HbA1c variability and long-term glycemic control are linked to peripheral neuropathy in patients with type 1 diabetes.

BACKGROUND: HbA1c variability has been linked to retinopathy, renal disease and autonomic neuropathy in patients with type 1 diabetes mellitus (T1D) and type 2 diabetes mellitus (T2D). Although the same relationship has been demonstrated for diabetic peripheral neuropathy (DPN) in patients with T2D, data for T1D are still lacking. METHODS: Patients older than 17 years of age with ≥ 10 years of T1D duration and follow-up were included. All patients underwent nerve conduction studies and neurological examination. Laboratorial data was retrospectively extracted from chart review. Mean HbA1c (mHbA1c) over 10 years was calculated, as well as HbA1c variability estimated by standard deviation (HbA1c-SD) and coefficient of variation (HbA1c-CV). RESULTS: Fifty patients with T1D were included (30 females and 21 non-caucasians), with mean age and T1D duration of 25.6 ± 5.0 and 17.9 ± 6.1 years, respectively. The frequency of DPN was 24%. Higher mHbA1c (10.4 ± % vs 8.1 ± %; p < 0.001), HbA1c-SD (1.8 ± 0.8 vs 0.9 ± 0.4; p < 0.001), and HbA1c-CV (1.7 ± 0.8 vs 1.2 ± 1.1; p = 0.006) were observed in patients with DPN compared to others. SD-HbA1c and HbA1c-CV were associated with DPN, diagnosed by either clinical or NCS criteria, independent of mHbA1c, age and gender. CONCLUSIONS: Not only long-term glycemic control, but also its variability is associated with DPN in patients with T1D. Larger studies are required to confirm this finding.

Acute Strongyloides venezuelensis infection did not prevent EAE development: implications for hygiene hypothesis.

Prevalence of allergic and autoimmune pathologies is clearly increasing in developed countries. This has been attributed to a decreased exposure to certain microorganisms and been referred as hygiene hypothesis. In this study we evaluated if a previous infection with Strongyloides venezuelensis would alter the progression of experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Animals were initially infected with 4000 L3 infective larvae of S. venezuelensis by subcutaneous route. Encephalomyelitis was then induced during the acute phase of the infection by immunization with myelin basic protein emulsified with Complete Freund's Adjuvant plus Mycobacterium butyricum. Previous infection downmodulated cytokine production but did not change clinical and histopathological EAE manifestations. Cytometric analysis with antibodies specific for CD4+CD25+Foxp3+ regulatory T cells indicated that infection also did not alter the frequency of these cells in spleen and regional lymph nodes. This finding could partly explain the failure of this worm to avoid EAE progression. Altogether these results demonstrated that infection with S. venezuelensis was not able to modify EAE progression in Lewis rats. In the context of the hygiene hypothesis, these results reinforce the necessity of a comparative study among different helminth species to identify the ones with immunoregulatory competence.

Bacille Calmette-Guérin/DNAhsp65 prime-boost is protective against diabetes in non-obese diabetic mice but not in the streptozotocin model of type 1 diabetes.

Type I diabetes is a disease caused by autoimmune destruction of the beta cells in the pancreas that leads to a deficiency in insulin production. The aim of this study was to evaluate the prophylactic potential of a prime-boost strategy involving bacille Calmette-Guérin (BCG) and the pVAXhsp65 vaccine (BCG/DNAhsp65) in diabetes induced by streptozotocin (STZ) in C57BL/6 mice and also in spontaneous type 1 diabetes in non-obese diabetic (NOD) mice. BCG/DNAhsp65 vaccination in NOD mice determined weight gain, protection against hyperglycaemia, decreased islet inflammation, higher levels of cytokine production by the spleen and a reduced number of regulatory T cells in the spleen compared with non-immunized NOD mice. In the STZ model, however, there was no significant difference in the clinical parameters. Although this vaccination strategy did not protect mice in the STZ model, it was very effective in NOD mice. This is the first report demonstrating that a prime-boost strategy could be explored as an immunomodulatory procedure in autoimmune diseases.

Modulation of anxiety-like behavior by the endocannabinoid 2-arachidonoylglycerol (2-AG) in the dorsolateral periaqueductal gray.

