Time course of changes in heart rate and blood pressure variability in streptozotocin-induced diabetic rats treated with insulin

Autonomic neuropathy is a frequent complication of diabetes associated with higher morbidity and mortality in symptomatic patients, possibly because it affects autonomic regulation of the sinus node, reducing heart rate (HR) variability which predisposes to fatal arrhythmias. We evaluated the time course of arterial pressure and HR and indirectly of autonomic function (by evaluation of mean arterial pressure (MAP) variability) in rats (164.5 ± 1.7 g) 7, 14, 30 and 120 days after streptozotocin (STZ) injection, treated with insulin, using measurements of arterial pressure, HR and MAP variability. HR variability was evaluated by the standard deviation of RR intervals (SDNN) and root mean square of successive difference of RR intervals (RMSSD). MAP variability was evaluated by the standard deviation of the mean of MAP and by 4 indices (P1, P2, P3 and MN) derived from the three-dimensional return map constructed by plotting MAPn x [(MAPn+1) - (MAPn)] x density. The indices represent the maximum concentration of points (P1), the longitudinal axis (P2), and the transversal axis (P3) and MN represents P1 x P2 x P3 x 10-3. STZ induced increased urinary glucose in diabetic (D) rats compared to controls (C). Seven days after STZ, diabetes reduced resting HR from 380.6 ± 12.9 to 319.2 ± 19.8 bpm, increased HR variability, as demonstrated by increased SDNN, from 11.77 ± 1.67 to 19.87 ± 2.60 ms, did not change MAP, and reduced P1 from 61.0 ± 5.3 to 51.5 ± 1.8 arbitrary units (AU), P2 from 41.3 ± 0.3 to 29.0 ± 1.8 AU, and MN from 171.1 ± 30.2 to 77.2 ± 9.6 AU of MAP. These indices, as well as HR and MAP, were similar for D and C animals 14, 30 and 120 days after STZ. Seven-day rats showed a negative correlation of urinary glucose with resting HR (r = -0.76, P = 0.03) as well as with the MN index (r = -0.83, P = 0.01). We conclude that rats with short-term diabetes mellitus induced by STZ presented modified autonomic control of HR and MAP which was reversible. The metabolic control may influence these results, suggesting that insulin treatment and a better metabolic control in this model may modify arterial pressure, HR and MAP variability

Cytokines produced by susceptible and resistant mice in the course of Paracoccidioides brasiliensis infection

Paracoccidioidomycosis (PCM) is the most prevalent deep mycosis in Latin America and presents a wide spectrum of clinical manifestations. We established a genetically controlled murine model of PCM, where A/Sn mice develop an infection which mimics the benign disease (immune responses which favor cellular immunity) and B10.A animals present the progressive disseminated form of PCM (preferential activation of B cells and impairment of cellular immune responses). To understand the immunoregulatory phenomena associated with resistance and susceptibility in experimental PCM, A/Sn and B10.A mice were studied regarding antigen-elicited secretion of monokines (TNF-a and TGF-ß) and type-1 (IL-2 and IFN-g) and type-2 (IL-4,5,10) cytokines. Total lymph node cells from resistant mice infected ip with P. brasiliensis produced early and sustained levels of IFN-g and IL-2; type-2 cytokines (IL-4 and IL-5) started to appear 8 weeks after infection. In contrast, susceptible mice produced low levels of IFN-g concomitant with significant levels of IL-5 and IL-10 early in the infection. In the chronic phase of the disease, susceptible animals presented a transitory secretion of IL-2, and IL-4. In the pulmonary infection IL-4, IL-5 and IL-10 were preferentially detected in the lung cells washings of susceptible animals. After in vitro challenge with fungal antigens, normal peritoneal macrophages from B10.A mice secreted high levels of TGF-ß and low levels of TNF-a. In contrast, macrophages from A/Sn animals released high levels of TNF-a associated with a small production of TGF-ß. The in vivo depletion of IFN-g not only abrogated the resistance of A/Sn mice but also diminished the relative resistance of B10.A animals. The in vivo depletion of IL-4 did not alter the disease outcome, whereas administration of rIL-12 significantly enhanced resistance in susceptible animals. Taken together, these results suggest that an early secretion of high levels of TNF-a and IFN-g followed by a sustained secretion of IL-2 and IFN-g plays a dominant role in the resistance mechanisms to P. brasiliensis infection. In contrast, an early and ephemeral secretion of low levels of TNF-a and IFN-g associated with production of IL-5, IL-10 and TGF-ß characterizes the progressive disease of susceptible animals.

