The contribution of transfusion to HCV infection in England

The English HCV lookback programme has identified some individuals with transfusion-transmitted HCV infection. The path from the collection of donations from HCV-infected donors to the identification of infected recipients was constructed. The probability of different outcomes at each branch was derived from data collected during this programme. This path of probabilities was then used to produce a complete estimate of the number of recipients infected by blood transfusions (dead and alive at the end of 1995) by re-entry of blood components that fell out of the lookback at various steps prior to recipient testing, and entry of components from HCV-infected donations that were never identified for lookback. Less than 14,000 recipients were estimated to have been infected with HCV during the decade prior to the start of donation testing. Over 60% of these were expected to have died by the end of 1995. Transfusion has infected a large group of individuals. However, this group constitutes a very small, and declining, proportion of all HCV infections in the population.     

Bed-blocking. Discharge of the late brigade

Delayed discharges are seen as a litmus test for how the whole health and social care system is working. The problem has been exacerbated by delays in developing intermediate care schemes. There has been less use of the private nursing homes for intermediate care than envisaged a year ago, possibly because of NHS concerns about standards. More support should be given to people with chronic conditions to keep them out of hospital.     

Enhanced uptake of ifosfamide into GH3 prolactinomas with hypercapnic hyperoxic gases monitored in vivo by (31)P MRS

Previously, ³¹P magnetic resonance spectroscopy (MRS) has been used to detect ifosfamide (IF) in vivo and to show that breathing carbogen (5% CO₂/95% O₂) enhances the uptake and increases the efficacy of IF in rat GH3 prolactinomas [Rodrigues LM, Maxwell RJ, McSheehy PMJ, Pinkerton CR, Robinson SP, Stubbs M, and Griffiths JR (1997). In vivo detection of ifosfamide by ³¹P MRS in rat tumours; increased uptake and cytotoxicity induced by carbogen breathing in GH3 prolactinomas. Br J Cancer 75, 62–68]. We now show that other hypercapnic and/or hyperoxic (5% CO₂ in air, 2.5% CO₂ in O₂) gas mixtures also increase the uptake of IF into tumors, measured by ³¹P MRS. All gases caused an increased uptake (C_max) of IF compared to air breathing, with carbogen inducing the largest increase (85% (P<.02) compared to 46% with 2.5% CO₂ in O₂ (P<.004) and 48% with 5% CO₂ in air (P<.004)). The T_max (time of maximum concentration in tumor posintravenous injection of IF) was significantly (P<.04) later in the cohort that breathed 5% CO₂ in air. The increased uptake of IF with carbogen breathing was selective to tumor tissue and there were no significant increases in any of the normal tissues studied, suggesting that any host tissue toxicity would be minimal. Carbogen breathing by patients causes breathlessness. There was no significant difference in IF uptake between breathing carbogen and 2.5% CO₂ in O₂ and, therefore, the ability of 2.5% CO₂ in O₂ to also increase IF uptake may be clinically useful as it causes less patient discomfort.     

New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents

Although malignant mesothelioma is not a classically immunogenic cancer, there is abundant evidence for immune recognition. The relative ease of obtaining tumor tissue makes mesothelioma ideal for studying surrogate biomarkers such as lymphocytic infiltration or expression of transduced genes. There is evidence that malignant mesothelioma patients as well as asbestos-exposed persons without mesothelioma have impaired immune responsiveness. Substantial progress has been made in animal models using several biological and immunological techniques, but clinical application has been problematic. Systems studied have included lysis by interleukin-2 (IL-2)-activated lymphokine-activated killer (LAK) cells, tumor necrosis factor-alpha (TNF-alpha), a p16-expressing adenovirus vector, suicide gene therapy using the herpes simplex virus-tyrosine kinase (HSV-tk) followed by ganciclovir, and immunomodulatory gene therapy with IL-2, IL-4, interferon-gamma (IFN-gamma), IFN-alpha, TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and IL-1beta transfected into tumors. Vaccinia virus has been studied as a vector for cytokine gene transfer. Suicide gene therapy has been combined with a tumor vaccine. The University of Western Australia is initiating a pilot study of autologous vaccination in malignant mesothelioma. Novel agents under study include the angiogenesis inhibitors SU5416, bevacizumab, and thalidomide. ZD1839, an orally administered, highly selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, is being tested in a phase II trial. Since platelet-derived growth factor (PDGF) is thought to be an autocrine growth factor for mesothelioma STI-571 (Gleevec; Novartis, Basel, Switzerland), a highly selective inhibitor of the PDGF receptor tyrosine kinase, is being tested in a phase II trial. The development of more active cytotoxic combinations in this disease should facilitate further studies of chemoimmunotherapy. It seems likely that no single treatment modality will be effective by itself.     

