The Polyol Pathway as a Mechanism for Diabetic Retinopathy: Attractive, Elusive, and Resilient

The polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol, which is then converted to fructose. It is one of the most attractive candidate mechanisms to explain, at least in part, the cellular toxicity of diabetic hyperglycemia because (i) it becomes active when intracellular glucose concentrations are elevated, (ii) the two enzymes are present in human tissues and organs that are sites of diabetic complications, and (iii) the products of the pathway and the altered balance of cofactors generate the types of cellular stress that occur at the sites of diabetic complications. Inhibition (or ablation) of aldose reductase, the first and rate-limiting enzyme in the pathway, reproducibly prevents diabetic retinopathy in diabetic rodent models, but the results of a major clinical trial have been disappointing. Since then, it has become evident that truly informative indicators of polyol pathway activity and/or inhibition are elusive, but are likely to be other than sorbitol levels if meant to predict accurately tissue consequences. The spectrum of abnormalities known to occur in human diabetic retinopathy has enlarged to include glial and neuronal abnormalities, which in experimental animals are mediated by the polyol pathway. The endothelial cells of human retinal vessels have been noted to have aldose reductase. Specific polymorphisms in the promoter region of the aldose reductase gene have been found associated with susceptibility or progression of diabetic retinopathy. This new knowledge has rekindled interest in a possible role of the polyol pathway in diabetic retinopathy and in methodological investigation that may prepare new clinical trials. Only new drugs that inhibit aldose reductase with higher efficacy and safety than older drugs will make possible to learn if the resilience of the polyol pathway means that it has a role in human diabetic retinopathy that should not have gone undiscovered

Mesangial cell abnormalities in spontaneously hypertensive rats before the onset of hypertension

Mesangial cell abnormalities in spontaneously hypertensive rats before the onset of hypertension. To identify kidney biosynthetic abnormalities that may precede the onset of hypertension, we studied the expression of flbronectin (FN) and collagen IV (Coll IV) in young SHR (4 weeks of age) whose systolic blood pressure was normal and similar to that of age-matched control WKY rats. In isolated glomeruli the level of FN protein assessed by immunoblotting tended to be lower in the SHR than in the WKY rats. By Northern analysis the FN/actin mRNA ratio was significantly lower in glomeruli from SHR (0.56 ± 0.47) than in glomeruli from WKY rats (2.0 ± 0.8). These abnormalities were maintained in vitro since the expression of FN was significantly lower in SHR than in WKY cultured mesangial cells (FN/actin mRNA ratio = 0.84 ± 0.46 vs. 1.9 ± 0.7, P = 0.029). No differences in Coll IV mRNA or protein levels were observed in SHR glomeruli and mesangial cells when compared with WKY rats. The levels of aortic FN and Coll IV mRNAs were not different in SHR and WKY rats. In addition, mesangial cells from SHR showed a significantly higher growth rate than those from WKY. The biosynthetic and proliferative abnormalities observed in the SHR mesangial cells appear to reflect genetic characteristics, and could provide novel insights into cellular mechanisms linking the genetics of hypertension with predisposition to glomerular pathology

Defective myogenic response of retinal vessels is associated with accelerated onset of retinopathy in type 1 diabetic individuals

PURPOSE: We seek to identify pathogenic mechanisms for diabetic retinopathy that can become therapeutic targets beyond hyperglycemia and hypertension. We investigated if a defective myogenic response of retinal arteries to increased perfusion pressure, which exposes capillaries to increased pressure and flow, is associated with the onset of clinical retinopathy. METHODS: We examined prospectively the incidence of retinopathy in type 1 diabetic individuals tested 4 years earlier for the retinal arterial myogenic response, and in a cross-sectional study the prevalence of defective myogenic response in type 1 patients who had diabetic retinopathy. Among these, we contrasted early-onset (after 15 \ub1 2 years of diabetes, E-DR; n = 5) to late-onset (after 26 \ub1 3 years of diabetes, L-DR; n = 7) retinopathy. We measured the myogenic response using a laser Doppler blood flowmeter after a change in posture from sitting to reclining, which increases retinal perfusion pressure. RESULTS: Five of seven participants who 4 years prior had a defective myogenic response had now developed clinical retinopathy; as compared with only one of six participants who 4 years prior had a normal response (P = 0.10). In the cross-sectional study, all participants had normal retinal hemodynamics at steady state. In response to the postural change, only the E-DR group showed defective myogenic response (P = 0.005 versus controls, P = 0.02 versus L-DR) and abnormally high retinal blood flow (P = 0.016 versus controls). CONCLUSIONS: In type 1 diabetic patients, a defective myogenic response of retinal arteries to pressure is not required for the development of clinical retinopathy, but is prominently associated with an accelerated onset of retinopathy

