3-Hydroxy-3-methylglutaryl-CoA-lyase deficiency

Journal of Inherited Metabolic Disease -     

ΠPOTEYΣ

In this issue, Proteus examines the merits and dismerits of an uncommonly voiced debate: the retention of the foreskin in preventing transmission of infectious diseases, as well as progress in Neisseria meningitidis research which is developing energy akin to the disease process itself.     

The Frequency of Kappa and Lambda Chains in Pathologic Serum γG, γA, γD and γμ Immunoglobulins

Light chain typing of M-components of non-macroglobulin nature from 500 sera gave a κ/γ quotient of 1.5. All the M-components contained either κ or γ chains. Irrespective of the electrophoretic charge the quotient in γG-M-components was 2, and in γA-M-components 0.9 and Bence-Jones proteinaemias 1.3. One serum contained a γGL- and a γAK-M-component, both in a concentration above 3 g per 100 ml.     

HB F-Yamaguchi (γ75THR, γ80ASN, γ136ALA) is associated with Gγ-thalassemia

Restriction endonuclease analyses of DNA from a known Hb F-Yamaguchi heterozygote and three of his relatives have shown a deletion of about 5 kb, which includes one of the γ genes. This abnormality is similar to the ^Gγ-thalassemia described recently [4] and is probably caused by an unequal crossing over between -^Gγ- and -^Aγ^T-genes. The abnormal -^Gγ^Aγ^T-X- (X = Asp→Asn at γ80) hybrid gene produces the γ-Yamaguchi chain at a level usually seen for ^Gγ chains only.     

肝癌术后干扰素治疗32个月未复发1例

1病历资料 1．1主诉患者,男性,45岁,因“发现HBsAg阳性3年,肝内结节1天”于2009年9月30日就诊于首都医科大学附属北京地坛医院。     

Homozygous G γλβ thalassaemia

Summary This report describes the clinical and haematological findings in three siblings homozygous for ^Gγ δβ thalassaemia in an Indian family. There was a mild to moderate anaemia and markedly abnormal red cell morphology. Haemoglobin analysis showed 100% Hb F, solely of the ^Gγ type, with a pancellular but uneven distribution. Considerable chain imbalance was detectable in globin synthesis studies. In contrast to the five previously reported cases, these children were essentially asymptomatic and have never required transfusions.     

Catecholamine hormone receptor differences identified on 3T3 and simian virus-transformed 3T3 cells.

Identification and characterization of hormone receptors on the cell surface is an effective tool for studying the plasma membrane. Using the direct binding of a radiolabeled antagonist, (-)[3H]alprenolol, to crude membrane preparations, and a physiological response (cellular cyclic AMP levels), I demonstrated a catecholamine (beta-adrenergic) hormone receptor site coupled to a catecholamine responsive adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] on 3T3 and simian virus 40 (SV40)-transformed 3T3 cells. At a concentration of 1 muM, epinephrine and isoproterenol elevate cellular cyclic AMP levels 8- and 12-fold, respectively, in both cell lines. Norepinephrine was also a potent agonist on 3T3 cells (8-fold stimulation), but SV3T3 cells showed a lesser (2-fold) response to this hormone. The specificity of the physiological response (as well as the direct binding studies using the alprenolol radiolabel) is indicated by the increased effectiveness of (-) compared to (+) stereoisomers, rapid and reversible kinetics (steady state within 2 min), high affinity (Kd approximately 30 nM) and saturability (indicating a finite number of hormone receptors). These hormone receptor studies indicate the 3T3 cells have a beta1 adrenergic receptor while the SV3T3 cells have a receptor with beta2 qualities. In addition, the number of beta-adrenergic hormone receptors appear to be increased in the normal 3T3 cells by approximately 2-fold over the SV3T3 cells (300 versus versus 120 femtomol/mg of protein).     

3-Hydroxyisovalerylcarnitine in 3-methylcrotonyl-CoA carboxylase deficiency

Summary A new acylcarnitine was observed in the plasma and urine of a patient with isolated 3-methylcrotonyl-CoA carboxylase deficiency. Analysis by tandem mass spectrometry of the methyl ester and butyl ester and their fragment ion spectra identified it as a 3-hydroxy-C5-acylcarnitine. Fibroblasts from a second patient were incubated with deuterium-labelled leucine. Incorporation of label in the new acylcarnitine identified its origin from leucine, and thus confirmed the structure as 3-hydroxyisovalerylcarnitine. The presence of elevated amounts of this metabolite, plus a small amount of 3-methylcrotonylcarnitine in plasma, was diagnostic for isolated 3-methylcrotonyl-CoA carboxylase deficiency. Other conditions in which a hydroxy-C5-acylcarnitine was present were readily differentiated by the abnormal elevation of other acylcarnitines.     

