HLA-B*5701 clinical testing: early experience in the United States

HLA-B*5701 testing to provide risk stratification for abacavir hypersensitivity has the potential to reduce incidence of hypersensitivity reactions in susceptible individuals. Early experience with clinical HLA-B*5701 testing of the first 100 specimens, from a large clinical reference laboratory in the United States, is presented. Patient samples were tested using a two-step approach. The first step allowed rapid identification of most HLA-B*5701-negative samples in a high throughput mode. The second step involved resolution of putative positives by DNA sequencing to identify B*5701 specifically as well as other B57 subtypes. Test reporting included a phone call from a genetic counselor to obtain the ethnic background and indication for testing and to provide a patient-specific interpretation. The patients population was comprised of Caucasians, 84%; Hispanics, 13%; and African Americans, 3%. Among the 100 samples tested, 92% were HLA-B*5701-negative and 8% were positive for the HLA-B*5701 allele. All HLA-B*5701 allele positives were identified in Caucasian patients. Where the indication for testing was obtainable (57 patients), pre-abacavir therapy screening was the indication 67% of the time. Clarification of previous suspected history of hypersensitivity was the indication 33% of the time. Among samples tested to help clarify a previous history of hypersensitivity, 16/19 or 84% did not carry the HLA-B*5701 allele whereas 3/19 (16%) were carriers of the HLA-B*5701 allele. Early utilization of HLA-B*5701 testing in community practice was not always consistent with the clinical indications for testing. Post-test communication assisted in providing physician education and interpretation of patient-specific results.     

Bioavailability of a pediatric amlodipine suspension

Currently, a suspension of crushed tablets of amlodidpine is widely used in children with hypertension without knowledge of its bioavailability. A comparative bioavailability study of a tablet and suspension formulation of amlodipine was completed in 20 healthy adult volunteers. Bioequivalence of the suspension was not different from the tablets. These results support the use of the suspension in children who cannot take the tablet.     

Carotid artery stenting in high surgical risk patients using the FiberNet® embolic protection system: The EPIC trial results

Objective: The multicenter EPIC (FiberNet Embolic Protection System in Carotid Artery Stenting Trial) single‐arm trial evaluated the 30‐day outcomes of a new design concept for embolic protection during carotid artery stenting (CAS). Background: Embolic protection filters available for use during CAS include fixed and over‐the‐wire systems that rely on embolic material capture within a “basket” structure. The FiberNet® Embolic Protection System (EPS), which features a very low crossing profile, consists of a three‐dimensional fiber‐based filter distally mounted on a 0.014 inch guidewire with integrated aspiration during filter retrieval. Methods: The trial enrolled 237 patients from 26 centers. Demographics, clinical and lesion characteristics, as well as adverse events through a 30‐day follow‐up were recorded. The mean age of the patients was 74 years, 64% were male and 20% had symptomatic carotid artery disease. Results: The combined major adverse event (MAE) rate at 30 days for all death, stroke, and myocardial infarction was 3.0%. There were three major strokes (two ischemic and one hemorrhagic) and two minor strokes (both ischemic) for a 2.1% 30‐day stroke rate. The procedural technical success rate was 97.5% and macroscopic evidence of debris was reported in 90.9% of the procedures. Conclusions: The FiberNet EPS, used with commercially available stents, produced low stroke rates following CAS in high surgical risk patients presenting with carotid artery disease. The unique filter design including aspiration during retrieval may have contributed to the low 30‐day stroke rate reported during CAS in patients considered at high risk for complications following carotid endarterectomy (CEA). © 2009 Wiley‐Liss, Inc.     

