Role of megalin and the soluble form of its ligand RAP in Cd-metallothionein endocytosis and Cd-metallothionein-induced nephrotoxicity in vivo

Orally administered Cd is predominantly distributed to the intestine, and the majority of this mucosal Cd is bound to metallothionein (MT). MT attenuates heavy metal-induced cytotoxicity by sequestering these metals and lowering their intracellular concentrations. In addition, MT acts as an extracellular transporter of orally administered Cd to the kidney. Because of its low molecular weight, the Cd-MT complex is freely filtered at the glomerulus, and the filtered Cd-MT is then incorporated into renal proximal tubular cells. Megalin, a multiligand endocytic receptor (also known as low-density lipoprotein receptor-related protein 2 or Lrp2), acts as the receptor for Cd-MT in a renal proximal tubular cell model. Here, we used the soluble form of 39-kDa receptor-associated protein (sRAP; also known as Lrpap1), a ligand of megalin, to inhibit megalin function, and then analyzed the effect of megalin loss on Cd-MT distribution and Cd-MT-induced nephrotoxicity in an animal model. Administration of sRAP to mice caused acute loss of megalin function by removing megalin in the brush border membrane. The pre-injection of sRAP decreased renal Cd content and decreased Cd-MT-induced kidney damage. Our results demonstrate that sRAP reduces Cd-MT-induced kidney toxicity in vivo.     

Bupropion: congenital heart defects (continued)

Bupropion, an amphetamine, is authorised as an aid to smoking cessation, despite its negative harm-benefit balance. In 2004, data from a registry of pregnancies exposed to bupropion drew attention to an increased risk of congenital heart defects. In 2010, a case-control study including more than 10 000 children showed a higher incidence of in utero exposure to bupropion among children who had congenital left heart defects. Other, less reliable studies did not show such a link. In practice, this risk of congenital heart defects is yet another reason to avoid using bupropion, including during pregnancy, and to monitor the cardiac status of exposed fetuses and newborns.     

Drug-induced congenital defects: strategies to reduce the incidence.

Approximately 1% of congenital anomalies relate to pharmacological exposure and are. in theory, preventable. Prevention consists of controlled administration of drugs known to have teratogenic properties (e.g. retinoids, thalidomide). When possible, prevention could take the form of the use of alternative pharmacological therapies during the pre-conception period for certain specific pathologies, selecting the most appropriate agent for use during pregnancy [e.g. haloperidol or a tricyclic antidepressant instead of lithium; anticonvulsant drug monotherapy in place of multitherapy; propylthiouracil instead of thiamazole (methimazole)], and substitution with the most suitable therapy during pregnancy (e.g. insulin in place of oral antidiabetics; heparin in place of oral anticoagulants; alpha-methyldopa instead of ACE inhibitors). Another strategy is the administration of drugs during pregnancy taking into account the pharmacological effects in relation to the gestation period (e.g. avoidance of chemotherapy during the first trimester, avoidance of nonsteroidal anti-inflammatory drugs in the third trimester, and avoidance of high doses of benzodiazepines in the period imminent to prepartum).     

Trichloroethylene-contaminated drinking water and congenital heart defects: a critical analysis of the literature

The organic solvent trichloroethylene (TCE) is a metal degreasing agent and an intermediate in the production of fluorochemicals and polyvinyl chloride. TCE is also a common, persistent drinking water contaminant. Several epidemiological studies have alleged links between TCE exposure during pregnancy and offspring health problems including congenital heart defects (CHDs); however, the results of these studies are inconsistent, difficult to interpret, and involve several confounding factors. Similarly, the results of animal studies examining the potential of TCE to elicit cardiac anomalies have been inconsistent, and they have often been performed at doses far exceeding the highest levels ever reported in the drinking water. To determine what is known about the relationship between TCE and the incidence of CHDs, a comprehensive analysis of all available epidemiological data and animal studies was performed. Additionally, in vivo and in vitro studies examining possible mechanisms of action for TCE were evaluated. The specific types of heart defects alleged to have been caused by TCE in animal and human epidemiology studies were categorized by the morphogenetic process responsible for the defect in order to determine whether TCE might disrupt any specific developmental process. This analysis revealed that no single process was clearly affected by TCE, providing support that gestational TCE exposure does not increase the prevalence of CHDs. As a final evaluation, application of Hill's causality guidelines to the collective body of data revealed no indication of a causal link between gestational TCE exposure at environmentally relevant concentrations and CHDs.     

