Previous studies have found a strong association between HLA-B*1502 and carbamazepine-induced Stevens-Johnson syndrome in Asian areas including Taiwan, Hongkong and Thailand. This study explores the association between HLA-B*1502 allele and carbamazepine-induced cutaneous adverse reactions in Han Chinese of southern China mainland, and find the genetic marker that can predict carbamazepine-induced cutaneous adverse reactions. HLA-B*1502 allele genotyping was performed by a polymerase chain reaction-sequence specific primers (PCR-SSP) method in 48 Han Chinese subjects who had carbamazepine-induced cutaneous adverse reactions, including 9 severe cutaneous adverse reaction patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) and 39 cutaneous adverse reaction patients with maculopapular eruption (MPE). Meanwhile 80 carbamazepine-tolerant controls and 62 healthy individuals were also tested. The frequency of HLA-B*1502 allele among SJS/TEN patients (100%) is significantly higher than carbamazepine-tolerant controls (13.75%, P<0.001) and healthy individuals (17.74%, P<0.001). But the frequency between MPE patients and carbamazepine-tolerant controls (25.64% vs.13.75%, P=0.110) did not have any significant difference. The data showed that HLA-B*1502 allele is strongly associated with carbamazepine-induced SJS/TEN but not MPE in Han Chinese of southern China mainland.
Statins have recently been shown to exert neuronal protection in ischemic stroke. Reactive oxygen species, specifically superoxide formed during the early phase of reperfusion, augment neuronal injury. NADPH oxidase is a key enzyme for superoxide production. The present study tested the hypothesis that atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in transient focal ischemia. Transient focal ischemia was created in halothane-anesthetized adult male Sprague-Dawley rats (250-300 g) by middle cerebral artery occlusion (MCAO). Atorvastatin (Lipitor, 10 mg/kg sc) was administered three times before MCAO. Infarct volume was measured by triphenyltetrazolium chloride staining. NADPH oxidase enzymatic activity and superoxide levels were quantified in the ischemic core and penumbral regions by lucigenin (5 microM)-enhanced chemiluminescence. Expression of NADPH oxidase membrane subunit gp91(phox) and membrane-translocated subunit p47(phox) and small GTPase Rac-1 was analyzed by Western blot. NADPH oxidase activity and superoxide levels increased after reperfusion and peaked within 2 h of reperfusion in the penumbra, but not in the ischemic core, in MCAO rats. Atorvastatin pretreatment prevented these increases, blunted expression of membrane subunit gp91(phox), and prevented translocation of cytoplasmic subunit p47(phox) to the membrane in the penumbra 2 h after reperfusion. Consequently, cerebral infarct volume was significantly reduced in atorvastatin-treated compared with nontreated MCAO rats 24 h after reperfusion. These results indicate that atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in transient focal ischemia.
OBJECTIVETo examine the effect of intensive glycemic control therapy (IT) on insulin sensitivity and β-cell function in newly diagnosed type 2 diabetic patients compared with subjects with normal glucose tolerance (NGT) and those with impaired glucose tolerance (IGT).RESEARCH DESIGN AND METHODSForty-eight newly diagnosed type 2 diabetic patients were randomly assigned to IT for 2 weeks and followed up for 1 year. Intravenous glucose tolerance tests were conducted in NGT, IGT, and diabetic subjects. Blood glucose and insulin were measured before and after IT and at the 1-year follow-up.RESULTSIT lowered the homeostasis model assessment (HOMA) for insulin resistance (IR) significantly, from 3.12 ± 1.4 (mean ± SD) to 1.72 ± 0.8, a level comparable to the IGT (1.96 ± 1.1) and NGT (1.37 ± 0.6) subjects in the remission group; however, no HOMA-IR improvement was observed in nonremission subjects. HOMA-β in the remission group was improved (mean, interquartile range) from 18.4 (8.3–28.5) to 44.6 (32.1–69.1) and acute insulin response of insulin (AIRins) from 1.50 ± 0.22 to 1.83 ± 0.19 μIU/mL after IT, but was still significantly lower than those in NGT individuals (HOMA-β: 86.4 [56.7–185.2], P < 0.01; AIRins: 2.54 ± 0.39 μIU/mL, P < 0.01). After IT and at 1 year, the hyperbolic relationship between HOMA-β and HOMA sensitivity of remission subjects shifted close to that of IGT subjects.CONCLUSIONSIT in newly diagnosed type 2 diabetes not only partially restored β-cell function but also greatly restored insulin sensitivity. Compared with IGT and NGT subjects, β-cell function was less restored than insulin sensitivity after IT in the remission subjects.
Background-Inducible NO synthase (NOS)-derived peroxynitrite (ONOO Ϫ ) during ischemia/reperfusion contributes to ischemic brain injury. However, inducible NOS (iNOS) regulation in ischemic stroke remains unknown. Tetrahydrobiopterin (BH 4 ) is an essential cofactor for NOS activity. The present study tested the hypothesis that inhibition of endogenous BH 4 rate-limiting enzyme GTP cyclohydrolase I (GTPCH I), and thus BH 4 synthesis, reduces cerebral infarction via inhibiting iNOS and ONOO Ϫ in transient focal ischemia. Methods-Focal ischemia (2 hours) was created in adult male Sprague-Dawley rats (250 to 300 g) by middle cerebral artery occlusion (MCAO). Rats were treated 12 hours before MCAO with vehicle or diamino-6-hydroxypyrimidine (DAHP; 0.5 g/kg IP), a selective GTPCH I inhibitor. Brains were harvested 24 hours after reperfusion for assays of infarct volume, blood-brain barrier (BBB) permeability, GTPCH I activity, BH 4 levels, GTPCH I and NOS mRNA, protein expression, and superoxide anion (O 2 ⅐ Ϫ ) and ONOO Ϫ levels. Results-Endogenous GTPCH I activity, BH 4 levels, iNOS activity, and (O 2 ⅐ Ϫ and ONOO Ϫ levels were all augmented after ischemia/reperfusion. DAHP treatment significantly reduced GTPCH I activity, resulting in decreased BH 4 levels, iNOS activity, and ONOO Ϫ levels. Consequently, DAHP treatment significantly reduced the infarct size compared with the nontreated group (22.3Ϯ5.6 versus 38.3Ϯ7.4%; nϭ6; PϽ0.05). Similarly, BBB permeability was significantly reduced after DAHP pretreatment compared with the control group (4.11Ϯ0.22 versus 7.78Ϯ0.44 g/g tissue; nϭ5; PϽ0.05).Conclusion-These results demonstrate that blockade of endogenous brain BH 4 synthesis attenuates cerebral infarction via inhibiting iNOS and ONOO Ϫ , which may provide a mechanistic basis of novel therapeutic strategies for ischemic stroke.
Background: Cerebral infarction caused by pituitary apoplexy (PA) is rare. To characterize the clinical features of cerebral infarction caused by PA, we performed a systematic review. Summary: The clinical symptoms are mainly sudden headache, hemiplegia, visual impairment, disturbance of consciousness, and ophthalmalgia in patients with cerebral infarction caused by PA. Treatment for this type of infarction is different from treatment for general acute cerebral infarction. Compared to patients who underwent emergency surgery and conservative treatment, patients treated with delayed surgery showed a better prognosis and a lower mortality rate. Compared to patients who underwent craniotomy or conservative treatment, patients who underwent transsphenoidal surgery (TSS) not only improved well but also showed a lower mortality rate. Key Messages: PA rarely causes cerebral infarction, which is a critical condition with a poor prognosis and is more common in men. Delayed surgery and TSS appear to confer a better prognosis in patients with this condition.
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