Genetic,Immunological, and Metabolic Determinants of Risk for Type 1 Diabetes Mellitus in Families

Prospective studies of the relatives of people with Type 1 diabetes can provide insights into risk factors for processes leading to the ultimate destruction of the pancreatic islet 8-cells. Relatives ascertained through the Children's Hospital of Pittsburgh diabetes registry were followed and rates of conversion to diabetes were determined. We studied the role of genetic and immunological markers, and used the oral glucose tolerance test (OGTT) to study metabolic disturbances among first-degree relatives. A group of siblings was serotyped for the HLA-A and -B antigens, and the degree of HLA haplotype sharing with the diabetic sibling was established. Later, islet cell antibody (ICA) assays were performed, and subjects were followed to determine the predictive value of ICA testing for the subsequent development of diabetes. The rate of conversion to diabetes among the siblings was 14 times greater than the rate observed in the general population from which they come. This is comparable to rates observed by other centres following relatives of people with Type 1 diabetes. Impaired glucose tolerance (by National Diabetes Data Group (USA) criteria) carried a three-fold greater risk for subsequent Type 1 diabetes than did a normal OGTT. Those relatives with detectable ICA were about 50 times more likely to convert to diabetes than were those without ICA. In a group of siblings in whom HLA haplotype sharing was determined, the prevalence of detectable ICA was greater among those who were HLA-identical to the diabetic sibling (9.9 %) than among those who were haplo-identical (5.3 %) or completely dissimilar (2.4 %) at the HLA-A and -B regions. Similarly, the incidence of Type 1 diabetes was greater among those who were HLA-identical (8.4 per 10³ sibling-years), than among those who were not HLA-identical to the proband (4.2 per 10³). The greatest risk for subsequent diabetes was found among HLA-identical siblings who were ICA-positive. Approximately 7 % of those who were HLA non-identical or haplo-identical and ICA-positive became diabetic within 5 years, while more than 30 % of HLA-identical siblings who were ICA-positive became diabetic during the 5 years after ICA were detected.     

The Acute Cardiorenal Syndrome Type I: Considerations on Physiology,Epidemiology, and Therapy

Acute cardiorenal syndrome, also known as cardiorenal syndrome type 1, is defined as an abrupt worsening of cardiac function that occurs in at least 30 % of patients with acute decompensated heart failure and can lead to the development of acute kidney injury. The changes in renal function that occur in this setting have variable prognostic implications, as both poorer and better outcomes have been reported when renal function worsens during treatment of heart failure decompensation. Furthermore, it remains unclear when worsening renal function is actually a manifestation of true acute kidney injury or simply an indicator of hemoconcentration. Given these gaps in the understanding of the significance of renal function changes in the setting of decompensated heart failure, it is not surprising that studies on the effects of available therapies, including diuretics, vasoactive drugs, and mechanical fluid removal have yielded inconsistent results. The purpose of this review is to analyze critically the current knowledge on the pathophysiology, epidemiology, prognosis, and treatment of acute cardiorenal syndrome.     

Type I and Type II Interferon Antagonism Strategies Used by Paramyxoviridae: Previous and New Discoveries,in Comparison

Paramyxoviridae is a viral family within the order of Mononegavirales; they are negative single-strand RNA viruses that can cause significant diseases in both humans and animals. In order to replicate, paramyxoviruses–as any other viruses–have to bypass an important protective mechanism developed by the host’s cells: the defensive line driven by interferon. Once the viruses are recognized, the cells start the production of type I and type III interferons, which leads to the activation of hundreds of genes, many of which encode proteins with the specific function to reduce viral replication. Type II interferon is produced by active immune cells through a different signaling pathway, and activates a diverse range of genes with the same objective to block viral replication. As a result of this selective pressure, viruses have evolved different strategies to avoid the defensive function of interferons. The strategies employed by the different viral species to fight the interferon system include a number of sophisticated mechanisms. Here we analyzed the current status of the various strategies used by paramyxoviruses to subvert type I, II, and III interferon responses.     

Type I Osteogenesis Imperfecta: Diagnostic Difficulties

A 65-year-old woman presented with vertebral fractures of the lumbar spine and a history of pathological fractures following minor trauma, which had occurred before the onset of menopause. Her past medical history was significant for intermittent low back pain since childhood, which was attributed to thoracolumbar scoliosis. A diagnosis of unclassifiable osteoporosis was made until invasive diagnostic procedures suggested a mild form of type I osteogenesis imperfecta (OI). In unclear or atypical perimenopausal osteoporosis and diagnosis of OI should be considered. Received: 16 February 1998 / Accepted: 4 May 1998     

Errors, mitochondrial dysfunction and ageing

Experiments in yeast have shown that increasing the accuracy of mitochondrial ribosomes increases cellular lifespan, which suggests that mitochondrial ribosomal inaccuracy could be a potential source age-related mitochondrial dysfunction. It is argued that experiments used to test the error-catastrophe theory of ageing could therefore be invalid because only proteins synthesized on 80S cytoplasmic ribosomes were analyzed. It is speculated that in elderly mammals, when growth and mitochondrial replacement rates decline, the increased organelle dwell-time allows manifestation of any loss of mito-ribosomal accuracy. The resultant aberrant polypeptides could then overload the Lon protease, which also degrades oxidatively damaged polypeptides, and thereby contribute to the accumulation of damaged macromolecules, mitochondrial dysfunction and senescence. It is suggested that a search for age-related changes in the accuracy of mitochondrial ribosomes be carried out to test the validity or otherwise of these ideas.     