Rehabilitation in severe head injury in children: outcome and provision of care

Functional outcome and provision of care to 82 children (males:females 2.7:1; age range 0 to 16 years) with severe head injury were investigated. The children were admitted to the intensive care units of the Regional Neuroscience Units of the Greater Manchester and Lancashire districts of the North West Region of the UK between 1994 and 1996. A questionnaire was devised based on 12 areas of recovery and data were collected at discharge and 6 weeks, 6 months and 12 months from discharge. Data were collected during home visits and at joint assessment at 12 months with the district consultant community paediatrician (CCP). Early involvement of the CCP enhanced the provision of needs at discharge and 6 weeks after discharge, as did a period of stay in district-level care before discharge home. CCPs received formal notification of the injured child in only 32% of cases by discharge, and 54% of cases by 6 months. Sixty-five per cent of children required early educational support but structured help reached only 55% of these children by the end of the study. Integrated planning between health and education was achieved in about half of the study population. Good physical recovery was achieved by the majority of children but parents said they did not feel prepared for the degree of help which their child still required 12 months after discharge. Children who required anticonvulsants at 12 months' follow-up scored significantly lower on cognitive potential. Psychosocial family functioning deteriorated in a substantial number of families according to parental perception. Prevalence of this perception did not diminish over the study period. Aspects of caregivers' understanding and the child's language deficits, self-care skills, fine and gross motor performance, as well as family, social, and financial consequences were assessed. A dedicated and integrated approach to assessment and provision of care across the domains of hospital, education, and community is discussed.     

Improved executive functioning following repetitive transcranial magnetic stimulation

The cognitive effects of active and sham repetitive transcranial magnetic stimulation (rTMS) were examined in 19 middle-aged and elderly patients with refractory depression. Patients received either active (n = 9) or sham (n = 10) rTMS targeted at the anterior portion of the left middle frontal gyrus. Patients in the active rTMS group improved significantly on a test of cognitive flexibility and conceptual tracking (Trail Making Test-B).     

Identity development in adolescents living with HIV

The purpose of this project was to qualitatively explore how identity formation may be affected by the presence of HIV disease. Eight HIV-infected adolescents (three males, five females), aged 17-21, participated in a semi-structured interview that combined measures of identity development with open-ended, qualitative questions aimed at eliciting the adolescents' personal stories and experiences of living with HIV. All participants fell into either Diffusion or Achievement identity statuses, which in turn impacted their response to having HIV. The impact that HIV had on the participants' values and future goals varied across the sample. Findings are discussed in terms of clinical intervention implications, contextual variables, and the need for larger, more comprehensive research efforts.     

The Genes and Genetics of Malignant Melanoma

Background: Population-based studies have identified several clinical variables associated with an increased risk of developing cutaneous melanoma that include phenotype, amount of and response to sun exposure, and family history. However, these observations are of limited relevance to clinical practice as the risk associated with each factor is individually modest and the characteristics of these variables lack precision when applied to a particular individual. Objective: To review the literature regarding recent advances made in the understanding of the genes and genetics of clinical variables associated with an increased risk of melanoma. Conclusion: Variants of the MC1R (melanocortin-1 receptor) have been identified as major determinants of high-risk phenotypes, such as red hair and pale skin, and the ability to tan in response to UV exposure. Several studies also suggest that such variants may increase melanoma risk independent of their contribution to phenotype. A strong genetic basis for both nevus density and size has been demonstrated and the link between nevi and the development of MM has become better defined. Finally, germline defects in several genes involved in cell cycle regulation, namely, p16 and CDK4, have been demonstrated in many familial melanoma kindreds. This progress has introduced the prospect of genetic testing as a means of identifying a limited number of high-risk individuals who can be targeted with regular screening and education regarding UV exposure and skin self-examination. Ultimately, through rational genetic therapy targeted to correcting the underlying molecular defect, altering the natural history of melanoma development may be possible.