Diabetes during Pregnancy: A Maternal Disease Complicating the Course of Pregnancy with Long-Term Deleterious Effects on the Offspring. A Clinical Review

In spite of the huge progress in the treatment of diabetes mellitus, we are still in the situation that both pregestational (PGDM) and gestational diabetes (GDM) impose an additional risk to the embryo, fetus, and course of pregnancy. PGDM may increase the rate of congenital malformations, especially cardiac, nervous system, musculoskeletal system, and limbs. PGDM may interfere with fetal growth, often causing macrosomia, but in the presence of severe maternal complications, especially nephropathy, it may inhibit fetal growth. PGDM may also induce a variety of perinatal complications such as stillbirth and perinatal death, cardiomyopathy, respiratory morbidity, and perinatal asphyxia. GDM that generally develops in the second half of pregnancy induces similar but generally less severe complications. Their severity is higher with earlier onset of GDM and inversely correlated with the degree of glycemic control. Early initiation of GDM might even cause some increase in the rate of congenital malformations. Both PGDM and GDM may cause various motor and behavioral neurodevelopmental problems, including an increased incidence of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Most complications are reduced in incidence and severity with the improvement in diabetic control. Mechanisms of diabetic-induced damage in pregnancy are related to maternal and fetal hyperglycemia, enhanced oxidative stress, epigenetic changes, and other, less defined, pathogenic mechanisms.     

Proteomics in aortic aneurysm – What have we learnt so far?

Aortic aneurysm is a deceptively indolent disease that can cause severe complications such as aortic rupture and dissection. In the normal aorta, vascular smooth muscle cells within the medial layer produce and sustain the extracellular matrix (ECM) that provides structural support but also retains soluble growth factors and regulates their distribution. Although the ECM is an obvious target to identify molecular processes leading to structural failure within the vessel wall, an in-depth proteomics analysis of this important sub-proteome has not been performed. Most proteomics analyses of the vasculature to date used homogenized tissue devoid of spatial information. In such homogenates, quantitative proteomics comparisons are hampered by the heterogeneity of clinical samples (i.e. cellular composition) and the dynamic range limitations stemming from highly abundant cellular proteins. An unbiased proteomics discovery approach targeting the ECM instead of the cellular proteome may decipher the complex, multivalent signals that are presented to cells during aortic remodelling. A better understanding of the ECM in healthy and diseased vessels will provide important pathogenic insights and has potential to reveal novel biomarkers.     

Efficacy,predictability and safety of long-term orthokeratology: An 18-year follow-up study

PurposeTo determine the efficacy, predictability and safety of long-term orthokeratology in children and adults.MethodsCase histories of 300 orthokeratology patients (596 eyes; 34.3% children; 65.7% adults) were reviewed to collect information on demographics, corneal and refractive parameters, visual acuity, residual refraction and adverse effects. Predictability was defined as the percentage of eyes with absolute values of spherical equivalent refraction ≤ 0.5 D of emmetropia, and efficacy as the ratio of post-orthokeratology uncorrected and pre-orthokeratology corrected distance visual acuity.ResultsMedian duration of treatment was 37 and 28.5 months in children and adults, respectively (p = 0.022). During the first year, 17.2% of children and 33% of adults ceased lens wear (p < 0.001). For children and adults with a successful ortho-k treatment of at least one year of duration, 88.7% and 95.9% of eyes had a predictable refractive outcome, and efficacy was 0.98 and 1.01, respectively. A larger percentage of children (65.7%) were free of complications than of adults (55.4%) (p = 0.015). One event of microbial keratitis occurred in adults (6.8 cases per 10,000 patient-years) and none in children. Corneal staining was the most frequent complication, with a higher incidence in adults (p = 0.007) and in higher myopia (p < 0.001), higher anterior corneal eccentricity (p = 0.019) and smaller anterior horizontal radius (p = 0.027).ConclusionOrthokeratology is a safe and predictable long-term procedure in children and adults, with a low incidence of serious adverse effects. Corneal staining episodes are relatively frequent throughout the course of the treatment, thus highlighting the relevance of education of experienced users.     

