Molecular mechanisms of diabetic complications

The main molecular process responsible for the development of diabetic complications is the activation of intracellular protein kinase C by long-term hyperglycemia. In ordinary somatic cells (e.g., endothelial or retinal cells) this activation disturbs the metabolism of these cells, whereas a transition into an "excited state" of effector cells such as monocytes or polymorphonuclear leukocytes causes an avalanche-like increase of various pathological processes damaging the body. In relatively compensated diabetes mellitus, when the duration of hyperglycemia is not long and levels of hyperglycemia are not too high, the intensity of the above-mentioned processes is low. However, due to the long time course of reparative processes, some damages which appear in short periods of decompensation can accumulate in the body, finally causing the clinical manifestation of vascular complications of diabetes mellitus.     

Potential complications of influenza A infections

A case of pure red cell aplasia appearing 6 months following thymectomy is reported in a 43-year-old man. Immunofluorescence studies of the patient's bone marrow have demonstrated the presence of membrane-bound IgG on the majority of erythroblasts and some mature erythrocytes. It is suggested that the IgG represents anti-erythroid autoantibodies. The number of Ig-bearing lymphocytes in peripheral blood was decreased as was the level of immunoglobulins indicating a B-lymphocyte deficiency. T-lymphocyte functions were without remarks. The patient was initially treated with corticosteroids and oxymetholone. He responded well to this therapy but relapsed 9 month later. Cyclophosphamide treatment was started and followed by a complete haematologic remission.     

Asbestosis: clinical spectrum and pathogenic mechanisms

Asbestosis is a diffuse pulmonary fibrotic process caused by the inhalation of asbestos fibers. Despite extensive investigations, the precise mechanisms regulating asbestos-induced lung damage are not fully understood. This review summarizes the important clinical manifestations and pathogenic mechanisms of asbestosis. We focus on the relatively new information that has emerged over the last several years. The diagnosis of asbestosis is often easily established by well-characterized criteria. Pulmonary physiologic testing and high-resolution computed tomography can detect clinically occult disease. The finding of asbestos bodies in the bronchoalveolar lavage fluid confirms that an individual has been exposed to asbestos but is of unclear significance in diagnosing asbestosis. Evidence reviewed herein suggests that asbestos pulmonary toxicity is due in part to the physical properties of the fibers, iron-catalyzed reactive oxygen species (ROS), and macrophage-derived cytokines and growth factors. Special emphasis is given to the hypothesis that iron-catalyzed hydroxyl radicals (HO.-) have a pivotal role in causing asbestosis. Definitive proof of this hypothesis is difficult to obtain since HO.- are highly reactive and their deleterious effects to cells may have occurred years prior to disease presentation. Despite these limitations, considerable data firmly support the notion that ROS have an important role in causing asbestos toxicity. Further, the iron content of asbestos or the redoxactive iron associated with or mobilized from the surface of the fibers is important in generating HO.- as well as in activating inflammatory cells. There also appears to be a close association between asbestos-induced ROS production and cellular toxicity and DNA damage. The full expression of asbestos-induced diseases likely involves the contribution of cytokines, growth factors, proteases, and other inflammatory cell products. Many of the mechanisms by which asbestos- and inflammation-induced ROS activate specific genes in pulmonary cells remain to be elucidated.     

Essential tremor: a review of pathogenic mechanisms

INTRODUCTION: Essential tremor (ET) is the commonest involuntary movement observed and is seen when a given posture is maintained. Although it does not affect life expectancy, it may cause considerable functional disability and serious psychological effects in the affected person. DEVELOPMENT: ET is a heterogeneous clinical condition. Its physiopathology is still not known, is very complex and involves many mechanisms, both structural and biochemical, although as yet there is no theory to include them all. In view of what is known at present, it may be accepted that there is a central oscillator at olive-cerebellar-thalamic-cortical-spinal level, which is the primary generator of ET, modulated by a peripheral component. The tremor results from interaction between increased central excitability and peripheral regulation, which in turn reinforces the central overactivity. It may also be that the monoaminergic system (catecholaminergic and serotoninergic), adrenoreceptors (especially the B2 muscular adreno-receptors) and the bodily structure itself, amongst other factors, may influence the pathogenic mechanism of ET. It is likely that there is a multifactorial genetic disorder which predetermines this physiopathogenic process, although this has not yet been determined. CONCLUSIONS: In this paper we review the various hypotheses and existing knowledge related to the aetiopathogenesis of TE.     