SE ESSA PRAÇA, SE ESSA PRAÇA FOSSE NOSSA...”: ESPAÇOS PÚBLICOS E POSSIBILIDADES PARA O LAZER DOS JOVENS DE CAÇADOR/SC

Os jovens, o lazer e as políticas públicas têm sido estudados por diferentes enfoques e objetivos. A produção científica em Educação Física demonstra a crescente visibilidade dessas temáticas também neste campo de conhecimento. Assim, o estudo partiu da seguinte indagação: como o lazer, em suas diversas dimensões culturais, manifesta-se como prática social de jovens de diferentes contextos sócio-econômicos em espaços públicos da cidade de Caçador/SC? Trata-se de estudo observacionaldescritivo cuja metodologia envolveu observações, questionários e grupo focal. Os dados gerados foram interpretados por meio de eixos temáticos/análise de conteúdo. Dentre os aspectos evidenciados, destacam-se o modo de ser dos jovens da cidade e os usos que fazem do espaço. De maneira geral, eles reconhecem o que está satisfatório na infraestrutura, apontam falhas nas ações do poder público e desejos de mudança, mas não se acham incluídos nos processos de elaboração de políticas públicas de lazer na cidade

Pleurotus ostreatus spent mushroom substrate for the degradation of polycyclic aromatic hydrocarbons: the case study of a pilot dynamic biopile for the decontamination of a historically contaminated soil

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are hazardous contaminants. Bio-based technology is among recommended practices for the recovery of PAH contaminatedmatrices. The objective of the study was to validate the exploitation of spent mushroom substrate (SMS), an organic waste deriving from the industrial production of Pleurotus ostreatus, as bulking agent in a dynamic biopile pilot plant, because of the SMS potential oxidative capacity towards aromatic recalcitrant compounds. The dynamic biopile pilot plant treated 7 tons of a historically PAH contaminated soil (6469±423mg PAHs kg−1), classified as dangerous waste. RESULTS: Themixing of SMSwith soilwasmandatory for the depletion of PAHs, which after 8months,were at significantly lower concentrations (112±5mg PAHs kg−1). The treated soil was capable of reintroduction to the industrial site of origin. However, a residual genotoxicity of soil elutriates at the end of the process wasmeasured on root tips of Vicia faba L. CONLUSIONS: The SMS derived from the industrial production of P. ostreatus is exploitable as a versatile low cost organic substrate with oxidative capacity towards PAHs and its exploitation as a bulking agent in biopiles is advantageous for the disposal of the organic waste

A new mouse model for the trisomy of the Abcg1–U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome

Mental retardation in Down syndrome (DS), the most frequent trisomy in humans, varies from moderate to severe. Several studies both in human and based on mouse models identified some regions of human chromosome 21 (Hsa21) as linked to cognitive deficits. However, other intervals such as the telomeric region of Hsa21 may contribute to the DS phenotype but their role has not yet been investigated in detail. Here we show that the trisomy of the 12 genes, found in the 0.59 Mb (Abcg1–U2af1) Hsa21 sub-telomeric region, in mice (Ts1Yah) produced defects in novel object recognition, open-field and Y-maze tests, similar to other DS models, but induces an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. Overall, we demonstrate the contribution of the Abcg1–U2af1 genetic region to cognitive defect in working and short-term recognition memory in DS models. Increase in copy number of the Abcg1–U2af1 interval leads to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpoints several genes, such as Ndufv3, Wdr4, Pknox1 and Cbs, as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. Our work unravels the complexity of combinatorial genetic code modulating different aspect of mental retardation in DS patients. It establishes definitely the contribution of the Abcg1–U2af1 orthologous region to the DS etiology and suggests new modulatory pathways for learning and memory

Increased expression of basement membrane components in human endothelial cells cultured in high glucose

Basement membrane thickening is the most prominent and characteristic feature of early diabetic microangiopathy. Unknown is not only the causative process but also whether the thickening reflects increased synthesis of specific components. Because collagen type IV is uniquely present in basement membranes and represents their predominant structural element, we studied its expression in retinas obtained postmortem from five patients with 8±3 yr of diabetes and six nondiabetic controls. The collagen IV transcript proved to be rare in adult human retina and undetectable by Northern analysis. We thus identified a set of primers and conditions to detect the transcript by the reverse transcriptase polymerase chain reaction and to measure its level relative to an endogenous internal standard (ft-actin mRNA). In the diabetic patients the levels of collagen IV mRNA were increased twofold over levels in controls, whereas the actin mRNA levels were similar in the two groups. Hence, the collagen IV/actin ratio was 0.53±0.15 in diabetic samples and 0.24±0.09 in control samples (P = 0.004). These results indicate that diabetes induces a twofold increase in the expression of collagen IV by the cells that synthesize basement membranes in the adult retina (vascular cells). Insofar as high ambient glucose in vitro elicits the same effect, it may be proposed that basement membrane thickening in diabetes results from enhanced synthesis of specialized component molecules sustained by hyperglycemia. (J. Clin. Invest. 1994. 93:438-442). Key words: basement membrane thickening * diabetic microangiopathy * type IV collagen * polymerase chain reactio

SISAIH: a Case-Based Reasoning Tool for Hospital Admission Authorization Management

In health care public programs, huge amounts of data are stored in computer systems: patient record, medical knowledge, or fi- nancial data. This paper describes the development process of a support tool for health care named SISAIH. This system reuses knowledge contained in hospital databases, and is aimed at detecting irregularities in the Brazilian health public system. The system was developed using an innovative approach to the knowledge acquisition process. Moreover a special case model is proposed, which aggregates two or more real patient admission cases to build a unique system case. This was motivated by the special requirements of the problem to solve, i.e., to support the decision making process in the control and evaluation of the Hospital admission authorization