The genetic basis for Glanzmann's thrombasthenia (GT) was elucidated on a compound heterozygote with glycoprotein (GP)IIb gene: an opal mutation at the end of exon 17 (CGA----TGA) results in only a trace amount of GPIIb mRNA, and a splicing mutation at the acceptor site of exon 26 (CAG----GAG) causes an in-frame, exon skipping process from exon 25 to 27. This aberrant transcript encodes a single-chain polypeptide characterized by a 42-amino acid deletion, which includes the proteolytic cleavage site(s) and a unique, proline-rich region at the location corresponding to the carboxyl-terminal of the normal GPIIb alpha-chain. These characteristics are shared by a previously reported defective GPIIb molecule, which is neither assembled with GPIIIa nor transported to the cellular surface. Despite its normal transcription level, expression of the present defective GPIIb molecule was significantly decreased (approximately 6% of the control level). Because the precursor GPIIb molecule is assembled with GPIIIa in the endoplasmic reticulum (ER) and its processing, as well as stability, is dependent on the GPIIIa subunit, the defective GPIIb molecule may be rapidly degraded by the intrinsic quality control system of the ER due to its inability to form a stable heterodimer complex as a consequence of its misfolded structure. Although we did not confirm that the GPIIIa genes of this individual were normal, GPIIIa may be secondarily decreased (approximately 11% of control), because a large part of it could not be complexed, making it vulnerable to proteolysis. To elucidate the molecular basis for GT, we propose here a classification of GT based on the biosynthetic pathway of the GPIIb-IIIa complex.

Oral antidepressants are currently the first-line pharmacotherapy for obsessive-compulsive disorder (OCD), but response rates can often be low and with delayed onset of therapeutic action. Some reports have suggested that intravenous (i.v.) anti-obsessive agents may have faster onset of action and greater efficacy. A Medline search was conducted for all reports pertaining to the use of i.v. antidepressants for OCD. Search terms included: 'intravenous', 'clomipramine', 'selective serotonin reuptake inhibitor', 'tricyclic', 'citalopram', 'sertraline', 'paroxetine', 'fluvoxamine', 'SSRIs' and 'intravenous antidepressants'. Relevant articles mainly investigated clomipramine (CMI) with one open trial examining citalopram. Intravenous agents appear to be well-tolerated, particularly in those who have failed oral agents, and may act more rapidly to produce initial clinical response, although this advantage is often lost over time. Preliminary evidence suggests subgroups of patients with severe treatment-refractory OCD may benefit from i.v. anti-obsessive agents, CMI and citalopram. Larger, controlled trials are needed for more definitive conclusions.

Objective: Some studies have evaluated the prognostic indicators associated with acute paraquat (PQ) poisoning. In this study, we externally validated the Yamaguchi index, which showed a good prognostic relevance in predicting the outcome of PQ poisoning. Methods: A retrospective analysis of 297 patients was performed. The Yamaguchi index was calculated using the following equation: Eq1 = (K+ × HCO3−)/(Creatinine × 0.088)(mEq/L) against time from PQ ingestion ( T). The patients were divided into three groups: group A: Eq1 > 1500 − 399 × log T, group B: 930 − 399 × log T < Eq1 ≤ 1500 − 399 × log T, and group C: Eq1 ≤ 930 − 399 × log T). Results: The overall mortality rate was 65.3% (194 of 297). The mortality rates of the three groups stratified by the Yamaguchi index were 7.1% (2 of 28), 22.4% (15 of 67), and 87.6% (177 of 202). The area under the receiver–operating characteristic curve for predicting mortality from the external validation of the Yamaguchi index was 0.842 (95% confidence interval: 0.795–0.882). Conclusion: The Yamaguchi index is a reliable prognostic factor and could be helpful in predicting mortality due to PQ poisoning.