The mental health of graduate students at the Federal University of São Paulo: a preliminary report

We present data regarding the care provided to graduate level health professionals at the mental health center of the Federal University of São Paulo. From September 1996 to September 2003, 146 graduate students (99 in the Master's degree program and 47 in the Doctoral program) were attended. This population was predominantly female (68.5%), with a mean (± SD) age of 28.6 ± 4.42 years, not married (71.9%). Most of the subjects were professionals who had not graduated from the Federal University (78.1%). The students who sought help for psychological and/or psychiatric problems were classified into two categories: situational-adaptive crises and psychopathological crises. The main diagnoses were depression and anxiety disorders (44%) causing 4.5% of the subjects to be temporarily suspended from their graduate studies; 19.2% reported that they had used psychotropic drugs within the previous month, and 47.9% referred to sleep disturbances. Suicidal tendencies were mentioned by 18% of those interviewed. Students with emotional disturbances and academic dysfunctions should be recognized at an early stage, and it is fundamental for them to have access to mental health programs that provide formal, structured and confidential care. Thus, it is important that professors and advisors in graduate programs build a warm and affective learning environment. If we consider the expressive growth in Brazilian scientific production resulting from the implementation of an extensive national system of graduate education, it is important to focus efforts on enhancing and upgrading the mental health care system.

Financial support of graduate programs in Brazil: quo vadis?

Graduate programs provide the highest level of formal education and thus are crucial for the development of any country. However, official Brazilian data clearly show a dramatic decrease in the number and values of scholarships available to graduate programs in Brazil over the last few years, despite the importance and growth of such programs. Between 1995 and 2004, investment by the Coordenadoria de Aperfeiçoamento de Pessoal do Ensino Superior (CAPES, subordinate to the Ministry of Education and Culture) in funding scholarships, corrected for inflation in the period, actually decreased by 51%. In addition, during the period between 1994 and 2004, there was a loss of about 60% in the purchasing power of the graduate scholarships provided by CAPES and the National Council for Science and Technology (CNPq). To reverse this trend, we propose the development of sectorial funding for Brazilian graduate programs to guarantee the availability and continuity of financial support for this strategic activity.

Glutamic acid decarboxylase antibodies are indicators of the course, but not of the onset, of diabetes in middle-aged adults: the Atherosclerosis Risk in Communities Study

To efficiently examine the association of glutamic acid decarboxylase antibody (GADA) positivity with the onset and progression of diabetes in middle-aged adults, we performed a case-cohort study representing the ~9-year experience of 10,275 Atherosclerosis Risk in Communities Study participants, initially aged 45-64 years. Antibodies to glutamic acid decarboxylase (GAD65) were measured by radioimmunoassay in 580 incident diabetes cases and 544 non-cases. The overall weighted prevalence of GADA positivity (³1 U/mL) was 7.3%. Baseline risk factors, with the exception of smoking and interleukin-6 (P £ 0.02), were generally similar between GADA-positive and -negative individuals. GADA positivity did not predict incident diabetes in multiply adjusted (HR = 1.04; 95%CI = 0.55, 1.96) proportional hazard analyses. However, a small non-significant adjusted risk (HR = 1.29; 95%CI = 0.58, 2.88) was seen for those in the highest tertile (³2.38 U/mL) of positivity. GADA-positive and GADA-negative non-diabetic individuals had similar risk profiles for diabetes, with central obesity and elevated inflammation markers, aside from glucose, being the main predictors. Among diabetes cases at study's end, progression to insulin treatment increased monotonically as a function of baseline GADA level. Overall, being GADA positive increased risk of progression to insulin use almost 10 times (HR = 9.9; 95%CI = 3.4, 28.5). In conclusion, in initially non-diabetic middle-aged adults, GADA positivity did not increase diabetes risk, and the overall baseline profile of risk factors was similar for positive and negative individuals. Among middle-aged adults, with the possible exception of those with the highest GADA levels, autoimmune pathophysiology reflected by GADA may become clinically relevant only after diabetes onset.