2H3R3E3Z3/4H3R3方案引起的药物性肝炎及其对抗结核效果的影响

目的　观察和研究2H₃R₃E₃Z₃/4H₃R₃治疗初治涂阳病人药物性肝炎的发生率和药物性肝炎对抗结核效果的影响。方法 对肝功正常、应用2H₃R₃E₃Z₃/4H₃R₃治疗的初治涂阳病人每月复查1次肝功,复查出现ALT升高的每周复查1次肝功,疗程完成后考核疗效。结果 （1）药物性肝炎发生率为23.1%,其中有基础性肝病患者药物性肝炎发生率为66.3%;（2）抗结核过程中肝功检查第1次发现ALT在50 U/L～100 U/L,且无明显肝损症状和胆红素增高者,有51.2%的患者属于一过性转氨酶升高;（3）73.2%的药物性肝炎发生在抗结核治疗的前2个月,26.8%的药物性肝炎发生在抗结核治疗的后4个月;（4）无因药物性肝炎而死亡的病例,药物性肝炎患者停用抗结核药物并行护肝等治疗后肝功恢复时间平均为2.3周,其中,有基础性肝病者肝功恢复时间平均为3.9周,无基础性肝病者肝功恢复时间平均为1.8周;（5）总的肺结核治愈率为94.6%,未发生药物性肝炎患者肺结核治愈率为97.0%,发生药物性肝炎患者肺结核治愈率为86.6%,有基础性肝病患者肺结核治愈率为78.6%。结论 （1）药物性肝炎是影响肺结核,尤其是影响有基础性肝病患者肺结核治疗效果的重要因素,2H₃R₃E₃Z₃/4H₃R₃不宜广泛应用于HBsAg（+）等有基础性肝病的初治涂阳肺结核病人;（2）抗结核过程中肝功检查第1次发现ALT在50 U/L～100 U/L,且无明显肝损症状和胆红素增高者,有51.2%的病例属于一过性转氨酶升高,只要加强护肝治疗,可以不停抗结核药物,但应密切观察患者反应和肝功变化;（3）药物性肝炎虽然全疗程中均可出现,但主要发生在强化期,故应注重强化期的护肝治疗和肝功监测。     

Reactive oxygen species up-regulates SOCS-3 in 3T3-L1 adipocytes

We investigated the effect of increased intracellular reactive oxygen species(ROS) on SOCS-3 expression in 3T3-L1 adipocytes. Increased intracellular ROS levels in 3T3-L1 adipocytes were achieved by two methods of exposure to H2O2 and the occurrence of oxidative stress in cells was assessed by flow cytometry . Expression of SOCS-3 mRNA and that of some adipokines were measured by real time PCR. The level of SOCS-3 protein was determined by western blot. The effect of the antioxidant alpha-lipoic acid was also investigated. Both the relatively mild increased intracellular ROS and the acute but transient increased ROS elevated the levels of SOCS-3 mRNA and protein in 3T3-L1 adipocytes, acompanied with elevated levels of TNF-α mRNA and resistin mRNA and the decreased levels of adiponectin mRNA and secretory adiponectin in culture medium. α-lipoic acid could attenuate the effects of ROS on 3T3-L1 adipocytes. We hypothesized that in mature 3T3-L1 adipocytes, SOCS-3 could be upregulated directly by the induction of increased intracellular ROS and to some extent which was up-regulated by adipokine modulation.

     

Genetic factors involved in human Gγ and Aγ globin gene expression

Gγ to Aγ globin ratios, haplotypes at the β globin gene cluster and the C →T substitution at -158 5′ to the Gγ globin gene were studied in three Algerian families that include SS or S-β°thal patients. Gγ to Aγ ratios were found similar, within a family, in subjects displaying the same combination of chromosomes 11, the ratio observed for a given combination depending on the chromosome haplotypes. Our data can be explained by the existence of several alleles of a genetic factor closely linked to the β globin gene cluster and involved in the determination of Gγ to Aγ globin ratio.     

