A randomized,double-blind,placebo-controlled,phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma

RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.     

New developments in animal models of Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by deterioration in mental function leading to dementia, deposition of amyloid plaques and neurofibrillary tangles (NFTs), and neuronal loss. The major component of plaques is the amyloid-b peptide (Ab), whereas NFTs are assemblies of hyperphosphorylated forms of the microtubule-associated protein tau. Electron microscopy of NFTs reveals structures known as paired helical filaments (PHFs). In familial AD (FAD), mutations in three distinct genes drive Aβ synthesis by favoring endoproteolytic secretase cleavages that liberate Aβ from the Alzheimer b-amyloid precursor protein (APP). This suggests that excess Ab initiates a pathogenic cascade in humans that culminates in all the pathologic and cellular hallmarks of AD. Building upon the knowledge of FAD mutations, incremental technical advances have now allowed reproduceable creation of APP transgenic mice that exhibit AD-like amyloid pathology and Aβ burdens. These transgenic mouse lines also exhibit deficits in spatial reference and working memory, with immunization against Aβ abrogating both AD-associated phenotypes. Besides establishing a proof of principle for Ab-directed therapies, these findings suggest a potential to identify individual elements in the pathogenic pathway that lead to cognitive dysfunction. Furthermore, transgenic APP mice with potent amyloid deposition will likely form a beachhead to capture the final elements of AD neuropathology—cell loss and NFTs composed of PHFs—that are missing from current transgenic models.     

Students'' expectations of postregistration degree programmes

The needs of postregistration students pursuing degree-linked clinical courses have received little attention and there are few insights concerning their aspirations when they enrol on such courses. Thus the aim of this study was to explore postregistration students' perceptions of the specific needs of their patient/client group and to examine how they envisaged the course on which they had just enrolled might help them to meet these needs in addition to their own requirements for professional and personal development. Data were collected by group interview from 62 students enrolling on eight different postregistration courses, all employed in an acute hospital trust. The results were analysed inductively. They indicated that students had internalized the state of the healthcare market and were keenly aware of the need to fulfil the expectations of employers and the public, while fulfilling their own needs for education and pursuing their own professional and career trajectories. They appeared ambitious and yet appeared to demonstrate empathy for patients and their families and felt a tremendous desire to provide care of a high quality through the optimal development of technical expertise. Students' emphasis on the importance of keeping abreast of technological developments should not be lightly dismissed considering its prominent position within the acute areas where they were employed, especially as it did not replace their desire to promote the caring aspects of their work.     

垂全催乳素瘤的诊断和治疗指南

3.男性:高催乳素血症通常导致阳痿、不孕和性功能低下.男性患者通常为大腺瘤,有神经系统症状.其原因可能是对症状认识的延误或者肿瘤生物学行为的差异.     

Breaking the habit: a retrospective analysis of desistance factors among formerly problematic heroin users

Introduction and Aims . The aim of this study was to examine heroin careers among former users to assess desistance factors and explanations for sustained abstinence. Design and Methods . The study surveyed 107 former problematic heroin users who have achieved long‐term abstinence about their experiences of achieving and sustaining abstinence. The cohort was recruited opportunistically from three sources, drawing heavily on former users working in the addictions field. Results . On average, the group had heroin careers lasting for just under 10 years, punctuated by an average of 2.6 treatment episodes and 3.1 periods of abstinence, and had been heroin abstinent for an average of 10 years at the time of completing the survey. The most commonly expressed reason for finally achieving abstinence was ‘tired of the lifestyle followed by reasons relating to psychological health. In contrast, when asked to explain how abstinence was sustained, clients quoted both social network factors (moving away from drug‐using friends and support from non‐using friends) and practical factors (accommodation and employment) as well as religious or spiritual factors. Treatment was not mentioned widely either in achieving or sustaining abstinence, in contrast to 12‐Step, which was endorsed widely. Discussion and Conclusions . The study supports a careers perspective for examining heroin careers and indicates that, while achieving abstinence is possible for chronic opiate users, the path to sustained abstinence is complex and often reliant upon external support systems.     