The time course of ethanol tolerance: associative learning

The effect of different contextual stimuli on different ethanol-induced internal states was investigated during the time course of both the hypothermic effect of the drug and of drug tolerance. Minimitters were surgically implanted in 16 Wistar rats to assess changes in their body temperature under the effect of ethanol. Rat groups were submitted to ethanol or saline trials every other day. The animals were divided into two groups, one receiving a constant dose (CD) of ethanol injected intraperitoneally, and the other receiving increasing doses (ID) during the 10 training sessions. During the ethanol training sessions, conditioned stimuli A (tone) and B (buzzer) were presented at "state +" (35 min after drug injection) and "state -" (170 min after drug injection), respectively. Conditioned stimuli C (bip) and D (white noise) were presented at moments equivalent to stimuli A and B, respectively, but during the saline training sessions. All stimuli lasted 15 min. The CD group, but not the ID group, developed tolerance to the hypothermic effect of ethanol. Stimulus A (associated with drug "state +") induced hyperthermia with saline injection in the ID group. Stimulus B (associated with drug "state -") reduced ethanol tolerance in the CD group and modulated the hypothermic effect of the drug in the ID group. These results indicate that contextual stimuli acquire modulatory conditioned properties that are associated with the time course of both the action of the drug and the development of drug tolerance.

Examining life-course influences on chronic disease: the Ribeirão Preto and São Luís birth cohort studies (Brazil)

More than any other low- and middle-income country, Brazil has the longest research tradition of establishing, maintaining and exploiting birth cohort studies. This research pedigree is highlighted in the present issue of the Brazilian Journal of Medical and Biological Research, which contains a series of twelve papers from the Ribeirão Preto and São Luis birth cohort studies from the Southeast and Northeast of Brazil, respectively. The topics covered in this raft of reports vary and include predictors of perinatal health and maternal risk factors, early life determinants of cardiovascular risk factors in childhood and adolescence, use of health services, and a description of dietary characteristics of young adults, amongst other topics. There is also a guide to the background, objectives, sampling and protocols employed across these studies, which, together with similar pieces published in past issues of the Brazilian Journal, serve as a very useful starting point, particularly for potential collaborators. In the fervent hope that further follow-up of these cohorts will take place - we provide our own justification for cohort maintenance and extension in this issue - future data collection could include: genetic material, atherosclerosis, ascertained, for instance, by intima-media thickness, and IQ testing in children - scores from which are emerging as potentially important predictors of adult health outcomes up to six decades later.

Examining life-course influences on chronic disease: the importance of birth cohort studies from low- and middle- income countries. An overview

The objectives of this overview are to describe the past and potential contributions of birth cohorts to understanding chronic disease aetiology; advance a justification for the maintenance of birth cohorts from low- and middle-income countries (LMIC); provide an audit of birth cohorts from LMIC; and, finally, offer possible future directions for this sphere of research. While the contribution of birth cohorts from affluent societies to understanding disease aetiology has been considerable, we describe several reasons to anticipate why the results from such studies might not be directly applied to LMIC. More than any other developing country, Brazil has a tradition of establishing, maintaining and exploiting birth cohort studies. The clear need for a broader geographical representation may be precipitated by a greater collaboration worldwide in the sharing of ideas, fieldwork experience, and cross-country cohort data comparisons in order to carry out the best science in the most efficient manner. This requires the involvement of a central overseeing body - such as the World Health Organization - that has the respect of all countries and the capacity to develop strategic plans for `global' life-course epidemiology while addressing such issues as data-sharing. For rapid progress to be made, however, there must be minimal bureaucratic entanglements.

Time course of training-induced microcirculatory changes and of vegf expression in skeletal muscles of spontaneously hypertensive female rats

Exercise-induced vessel changes modulate arterial pressure (AP) in male spontaneously hypertensive rats (SHR). Vascular endothelial growth factor (VEGF) is important for angiogenesis of skeletal muscle. The present study evaluated the time course of VEGF and angiogenesis after short- and long-term exercise training of female SHR and Wistar Kyoto (WKY) rats, 8-9 weeks (200-250 g). Rats were allocated to daily training or remained sedentary for 3 days (N = 23) or 13 weeks (N = 23). After training, the carotid artery was catheterized for AP measurements. Locomotor (tibialis anterior and gracilis) and non-locomotor skeletal muscles (temporalis) were harvested and prepared for histologic and protein expression analyses. Training increased treadmill performance by all groups (SHR = 28%, WKY = 64%, 3 days) and (SHR = 141%, WKY = 122%, 13 weeks). SHR had higher values of AP than WKY (174 ± 4 vs 111 ± 2 mmHg) that were not altered by training. Three days of running increased VEGF expression (SHR = 28%, WKY = 36%) simultaneously with an increase in capillary-to-fiber ratio in gracilis muscle (SHR = 19%, WKY = 15%). In contrast, 13 weeks of training increased gracilis capillary-to-fiber ratio (SHR = 18%, WKY = 19%), without simultaneous changes in VEGF expression. Training did not change VEGF expression and capillarity of temporalis muscle. We conclude that training stimulates time- and tissue-dependent VEGF protein expression, independent of pressure levels. VEGF triggers angiogenesis in locomotor skeletal muscle shortly after the exercise starts, but is not involved in the maintenance of capillarity after long-term exercise in female rats.

