Molecular defects in the beta-globin gene identified in different ethnic groups/populations during prenatal diagnosis for beta-thalassemia: a Malaysian experience

Abstract   β-thalassemia is the most-common genetic disorder of hemoglobin synthesis in Malaysia, and about 4.5% of the population are heterozygous carriers of the disorder. Prenatal diagnosis was performed for 96 couples using the Amplification Refractory Mutation System and Gap-Polymerase Chain Reaction. We identified 17 β-globin defects-initiation codon for translation (T-G), -29 (A-G), -28 (A-G), CAP +1 (A-C), CD 8/9 (+G), CD 15 (G-A), CD 17 (A-T), CD 19 (A-G), Hb E (G-A), IVS1-1 (G-T), IVS1-5 (G-C), CD 41/42 (-CTTT), CD 71–72 (+A), IVS2-654 (CT), poly A(A-G), 100-kb ^Gγ(^Aγδβ)° and 45-kb Filipino deletions. The 192 β-alleles studied comprised Chinese (151 patients), Malay (21), Orang Asli from East Malaysia (15), Filipino (1), Indian (1), Indonesian Chinese (2), and Thai (1). In the Chinese, 2 β-globin defects at CD 41/42 and IVS2-654 were responsible for 74% of β-thalassemia. β-mutations at CD 19, IVS1-1 (G-T), IVS1-5, poly A, and hemoglobin E caused 76% of the hemoglobin disorders in the Malays. The Filipino 45-kb deletion caused 73.3% of bthalassemia in the Orang Asli. Using genomic sequencing, the rare Chinese β-mutation at CD 43 (G-T) was confirmed in 2 Chinese, and the Mediterranean mutation IVS1-1 (G-A) was observed in a Malay β-thalassemia carrier. The β-globin mutations confirmed in this prenatal diagnosis study were heterogenous and 65 (68%) couples showed a different globin defect from each other. The use of specific molecular protocols has allowed rapid and successful prenatal diagnosis of β-thalassemia in Malaysia.     

Niacin affects cell adhesion molecules and plasminogen activator inhibitor-1 in HepG2 cells

BACKGROUND: Beyond lipid-modifying actions, niacin lowers the risk of atherothrombotic events by lowering prothrombotic factors like fibrinogen. Plasminogen activator inhibitor type 1 (PAI-1) is a potential factor for atherogenesis and thrombosis, increased in acute myocardial infarctions and restenosis after angioplasty. Cell adhesion molecules (CAM) mediate adhesion, recruitment and migration of white blood cells through vascular surfaces, an essential process in atherogenesis. ICAM-1 is a significant predictor of future coronary events. Whether niacin affects ICAM-1 expression is unknown. We studied the effects of niacin on PAI-1 and CAM using HepG2 cells. METHODS: HepG2 cells were cultured in DMEM until 90% confluent. After serum starvation, cells were exposed to DME/F12 containing niacin. Transforming growth factor-beta (TGF-beta) was added directly to cell media. Cell lysate and conditioned media were collected for measurement of PAI-1 by ELISA. For measurement of ICAM, cells were treated with tumor necrosis factor-alpha (TNF-alpha) instead. The effect of niacin on mRNA expression of ICAM-1 was studied using RT-PCR. RESULTS: Niacin reduced the TGF-beta-induced rise by 30% to 55% (p=0.002). The differences in degree of PAI-1 reduction, between different niacin concentrations, were not statistically significant. Niacin reduced TNF-alpha-induced rise in ICAM-1 levels by 66% to 89% (p<0.0001), but did not significantly affect TNF-alpha-induced rise in PECAM-1. Semiquantitative RT-PCR analysis showed that reduced TNF-alpha-induced rise in ICAM-1 mRNA expression significantly by 17% (p=0.001). CONCLUSIONS: Treatment with niacin suppressed PAI-1 and ICAM-1 levels in HepG2 cells. Further studies to understand the mechanistic pathways of this suppression, could further explain benefits of niacin in prevention of atherosclerotic disease, and offer therapeutic avenues against the rising burden of atherothrombotic disease.     

Anesthesia for removal of inhaled foreign bodies in children

BACKGROUND: Foreign body aspiration may be a life-threatening emergency in children requiring immediate bronchoscopy under general anesthesia. Both controlled and spontaneous ventilation techniques have been used during anesthesia for bronchoscopic foreign body removal. There is no prospective study in the literature comparing these two techniques. This prospective randomized clinical trial was undertaken to compare spontaneous and controlled ventilation during anesthesia for removal of inhaled foreign bodies in children. METHODS: Thirty-six children posted for rigid bronchoscopy for removal of airway foreign bodies over a period of 2 years and 2 months in our institution were studied. After induction with sleep dose of thiopentone or halothane, they were randomly allocated to one of the two groups. In group I, 17 children were ventilated after obtaining paralysis with suxamethonium. In group II, 19 children were breathing halothane spontaneously in 100% oxygen. RESULTS: All the patients in the spontaneous ventilation group had to be converted to assisted ventilation because of either desaturation or inadequate depth of anesthesia. There was a significantly higher incidence of coughing and bucking in the spontaneous ventilation group compared with the controlled ventilation group (P = 0.0012). CONCLUSION: Use of controlled ventilation with muscle relaxants and inhalation anesthesia provides an even and adequate depth of anesthesia for rigid bronchoscopy.     

Leiomyoma of the vagina: an unusual presentation

Vaginal leiomyomas are rare. They usually arise from the anterior vaginal wall. We report a case of a vaginal leiomyoma arising from the right lateral wall that presented as a gluteal swelling with pus discharging per vagina, creating a clinical dilemma in diagnosis. Preoperative imaging and biopsy may help to rule out malignancy. The size of the tumor necessitated abdominoperineal approach and hysterectomy for better surgical access. To the best of our knowledge such a clinical presentation of a vaginal leiomyoma has not been reported in the literature.     

The benefits of niacin in atherosclerosis

Niacin favorably alters all major lipid subfractions at pharmacologic doses. Alone or in combination, it promotes regression of coronary artery disease, decreases coronary events, stroke, and total mortality. Major recent progress in niacin is in four areas. Firstly, recent data indicate that it increases high-density lipoprotein (HDL) and lowers triglycerides and low-density lipoprotein (LDL) by mechanisms different from statins, fibrates, and bile-sequestrants, giving rationale for combination therapy to achieve synergistic effects for complete lipid goal achievement. Secondly, new data on an extended-release preparation of niacin given once nightly indicates that it is as effective and has greater tolerability than immediate-release niacin. Thirdly, preliminary data with a single tablet formulation extended-release niacin and an HMG CoA reductase inhibitor (lovastatin) shows it to be safe and very effective, especially for raising HDL. Finally, emerging evidence indicates that niacin can be used effectively and safely in patients with type 2 diabetes mellitus, who often have low HDL levels.