C-Peptide Levels and Insulin Independence Following Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in Newly Diagnosed Type 1 Diabetes Mellitus

Context In 2007, the effects of the autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in 15 patients with type 1 diabetes mellitus (DM) were reported. Most patients became insulin free with normal levels of glycated hemoglobin A(1c) (HbA(1c)) during a mean 18.8-month follow-up. To investigate if this effect was due to preservation of beta-cell mass, continued monitoring was performed of C-peptide levels after stem cell transplantation in the 15 original and 8 additional patients. Objective To determine C-peptide levels after autologous nonmyeloablative HSCT in patients with newly diagnosed type 1 DM during a longer follow-up. Design, Setting, and Participants A prospective phase 1/2 study of 23 patients with type 1 DM(aged 13-31 years) diagnosed in the previous 6 weeks by clinical findings with hyperglycemia and confirmed by measurement of serum levels of anti glutamic acid decarboxylase antibodies. Enrollment was November 2003-April 2008, with follow-up until December 2008 at the Bone Marrow Transplantation Unit of the School of Medicine of Ribeirao Preto, Ribeirao Preto, Brazil. Hematopoietic stem cells were mobilized via the 2007 protocol. Main Outcome Measures C-peptide levels measured during the mixed-meal tolerance test, before, and at different times following HSCT. Secondary end points included morbidity and mortality from transplantation, temporal changes in exogenous insulin requirements, and serum levels of HbA1c. Results During a 7- to 58-month follow-up (mean, 29.8 months; median, 30 months), 20 patients without previous ketoacidosis and not receiving corticosteroids during the preparative regimen became insulin free. Twelve patients maintained this status for a mean 31 months (range, 14-52 months) and 8 patients relapsed and resumed insulin use at low dose (0.1-0.3 IU/kg). In the continuous insulin-independent group, HbA(1c) levels were less than 7.0% and mean (SE) area under the curve (AUC) of C-peptide levels increased significantly from 225.0 (75.2) ng/mL per 2 hours pretransplantation to 785.4 (90.3) ng/mL per 2 hours at 24 months posttransplantation (P<.001) and to 728.1 (144.4) ng/mL per 2 hours at 36 months (P=.001). In the transient insulin-independent group, mean (SE) AUC of C-peptide levels also increased from 148.9 (75.2) ng/mL per 2 hours pretransplantation to 546.8 (96.9) ng/mL per 2 hours at 36 months (P=.001), which was sustained at 48 months. In this group, 2 patients regained insulin independence after treatment with sitagliptin, which was associated with increase in C-peptide levels. Two patients developed bilateral nosocomial pneumonia, 3 patients developed late endocrine dysfunction, and 9 patients developed oligospermia. There was no mortality. Conclusion After a mean follow-up of 29.8 months following autologous nonmyeloablative HSCT in patients with newly diagnosed type 1 DM, C-peptide levels increased significantly and the majority of patients achieved insulin independence with good glycemic control. Trial Registration clinicaltrials.gov Identifier: NCT00315133

The involvement of CD4(+)CD25(+) T cells in the acute phase of Trypanosoma cruzi infection

The infection with Trypanosoma cruzi leads to a vigorous and apparently uncontrolled inflammatory response in the heart. Although the parasites trigger specific immune response, the infection is not completely cleared out, a phenomenon that in other parasitic infections has been attributed to CD4(+)CD25(+) T cells (Tregs). Then, we examined the role of natural Tregs and its signaling through CD25 and GITR in the resistance against infection with T. cruzi. Mice were treated with mAb against CD25 and GITR and the parasitemia, mortality and heart pathology analyzed. First, we demonstrated that CD4(+)CD25(+)GITR(+)Foxp3(+) T cells migrate to the heart of infected mice. The treatment with anti-CD25 or anti-GITR resulted in increased mortality of these infected animals. Moreover, the treatment with anti-GITR enhanced the myocarditis, with increased migration of CD4(+), CD8(+), and CCR5(+) leukocytes, TNF-alpha production, and tissue parasitism, although it did not change the systemic nitric oxide synthesis. These data showed a limited role for CD25 signaling in controlling the inflammatory response during this protozoan infection. Also, the data suggested that signaling through GITR is determinant to control of the heart inflammation, parasite replication, and host resistance against the infection. (C) 2008 Elsevier Masson SAS. All rights reserved.