The immunomodulator glatiramer acetate influences spinal motoneuron plasticity during the course of multiple sclerosis in an animal model

The immunomodulador glatiramer acetate (GA) has been shown to significantly reduce the severity of symptoms during the course of multiple sclerosis and in its animal model - experimental autoimmune encephalomyelitis (EAE). Since GA may influence the response of non-neuronal cells in the spinal cord, it is possible that, to some extent, this drug affects the synaptic changes induced during the exacerbation of EAE. In the present study, we investigated whether GA has a positive influence on the loss of inputs to the motoneurons during the course of EAE in rats. Lewis rats were subjected to EAE associated with GA or placebo treatment. The animals were sacrificed after 15 days of treatment and the spinal cords processed for immunohistochemical analysis and transmission electron microscopy. A correlation between the synaptic changes and glial activation was obtained by performing labeling of synaptophysin and glial fibrillary acidic protein using immunohistochemical analysis. Ultrastructural analysis of the terminals apposed to alpha motoneurons was also performed by electron transmission microscopy. Interestingly, although the GA treatment preserved synaptophysin labeling, it did not significantly reduce the glial reaction, indicating that inflammatory activity was still present. Also, ultrastructural analysis showed that GA treatment significantly prevented retraction of both F and S type terminals compared to placebo. The present results indicate that the immunomodulator GA has an influence on the stability of nerve terminals in the spinal cord, which in turn may contribute to its neuroprotective effects during the course of multiple sclerosis.

Can course format influence the performance of students in an advanced cardiac life support (ACLS) program?

Advanced cardiac life support (ACLS) is a problem-based course that employs simulation techniques to teach the standard management techniques of cardiovascular emergencies. Its structure is periodically revised according to new versions of the American Heart Association guidelines. Since it was introduced in Brazil in 1996, the ACLS has been through two conceptual and structural changes. Detailed documented reports on the effect of these changes on student performance are limited. The objective of the present study was to evaluate the effect of conceptual and structural changes of the course on student ACLS performance at a Brazilian training center. This was a retrospective study of 3266 students divided into two groups according to the teaching model: Model 1 (N = 1181; 1999-2003) and Model 2 (N = 2085; 2003-2007). Model 2 increased practical skill activities to 75% of the total versus 60% in Model 1. Furthermore, the teaching material provided to the students before the course was more objective than that used for Model 1. Scores greater than 85% in the theoretical evaluation and approval in the evaluation of practice by the instructor were considered to be a positive outcome. Multiple logistic regression was used to adjust for potential confounders (specialty, residency, study time, opportunity to enhance practical skills during the course and location where the course was given). Compared to Model 1, Model 2 presented odds ratios (OR) indicating better performance in the theoretical (OR = 1.34; 95%CI = 1.10-1.64), practical (OR = 1.19; 95%CI = 0.90-1.57), and combined (OR = 1.38; 95%CI = 1.13-1.68) outcomes. Increasing the time devoted to practical skills did not improve the performance of ACLS students.

Leptin and adiponectin in the female life course

Adipose tissue secretes a variety of adipokines, including leptin and adiponectin, which are involved in endocrine processes regulating glucose and fatty metabolism, energy expenditure, inflammatory response, immunity, cardiovascular function, and reproduction. The present article describes the fluctuations in circulating leptin and adiponectin as well as their patterns of secretion in women from birth to menopause. During pregnancy, leptin and adiponectin seem to act in an autocrine/paracrine fashion in the placenta and adipose tissue, playing a role in the maternal-fetal interface and contributing to glucose metabolism and fetal development. In newborns, adiponectin levels are two to three times higher than in adults. Full-term newborns have significantly higher leptin and adiponectin levels than preterms, whereas small-for-gestational-age infants have lower levels of these adipokines than adequate-for-gestational-age newborns. However, with weight gain, leptin concentrations increase significantly. Children between 5 and 8 years of age experience an increase in leptin and a decrease in adiponectin regardless of body mass index, with a reversal of the newborn pattern for adiponectin: plasma adiponectin levels at age five are inversely correlated with percentage of body fat. In puberty, leptin plays a role in the regulation of menstrual cycles. In adults, it has been suggested that obese individuals exhibit both leptin resistance and decreased serum adiponectin levels. In conclusion, a progressive increase in adiposity throughout life seems to influence the relationship between leptin and adiponectin in women.

