Complete recovery from acute encephalopathy of late-onset ornithine transcarbamylase deficiency in a 3-year-old boy

Ornithine transcarbamylase deficiency is the commonest urea cycle disorder which is transmitted in X-linked inheritance. It is mainly characterized in males by acute encephalopathy and hyperammonaemia with fatal outcomes in both classical neonatal and late-onset types. We report a 3-year-old healthy Hong Kong Chinese boy who presented with acute encephalopathy and coma after three days of gastroenteritis. He had no focal neurological deficit and brain CT imaging was normal. His plasma ammonia (54 micromol/L) and glutamine (747 micromol/L) concentrations were normal. The only biochemical abnormalities detected were marked orotic aciduria (700 micromol/mmol creatinine) and elevated urinary uracil. He regained consciousness spontaneously after three days under intensive care with parenteral fluid therapy. He recovered completely without any neurological deficits. Five months after discharge, urinary uracil concentration remained elevated despite normalized orotic acid concentration. Finally, ornithine transcarbamylase deficiency was diagnosed by DNA analysis. A missense mutation of arginine-to-glutamine substitution on amino acid 277 (p.R277Q) was revealed to be a late-onset mutant. Our case strengthens the argument that in any child with coma or acute encephalopathy of undetermined cause, genetic analysis of the OTC gene and the measurement of urinary uracil concentration remain the most reliable indicators of late-onset OTCD during acute and even quiescent phases. Existing neonatal screening programmes for inheritable metabolic disorders fail to detect late-onset variants. Therefore, a high clinical suspicion is a key to correct and timely diagnosis, especially in those patients with atypical presentations.     

Microsomal glutathione S-transferase gene polymorphisms and colorectal cancer risk in a Han Chinese population

BACKGROUND AND AIMS: Glutathione S-transferases (GSTs) are phase II detoxification enzymes. Human GSTs have been classified into cytosolic, mitochondrial, and microsomal families. Several studies reported the association of colorectal cancer (CRC) risk with the genetic polymorphisms of cytosolic GSTs. The microsomal GSTs are structurally distinct but functionally similar to cytosolic GSTs; their association with CRC has not been reported. In this report, we summarized the result of a case-control study aimed at investigating the association of MGST1 gene locus polymorphisms with CRC risk among Han Chinese. PATIENT/METHODS: Three hundred and seventy-two healthy controls and 238 sporadic CRC patients participated in this study. DNA resequencing was conducted for the 3.4 kb genomic DNA region containing the promoter, exons, exon-intron junctions, and the 5' and 3' untranslated regions. RESULTS: We detected 13 single nucleotide polymorphisms (SNPs) including four novel SNPs not reported in database/literature. The gene shows a much higher nucleotide diversity than most human genes. The linkage and recombination analysis revealed 24 common haplotypes (13% > or = freq > or = 1%) and identified extensive intragenic recombination throughout the MGST1 locus (R = 81.8). Significant CRC association (P < or = 0.005) was not detected for each individual SNP. However, SNPs 102G>A and 16416G>A reached a marginal level of statistical significance with P values of 0.016 and 0.078, respectively. A combined genotype analysis detected a statistically significant CRC association for individuals carrying 102G>A/16416G>A (GG/GG) genotype (adjusted OR, 1.682; 95% confidence interval (CI), 1.177-2.404; P = 0.004). Consistent with the results of genotype analysis, the GG haplotype (102G>A/16416G>A) with two risk alleles was associated with a significantly higher CRC risk comparing with the haplotypes with one or no risk allele (adjusted OR 1.744; 95% CI 1.309-2.322; P = 0.0001). CONCLUSION: The results suggest that MGST1 polymorphisms may contribute to CRC risk among Han Chinese.     

DMY gene induces male development in genetically female (XX) medaka fish

Although the sex-determining gene SRY/Sry has been identified in mammals, homologues and genes that have a similar function have yet to be identified in nonmammalian vertebrates. Recently, DMY (the DM-domain gene on the Y chromosome) was cloned from the sex-determining region on the Y chromosome of the teleost fish medaka (Oryzias latipes). DMY has been shown to be required for the normal development of male individuals. In this study, we show that a 117-kb genomic DNA fragment that carries DMY is able to induce testis differentiation and subsequent male development in XX (genetically female) medaka. In addition, overexpression of DMY cDNA under the control of the CMV promoter also caused XX sex reversal. These results demonstrate that DMY is sufficient for male development in medaka and suggest that the functional difference between the X and Y chromosomes in medaka is a single gene. Our data indicate that DMY is an additional sex-determining gene in vertebrates.     