Seipin Deficiency as a Model of Severe Adipocyte Dysfunction: Lessons from Rodent Models and Teaching for Human Disease

Obesity prevalence is increasing worldwide, leading to cardiometabolic morbidities. Adipocyte dysfunction, impairing white adipose tissue (WAT) expandability and metabolic flexibility, is central in the development of obesity-related metabolic complications. Rare syndromes of lipodystrophy characterized by an extreme paucity of functional adipose tissue should be considered as primary adipocyte dysfunction diseases. Berardinelli-Seip congenital lipodystrophy (BSCL) is the most severe form with a near absence of WAT associated with cardiometabolic complications such as insulin resistance, liver steatosis, dyslipidemia, and cardiomyopathy. Twenty years ago, mutations in the BSCL2 gene have been identified as the cause of BSCL in human. BSCL2 encodes seipin, an endoplasmic reticulum (ER) anchored protein whose function was unknown back then. Studies of seipin knockout mice or rats demonstrated how seipin deficiency leads to severe lipodystrophy and to cardiometabolic complications. At the cellular levels, seipin is organized in multimers that are particularly enriched at ER/lipid droplet and ER/mitochondria contact sites. Seipin deficiency impairs both adipocyte differentiation and mature adipocyte maintenance. Experiments using adipose tissue transplantation in seipin knockout mice and tissue-specific deletion of seipin have provided a large body of evidence that liver steatosis, cardiomyopathy, and renal injury, classical diabetic complications, are all consequences of lipodystrophy. Rare adipocyte dysfunctions such as in BSCL are the key paradigm to unravel the pathways that control adipocyte homeostasis. The knowledge gathered through the study of these pathologies may bring new strategies to maintain and improve adipose tissue expandability.     

硫酸吲哚酚在慢性肾病并发症中的作用

慢性肾病（chronic kidney disease, CKD）是全球性公共卫生问题,其发生发展与体内尿毒症毒素暴露密切相关。硫酸吲哚酚（indoxyl sulfate, IS）是一种肠源性的蛋白结合型尿毒症毒素,由于CKD患者肾脏排泄功能被破坏,IS在CKD患者体内蓄积。IS不仅促进CKD进展,还诱导其他组织器官病变,进而引起CKD相关的并发症。本文综述了IS对CKD患者血管、肌肉、骨骼以及大脑的影响及其相应的机制,并总结通过清除IS治疗CKD的方法。     

Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis—Driver of Insulin Resistance and Development of Vascular Complications of Diabetes

The recent discovery of the glucose-induced stabilization of hexokinase-2 (HK2) to proteolysis in cell dysfunction in model hyperglycemia has revealed a likely key initiating factor contributing to the development of insulin resistance and vascular complications in diabetes. Consequently, the increased flux of glucose metabolism without a change in the expression and activity of glycolytic enzymes produces a wave of increased glycolytic intermediates driving mitochondrial dysfunction and increased reactive oxygen species (ROS) formation, the activation of hexosamine and protein kinase C pathways, the increased formation of methylglyoxal-producing dicarbonyl stress, and the activation of the unfolded protein response. This is called HK2-linked glycolytic overload and unscheduled glycolysis. The conditions required to sustain this are GLUT1 and/or GLUT3 glucose uptake and the expression of HK2. A metabolic biomarker of its occurrence is the abnormally increased deposition of glycogen, which is produced by metabolic channeling when HK2 becomes detached from mitochondria. These conditions and metabolic consequences are found in the vasculature, kidneys, retina, peripheral nerves, and early-stage embryo development in diabetes and likely sustain the development of diabetic vascular complications and embryopathy. In insulin resistance, HK2-linked unscheduled glycolysis may also be established in skeletal muscle and adipose tissue. This may explain the increased glucose disposal by skeletal uptake in the fasting phase in patients with type 2 diabetes mellitus, compared to healthy controls, and the presence of insulin resistance in patients with type 1 diabetes mellitus. Importantly, glyoxalase 1 inducer—trans-resveratrol and hesperetin in combination (tRES-HESP)—corrected HK2-linked glycolytic overload and unscheduled glycolysis and reversed insulin resistance and improved vascular inflammation in overweight and obese subjects in clinical trial. Further studies are now required to evaluate tRES-HESP for the prevention and reversal of early-stage type 2 diabetes and for the treatment of the vascular complications of diabetes.     

