Inactivation of human immunodeficiency virus by gamma radiation and its effect on plasma and coagulation factors

The inactivation of HIV by gamma-radiation was studied in frozen and liquid plasma; a reduction of the virus titer of 5 to 6 logs was achieved at doses of 5 to 10 Mrad at -80 degrees C and 2.5 Mrad at 15 degrees C. The effect of irradiation on the biologic activity of a number of coagulation factors in plasma and in lyophilized concentrates of factor VIII (FVIII) and prothrombin complex was examined. A recovery of 85 percent of the biologic activity of therapeutic components present in frozen plasma and in lyophilized coagulation factor concentrates was reached at radiation doses as low as 1.5 and 0.5 Mrad, respectively. As derived from the first-order radiation inactivation curves, the radiosensitive target size of HIV was estimated to be 1 to 3 MDa; the target size of FVIII was estimated to be 130 to 160 kDa. Gamma radiation must be disregarded as a method for the sterilization of plasma and plasma-derived products, because of the low reduction of virus infectivity at radiation doses that still give acceptable recovery of biologic activity of plasma components.     

Resolution of infection status of human immunodeficiency virus (HIV)- seroindeterminate donors and high-risk seronegative individuals with polymerase chain reaction and virus culture: absence of persistent silent HIV type 1 infection in a high-prevalence area

To address concerns over the prevalence of silent (antibody-negative) infections among blood donors and high-risk populations, a combination of proviral amplification by polymerase chain reaction (PCR) and viral isolation by co-culture techniques was employed to resolve the human immunodeficiency virus type 1 (HIV-1) infection status of well-characterized groups of suspect blood donors and others identified in the blood bank setting. No silent infections were found in 65 follow-up samples from 26 persistently HIV-1-seroindeterminate blood donors, 16 persistently seronegative heterosexual partners of infected transfusion recipients, and 6 high-risk seronegative homosexual men identified through donor look-back investigations. In contrast, 21 seropositive controls tested positive. These results suggest a low prevalence of persistently silent infections in at-risk populations, even in high HIV prevalence regions. The PCR assay, with a co-detected internal positive control, and appropriate confirmatory algorithms, was found to be a useful direct assay to rule out infection, especially in concert with confirmatory virus isolation.     

Catecholamine synthesis and metabolism in the central nervous system of mice lacking α2-adrenoceptor subtypes

Background and purpose:

This study investigates the role of α₂-adrenoceptor subtypes, α_2A, α_2B and α_2C, on catecholamine synthesis and catabolism in the central nervous system of mice.

Experimental approach:

Activities of the main catecholamine synthetic and catabolic enzymes were determined in whole brains obtained from α_2A-, α_2B- and α_2C-adrenoceptor knockout (KO) and C56Bl\7 wild-type (WT) mice.

Key results:

Although no significant differences were found in tyrosine hydroxylase activity and expression, brain tissue levels of 3,4-dihydroxyphenylalanine were threefold higher in α_2A- and α_2C-adrenoceptor KO mice. Brain tissue levels of dopamine and noradrenaline were significantly higher in α_2A and α_2CKOs compared with WT [WT: 2.8 ± 0.5, 1.1 ± 0.1; α_2AKO: 6.9 ± 0.7, 1.9 ± 0.1; α_2BKO: 2.3 ± 0.2, 1.0 ± 0.1; α_2CKO: 4.6 ± 0.8, 1.5 ± 0.2 nmol·(g tissue)⁻¹, for dopamine and noradrenaline respectively]. Aromatic L-amino acid decarboxylase activity was significantly higher in α_2A and α_2CKO [WT: 40 ± 1; α_2A: 77 ± 2; α_2B: 40 ± 1; α_2C: 50 ± 1, maximum velocity (V_max) in nmol·(mg protein)⁻¹·h⁻¹], but no significant differences were found in dopamine β-hydroxylase. Of the catabolic enzymes, catechol-O-methyltransferase enzyme activity was significantly higher in all three α₂KO mice [WT: 2.0 ± 0.0; α_2A: 2.4 ± 0.1; α_2B: 2.2 ± 0.0; α_2C: 2.2 ± 0.0 nmol·(mg protein)⁻¹·h⁻¹], but no significant differences were found in monoamine oxidase activity between all α₂KOs and WT mice.

Conclusions and implications:

In mouse brain, deletion of α_2A- or α_2C-adrenoceptors increased cerebral aromatic L-amino acid decarboxylase activity and catecholamine tissue levels. Deletion of any α₂-adrenoceptor subtypes resulted in increased activity of catechol-O-methyltransferase. Higher 3,4-dihydroxyphenylalanine tissue levels in α_2A and α_2CKO mice could be explained by increased 3,4-dihydroxyphenylalanine transport.     