Discovery of growth hormone-releasing hormones and receptors in nonmammalian vertebrates

In mammals, growth hormone-releasing hormone (GHRH) is the most important neuroendocrine factor that stimulates the release of growth hormone (GH) from the anterior pituitary. In nonmammalian vertebrates, however, the previously named GHRH-like peptides were unable to demonstrate robust GH-releasing activities. In this article, we provide evidence that these GHRH-like peptides are homologues of mammalian PACAP-related peptides (PRP). Instead, GHRH peptides encoded in cDNAs isolated from goldfish, zebrafish, and African clawed frog were identified. Moreover, receptors specific for these GHRHs were characterized from goldfish and zebrafish. These GHRHs and GHRH receptors (GHRH-Rs) are phylogenetically and structurally more similar to their mammalian counterparts than the previously named GHRH-like peptides and GHRH-like receptors. Information regarding their chromosomal locations and organization of neighboring genes confirmed that they share the same origins as the mammalian genes. Functionally, the goldfish GHRH dose-dependently activates cAMP production in receptor-transfected CHO cells as well as GH release from goldfish pituitary cells. Tissue distribution studies showed that the goldfish GHRH is expressed almost exclusively in the brain, whereas the goldfish GHRH-R is actively expressed in brain and pituitary. Taken together, these results provide evidence for a previously uncharacterized GHRH-GHRH-R axis in nonmammalian vertebrates. Based on these data, a comprehensive evolutionary scheme for GHRH, PRP-PACAP, and PHI-VIP genes in relation to three rounds of genome duplication early on in vertebrate evolution is proposed. These GHRHs, also found in flounder, Fugu, medaka, stickleback, Tetraodon, and rainbow trout, provide research directions regarding the neuroendocrine control of growth in vertebrates.     

Mannose-binding lectin and susceptibility to infection in Chinese patients with systemic lupus erythematosus

OBJECTIVE: To test the hypothesis that low serum mannose-binding lectin (MBL) levels, as a result of the single-nucleotide polymorphisms in the promoter region (-221 X/Y) and exon 1 (codon 54 A/B) of the MBL2 gene, predispose to infection in Chinese patients with systemic lupus erythematosus (SLE). METHODS: Two hundred forty-five patients with SLE were prospectively followed for the development of major infective episodes that required hospitalization and antibiotic treatment during 1992-2005. MBL genotypes were determined by polymerase chain reaction and serum MBL levels were measured by ELISA. RESULTS: In total, 254 major infections developed in 130 patients. Serum MBL levels were shown to correlate inversely with the number of bacterial infections (r = -0.13, p = 0.03). The distribution of MBL genotypes was similar in patients with and without major infection (p = 0.84). Patients with major infection also had more major lupus exacerbations that required daily prednisolone dose > or = 15 mg. Logistic regression showed that log MBL level (odds ratio 0.516, 95% confidence interval 0.305-0.873; p = 0.01) and major lupus exacerbation (OR 1.382, 95% CI 1.154-1.654; p < 0.001) were independent risk factors to major bacterial infection after adjustment for age and disease duration. Multiple regression analysis showed an increase in risk of bacterial infection by 34.2% for every decrease in serum MBL level by one log, and by 22.8% for each increase in number of major lupus exacerbations. CONCLUSION: Low serum MBL level predisposes Chinese patients with SLE to more major infections, in particular bacterial ones.     

Transient atrial fibrillation complicating acute inferior myocardial infarction: implications for future risk of ischemic stroke

BACKGROUND: Atrial fibrillation (AF) that occurs as a frequent complication of myocardial infarction (MI) is associated with a poor clinical outcome. It nonetheless remains uncertain whether AF that occurs transiently during MI is associated with a subsequent increased risk of the development of AF and ischemic stroke. METHODS: We retrospectively studied the impact of transient AF on the long-term risk of the occurrence of AF, ischemic stroke, and mortality in 431 consecutive patients (mean [+/- SEM] age, 64 +/- 1 years; 75% men). All patients had experienced an acute inferior ST-segment-elevation MI and had preserved left ventricular ejection fraction (LVEF) [> 45%]. RESULTS: All patients were in sinus rhythm on hospital admission, and transient AF was observed in 59 patients (13.7%) during their hospitalization for MI. On hospital discharge, all patients were in sinus rhythm and had been prescribed antiplatelet agents alone as antithrombotic therapy. Patients in whom transient AF developed during MI were older (mean age, 70 +/- 1.4 vs 64 +/- 0.7 years, respectively; p < 0.01) and more likely to be women (37% vs 23%, respectively; p < 0.02) compared with those without AF. At 1-year follow-up, the incidence of AF (22.0% vs 1.3%, respectively; p < 0.01) and ischemic stroke (10.2% vs 1.8%, respectively; p < 0.01) was higher in patients with transient AF than in those without transient AF. The total mortality rate was nonetheless similar (5.6% vs 6.8%, respectively; p = 0.73); Cox regression analysis demonstrated that age > 65 years and transient AF during MI were independent predictors of the subsequent occurrence of AF and the development of ischemic stroke. CONCLUSION: Transient AF complicating acute inferior MI is associated with an increased future risk of AF occurrence and ischemic stroke in patients with preserved LVEF, despite the use of antiplatelet therapy.     