Citations to papers from Brazilian institutions: a more effective indicator to assess productivity and the impact of research in graduate programs

A recent assessment of 4400 postgraduate courses in Brazil by CAPES (a federal government agency dedicated to the improvement of the quality of and research at the postgraduate level) stimulated a large amount of manifestations in the press, scientific journals and scientific congresses. This gigantic effort to classify 16,400 scientific journals in order to provide indicators for assessment proved to be puzzling and methodologically erroneous in terms of gauging the institutions from a metric point of view. A simple algorithm is proposed here to weigh the scientometric indicators that should be considered in the assessment of a scientific institution. I conclude here that the simple gauge of the total number of citations accounts for both the productivity of scientists and the impact of articles. The effort spent in this exercise is relatively small, and the sources of information are fully accessible. As an exercise to estimate the value of the methodology, 12 institutions of physics (10 from Brazil, one from the USA and one from Italy) have been evaluated.

Time course of the hemodynamic responses to aortic depressor nerve stimulation in conscious spontaneously hypertensive rats

The time to reach the maximum response of arterial pressure, heart rate and vascular resistance (hindquarter and mesenteric) was measured in conscious male spontaneously hypertensive (SHR) and normotensive control rats (NCR; Wistar; 18-22 weeks) subjected to electrical stimulation of the aortic depressor nerve (ADN) under thiopental anesthesia. The parameters of stimulation were 1 mA intensity and 2 ms pulse length applied for 5 s, using frequencies of 10, 30, and 90 Hz. The time to reach the hemodynamic responses at different frequencies of ADN stimulation was similar for SHR (N = 15) and NCR (N = 14); hypotension = NCR (4194 ± 336 to 3695 ± 463 ms) vs SHR (3475 ± 354 to 4494 ± 300 ms); bradycardia = NCR (1618 ± 152 to 1358 ± 185 ms) vs SHR (1911 ± 323 to 1852 ± 431 ms), and the fall in hindquarter vascular resistance = NCR (6054 ± 486 to 6550 ± 847 ms) vs SHR (4849 ± 918 to 4926 ± 646 ms); mesenteric = NCR (5574 ± 790 to 5752 ± 539 ms) vs SHR (5638 ± 648 to 6777 ± 624 ms). In addition, ADN stimulation produced baroreflex responses characterized by a faster cardiac effect followed by a vascular effect, which together contributed to the decrease in arterial pressure. Therefore, the results indicate that there is no alteration in the conduction of the electrical impulse after the site of baroreceptor mechanical transduction in the baroreflex pathway (central and/or efferent) in conscious SHR compared to NCR.

Interleukin-10-dependent down-regulation of interferon-gamma response to Leishmania by Mycobacterium leprae antigens during the clinical course of a coinfection

We have described a case of a patient with an intriguing association of mucocutaneous leishmaniasis with lepromatous leprosy, two opposite polar forms of these spectral diseases. In the present follow-up study, we investigated the effect of the addition of Mycobacterium leprae antigens on interferon-gamma (IFN-γ) production in Leishmania antigen-stimulated cultures of peripheral blood mononuclear cells (PBMC) from this patient. For this purpose, PBMC cultures were stimulated with crude L. braziliensis and/or M. leprae whole-cell antigen extracts or with concanavalin A. In some experiments, neutralizing anti-human interleukin (IL)-10 antibodies were added to the cultures. IFN-γ and IL-10 levels in culture supernatants were measured by ELISA. During active leprosy, M. leprae antigens induced 72.3% suppression of the IFN-γ response to L. braziliensis antigen, and this suppression was abolished by IL-10 neutralization. Interestingly, the suppressive effect of M. leprae antigen was lost after the cure of leprosy and the disappearance of this effect was accompanied by exacerbation of mucosal leishmaniasis. Considered together, these results provide evidence that the concomitant lepromatous leprosy induced an IL-10-mediated regulatory response that controlled the immunopathology of mucosal leishmaniasis, demonstrating that, in the context of this coinfection, the specific immune response to one pathogen can influence the immune response to the other pathogen and the clinical course of the disease caused by it. Our findings may contribute to a better understanding of the Leishmania/M. leprae coinfection and of the immunopathogenesis of mucosal leishmaniasis.