Pathogenetic Mechanisms of Hypertension–Brain-Induced Complications: Focus on Molecular Mediators

There is growing evidence that hypertension is the most important vascular risk factor for the development and progression of cardiovascular and cerebrovascular diseases. The brain is an early target of hypertension-induced organ damage and may manifest as stroke, subclinical cerebrovascular abnormalities and cognitive decline. The pathophysiological mechanisms of these harmful effects remain to be completely clarified. Hypertension is well known to alter the structure and function of cerebral blood vessels not only through its haemodynamics effects but also for its relationships with endothelial dysfunction, oxidative stress and inflammation. In the last several years, new possible mechanisms have been suggested to recognize the molecular basis of these pathological events. Accordingly, this review summarizes the factors involved in hypertension-induced brain complications, such as haemodynamic factors, endothelial dysfunction and oxidative stress, inflammation and intervention of innate immune system, with particular regard to the role of Toll-like receptors that have to be considered dominant components of the innate immune system. The complete definition of their prognostic role in the development and progression of hypertensive brain damage will be of great help in the identification of new markers of vascular damage and the implementation of innovative targeted therapeutic strategies.     

Cardiomyopathy associated with clozapine.

Clozapine is an atypical antipsychotic agent that is more effective than the standard neuroleptics currently used for treating refractory schizophrenia. In addition, clozapine is a drug with few extrapyramidal side effects. However, clozapine is also associated with potentially serious adverse effects, such as cardiac complications as well as agranulocytosis. Clozapine-related cardiomyopathy has not been previously reported in East Asia. This report describes a 31-year-old Korean male patient with schizophrenia who developed dilated cardiomyopathy on treatment with clozapine. The removal of clozapine caused subsequent physical improvement. However, the readministration of clozapine for managing relapse of psychosis caused a recurrence of dilated cardiomyopathy in this patient. Therefore, this is the 1st report showing that the 2nd trial of clozapine caused recurrence of cardiomyopathy associated with clozapine. Thus, this report adds important support for a causal relation between clozapine and cardiac complications. In conclusion, this report attempts to raise awareness of clozapine-related cardiomyopathy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

维格列汀联合二甲双胍治疗对2型糖尿病合并心脑血管疾病 IMT、血清 APN 及 Hcy 水平的影响

目的：观察维格列汀联合二甲双胍治疗对2型糖尿病合并心脑血管疾病颈动脉内膜中层厚度（carotid inti-ma-media thickness,IMT）、血清脂联素（adiponectin,APN）和同型半胱氨酸（homocysteine,Hcy）水平的影响,探讨2型糖尿病并发心脑血管疾病的危险因素。方法将150例初诊2型糖尿病合并心脑血管疾病患者随机分为3组：A 组50例采用维格列汀治疗,B 组50例采用二甲双胍治疗,C 组50例采用维格列汀联合二甲双胍治疗,治疗3个月后,比较3组治疗前后血糖控制情况及 IMT、APN 和 Hcy 水平改善情况。结果治疗后 A、C 组 IMT、Hcy 均较治疗前明显降低,APN 较治疗前明显增加,且 C 组改善程度较 A、B 组更为显著（P ＜0．05）。相关分析结果显示,IMT 与 HOMA-IR（r＝0．356,P ＝0．013）、LDL（r＝0．363,P ＝0．009）、Hcy（r＝0．756,P ＝0．022）呈正相关,与HDL（r＝－0．461 P ＝0．001）、APN（r＝－0．482,P ＝0．000）呈负相关。结论 HOMA-IR、LDL、Hcy 升高,HDL、APN 降低是2型糖尿病患者 IMT 增厚的危险因素。维格列汀联合二甲双胍治疗可有效降低其 IMT 值及 Hcy 水平,增加 APN 含量。