Hemodynamic changes in hyperthyroidism-related pulmonary hypertension: a prospective echocardiographic study

CONTEXT: Recent reports suggest an association between hyperthyroidism and pulmonary hypertension (PHT), although the potential mechanisms and clinical implications remain unclear. OBJECTIVE: Our objective was to determine the prevalence of PHT related to hyperthyroidism and the associated hemodynamic changes and outcome. METHODS AND RESULTS: We performed serial echocardiographic examinations in 75 consecutive patients with hyperthyroidism (43 +/- 2 yr, 47 women) to estimate pulmonary artery systolic pressure (PASP), cardiac output (CO), total vascular resistance (TVR), and left ventricular (LV) filling pressure. Examinations were performed at baseline and 6 months after initiation of antithyroid treatment. Results were compared with 35 age- and sex-matched healthy controls. All hyperthyroid patients had normal LV systolic function, and 35 patients (47%) had PHT with PASP of at least 35 mm Hg. There were no significant differences in the clinical characteristics of hyperthyroid patients with or without PHT (all P > 0.05). Nonetheless, those with PHT had significantly higher CO, PASP, peak transmitral early diastolic flow velocity (E), and ratio of E to early diastolic mitral annular velocity (E') compared with those without PHT and controls (all P < 0.05). Hyperthyroid patients with PHT also had significantly lower TVR than controls (P < 0.05). Among the 35 hyperthyroid patients with PHT, 25 (71%) had pulmonary arterial hypertension (PAH) with normal E/E', and 10 (29%) had pulmonary venous hypertension (PVH) with elevated E/E'. Hyperthyroid patients with PAH had a significantly higher CO and a lower TVR compared with those with PVH. In contrast, hyperthyroid patients with PVH had lower E' and a higher E/E' ratio compared with those with PAH. These hemodynamic abnormalities and PHT were reversible in patients with PAH or PVH after restoration to a euthyroid state. CONCLUSION: In patients with hyperthyroidism and normal LV systolic function, up to 47% had PHT due to either PAH with increased CO (70%) or PVH with elevated LV filling pressure (30%). Most importantly, hyperthyroidism-related PHT was largely asymptomatic and reversible after restoration to a euthyroid state.     

Burden of carotid atherosclerosis in patients with stroke: relationships with circulating endothelial progenitor cells and hypertension

Recent studies suggest that reductions in circulating endothelial progenitor cells (EPCs) may contribute to the development of atherosclerosis. However, whether reduced circulating EPCs contribute to cerebrovascular disease remains undefined. We tested the hypothesis that reduced circulating EPCs was associated with an increased burden of carotid atherosclerosis. The level of circulating CD34+/KDR+ EPCs and the extent of carotid atherosclerosis were determined in 30 patients with a history of atherothrombotic ischaemic stroke and 30 age- and sex-matched controls (mean age: 63+/-2 years; 63% men). Stroke patients, compared with controls, had significantly higher carotid mean maximum intima-media thickness (mmIMT) (1.08+/-0.05 versus 0.90+/-0.02 mm, P=0.002), prevalence of carotid plaque (60.0 versus 23.3%, P=0.004) and a lower number of circulating CD34+/KDR+ EPCs (235.7+/-45.5 versus 400.4+/-56.8 cells/mul, P=0.027). The circulating CD34+/KDR+ EPC count correlated negatively with carotid mmIMT (r=-0.50, P<0.001), and was an independent risk factor for increased carotid mmIMT>1 mm (odds ratio (OR): 7.71; 95% confidence interval (CI): 1.62-36.74, P=0.010) and the presence of carotid plaque (OR: 7.04; 95% CI: 1.95-25.43, P=0.003). Furthermore, stroke patients with low (<25th percentile of controls) as compared to those with normal CD34+/KDR+ EPC count had a significantly greater carotid mmIMT (1.21+/-0.07 versus 0.93+/-0.05 mm, P=0.005) and a significantly higher prevalence of carotid plaque (87.5% versus 28.6%; P=0.001). Our observations suggested that reduced circulating EPC may contribute to the progression of carotid atherosclerosis. Circulating EPC count may provide a novel marker for the burden of carotid atherosclerosis.