had 3 or 4 IgG subtypes present. These results suggest complement anaphylatoxin levels are higher in acute TTP cases than in remission, and the complement response seen acutely may relate to anti‐ADAMTS13 IgG antibody and IL‐10 levels.     

The protective effect of a DNA vaccine encoding the Toxoplasma gondii cyclophilin gene in BALB/c mice

Toxoplasmosis is a world‐wide zoonosis that causes significant public health and veterinary problems. The study of vaccines remains the most promising method for the future prevention and control of toxoplasmosis. Recombinant Toxoplasma gondii cyclophilin has been shown to have potent PPIase and IL‐12‐inducing activities, thus promoting the stabilization of T. gondii's life cycle and maintaining the survival of its host during evolution. In this study, the T. gondii cyclophilin gene was used to construct a DNA vaccine (pVAX1‐TgCyP). The immune response and protective efficacy of the vaccine against T. gondii infection in BALB/c mice were evaluated. All BALB/c mice that were vaccinated with pVAX1‐TgCyP developed a high response with TgCyP‐specific antibodies, and significant splenocyte proliferation (P < 0·05) compared with pVAX1 vector and PBS groups. pVAX1‐TgCyP also induced a significant Th1 type immune response, indicated by the higher production of IL‐2 and IFN‐γ (P < 0·05). The survival rate of BALB/c mice increased significantly after vaccination with pVAX1‐TgCyP (37·5%) (P < 0·05). These results indicate that TgCyP is a highly efficacious vaccine candidate that can generate protective immunity against T. gondii infection in BALB/c mice.     

Administration of naloxone in combination with recombinant Plasmodium vivax AMA‐1 in BALB/c mice induces mixed Th1/Th2 immune responses

Naloxone (NLX) has the ability to shift the immune response to a Th1 profile. Therefore, the adjuvant efficacy of NLX with recombinant P. vivax apical membrane antigen‐1(rPvAMA‐1) in BALB/c mice was evaluated. Mice were immunized subcutaneously with purified rPvAMA‐1 formulated with NLX (doses of 5 mg/kg body weight) alone or in combination with IFA. A significant increase in anti‐PvAMA‐1 IgG antibody after the second boost (mean OD₄₉₀ = 2·08 and 2·17, in groups received, rPvAMA‐1/NLX and rPvAMA‐1/NLX/IFA, respectively) was detected. IgG1 and IgG2b were the predominant isotypes in all immunized mouse groups. In immunized mice with rPvAMA‐1/NLX (mean: 1036 pg/mL) and with rPvAMA‐1/NLX/IFA (mean: 1024 pg/mL), IFN‐γ was elicited in response to rPvAMA‐1 after the second boost. No detectable IL‐4 secretion was determined in all tested groups. In conclusion, the administration of NLX alone or NLX/IFA with rPvAMA‐1 in BALB/c mice, which induced mixed Th1/Th2 immune responses, was comparable with that of the same recombinant antigen with CFA/IFA adjuvant. The results indicate that NLX alone may possibly not be considered as a potent Th1 adjuvant in PvAMA‐1‐based vaccine. However, in order to modulate immune responses from mixed Th1/Th2 to strong and protective Th1 response, further study is warranted on combination of NLX with other adjuvants such as CpG motifs or MPL in proper vaccine formulation. Additionally, dose–response study is necessary to determine the effect of different doses of antigen combined with NLX (at various doses) in Balb/c mice.     

research paper: IL1RN VNTR and IL2−330 polymorphic genes are independently associated with chronic immune thrombocytopenia

Chronic Immune Thrombocytopenia (cITP) is an acquired immune‐mediated disease associated with a T‐helper cell type 1 (Th1) immune polarization, whose genetic risk factors, however, are largely unknown. We investigated polymorphisms in promoter regions of genes that code molecules involved in proinflammatory immune response [IL1B?31T/C, IL1RN variable number tandem repeats (VNTR), IL2?330T/G, and TNF?307G/A] as well as in genes that code Toll like receptors (TLR) (TLR2 Arg753Gln, TLR4 Asp299Gly and TLR5 Arg^392stop) in 122 patients with cITP and 541 blood donors. The frequencies of the IL1RN polymorphic allele 2 (P = 0·001) and of the IL2?330 polymorphic allele G (P = 0·004) were significantly higher in cITP patients than in blood donors. In logistic analysis adjusting for age and gender, the polymorphisms remained independently associated with cITP. Enhanced serum concentrations of interleukin (IL)‐1α and IL‐1β were observed in cITP (P < 10^?3) and blood donor (P = 0·04) carriers of the IL1RN*2. Also, the serum levels of IL‐2 and γ‐interferon (IFN‐γ) were increased in cITP patients (P < 10^?3 and P = 0·04 respectively) and blood donors (P < 10^?3 and P = 0·03 respectively) harbouring the IL2?330G allele. Here we demonstrated that IL2?330G and IL1RN*2 are independently associated with cITP and are functional in vivo, which strongly suggests that they contribute to the pathogenesis of cITP.     

