Subcutaneous insulin B:9-23/IFA immunisation induces Tregs that control late-stage prediabetes in NOD mice through IL-10 and IFNγ

Aims/hypothesis  

Subcutaneous immunisation with the 9–23 amino acid region of the insulin B chain (B:9-23) in incomplete Freund’s adjuvant (IFA) can protect the majority of 4- to 6-week-old prediabetic NOD mice and is currently in clinical trials. Here we analysed the effect of B:9-23/IFA immunisation at later stages of the disease and the underlying mechanisms.     

The fetal and neonatal brain protein neuronatin protects PC12 cells against certain types of toxic insult

The protein neuronatin is expressed in the nervous system of the fetus and neonate at a much higher level than in the adult. Its function is unknown. As a result of variable splicing, neuronatin mRNA exists in two forms, alpha and beta. Wild type PC12 cells express neuronatin-alpha. We have isolated a PC12 variant, called 1.9, that retains many of the neuron-like properties of wild type PC12 cells, but it does not express neuronatin and it exhibits markedly increased sensitivity to the toxic effects of nigericin, rotenone and valinomycin. Pretreatment of the 1.9 cells with alpha-methyltyrosine, which inhibits dopamine synthesis, had little effect on the cells' sensitivity to nigericin, rotenone or valinomycin indicating that dopamine-induced oxidative stress was not involved in the toxicity of these compounds. However, flattened cell subvariants of the 1.9 cells, which do not have any neuron-specific characteristics, did not exhibit increased sensitivity to nigericin indicating that some neuronal characteristic of the 1.9 cells contributed to the toxicity of nigericin. After the neuronatin-beta gene was transfected into and expressed in the 1.9 cells, they regained wild type PC12 levels of resistance to nigericin, rotenone and valinomycin. These studies suggest that the function of neuronatin during development could be to protect developing cells from toxic insult occurring during that period.     

Comparative evaluation of two fixed doses of 185 and 370 MBq 131I, for the treatment of Graves' disease resistant to antithyroid drugs

Radioiodine (131I) treatment is often applied for the treatment of Graves' disease (GD). The optimal dose of 131I for Graves' hyperthyroidism is debated. Various techniques suggest either fixed doses or varying doses based on elaborate calculations of the gland size, 131I uptake, and 131I turnover. Fixed dose regimens avoid dose calculations but there is no consensus on the actual dose to be administered. We compared two routinely recommended fixed 131I doses of 185 and 370 MBq for this purpose. Fifty nine patients with GD who had not been previously treated with 131I were randomized in two groups. Group A consisted of 33 patients who were treated with 185 MBq of 131I. Group B consisted of 26 patients who were treated with 370 MBq of 131I. Group A patients were 21% male and 78% female, mean age 38.1+/-14.4, range 15 to 77 y. Group B patients were 27% male and 73% female, mean age 40.7+/-11.7, range 27 to 72 y. All patients were reexamined every six months for two years. The following clinical outcomes were noticed: a) Persistent hyperthyroidism, which was considered as failure to treatment, requiring further 131I treatment. b) Hypothyroidism; requiring life-long replacement treatment. c) Euthyroid state. Euthyroid and hypothyroid states were considered as a response to treatment of hyperthyroidism. In Group A, 10 patients (30.3%) became euthyroid and 6 (18.2%) hypothyroid (an overall response of 48.5%), while 17 (51.5%) remained hyperthyroid by the end of the follow-up period. In Group B, 10 patients (38%) became euthyroid and 13 (50%) hypothyroid, an overall response of 88.5%. Non responders were 3 patients (11.5%). No correlation was noted between the outcome of treatment and age, sex, size of the thyroid gland or thyroid uptake in each Group of patients, while a significant correlation was noted between the disease outcome and the amount of administered 131I (P<0.003). The incidence of hypothyroidism by the end of two years of follow up was less in Group A than in Group B and the incidence of non responders to treatment was lower in Group A. In view of the higher cost of treatment, the longer time elapsing to treatment, the number of office visits by the patients and the higher number of patients with persistent hyperthyroidism in Group A, we conclude that a fixed dose of 131I of 370 MBq is more useful and effective for the treatment of GD as compared to 185 MBq of 131I.     