Effects of progressive exercise during phase I cardiac rehabilitation on the heart rate variability of patients with acute myocardial infarction

Purpose. aEuro integral Heart rate variability (HRV) decreases after an acute myocardial infarction (AMI) due to changes in cardiac autonomic balance. The purpose of the present study, therefore, was to evaluate the effects of a progressive exercise protocol used in phase I cardiac rehabilitation on the HRV of patients with post-AMI. Material and methods. aEuro integral Thirty-seven patients who had been admitted to hospital with their first non-complicated AMI were studied. The treated group (TG, n == 21, age == 52 +/-+/- 12 years) performed a 5-day programme of progressive exercise during phase I cardiac rehabilitation, while the control group (CG, n == 16, age == 54 +/-+/- 11 years) performed only respiratory exercises. Instantaneous heart rate (HR) and RR interval were acquired by a HR monitor (Polar (R) A (R) S810i). HRV was analysed by frequency domain methods. Power spectral density was expressed as normalised units (nu) at low (LF) and high (HF) frequencies, and as LF/HF. Results. aEuro integral After 5 days of progressive exercise, the TG showed an increase in HFnu (35.9 +/-+/- 19.5 to 65.19 +/-+/- 25.4) and a decrease in LFnu and LF/HF (58.9 +/-+/- 21.4 to 32.5 +/-+/- 24.1; 3.12 +/-+/- 4.0 to 1.0 +/-+/- 1.5, respectively) in the resting position (p < 0.05). No changes were observed in the CG. Conclusions. aEuro integral A progressive physiotherapeutic exercise programme carried out during phase I cardiac rehabilitation, as supplement to clinical treatment increased vagal and decreased sympathetic cardiac modulation in patients with post-AMI.

Estimation of R(0) from the initial phase of an outbreak of a vector-borne infection

The magnitude of the basic reproduction ratio R(0) of an epidemic can be estimated in several ways, namely, from the final size of the epidemic, from the average age at first infection, or from the initial growth phase of the outbreak. In this paper, we discuss this last method for estimating R(0) for vector-borne infections. Implicit in these models is the assumption that there is an exponential phase of the outbreaks, which implies that in all cases R(0) > 1. We demonstrate that an outbreak is possible, even in cases where R(0) is less than one, provided that the vector-to-human component of R(0) is greater than one and that a certain number of infected vectors are introduced into the affected population. This theory is applied to two real epidemiological dengue situations in the southeastern part of Brazil, one where R(0) is less than one, and other one where R(0) is greater than one. In both cases, the model mirrors the real situations with reasonable accuracy.

Experimental infection with Rangelia vitalii in dogs: Acute phase, parasitemia, biological cycle, clinical-pathological aspects and treatment

Recently we conducted the molecular characterization of Rangelia vitalii, a protozoan with high pathogenicity for young dogs in southern Brazil. To date, the descriptions of the disease have been restricted to natural infection cases. Therefore, this study aimed to evaluate the parasitemia, biological cycles and clinical-pathological findings in dogs experimentally infected with R. vitalii in the acute phase of disease, and also aimed to test a therapeutic protocol based on the diminazene aceturate. For this study, we used 12 young dogs (females), separated into two groups. Group A was composed of healthy dogs, not-infected (n = 5), and Group B consisted of animals infected with R. vitalii (n = 7). After infection, the animals were monitored by blood smear examinations, which showed intra-erythrocytic forms of the parasite 5 days post-infection (PI). Parasitemia increased progressively in these animals and had the highest peak of circulating parasites between 9 and 11 days PI. Subsequently, the parasitemia reduced and the protozoan was seen inside the leukocytes in days 17, 19 and 21 PI. The most prominent clinical signs observed at the 20 day PI of experiment were lethargy, fever and anorexia. We observed a decrease of hematocrit of infected animals compared with not-infected dogs, featuring a moderate anemia. Pathological evaluation of one dog in Group B at day 21 PI revealed splenomegaly, hepatomegaly, lymphadenopathy, and hemorrhages at necropsy. Histological examination showed only follicular hyperplasia in the spleen and lymph nodes, and the etiologic agent in the vascular endothelium. At 21 days PI, it was performed the treatment of dogs in Group B (n = 6) with a single dose of diminazene aceturate, which showed a curative efficacy of 100% in cleaning R. vitalii from blood of infected dogs. (C) 2011 Elsevier Inc. All rights reserved.