2H3R3Z3S3(E3)/4H3R3方案治疗对乙肝病毒标志物阳性患者肝功能的影响

目的 探讨2H₃R₃Z₃S₃(E₃)/4H₃R₃方案治疗对合并乙型肝炎病毒标习物HBsAg(+)、HBeAb(+)、HBcAb(+)肺结核患者肝功能的影响。方法 回顾性分析1994年12月至1998年12月采用2H₃R₃Z₃S₃(E₃)/4H₃R₃方案治疗的初治涂阳并乙肝标志物HBsAg(+)、HBeAg(+)、HBcAg(+)肺结核患者肝功能的情况。以同期采用同样方案治疗的乙肝标志物五项阴性肺结核患者为对照。结果 乙肝阳性组肝损率 (15.6%)高于乙肝阴性组 (12.0%)。两组经统计学处理无显著性差异。 (P＞0.05)。结论2H₃R₃Z₃S₃(E₃)/4H₃R₃方案治疗对合并乙肝病毒标志物HBsAg(+)、HBeAg(+)、HBcAg(+)肺结核患者肝功能损害小,值得推广。     

3-Hydroxy-3-methylglutaric aciduria combined with 3-methylglutaconic aciduria: A new case

The urinary organic acids of a new case of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency have been analysed by gas chromatography-mass spectrometry. This patient's fibroblasts showed a reduced ability to oxidize leucine.     

Relaxin-3/RXFP3 system regulates alcohol-seeking

Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the highly conserved neuropeptide, relaxin-3, decreased self-administration of alcohol in a dose-related manner and attenuated cue- and stress-induced reinstatement following extinction. By comparison, RXFP3 antagonist treatment did not significantly attenuate self-administration or reinstatement of sucrose-seeking, suggesting a selective effect for alcohol. RXFP3 is densely expressed in the stress-responsive bed nucleus of the stria terminalis, and bilateral injections of RXFP3 antagonist into the bed nucleus of the stria terminalis significantly decreased self-administration and stress-induced reinstatement of alcohol, suggesting that this brain region may, at least in part, mediate the effects of RXFP3 antagonism. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity, or procedural memory for lever pressing in the paradigms assessed. These data suggest that relaxin-3/RXFP3 signaling regulates alcohol intake and relapse-like behavior, adding to current knowledge of the brain chemistry of reward-seeking.Alcohol abuse is a major cause of morbidity and mortality worldwide, accounting for an estimated 3.8% of all global deaths and 4.6% of the global burden of disease and injury (1). Excessive alcohol use may also lead to alcohol dependence (also termed “alcohol addiction”) (2, 3), which has a lifetime prevalence of ∼12.5% (4). Economic costs due to alcohol abuse were in the order of $235 billion in the United States in 2007, or ∼2.7% of GDP (1, 5). Despite the huge impact of alcohol use disorders on society, current first-line therapeutic agents, such as naltrexone and acamprosate, are far from adequate, with high relapse rates during treatment and problems with compliance (6–8). New therapeutic agents are clearly required, particularly for the reduction of hazardous drinking and prevention of relapse (9). To this end, a major goal in addiction neuroscience is to understand the neurobiology and neurocircuitry affected by alcohol use disorders and to identify factors implicated in these conditions, which may lead to improved and more targeted therapies (7–10). Here we investigate the neuropeptide relaxin-3 for its involvement in rodent models of alcohol-seeking and consumption.Relaxin-3 is the highly conserved, ancestral neuropeptide of the relaxin/insulin superfamily, and its cognate G-protein–coupled receptor is relaxin family peptide 3 receptor (RXFP3) (11–16). Relaxin-3 is predominantly expressed in gamma-aminobutyric acid (GABA) neurons in the hindbrain nucleus incertus, which projects widely to forebrain areas, including the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus, and lateral hypothalamus, which also express high levels of RXFP3 (11, 15, 17–22). This pattern of innervation, along with findings that relaxin-3 can modulate (i) food intake (23–25), (ii) responses to stress (20, 26, 27), (iii) arousal (28, 29), and (iv) interactions with the corticotropin-releasing factor (CRF) systems (20, 26), led us to hypothesize that relaxin-3 may modulate aspects of behavior related to substance use and abuse. Such a role would parallel that of other neuropeptides, such as orexin/hypocretin (30, 31), galanin (32), and melanin-concentrating hormone (33).The relaxin-3/RXFP3 system was investigated using rat models of alcohol self-administration followed by cue- and stress-induced reinstatement, which are considered robust models for the human experience of relapse (34, 35). Because native relaxin-3 displays some pharmacological cross-reactivity with other relaxin family receptors, peptide ligands selective for RXFP3 have been developed and characterized (36–38). Central injection of a RXFP3-selective agonist increases food intake in rats, which is prevented by prior injection of a RXFP3-selective antagonist (37, 38). Here, we demonstrate that the RXFP3-selective antagonists R3(B1-22)R and R3(BΔ23–27)R/I5 (37, 38) decrease alcohol intake and reinstatement behavior in rats.