Anandamide and 2-arachidonoylglycerol (2-AG) are the two main endocannabinoids, exerting their effects by activating type 1 (CB1r) and type 2 (CB2r) cannabinoid receptors. Anandamide inhibits anxiety-like responses through the activation of CB1r in certain brain regions, including the dorsolateral periaqueductal gray (dlPAG). 2-AG also attenuates anxiety-like responses, although the neuroanatomical sites for these effects remained unclear. Here, we tested the hypothesis that enhancing 2-AG signaling in the dlPAG would induce anxiolytic-like effects. The mechanisms involved were also investigated. Male Wistar rats received intra-dlPAG injections of 2-AG, URB602 (inhibitor of the 2-AG hydrolyzing enzyme, mono-acylglycerol lipase--MGL), AM251 (CB1r antagonist) and AM630 (CB2r antagonist). The behavior was analyzed in the elevated plus maze after the following treatments. Exp. 1: vehicle (veh) or 2-AG (5 pmol, 50 pmol, and 500 pmol). Exp. 2: veh or URB602 (30 pmol, 100 pmol or 300 pmol). Exp. 3: veh or AM251 (100 pmol) followed by veh or 2-AG (50 pmol). Exp. 4: veh or AM630 (1000 pmol) followed by veh or 2-AG. Exp. 5: veh or AM251 followed by veh or URB602 (100 pmol). Exp. 6: veh or AM630 followed by veh or URB602. 2-AG (50 pmol) and URB602 (100 pmol) significantly increased the exploration of the open arms of the apparatus, indicating an anxiolytic-like effect. These behavioral responses were prevented by CB1r (AM251) or CB2r (AM630) antagonists. Our results showed that the augmentation of 2-AG levels in the dlPAG induces anxiolytic-like effects. The mechanism seems to involve both CB1r and CB2r receptors.

Experimental autoimmune encephalomyelitis evolution was not modified by multiple infections with Strongyloides venezuelensis.

According to the hygiene hypothesis, the increased incidence of allergic and autoimmune diseases in developed countries is mainly explained by the decreased contact between the human population and certain environmental agents as lactobacillus, mycobacteria and helminths. In this study, we evaluated the effect of multiple infections with Strongyloides venezuelensis on the development of experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Multiple infections before EAE induction were not able to change the evolution of the disease. No alterations were observed in weight loss, clinical score and inflammation intensity at the central nervous system. The presence of significant levels of parasite-specific IgG1 but not IgG2b suggested a Th2 polarization. However, the percentage and absolute number of CD4+CD25+Foxp3+ T cells were not changed, being their levels in the spleen and lymph nodes of infected rats comparable to the ones found in normal animals. These results suggest that a Th2-polarized response without concomitant expansion of Foxp3+ regulatory T cells was not able to modify EAE progression. Even though these results do not threaten the hygiene hypothesis, they suggest that this paradigm might be an oversimplification. They also emphasize the need of a study to compare the immunoregulatory ability associated with different helminth spp.

[Hypomelanosis of Ito - case report] / Hipomelanose de Ito - relato de um caso.

OBJECTIVES: The authors report a case of hypomelanosis of Ito (HI), a rare neurocutaneous syndrome with neurological and chromosomal alterations associated with cutaneous involvement and recurrent pneumonia. CASE REPORT: A male patient, age 1 year and 11 months, was admitted with bilateral bronchopneumonia to the São Vicente de Paulo Hospital. Examination revealed hypochromic maculas on the skin, compatible with HI, and a delay in neuropsychomotor development. The patient was submitted to incisive biopsy of the abdominal skin lesions, electroencephalogram, magnetic resonance, and cytogenetic evaluation. RESULTS: Histology and immunohistochemistry evinced absence of melanin and reductio of melanocyte in focal areas of the epidermis. The electroencephalogram revealed diffuse cortico-subcortical dysfunction. Encephalic magnetic resonance imaging was compatible with arachnoid cyst in the temporal region. Karyotype showed chromosome mosaicism (46, XY) and interstitial deletion of bands 22.2 to 24.4 of the long arm of chromosome 10 (25%). CONCLUSIONS: Analysis of skin lesions is important for the etiologic definition of neuropediatric disorders.