High-pressure phase diagram of the drug mitotane in compressed and/or supercritical CO(2)

This work provides experimental phase diagram of mitotane, a drug used in the chemotherapy treatment of adrenocortical carcinoma, in compressed and/or supercritical CO(2). The synthetic-static method in a high-pressure variable-volume view cell coupled with a transmitted-light intensity probe was used to measure the solid-fluid (SF) equilibrium data. The phase equilibrium experiments were determined in temperature ranging from (298.2 to 333.1) K and pressure up to 22 MPa. Peng-Robinson equation of state (PR-EoS) with classical mixing rule was used to correlate the experimental data. Excellent agreement was found between experimental and calculated values. (C) 2009 Elsevier Ltd. All rights reserved.

Immunohistochemical approach reveals involvement of inducible nitric oxide synthase in rat late development

To better understand the role of nitric oxide (NO) in mammal development, specifically in the transition of the fetal stages at birth, we studied the timing of cell-specific expression of inducible NO synthase (iNOS) isoform during gestational periods of rats, mainly at the late stages of intra-uterine development. Before experimentation, the samples were collected (from 17th to 21st gestational days), fixed in 10% buffered formalin and embedded in paraffin for histological procedures. Hereafter, the sections (5 mu m thickness) obtained from different embryos were immunostained by avidin-biotin-immunoperoxidase technique, by using antibody against iNOS isoform. The most of cell immunopositive was suggestive of granulocyte-like cells and those cells were resident close to the blood vessels in different organs, such as: lung, liver or bone marrow environment. Sometimes we noted immunopositive cells in the blood flow, as reported in the thymus. In agreement, iNOS expression, obtained by western blotting analysis, showed the same profile. Together, our data shows that iNOS expression increased gradually during the late stages of rat development (from E17 to E21) and it was executed by cells close to blood vessels. Thus, we can clearly to predict that this expression was finely modulated and it contributes for time-line dependent NO production during rat late development.

Occlusal outcomes and efficiency of 1-and 2-phase protocols in the treatment of Class II Division 1 malocclusion

Introduction: The purpose of this study was to compare the occlusal outcomes and the efficiency of 1-phase and 2-phase treatment protocols in Class II Division 1 malocclusions. Treatment efficiency was defined as a change in the occlusal characteristics in a shorter treatment time. Methods: Class II Division 1 subjects ( n = 139) were divided into 2 groups according to the treatment protocol for Class II correction. Group 1 comprised 78 patients treated with a 1-phase treatment protocol at initial and final mean ages of 12.51 and 14.68 years. Group 2 comprised 61 patients treated with a 2-phase treatment protocol at initial and final mean ages of 11.21 and 14.70 years. Lateral cephalometric radiographs were taken at the pretreatment stage to evaluate morphological differences in the groups. The initial and final study models of the patients were evaluated by using the peer assessment rating index. Chi-square tests were used to test for differences between the 2 groups for categorical variables. Variables regarding occlusal results were compared by using independent t tests. A linear regression analysis was completed, with total treatment time as the dependent variable, to identify clinical factors that predict treatment length for patients with Class II malocclusions. Results: Similar occlusal outcomes were obtained between the 1-phase and the 2-phase treatment protocols, but the duration of treatment was significantly shorter in the 1-phase treatment protocol group. Conclusions: Treatment of Class II Division 1 malocclusions is more efficient with the 1-phase than the 2-phase treatment protocol.