Obstetric complications in Marfan's syndrome pregnancy

Marfan syndrome is usually inherited as an autosomal dominant trait with high degree of penetrance. It is caused by an abnormal fibrillin gene located on chromosome 15q. Cardiovascular involvement in Marfan syndrome has been overstressed, although very little attention has been given to obstetric complications. Marfan syndrome may be responsible of cervical incompetence, abnormal placental site and post partum haemorrhagic complications. A 22-year-old woman with Marfan syndrome had mitral regurgitation since childhood. In addition aortic root dilatation was documented over six years by means of echocardiography and had been followed up regularly in a district hospital. Echocardiography six months before pregnancy had shown minimal mitral and aortic regurgitation and aortic root dilatation of 4.1 cm; left ventricular function was normal. Repeat echocardiography evaluations during pregnancy confirmed an aortic root dilatation. Routine booking and screening investigations were all within normal limits. At the 25th week, admission was necessary following a vaginal bleeding, without pain contraction. Echography showed a placenta praevia and cervical dilatation 2.8 cm of diameter. Bed rest and intravenous thocolitic therapy were immediately enhanced. A cervical cerclage, as described by McDonald, was placed. At the 37th week the patient was admitted and cerclage removed before the caesarean section. A healthy female of 2900 g was born. The postoperative period was favourable and patient was discharge after 7 days. In the present case, it is suggested that cervical incompetence and placenta praevia may be caused by an alteration of microfibrillar fibers.     

Clinical parameters associated with periodontitis in untreated persons

The purpose of this study was to investigate the relationship between clinical parameters and periodontitis in a population receiving no regular prophylactic dental care. From a sample of 164 adult rural and urban Tanzanian subjects aged between 30 and 44 years, 16% were identified with periodontitis according to the criteria that at least three teeth had a probing depth > or = 6 mm. Subjects with periodontitis in this sample exhibited a much higher bleeding tendency (at sites where periodontal pockets and did not exist) than subjects without periodontitis, but dental plaque scores were comparable. Sensitivity and specificity values and odds ratios indicated a strong association between bleeding on probing and the presence of periodontitis. This may indicate that people from a population deprived of regular dental care with a high tendency of bleeding on probing are more prone to develop periodontitis. Whether bleeding on probing could serve as a marker in this population to identify subjects who develop future periodontal destruction has to be explored through further longitudinal studies.     

足月羊水过少与妊娠并发症及结局分析

目的:探讨不同孕周羊水过少与妊娠并发症的关系及对妊娠结局的影响.方法:收集我院2008年1月至2008年9月住院治疗的羊水过少孕妇178例,并随机抽取同期我院正常妊娠孕妇190例作为对照组,两组孕妇就妊娠并发症、分娩方式及围生儿结局进行比较.结果:羊水过少孕妇妊娠期肝内胆汗淤积症(ICP)、胎儿宫内生长受限(FGR)、妊娠高血压疾病及胎儿畸形发生率均高于对照组,差异有统计学意义(P<0.05).胎儿宫内窘迫、新生儿窒息、羊水粪染的发生率也明显升高(P<0.05).伴有妊娠并发症的羊水过少孕妇,发生胎儿宫内窘迫、新生儿窒息、羊水粪染的机率较无妊娠并发症的的孕妇高(P<0.05).且其剖宫产率较对照组高(P<0.05).结论:羊水过少易增加妊娠并发症的发生率,造成不良妊娠结局,如果同时合并妊娠并发症则风险更大.因此做好严密产前监测,适时地选择分娩方式及时机是提高围生儿质量的重要方法.     

Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms

This study, addressing etiologic and pathogenic aspects of fibromyalgia (FM), aimed at examining whether sensory abnormalities in FM patients are generalized or confined to areas with spontaneous pain. Ten female FM patients and 10 healthy, age-matched females participated. The patients were asked to rate the intensity of ongoing pain using a visual analogue scale (VAS) at the site of maximal pain, the homologous contralateral site and two homologous sites with no or minimal pain. Quantitative sensory testing was performed for assessment of perception thresholds in these four sites. Von Frey filaments were used to test low-threshold mechanoreceptive function. Pressure pain sensitivity was assessed with a pressure algometer and thermal sensitivity with a Thermotest. In addition the stimulus-response curve of pain intensity as a function of graded nociceptive heat stimulation was studied at the site of maximal pain and at the homologous contralateral site. FM patients had increased sensitivity to non-painful warmth (P < 0.01) over painful sites and a tendency to increased sensitivity to non-painful cold (P < 0.06) at all sites compared to controls, but there was no difference between groups regarding tactile perception thresholds. Compared to controls, patients demonstrated increased sensitivity to pressure pain (P < 0.001), cold pain (P < 0.001) and heat pain (P < 0.02) over all tested sites. The stimulus-response curve was parallely shifted to the left of the curve obtained from controls (P < 0.003). Intragroup comparisons showed that patients had increased sensitivity to pressure pain (P < 0.01) and light touch (P < 0.05) in the site of maximal pain compared to the homologous contralateral site. These findings could be explained in terms of sensitization of primary afferent pathways or as a dysfunction of endogenous systems modulating afferent activity. However, the generalized increase in sensitivity found in FM patients was unrelated to spontaneous pain and thus most likely due to a central nervous system (CNS) dysfunction. The additional hyperphenomena related to spontaneous pain are probably dependent on disinhibition/facilitation of nociceptive afferent input from normal (or ischemic) muscles.     