经食管超声心动图在先天性心脏病手术中的应用

目的 探讨经食管超声心动图(TEE)在先天性心脏病手术中的应用价值.方法 对254例先天性心脏病患者术中使用TEE检查.结果 转流前11例(4.33%)有新的发现,6例(2.36%)更改了手术方案;转流后10例(3.94 %)有新的发现,4例(1.58%)更改了手术方案.未发生与TEE相关的严重并发症,发生口咽黏膜出血1例(0.39%)、牙齿损伤1例(0.39%).结论 在先天性心脏病手术中常规使用TEE能够在转流前修正诊断,转流后评价手术效果,减少了手术并发症,避免再次手术,使手术更加安全.     

Estimation of the risk factors of the congenital urinary system defects

Material and methods  

Analysis covered a retrospective group of 334 neonates (194 male neonates and 140 female neonates), reported to the Polish Registry of Congenital Malformations (PRCM), between 2001–2005.     

The substrates of memory: defects, treatments, and enhancement

Recent work has added strong support to the long-standing hypothesis that the stabilization of both long-term potentiation and memory requires rapid reorganization of the spine actin cytoskeleton. This development has led to new insights into the origins of cognitive disorders, and raised the possibility that a diverse array of memory problems, including those associated with diabetes, reflect disturbances to various components of the same mechanism. In accord with this argument, impairments to long-term potentiation in mouse models of Huntington's disease and in middle-aged rats have both been linked to problems with modulatory factors that control actin polymerization in spine heads. Complementary to the common mechanism hypothesis is the idea of a single treatment for addressing seemingly unrelated memory diseases. First tests of the point were positive: Brain-Derived Neurotrophic Factor (BDNF), a potent activator of actin signaling cascades in adult spines, rescued potentiation in Huntington's disease mutant mice, middle-aged rats, and a mouse model of Fragile-X syndrome. A similar reversal of impairments to long-term potentiation was obtained in middle-aged rats by up-regulating BDNF production with brief exposures to ampakines, a class of drugs that positively modulate AMPA-type glutamate receptors. Work now in progress will test if chronic elevation of BDNF enhances memory in normal animals.     

Finding of O-mannosyl glycan in mammals and congenital muscular dystrophies due to glycosylation defects

Most proteins within living organisms contain glycans. Glycan structures can modulate the biological properties and function of glycoproteins. Developments in glycobiology have revealed a new type of glycosidic linkage to the peptide portion, the O-mannosyl linkage in mammals, although heretofore it had been thought to be specific to yeast. One of the best known O-mannosyl-modified glycoproteins is dystroglycan, which is a central component of dystrophinglycoprotein complex isolated from skeletal muscle membranes. We identify and characterize a glycosyltransferase, UDP-N-acetylglucosamine: protein O-mannose beta 1,2-N-acetylglucosaminyltransferase (POMGnT1), involved in the biosynthesis of mammalian type O-mannosyl glycans. Finally, we find that the POMGnT1 gene is responsible for muscle-eye-brain disease (MEB). MEB is an autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities and brain malformation (type II lissencephaly). Like MEB, recent data suggest that the aberrant protein glycosylation of a specific glycoprotein, alpha-dystroglycan, is the primary cause of some forms of congenital muscular dystrophy. Here I review the new insight into glycobiology of muscular dystrophy and neuronal migration disorder.     

Maternal exposure to arsenic and cadmium and the risk of congenital heart defects in offspring

Hair arsenic and cadmium from 339 women with congenital heart defect (CHD)-affected pregnancies (case women) and 333 women with normal live births (control women) in China were estimated using inductively coupled plasma mass spectrometry. The median levels of hair arsenic and cadmium in the case women were 98.30 (74.30–136.30) ng/g and 14.60 (8.30–32.50) ng/g, respectively, which were significantly higher than the levels in the control group (P < 0.05). Arsenic concentrations ≥62.03 ng/g were associated with increased risk for almost every CHD subtype, with a dose-response relationship. However, only the group with the highest cadmium levels (≥25.85 ng/g) displayed an increased risk of CHDs (AOR 1.96; 95% CI 1.24–3.09), with a 2.81-fold increase found for the occurrence of conotruncal defects in their offspring. Furthermore, an interaction between arsenic and cadmium was observed. Our findings suggest that maternal exposure to arsenic and cadmium may be a significant risk factor for CHDs in offspring. Cadmium may have an enhancing effect on the association between arsenic and the risk of CHDs in offspring.     

Using a national register for the epidemiological study of congenital heart defects

Data validity is a fundamental problem in epidemiology. An objective of birth defect registers is the collection of high quality data, often from a number of sources, for use in epidemiological research. This paper examines the use of data from a national register in New Zealand in the study of congenital heart defects. The prevalence rates of congenital heart defects are shown to depend on the definition of the terms employed, the methods and completeness of the case ascertainment, the correctness of the diagnoses, the nature and size of the population under study, and the duration of followup. Recommendations are made for increasing the utility of this register in the study of this major group of malformations.