Role of regulatory dendritic cells in allergy and asthma

Dendritic cells (DCs) are the most efficient inducers of all immune responses, and are capable of either inducing productive immunity or maintaining the state of tolerance to self antigens and allergens. In this review, we summarize the emerging literature on DCs, with emphasis on the regulatory function of DCs in allergy and asthma. In particular, we summarize recent data regarding the relationship between DC subsets and T_H1, T_H2, and regulatory T (T_Reg) cells. The diverse functions of DCs have been attributed to distinct lineages of DCs, which arise from common immature precursor cells that differentiate in response to specific maturationinducing or local microenvironment conditions. These subsets of DCs induce different lineages of T cells, such as T_H1, T_H2, and T_Reg cells, including Th1_Reg and Th2_Reg cells, which regulate allergic diseases and asthma. Subsets of DCs regulate the induction of a variety of T-cell subtypes, which suppress the development of allergy and asthma, thus providing antiinflammatory responses and protective immunity.     

Screening for vesicoureteral reflux and renal scars in siblings of children with known reflux

The incidence of vesicoureteral reflux (VUR) in the general population is less than 1%, but it is high in families with reflux. The reported prevalence of VUR among siblings of index patients with reflux has ranged from 4.7% to 51%. Reflux carries an increased risk of pyelonephritis and long-term renal impairment. The purpose of this study was to identify the age-related incidence and severity of reflux, and the frequency of associated renal parenchymal damage in siblings of children with reflux in order to assess the use of screening at different ages. Between October 1994 and February 2003, 40 siblings of 34 index patients were screened with direct voiding cystography. 99( m ) technetium (Tc)-dimercaptosuccinic acid (DMSA) nuclear renal scans were performed in siblings with VUR to detect renal scarring. The cystograms were interpreted as showing the presence or absence of VUR and the DMSA scan as symmetrical or asymmetrical differential function, with or without renal scarring. Of 40 siblings, 17 had VUR, representing an incidence of 42.5%. The mean age at study entry of the 15 boys and 25 girls was 63 months (range 6 months to 12 years). The majority of siblings with abnormal DMSA scans were asymptomatic. Reflux was unilateral in 12 siblings and bilateral in 5. Of the 17 refluxing siblings (22 refluxing ureters), 7 (41.17%) had a history of symptomatic urinary tract infection (UTI). The frequency of VUR was nearly equal in siblings over 6 years and those younger than 6 years. Of the 17 siblings with VUR, 16 had DMSA scintigraphy. Of these, 5 were normal and 11 (68.75%) showed abnormalities (7 asymmetrical differential function and 4 parenchymal defect), which was bilateral in 7 and unilateral in 4. In conclusion, this study confirms a significant overall incidence of VUR and renal parenchymal damage in the siblings of patients with known reflux. The prevalence of reflux in older siblings is similar to that in younger siblings. Our review suggests that all siblings over 6 years should undergo a screening cystogram, even in the absence of urinary tract infection. DMSA scintigraphy of asymptomatic siblings appears to be beneficial in preventing renal injury.     

Alterations in expression of endometrial endothelial nitric oxide synthase and alpha(v)beta(3) integrin in women with endometriosis

OBJECTIVE: To determine the expression of endometrial endothelial nitric oxide synthase (eNOS) protein and alpha(v)beta(3) integrin in patients with and without endometriosis. DESIGN: Case-control cohort study. SETTING: University-based tertiary care center. PATIENT(S): Endometrial biopsy samples were obtained from 9 fertile women with regular cycles and 30 infertile women with varying severity of endometriosis. Peritoneal fluid levels of nitric oxide were determined in 13 infertile women with a normal pelvis and 12 infertile women with endometriosis. MAIN OUTCOME MEASURE(S): Expression of eNOS and alpha(v)beta(3) integrin protein in the endometrium and peritoneal fluid levels of nitric oxide. RESULTS: In patients with endometriosis, expression of eNOS was significantly increased in the glandular and luminal epithelium, with no significant changes in the stroma. Peritoneal fluid levels of nitric oxide were unchanged, and expression of alpha(v)beta(3) integrin expression in glandular and luminal epithelium was significantly decreased compared with controls. A significant negative correlation was observed between luminal expression of eNOS and alpha(v)beta(3) integrin and between glandular expression of eNOS and luminal expression of alpha(v)beta(3) integrin. CONCLUSION(S): The nitric oxide pathway may play a role in the pathogenesis of endometriosis.     

Thymoma associated with malignancies may herald a hereditary cancer syndrome

Two probands with thymoma and other primary malignancies with multiple cancer patients in the family are described. Types of malignancies, pattern of pedigree and age of the patients do not match the known familial cancer syndromes. One proband was a very rare case with five discrete primary malignancies; TP53 sequencing and karyotyping did not reveal any mutations. These cases suggest thymoma associated malignancies may herald a hereditary cancer syndrome.