Mechanism of endothelial nitric oxide synthase phosphorylation and activation by thrombin

Thrombin has been shown to activate endothelial NO synthase (eNOS) leading to endothelium-dependent vasorelaxation. In addition to its activation by Ca2+/calmodulin, eNOS has several regulatory sites. Ser1179 phosphorylation of eNOS by the phosphatidylinositol 3-kinase-dependent Akt stimulates its catalytic activity. In this study, we have elucidated the signaling mechanism of thrombin-induced phosphorylation of eNOS in the regulation of NO production. Immunoblot analysis showed that thrombin rapidly phosphorylates eNOS at Ser1179 in cultured bovine aortic endothelial cells. Also, thrombin was unable to stimulate eNOS if the Ser1179 was mutated to Ala. Akt is phosphorylated in response to thrombin at Ser473 at a later time point than eNOS. In this regard, a phosphatidylinositol 3-kinase inhibitor, LY294002, blocked Akt phosphorylation without affecting eNOS phosphorylation and cGMP production by thrombin. The Ca2+ ionophore A23187 stimulated eNOS phosphorylation, as well as cGMP production, and pretreatment with intracellular or extracellular Ca2+ chelators inhibited thrombin-induced eNOS phosphorylation and cGMP production. Moreover, infection of bovine aortic endothelial cell with adenovirus encoding dominant-negative mutants of protein kinase C (PKC) and PKC or pretreatment of bovine aortic endothelial cells with PKC inhibitors revealed that PKC is indispensable for thrombin-induced eNOS phosphorylation and activation. From these data, we concluded that thrombin induces the Ser1179 phosphorylation-dependent eNOS activation through a Ca2+-dependent, PKC-sensitive, but phosphatidylinositol 3-kinase/Akt-independent pathway.     

Phase II study of neoadjuvant treatment with doxorubicin,docetaxel, and capecitabine (ATX) in locally advanced or inflammatory breast cancer

Background  

Pathologic complete response (pCR) after preoperative systemic chemotherapy (PSCh) is associated with better outcome in locally advanced breast cancer (LABC).     

Prenatal cocaine exposure does not alter working memory in adult rats

The present study was designed to assess working memory in adult rats exposed to intravenous cocaine in utero, as part of an examination of various cognitive and affective functions. The study included four groups: a saline control and three groups exposed to ascending doses of cocaine from gestational days 8 to 21 (0.5, 1.0, or 3.0 mg/kg). This exposure regimen (route of administration and dose) has been shown to accurately reproduce the pharmacokinetic profile and physiological effects of human recreational cocaine use. This report describes the results of a series of automated alternation tasks, in which the animals were rewarded for alternating their responses between two response ports on successive trials. In the final task, the delay between trials varied randomly between 0, 20, 40, and 80 s, thereby varying the retention interval. Although performance declined dramatically as the retention interval increased, the rate of this decline did not differ across treatment groups. These results suggest that prenatal cocaine exposure, at doses that model recreational use, does not produce lasting changes in explicit memory or working memory. However, subtle, sex-specific effects of prenatal cocaine exposure were seen on measures that indicate impairments in sustained attention and "readiness", as well as altered reactivity to task-related stressors such as waiting for long and unpredictable delays.     

Morgagni-Larrey Hernia- a Review of 20 Cases

Morgagni-Larrey hernia is an uncommon entity. The majority of the literature describes hernia occurring mostly on the right side, a few on the left side and rarely bilateral. Retrospective chart review was done for the patients with the diagnosis of adult diaphragmatic hernia from January 1997 to December 2010. Post-operative course was evaluated for outcome, morbidity and mortality. Out of 20 patients, 13 (65 %) were males and 7 (35 %) were females. Their age ranged from 17 to 50 years (mean = 29.6). Abdominal discomfort was the most common presentation. Eight patients (40 %) were asymptomatic at presentation. Plain X-Ray chest was done for all. Ten patients (50 %) underwent suture repair, 6 (30 %) had mesh placement and the other 4 (25 %) underwent both: suture repair buttressed with mesh. Volvulus of stomach was noted in 5 (25 %) cases. All patients had left sided hernia. There was insignificant morbidity and no mortality. There was no recurrence in 16 patients followed up for a mean duration of 20 months (range = 8 to 32 months). In Morgagni-Larrey hernia, abdominal approach gives good accessibility to reduce the hernia and to undertake repair. When complicated with incarceration, perforation, gangrene or volvulus of the herniated bowel; this can be dealt with ease. Plain X Ray of the chest is fairly accurate in suggesting the diagnosis of Morgagni-Larrey hernia.