Trends in blood lead levels in Christchurch (NZ) and environs 1978-85.

Blood lead levels have been monitored since 1974 and have shown a significant decrease (p less than 0.001) from 1978 to 1985 in 2830 subjects from Christchurch and environs. From a baseline in August 1978-81 to August 1985 blood lead levels in a population which had no relevant exposure to lead other than that from the general environment have fallen in adult males and females (greater than 17 years) by 42%, and in school and pre-school children greater than 9 months by 44% and 46% respectively. Reduction of blood lead has accelerated during the last three years. This can be linked to changes in dietary intake and clean up of lead in domestic and industrial environments. Over this decade the lead content of petrol (0.84 g/l) and petrol sales have remained unchanged.     

Anaphylaxis after treatment with recombinant factor VIII

BACKGROUND: Treatment of hemophilia patients with recombinant factor VIII concentrates has not previously been associated with anaphylaxis. STUDY DESIGN AND METHODS: A 5-week-old boy with severe hemophilia A developed dyspnea, cyanosis, hypotension, and a diffuse urticarial rash following treatment with a recombinant factor VIII (Recombinate). To identify the cause of anaphylaxis in this patient, the vial lot was examined for the presence of endotoxin, and a checkerboard immunoblotting technique was used to test serum and/or plasma samples from the patient and mother for the presence of antibodies (IgA, IgG, IgE, and IgM) to Recombinate-related antigens (recombinant factor VIII, von Willebrand factor, human serum albumin, Chinese hamster ovary proteins, bovine serum albumin, mouse monoclonal anti-human factor VIII, polyethylene glycol 3350), and to ethylene oxide, the agent used to sterilize the infusion equipment. RESULTS: No immune response directed against the Recombinate-related antigens or ethylene oxide that could be associated with the anaphylactic reaction was identified. Endotoxin was not present upon rabbit pyrogen testing of the therapeutic product. CONCLUSION: These studies failed to show any association between Recombinate and the onset of the allergic reaction. This seems to be the first reported case of anaphylaxis following the infusion of a recombinant form of factor VIII concentrate.     

Extracorporeal blood volume of donors during automated intermittent-flow plasmapheresis and its relevance to the prevention of circulatory reactions

BACKGROUND: Intermittent-flow plasmapheresis often involves a large extracorporeal blood volume of the donor during the procedure with the concomitant risk of circulatory reactions. Guidelines governing donor recruitment often apply an arbitrary threshold of 15 percent of the donors' blood volume not to be exceeded during hemapheresis procedures. No data demonstrating the suitability of this approach exist. STUDY DESIGN AND METHODS: The blood volumes of 1204 plasmapheresis donors were calculated with different formulae that utilized either body weight or body surface area. Extracorporeal blood volumes of these donors were determined for a commonly used intermittent-flow plasmapheresis machine known to result in a large extracorporeal blood volume. A validated model was employed that calculated the fluid volume shifts occurring during the procedure. The records of all plasmapheresis procedures of these donors were retrospectively reviewed for circulatory reactions. RESULTS: The median extracorporeal volumes ranged from 14 to 17 percent of the blood volume at a donor Hct level of 0.40 to 0.48 L per L for men and from 17 to 20 percent at a Hct level of 0.36 to 0.44 L per L for women. In more than 60 percent of male and more than 90 percent of female donors, extracorporeal volumes exceeded 15 percent of the blood volume during plasmapheresis. In this subgroup, 65 percent of male and 75 percent of female donors never presented with any signs of circulatory reactions. CONCLUSION: Application of an arbitrary threshold of 15 percent of the donors' blood volume not to be exceeded during hemapheresis procedures is expected to lead to an unjustified deferral rate in plasmapheresis donors.