The impact of liver steatosis on the ability of serum ferritin levels to be predictive of liver iron concentration in non‐transfusion‐dependent thalassaemia patients

This study analysed the impact of liver steatosis (LS) on the parameters of iron overload in 110 patients with non‐transfusion dependent thalassaemia (NTDT). LS was diagnosed by ultrasound. Liver iron concentration (LIC) measurements were available for 64 patients who underwent a magnetic resonance imaging (MRI) scan. LS was frequent (35·5%) and was significantly more prevalent in males than in females (49·0% vs. 24·6%, P = 0·008). Patients with LS had significant higher levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST ratio and ferritin than those without, but LIC values were comparable. An ALT/AST ratio >0·89 predicted the presence of LS with a sensitivity of 0·872 and a specificity of 0·901 (P < 0·0001). Ferritin levels correlated with LIC values (R = 0·558, P < 0·0001) but the correlation was stronger in patients without LS (R = 0·656, P < 0·0001) than in patients with LS (R = 0·426, P = 0·05). LS is a frequent issue in NTDT patients and should be suspected in the presence of an ALT/AST ratio >0·89. Recently, serum ferritin thresholds that predict clinically relevant LIC for guiding iron chelation therapy when MRI is unavailable have been determined. Our data show that LS may cause increase in ferritin levels and may be responsible for anticipating/exceeding chelation treatment in NTDT patients in the absence of LIC evaluation.     

Peripheral blood late mixed chimerism in leucocyte subpopulations following allogeneic stem cell transplantation for childhood malignancies: does it matter?

The impact of persistent mixed chimerism (MC) after haematopoietic stem cell transplantation (HSCT) remains unclarified. We investigated the incidence of MC in peripheral blood beyond day +50 after HSCT and its impact on rejection, chronic graft‐versus‐host disease (c‐GvHD) and relapse in 161 children receiving allogeneic HSCT for haematological malignancies. The 1‐year incidence of late MC was 26%. Spontaneous conversion to complete donor chimerism (CC) occurred in 43% of patients as compared to 62% after donor lymphocyte infusions. No graft rejection occurred. The 1‐year incidence of c‐GvHD was 20 ± 7% for MC, and 18 ± 4% for CC patients (P = 0·734). The 3‐year cumulative incidence of relapse (CIR) according to chimerism status at days +50 and +100 was 22 ± 4% for CC patients vs. 22 ± 8% for MC patients (day +50; P = 0·935) and 21 ± 4% vs. 20 ± 7% (day +100; P = 0·907). Three‐year CIRs in patients with persistent MC and patients with CC/limited MC were comparable (8 ± 7% vs. 19 ± 4%; P = 0·960). HSCT for acute leukaemia or myelodysplastic syndrome as secondary malignancies (hazard ratio (HR) 4·7; P = 0·008), for AML (HR 3·0; P = 0·02) and from mismatched donors (HR 3·1; P = 0·03) were independent factors associated with relapse. Our data suggest that late MC neither protects from c‐GvHD nor does it reliably predict impending disease relapse.     

Transmission dynamics and risk factors for pandemic H1N1-related illness: outbreak investigation in a rural community of British Columbia, Canada