Basic pathogenic mechanisms operating in experimental models of acute anterior uveitis

BACKGROUND: Determining how representative the known structures are of the proteins encoded by a complete genome is important for assessing to what extent our current picture of protein stability and folding is overly influenced by biases in the structure databank (PDB). It is also important for improving database-based methods of structure prediction and genome annotation. RESULTS: The known structures are compared to the proteins encoded by eight complete microbial genomes in terms of simple statistics such as sequence length, composition and secondary structure. The known structures are represented by a collection of nonhomologous domains from the PDB and a smaller list of 'biophysical proteins' on which folding experiments have concentrated. The proteins encoded by the genomes are considered as a whole and divided into various regions, such as known-structure homologue, low complexity (nonglobular), transmembrane or linker. Various tests are performed to assess the significance of the reported differences, in both a practical and a statistical sense. CONCLUSIONS: The proteins encoded by the genomes are significantly different from those in the PDB. Their sequence lengths, which follow an extreme value distribution, are longer than the PDB proteins and much longer than the biophysical proteins. Their composition differs from the PDB proteins in having more Lys, Ile, Asn and Gln and less Cys and Trp. This is true overall and especially for the regions corresponding to soluble proteins of as yet unknown fold. Secondary-structure prediction on these uncharacterized regions indicates that they contain on average more helical structure than the PDB; differences about this mean are small, with yeast having slightly more sheet structure and Haemophilus influenzae and Helicobacter pylori more helical structure. Further information is available through the GeneCensus system at http://bioinfo.mbb.yale.edu/genome.     

Uterine angiomyolipoma associated with pregnancy

Uterine angiomyolipomas are rare lesions composed of mature adipose tissue, smooth muscle, fibrous connective tissue, and blood vessels in varying proportions. We reported the first case of angiomyolipoma associated with a normal pregnancy. Initially, the tumor developed intramurally and could have been confused with a partial molar gestation. After delivery, tumor development was extensive and subserosal, making differential diagnosis from a sarcoma difficult. The question of histological diagnosis, as well as that of immunocytochemical analysis which seems to be helpful in such cases, is discussed here.     

Severe neuromuscular complications possibly associated with amlodipine

OBJECTIVE: To document a case of severe, progressive myopathy, myalgias, arthralgias, and weakness possibly caused by amlodipine in a patient with benign essential hypertension. CASE SUMMARY: A 52-year-old white woman with asthma and newly diagnosed hypertension was initiated on zafirlukast therapy for asthma and amlodipine therapy for hypertension. Two months later, the patient reported severe, generalized muscle and joint pain, muscle stiffness, and weakness. The zafirlukast was discontinued without resolution of symptoms. Laboratory tests revealed an elevated C-reactive protein. The amlodipine dosage was increased. Her symptoms persisted and further laboratory tests revealed a positive anti-nuclear antibody screen, and negative single- and double-stranded DNA antibody tests. After another amlodipine dosage increase, the patient experienced a sudden onset of left-sided facial numbness, facial weakness, and a severe headache.The patient was admitted to rule out a possible cerebrovascular event or a metabolic neurologic process. Magnetic resonance imaging showed no abnormalities. The patient discontinued the amlodipine and reported complete resolution of the neurologic symptoms after 4 days. One month later, zafirlukast was reinitiated without a return of symptoms. CONCLUSIONS: Amlodipine was not initially suspected as a cause of these symptoms because these effects are not commonly associated with amlodipine therapy. However, due to the temporal relationship and progression of symptoms with increasing amlodipine dosage, drug-related causes were eventually explored. Review of the medical literature suggests myalgias and arthralgias may be adverse effects common to dihydropyridine calcium-channel antagonists.     