Locally transplanted enteric glia improve functional and structural recovery in a rat model of spinal cord injury

BACKGROUND： We have previously reported that adult enteric glia （EG） facilitate the growth of transected dorsal root axons into the uninjured spinal cord to form functional connections with their targets. OBJECTIVE： The present study investigated the effects of EG on spinal cord function, tissue injury, and axonal regeneration following transplantation into injured rat spinal cords, according to histological and functional outcomes. DESIGN, TIME AND SETTING： A randomized controlled animal experiment was performed at McMaster University, Canada from January 2006 to March 2008. MATERIALS： EG were isolated from rat intestine, METHODS： One week following spinal cord crush, female Wistar rats were injected with an EG suspension （2 μL, 1 × 10^5/μL, n = 10） or with the same volume of fresh culture medium alone （control animals, n = 11）. The third group did not receive any injection following laminectomy and served as the sham-operated controls （n = 5）. MAIN OUTCOME MEASURES： Behavior was tested prior to transplantation and weekly following transplantation, with nine behavioral examinations in total. Open field, hind limb placement response foot orientation response, and inclined plane test were utilized. Immediately following the final behavioral examination, spinal cord T9 to L1 segments were harvested for immunohistochemical and hematoxylin-eosin staining to determine astroglial scarring, axonal regeneration and spinal cord lesion size. RESULTS： Rats with EG transplantation exhibited significantly better locomotor function with reduced tissue damage, compared with the control rats. Cystic cavities were present 2 months after injury in spinal cords from both control groups. In contrast, rats injected with EG did not present with cystic lesions. In addition, the injury site consisted of cellular material and nerve fibers, and axonal regeneration was apparent, with dense labeling of neurofilament-positive axons within the injury site. Moreover, regenerating axons were intimately associated with transplanted EG. CONCLUSION： These data indicated that EG enhanced functional improvement, which was associated with reduced tissue damage and axonal regeneration following transplantation into injured spinal cords.     

Effect of tecarfarin,a novel vitamin K epoxide reductase inhibitor,on coagulation in beagle dogs

Background and purpose:

Tecarfarin (ATI-5923) is a novel vitamin K epoxide reductase inhibitor that is metabolized by esterase (mainly human carboxylesterase 2) to a single major metabolite, ATI-5900, in rats, dogs and humans. Tecarfarin is not significantly metabolized by CYP450 enzymes. The objective of this study was to test and compare the efficacy of tecarfarin with that of warfarin, when administered either intravenously or once a day orally, to produce stable anticoagulation in beagle dogs.

Experimental approach:

Effects on coagulation were assessed by measuring the activity levels of Factor VII and Factor X and thromboplastin-induced coagulation times, reported as prothrombin time (PT).

Key results:

Continuous intravenous infusions and oral administration of tecarfarin and warfarin caused a dose-dependent decrease in activity of Factor VII and Factor X, and associated increase in PT. Intravenous fresh frozen canine plasma or subcutaneous vitamin K₁ treatment reversed the anticoagulant effects of orally administered tecarfarin. Consistent with the inhibitory effects of amiodarone on CYP2C9, co-administration of amiodarone significantly increased the anticoagulation effect of warfarin and plasma warfarin concentrations. In contrast, amiodarone had no effect on the anticoagulation induced by tecarfarin or tecarfarin plasma concentrations in this model.

Conclusions and implications:

Overall, the data presented herein indicate that tecarfarin, via a vitamin K-dependent mechanism, causes changes in key parameters of haemostasis in beagle dogs that are consistent with effective anticoagulation. Compared to warfarin it has a decreased potential to interact metabolically with drugs that inhibit CYP450 enzymes and, therefore, may offer an improved safety profile for patients.     

Development of the Manchester framework for the evaluation of emergency department pharmacy services

International Journal of Clinical Pharmacy - Many countries, including the United Kingdom, have established Emergency Department (ED) pharmacy services where some ED pharmacists now work as...     

Rehabilitation in primary and metastatic brain tumours

OBJECTIVES: Patients with brain tumours have major disabilities and guarded prognosis but may benefit from inpatient rehabilitation.The objectives were to compare functional outcomes inpatients with glioblastoma multiforme(GBM), brain metastases and other brain tumours, and to determine predictors of survival. METHODS: Demographic, clinical,functional, and survival data were collected for 63 patients.Kaplan-Meier and Cox regression were used for survival analyses. RESULTS: Functional Independence Measure(FIM ) scores improved from admission to discharge for patients with GBM, brain metastases and other tumours. Estimated median survival was 141 days for brain metastases, 214 days for GBM and 439 days for other tumours. Low admission dexamethasone dose and high FIM gain predicted better survival in GBM. For brain metastases, high FIM gain, low dexamethasone dose and no organ metastases were positive prognostic factors. CONCLUSIONS: Patients with primary and metastatic brain tumours achieved functional gains after rehabilitation. High functional improvement is a significant predictor of longer survival in brain metastases and GBM. This study has implications for rehabilitation in the post-acute management of patients who have disabilities due to brain tumours.