Please cite this paper as: Janjua et al. (2012) Transmission dynamics and risk factors for pandemic H1N1‐related illness: outbreak investigation in a rural community of British Columbia, Canada. Influenza and Other Respiratory Viruses 6(3), e54–e62. Objective To characterize the first‐wave epidemiologic features of influenza‐like illness (ILI) associated with the novel pandemic A/H1N1 [A(H1N1)pdm09] virus. Methods We used generalized linear mixed models (GLMM) to assess risk factors and non‐parametric and/or parametric distributions to estimate attack rates, secondary attack rates (SAR), duration of illness, and serial interval during a laboratory‐confirmed community outbreak of A(H1N1)pdm09 clustered around on‐reserve residents and households of an elementary school in rural British Columbia, Canada, in late April/early May 2009. ILI details were collected as part of outbreak investigation by community telephone survey in early June 2009. Results Overall, 92/408 (23%) of participants developed ILI and 36/408 (9%) experienced medically attended ILI (MAILI). The overall SAR in households was 22%: highest among participants 1–4 years of age (yoa) (50%) followed by <1 yoa (38%), 5–8 yoa (20%), 10–19 yoa (13%), 20–49 yoa (20%), and 50–64 yoa (0%). The median serial interval was estimated at 3·5 days (95% CI: 2·1–5·1). In multivariable GLMM analysis, having a chronic condition (OR: 2·58; 95% CI: 1·1–6·04), younger age [1–8 yoa: OR: 4·63; 95% CI: 2·25–9·52; 9–19 yoa: OR: 1·95; 95% CI: 0·97–3·9 (referent: ≥20 yoa)] and receipt of 2008–2009 influenza vaccine (OR: 2·68; 95% CI: 1·37–5·25) were associated with increased risk of ILI. Median duration of illness was 9 days, longer among those with chronic conditions (21 days). Median time to seeking care after developing illness was 4·5 days. On‐reserve participants had higher chronic conditions, household density, ILI, MAILI, and SAR. Conclusions During a community outbreak of A(H1N1)pdm09‐related illness, we identified substantial clinical ILI attack rates exceeding 20% with secondary household attack rates as high as 50% in young children. The serial interval was short suggesting a narrow period to prevent transmission.     

Circulating Th17 cells frequency is associated with the disease progression in HBV infected patients

Background and Aims: Th17 cells have been shown to mediate host defensive mechanisms in various infections, but their role in HBV infection in humans has not been well characterized. In this study, we analyzed the frequency and cytokines secretion of circulating Th17 cells in HBV infected patients with different statuses, and also evaluated the potential association of Th17 frequency with the levels of liver injury. Methods: The study population consisted of 133 subjects, including 40 mild chronic hepatitis B (CHB) patients, 37 severe CHB patients, 20 acute hepatitis B (AHB) patients and 36 healthy controls. The frequency of circulating Th17 cells were carried out by intracellular cytokine staining analysis and serum IL‐10 levels were measured by ELISA. Results: Our data shown that AHB and severe CHB patients had a significant increase of Th17 cells frequency in peripheral blood compared with mild CHB patients and healthy control (both P < 0.05). The elevated prevalence of Th17 cells is positively associated with the increased serum ALT levels in severe CHB patients (r= 0.457, P= 0.004) but had no correlation with serum HBV DNA load. In addition, the serum IL‐10 were negatively correlated with the frequency of Th17 cells in PBMC from patients with chronic HBV infection (r=?0.452, P < 0.01). Conclusion: Th17 cells may contribute to the disease progression and pathogenesis of liver injury in HBV infected patients, and the induction of IL‐10 may be one mechanism of constraining pro‐inflammatory Th17 responses.     

Increased levels and adipose tissue expression of visfatin in morbidly obese women: the relationship with pro-inflammatory cytokines

Objective The controversial results on the physiopathological role of visfatin led us to examine both circulating visfatin levels and gene expression in visceral (VAT) and subcutaneous fat (SAT) in a homogeneous group of morbidly obese women. Design, patients and measurements We analysed circulating levels of several adipo/cytokines in 133 Spanish women: 40 lean (C) [body mass index (BMI) < 25 kg/m²] and 93 morbidly obese (MO) (BMI > 40 kg/m²). In the MO group, we found 31 diabetic and 62 nondiabetic subjects. We obtained follow‐up blood samples at 6 and 12 months after bariatric surgery from 30 MO patients. We determined the circulating levels of visfatin, adiponectin, interleukin‐6 (IL6), C‐reactive protein (CRP), resistin and tumour necrosis factor‐α (TNFα) by ELISA, and visfatin, adiponectin, IL6, resistin and TNFα gene expression in SAT and VAT by real‐time RT‐PCR. Results Circulating visfatin levels were higher in MO women compared with lean controls (C = 1·43 ± 0·14 μg/l, MO = 3·60 ± 0·29 μg/l, P < 0·001). After bariatric surgery‐induced weight loss, visfatin levels were reduced significantly over 12 months. Visfatin expression in SAT and VAT was similar, but significantly higher in MO compared to C and independent of the presence of diabetes mellitus. Circulating visfatin levels were positively related to IL6 and CRP levels. Visfatin gene expression in VAT and SAT was strongly related to IL6 and TNFα expression. Conclusion In a homogeneous cohort of morbidly obese women, our findings show that visfatin has a strong relationship with pro‐inflammatory factors in severe obesity.