We describe an individual with abnormal platelet glycoprotein (GP) IIb of different molecular weight (mol wt), a defect that distinguishes this patient from previously reported thrombasthenics. The patient, a 21-year-old female, has a mild bleeding tendency; her platelets lack adenosine diphosphate (ADP) aggregation and have severely suppressed collagen aggregation but a normal response to ristocetin. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of her platelets indicates that they contain two types of GPIIb molecules: one with an abnormal mol wt (122 kd, unreduced; 128 kd, reduced) and one with a normal mol wt (128 kd, unreduced; 118 kd, reduced). Relative to the amount of GPIIb in normal platelets, her platelets contain approximately 35% abnormal GPIIb and 20% normal GPIIb. Fibrinogen binding assays on the patient's platelets indicated that they contained 25% of the normal amount of fibrinogen receptors. Crossed immunoelectrophoresis of the patient's platelets demonstrated the formation of a GPIIb/IIIa complex that was mainly composed of normal mol wt GPIIb and GPIIIa. The patient's father has decreased ADP aggregability, and his platelets also contained both abnormal and normal GPIIb (about 50% of the normal level and about 50% of the normal number of fibrinogen receptors); her mother has only normal GPIIb. These results indicate that the patient has heterozygous GPIIb molecules with an abnormality of GPIIb at the molecular level. Studies on this abnormal GPIIb should provide information about the function of GPIIb and the mechanism of its biosynthesis.

BackgroundIn chronic kidney disease (CKD) patients, hyperuricemia is a common finding and might be one of modifiable risk factors for renal progression. However, dosing adjustments and increased risk of serious side effects of uric acid lowering agents in patients with reduced renal function lead to undercorrection of hyperuricemia, especially in patients with advanced CKD. Febuxostat is highly effective and well-tolerated to treat hyperuricemia in CKD patients. Although several evidences demonstrated the usefulness of febuxostat in hyperuricemic CKD patients, clinical studies aimed at the CKD patients with inappropriately controlled hyperuricemia by allopurinol have been relatively lacking.ObjectivesThe study objective is to evaluate the safety and efficacy of febuxostat in patients, who had CKD with severe renal impairment and did not meet with the target uric acid levels using allopurinol.MethodsData were collected from 168 patients who had CKD with more than stage 3b and changed from allopurinol to febuxostat due to uncontrolled hyperuricemia between 2005 and 2014 at Yonsei University Medical Center. Uric acid and creatinine were analyzed at baseline and during the first 6 and 12 months after conversion of febuxostat. Estimated glomerular filtration rate was calculated using the formula of MDRD equation. The patients were defined as a well-controlled state when the uric acid values of the study subjects reached within 6.0 mg/dL.ResultsThe mean age was 60.7±14.6 years, and 129 patients (76.8%) were male. The number of patients was 25 (14.9%) in CKD stage 3b, 75 (44.6%) in stage 4, 8 (4.8%) in stage 5, 38 (22.8%) in patients treated with maintenance dialysis, 22 (13.1%) in patients underwent kidney transplantation. The mean estimated GFR (eGFR) and uric acid levels at baseline was 23.1±17.3 ml/min/1.73m2 and 8.3±2.4 mg/dL, respectively. Most of the patients was treated with 40 or 80mg of febuxostat during the study period. The mean uric acid levels at 6- and 12-month after febuxostat treatment were significantly reduced compared to uric acid levels at baseline (5.2±2.1 mg/dL at 6-month and 4.9±2.2 mg/dL at 12-month, p<0.001, respectively). More than 70% of study subjects reached to the target of uric acid levels less than 6mg/dL at 6- and 12-months after treatment of febuxostat [122 (72.6%) patients at 6-month and 133 (79.2%) patients]. The creatinine levels at baseline and 6-month were comparable (3.42±2.03 vs. 3.38±2.16 mg/dL at baseline and 6-month, p=0.61), meanwhile, the creatinine levels were significantly increased after 12-month compared to those at baseline (3.69±2.46 mg/dL, p<0.01). Abnormality of liver function test was observed in only one patient during the follow up period. None of the patients did not discontinue drug due to adverse events.ConclusionsPresent study demonstrated that substantial hyperuricemic CKD patients treated with febuxostat were achieved the target of uric acid levels without adverse events. Febuxostat is an effective and safe uric acid lowering drug in allopurinol-intolerant p...