Families, parks, gardens and toxocariasis.

Toxocara canis antibody titres were measured in members of 30 families. 73/140 (52.1%) family members were seropositive for T. canis at a dilution greater than or equal to 1:50 and 11 (7.8%) had reciprocal titres greater than or equal to 800. Toxocara ova were sought (a) in relation to the 30 families and (b) in the community. No toxocara ova were found in household dust samples. 38% of family gardens contained toxocara ova while 6% of soil samples from public parks and open spaces around housing estates were positive. None of the faecal specimens from pet dogs were positive for toxocara ova as compared to 6.2% of stray dogs. 5.3% of canine faecal samples from the streets contained toxocara ova. In this study household garden soil was a potentially greater source of toxocara infection than soil in public parks and open spaces.     

Errors in Pressure Gradient Measurement in Prosthetic Aortic Valves Due To Pressure Recovery: Type, Size, and Flow Rate Effects In Vitro

We assessed errors in valvular pressure gradients due to pressure recovery, the variation in aortic pressure with distance from the valve, to explain errors in catheter measurements and simultaneous continuous-wave Doppler/catheter studies. Ten types and three sizes of valves were tested in vitro. Aortic pressure was measured by catheter between 1 and 6 cm from the valve. Pressure recovery was quantified as the slope of the gradient with distance from the annulus. Valve type, size, and flow rate effects were determined by analysis of variance. Relationships between Doppler and maximal catheter gradients were also analyzed statistically. The slope of pressure recovery was significantly higher in smaller valves (P< 0.01), in bioprosthetic rather than mechanical valves (P < 0.001), and at higher flows (P < 0.0001). Doppler I catheter slopes were dependent on valve type and size, with more overestimation by Doppler in mechanical (P < 0.01) and larger valves (P < 0.01). Errors due to catheter positioning are more likely wherever effects of pressure recovery are higher: in bioprosthetic valves, smaller valves, and at higher flow rates. Pressure recovery can explain overestimation by Doppler only if localized gradients closer than 1 cm from the valve exist. Clinicians should be aware of these effects of pressure recovery when making major diagnostic and therapeutic decisions.     

日本血吸虫感染兔Ⅰ型和Ⅲ型胶原动态变化及干扰素-γ对其的作用

目的　观察感染日本血吸虫的新西兰兔肝脏Ⅰ型和Ⅲ型胶原的动态变化以及γ 干扰素 (IFN γ)对Ⅰ型和Ⅲ型胶原的降解作用。方法　日本血吸虫感染兔在感染后不同时期取 8只病兔肝脏 ,作常规石蜡切片 ,分别进行免疫组织化学α SMA染色、伊红染色和天狼红染色 ,并在偏光显微镜下观察Ⅰ型和Ⅲ型胶原分布情况 ,计算机图像分析计算胶原含量。感染 16wk后 ,给予吡喹酮治疗 ,IFN γ治疗 8wk ,停药观察 4wk。观察IFN γ对Ⅰ型和Ⅲ型胶原沉积的降解作用。结果　感染日本血吸虫的病兔Ⅰ型胶原在第 8周时占总面积百分比的 5 73± 3 40 ,至第2 8周时达总面积百分比的 40 14± 17 0 0 ,约增加了 7倍 ;Ⅲ型胶原则由第 8周时总面积百分比的 1 15± 1 34增加到6 80± 5 19。α SMA阳性细胞表达数则由 2 8± 1 0增加至 7 3± 1 5。自血吸虫感染 16wk开始采用IFN γ治疗 ,8wk后 ,IFN γ治疗组的Ⅰ型和Ⅲ型胶原所占面积百分比分别由原来的 18 5 1± 7 5 2和 4 63± 3 64下降为 2 4wk时的3 0 9± 1 5 4和 0 40± 0 37(P <0 0 1) ,模型对照组和吡喹酮治疗组比较差异具有显著性 (P <0 0 1)。停药 4wk后IFN γ治疗组的Ⅰ型和Ⅲ型胶原所占面积百分比均有所回升 (P <0 0 5 )。结论　IFN γ对日本血吸虫感染的新西兰兔肝纤