Evaluation of prosthetic valve function and associated complications

Significant advances in imaging modalities have occurred to evaluate prosthetic valve function and associated complications. These developments involve predominantly the introduction of Doppler technology for the non-invasive determination of gradients and valve areas and TEE for an improved assessment of valve structure, function, and associated complications. The current role of cinefluoroscopy is mostly to complement TEE in the evaluation of motion of mechanical prosthetic valves in the aortic position. Cardiac catheterization is now rarely needed to assess valve function. Diagnosis of prosthetic valve obstruction can be performed in the majority of cases with transthoracic Doppler echocardiography. Differentiation of valve obstruction from normal valve function in small valves with high flow conditions, however, may be difficult. Because of this and the variability in normal valves among different prostheses, knowledge of the type and size of the implanted valve is essential. Patients and ultrasound laboratories are encouraged to seek and provide this information on a routine basis. Although transthoracic echocardiography is the main diagnostic modality for the serial evaluation of prosthetic valve function, it is important to recognize its limitations in assessing prosthetic mitral regurgitation and evaluating structural abnormalities of prosthetic valves. These are the situations in which TEE has the most impact. A summary of general indications of TEE in prosthetic valves is provided in Table 6. Finally, a baseline transthoracic Doppler study is essential in the overall follow-up and serial evaluation of valve function. For future comparisons, the best indices of valve functions are those obtained for patients as their own control, from a baseline Doppler echocardiographic study performed early after the operation.     

Leiomyomatosis peritonealis disseminata associated with pregnancy

The first reported case in the English literature involving leiomyomatosis peritonealis disseminata (LPD) and a subsequent pregnancy is presented. A review of the literature revealed only 8 previous cases-all of which were treated by tubal ligation or surgical castration. The patient in this report was 22 years of age at the time of diagnosis, the youngest age at which LPD is known to have occurred. The LPD was first noted at primary cesarean section, and 20 months later at a second cesarean section performed at 35 1/2 weeks' gestation, the LPD had advanced to a stage that suggested possible malignancy. All biopsy specimens were subsequently reported as benign LPD.     

Thrombotic thrombocytopenic purpura associated with pregnancy

The prevalence of syphilis and its cardiovascular complications were investigated in the living population more than 60 years of age. The prevalence of positive serologic test for syphilis (STS) were 16.9% (124/736) in males and 17.1% (236/1380) in females, which were not statistically different. Aortic regurgitation (AR) was significantly more frequent in those with positive STS (9.68% in males, 5.08% in females) compared with negative STS (0.98% in males, 1.75% in females) in both sexes (p less than 0.01) and it was marked in males. AR with positive STS had a significantly lower minimal blood pressure than AR with negative STS (p less than 0.05). Calcifications in the ascending aorta were noticed in 5 out of 24 syphilitic AR. Myocardial infarctions were almost equally found among those with positive STS (1.67%) and negative STS (1.65%), and 2 out of 6 syphilitic cases were complicated by AR. The measurement of the aortic width was not valuable for the diagnosis of uncomplicated syphilitic aortitis.     

Potential mechanisms of metabolic imprinting that lead to chronic disease

This review synthesizes a subset of human epidemiologic and experimental animal studies that suggest that early nutrition affects susceptibility to chronic diseases in adulthood. These studies provide evidence that biological mechanisms may exist to "memorize" the metabolic effects of early nutritional environments. However, hypothesis-driven investigations of potential mechanisms have been scant. Thus, our understanding of the biology underlying metabolic imprinting is incomplete. A working definition of metabolic imprinting is proposed, emphasizing the adaptive nature and limited ontogenic window of the mechanisms putatively responsible for these relations. Five specific candidate mechanisms of metabolic imprinting are elaborated: 1) induced variations in organ structure, 2) alterations in cell number, 3) clonal selection, 4) metabolic differentiation, and 5) hepatocyte polyploidization. Last, experimental approaches for probing potential mechanisms with animal models are discussed.     

Potential complications associated with normothermic lonidamine infusion and with systemic acidosis in dogs receiving lonidamine during whole body hyperthermia (WBH)

We have developed a new small animal model for acute inhalation studies on combined effects of cold air and gaseous urban air pollutants. The anaesthetised, tracheostomised and paralysed guinea-pig was placed inside a small, sealed whole-body-box, in which it was ventilated mechanically by using cyclic negative pressure (Pbox) for active expansion of the chest. During a 2-h normal ventilation with warm humid air (n=6), there was a need for increasing Pbox with time to maintain the fixed tidal volume (VT) of 11 ml/kg. No such need was seen in the experiments with 15-min periods of isocapnic hyperventilation at 80 and 120 breaths/min (n=13). During the 2-h normal ventilation and in experiments with hyperventilation, there was a gradual increase in heart rate and small gradual decreases in PaCO2 and pH with time. Cold air + SO2 2.5 ppm produced a significantly stronger bronchoconstriction (deltaVT=-30.3+/-7.2%, n=6, P < 0.05) than clean cold dry air (deltaVT=-10.6+/-1.3%, n=6) and cold air + NO2 2.5 ppm (deltaVT=-13.2+/-3.3%, n=6), although these three exposure conditions produced similar decreases in tracheal air and retrotracheal tissue temperatures. With the present guinea-pig model, the combined respiratory effects of cold air and gaseous urban air pollutants can be investigated in a highly controlled manner.