In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells

Topotecan [(S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride; SK&F 104864-A, NSC 609699], a water soluble semisynthetic analogue of the alkaloid camptothecin, is a potent topoisomerase I inhibitor. Here we show that topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B- lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell in vitro clonogenic growth in a dose-dependent fashion. Furthermore, topotecan elicited potent antileukemic activity in three different severe combined immunodeficiency (SCID) mouse models of human poor prognosis ALL and markedly improved event-free survival of SCID mice challenged with otherwise fatal doses of human leukemia cells at systemic drug exposure levels that can be easily achieved in children with leukemia.     

The Presentation and Outcome of HIV-related Disease in Nairobi

The range of clinical presentations of HIV-related disease inAfrica has not been adequately described, despite the fact thatmany hospitals have to rely heavily on clinical diagnosis. Sixhundred adult medical patients seen in the Casualty Departmentof the main Government hospital in Nairobi were enrolled ina study of the presentation and outcome of HIV-related disease:506 of these patients were admitted, of whom 19 per cent (95)were HIV seropositive. The remaining 94 were dealt with as outpatients:11 percent (10) of these were seropositive. A history of priortreatment for sexually transmitted disease and, if male, beinguncircumcised, were associated with being seropositive. Threepresentations were strongly associated with HIV infection: acutefever with no focus except the gastrointestinal tract (entericfever-like illness), acute cough with fever (community-acquiredpneumonia) and chronic diarrhoea with wasting. The WHO clinicalcase definition (CCD) for AIDS missed a substantial amount ofHIV-related morbidity (sensitivity 39 per cent) and misidentifiedmany seronegative patients (positive predictive value 59 percent). In comparison with the Centers for Disease Control surveillancedefinition for AIDS, the CCD was specific (91 per cent) andsensitive (79 per cent) but only had a positive predictive valuesof 30 per cent: the CCD may therefore be a poor surveillancetool for AIDS. Seropositive patients were much more likely todie than were seronegative patients (39 per cent vs. 15 percent mortality). Enteric fever-like illness was the presentationwhich most commonly proved fatal. A wider spectrum of diseaseis associated with underlying HIV immunosuppression than haspreviously been described in Africa.     

Quantitation of MR relaxation effects of iron oxide particles in liver and spleen

The relaxation effects and organ distribution of superparamagnetic iron oxide particles for magnetic resonance imaging were measured in rats. T1 and T2 were measured for excised organs, and tissue iron levels were quantified with radiolabeling. Approximately 70% of the injected dose is present in the liver and 10% in the spleen 1 hour after injection. At 20 MHz, the doses required to reduce liver and spleen T2 to half the normal value, as measured with a Carr-Purcell-Meiboom-Gill sequence, were, respectively, 420 and 830 mumol iron injected per kilogram of rat. The transverse relaxation rates increase linearly with injected dose and showed no evidence of saturation. These results suggest that this material is less effective than previously suggested.     

Structurally diverse amphiphiles exhibit biphasic modulation of GABAA receptors: similarities and differences with neurosteroid actions

Background and purpose:

Some neurosteroids, notably 3α-hydroxysteroids, positively modulate GABA_A receptors, but sulphated steroids negatively modulate these receptors. Recently, other lipophilic amphiphiles have been suggested to positively modulate GABA receptors. We examined whether there was similarity among the actions of these agents and the mechanisms of neurosteroids. Significant similarity would affect theories about the specificity of steroid actions.

Experimental approach:

Xenopus laevis oocytes were challenged with Triton X-100, octyl-β-glucoside, capsaicin, docosahexaenoic acid and sodium dodecyl sulphate (SDS), along with different GABA concentrations.

Key results:

These compounds have both positive and negative effects on GABA currents, which can be accentuated according to the degree of receptor activation. A low GABA concentration (1 µM) promoted potentiation and a high concentration (20 µM) promoted inhibition of current, except for SDS that inhibited function even at low GABA concentrations. Amphiphile inhibition was characterized by enhanced apparent desensitization and by weak voltage dependence, similar to pregnenolone sulphate antagonism. We then tested amphiphile effects on mutated receptor subunits that are insensitive to negative (α1V256S) and positive (α1Q241L or α1N407A/Y410F) steroid modulation. Negative regulation by amphiphiles was nearly abolished in α1V256S-mutated receptors, but potentiation was unaffected. In α1Q241L- or α1N407A/Y410F-mutated receptors, potentiation by amphiphiles remained intact.

Conclusions and implications:

Structurally diverse amphiphiles have antagonist actions at GABA_A receptors very similar to those of sulphated neurosteroids, while the potentiating mechanisms of these amphiphiles are distinct from those of neurosteroid-positive modulators. Thus, such antagonism at GABA_A receptors does not have a clear pharmacophore requirement.     

护士生注射练习发生晕厥原因与对策

1临床资料 1998-03／2002-06参与注射练习的护士生336名,均为女性,发生晕厥15例,发生率4．5％;其中3例发生在注射过程中,余12例发生在注射后2min内．静脉注射练习过程中发生晕厥2例,肌肉注射练习过程中、后发生晕厥者分别为3例和10例;年龄19～21（平均20．3）岁．均排除癫痫、癔病等器质性疾病．静脉注射练习用药为250g／L葡萄糖注射液20mL,肌肉注射练习用药为维生素B12250μg,均在有效期内,且无混浊、变质等不良情况．晕厥原因有：     

Rapid sequence induction

Rapid sequence induction (RSI) is an established method of inducinganaesthesia in patients who are at risk of aspiration of gastriccontents into the lungs. It involves loss of consciousness duringcricoid pressure followed by intubation without face mask ventilation.The aim is to intubate the trachea as quickly and as safelyas possible. This technique is employed daily during emergencysurgery.     

Acute injury and chronic disability resulting from surfboard riding

We undertook a cross-sectional survey of surfers at eight Victorian beaches between February and May 2003 and analysed acute injury and chronic disability sustained while surfing during the preceding 12 months. Significant injuries were defined as requiring medical attention or time off surfing/work. 646 surfers were enrolled (90.2% male, median age 27 years, median years of surfing 10). 145 surfers sustained 168 significant acute injuries in the preceding 12 months (0.26 injuries/surfer/year, 95% CI 0.22-0.30). Most were caused by striking a surfboard or another surfer (45.2%, 95% CI 37.6-53.1), "wiping out" (36.3%, 95% CI 29.1-44.1) or striking the seabed (17.9%, 95% CI 12.6-24.7). Injuries included lacerations (46.4%, 95% CI 38.8-54.3), sprains (28.6%, 95% CI 22.0-36.1), dislocations (10.7%, 95% CI 6.7-16.6) and fractures (8.9%, 95% CI 5.3-14.6). Body parts most frequently injured were the lower limb (45.8%, 95% CI 38.2-53.7) and the head/face (26.2%, 95% CI 19.9-33.6). Surfing injuries that were treated in Victorian emergency departments over a six year period revealed a similar pattern, although there was a greater proportion of head/face injuries (42.0%, 95% CI 36.0-48.1, p = 0.001). 20 surfers reported long-term effects from acute injuries, mainly unstable/stiff/painful joints. 136 surfers reported chronic health problems not related to acute injury including chronic/recurrent otitis externa and exostoses, muscle and joint pain/stiffness and pterygium. Significant injury while surfing is not uncommon. Although head injury accounts for a considerable proportion, very few surfers wear protective headgear. Greater use of protective headgear should be considered.