Subtelomeric imbalances in phenotypically normal individuals

Subtelomeric imbalances are identified in approximately 5% of patients with idiopathic mental retardation (MR) and multiple congenital anomalies (MCA). Because of this high incidence, screening for subtelomeric anomalies became part of the routine genetic evaluation of MCA/MR patients. In contrast to the general view that subtelomeric imbalances cause MCA/MR, we report here 15 subtelomeric copy-number changes in 12 families in which the imbalance is inherited from a phenotypically normal parent. We detected inherited deletions at subtelomeres 2q, 3p, 4p, 4q, 6q, 10q, 17p, 17q, Xp, and Yq and duplications at 1q, 4q, 10q, and 11q. Interestingly, in addition to small deletions (<1 Mb) also unexpected large deletions and duplications up to 7.8 Mb were detected. Taken together with previous reports, a total of 16 subtelomeric duplications and 18 deletions inherited from a phenotypically normal parent have now been reported. Clearly, more extensive genotype-phenotype correlations are needed to better understand the phenotypic consequences of these subtelomeric copy number variations and to resolve the current uncertainty for genetic counseling in postnatal and prenatal diagnosis.     

Highly efficient transduction and expression of cytokine genes in human tumor cells by means of autonomous parvovirus vectors; generation of antitumor responses in recipient mice

The possible use of recombinant autonomous parvoviruses as vectors to efficiently express therapeutic cytokines in human tumor cells was evaluated in vitro and in vivo. The parvovirus H1 was used to generate recombinant viruses (rH1) that carried transgenes encoding either human interleukin 2 (IL-2) or monocyte chemotactic protein 1 (MCP-1), in replacement of part of the capsid genes. Such rH11 viruses have been shown to retain in vitro the intrinsic oncotropic properties of the parental virus. On infection with the recombinant viruses at an input multiplicity of 1 replication unit (RU) per cell, HeLa cultures were induced to release 4-10 microg of cytokine per 10(6) cells over a period of 5 days. The expression of the rH1-transduced human cytokine/chemokine could also be detected in tumor material recovered from nude mice that had been subcutaneously engrafted with in vitro-infected HeLa cells. The formation of tumors from HeLa xenografts was reduced by 90% compared with wild-type or mock-infected cells as a result of cells preinfected with IL2-expressing virus at an input multiplicity as low as 1 RU per cell. Tumors arising from HeLa cells infected with transgene-free or MCP1-expressing vectors or with wild-type H1 virus were not rejected at this virus dose. Tumors infected with rH1/IL-2 virus displayed markers indicative of their infiltration with NK cells in which the cytocidal program was activated, whereas little NK activity was detected in wild-type virus or mock-infected tumors. Altogether, these data show that the IL-2 expressing H1 vector was a more potent antineoplastic agent than the parental virus, and point to the possible application of recombinant autonomous parvoviruses toward therapy of some human tumors.     

A multicenter study of the tolerability of tirofiban versus placebo in patients undergoing planned intracoronary stent placement

BACKGROUND: The use of intravenous glycoprotein IIb/IIIa-receptor antagonists has been shown to improve outcomes in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Tirofiban has shown benefit in a wide range of patients presenting with acute coronary syndromes. Although this agent has been used in patients undergoing percutaneous coronary intervention, a literature search identified no prospective data comparing tirofiban with placebo in patients undergoing planned intracoronary stent placement. OBJECTIVE: This study examined the tolerability of tirofiban in patients undergoing percutaneous intervention with planned intracoronary stent placement. METHODS: This was a multinational, multicenter, prospective, randomized, double-blind, placebo-controlled trial in patients scheduled to undergo PTCA with planned intracoronary stent placement. Patients were randomized in a 3:2 ratio to receive tirofiban as an intravenous bolus (10 microg/kg over 3 minutes) and maintenance infusion (0.10 microg/kg per minute for 36 hours) or a bolus and infusion of placebo. All patients received periprocedural aspirin and heparin and an optional postprocedural thienopyridine (ticlopidine or clopidogrel). Laboratory and safety monitoring were performed throughout the 36 hours after the procedure and at hour 40 or hospital discharge. The primary end point was the proportion of patients with bleeding, defined according to Thrombolysis in Myocardial Infarction (TIMI) trial criteria. The number of patients with cardiac events (death, myo- cardial infarction, urgent revascularization) during the first 30 days after stent placement was also assessed. RESULTS: Eight hundred ninety-four patients (536 tirofiban, 358 placebo) were enrolled, all of whom received aspirin and heparin periprocedurally and optional ticlopidine or clopidogrel after the procedure. No significant between-group differences were observed in the incidence of TIMI major bleeding (0.2% tirofiban, 0.6% placebo) or any TIMI bleeding (3.2% and 1.7%, respectively). The incidence of TIMI minor bleeding was higher with tirofiban than with placebo (2.8% vs 0.6%). The 30-day incidence of the composite end point of any cardiac event was 3.9% in both groups. CONCLUSIONS: On a background of concomitant aspirin, heparin, and a thienopyridine, tirofiban was generally well tolerated in patients undergoing PTCA with planned intracoronary stent placement. Further investigation is needed to ascertain the optimal dosing of tirofiban and heparin to achieve reductions in ischemic complications of intracoronary stenting with an acceptable incidence of bleeding complications.     

Palliative sedation: a review of the research literature

The overall aim of this paper is to systematically review the following important aspects of palliative sedation: prevalence, indications, survival, medication, food and fluid intake, decision making, attitudes of physicians, family experiences, and efficacy and safety. A thorough search of different databases was conducted for pertinent research articles published from 1966 to June 2007. The following keywords were used: end of life, sedation, terminal sedation, palliative sedation, refractory symptoms, and palliative care. Language of the articles was limited to English, French, German, and Dutch. Papers reporting solely on the sedatives used in palliative care, without explicitly reporting the prevalence or intensity of sedation, and papers not reporting on primary research (such as reviews or theoretical articles) were excluded. Methodological quality was assessed according to the criteria of Hawker et al. (2002). The search yielded 130 articles, 33.8% of which were peer-reviewed empirical research studies. Thirty-three research papers and one thesis were included in this systematic review. This review reveals that there still are many inconsistencies with regard to the prevalence, the effect of sedation, food and fluid intake, the possible life-shortening effect, and the decision-making process. Further research to clarify all of this should be based on multicenter, prospective, longitudinal, and international studies that use a uniform definition of palliative sedation, and valid and reliable instruments. Only through such research will it be possible to resolve some of the important ethical issues related to palliative sedation.     

Increased Risk for Severe Malaria in HIV-1�Cinfected Adults, Zambia

To determine whether HIV-1 infection and HIV-1–related immunosuppression were risk factors for severe malaria in adults with some immunity to malaria, we conducted a case–control study in Luanshya, Zambia, during December 2005–March 2007. For each case-patient with severe malaria, we selected 2 matched controls (an adult with uncomplicated malaria and an adult without signs of disease). HIV-1 infection was present in 93% of case-patients, in 52% of controls with uncomplicated malaria, and in 45% of asymptomatic controls. HIV-1 infection was a highly significant risk factor for adults with severe malaria compared with controls with uncomplicated malaria (odds ratio [OR] 12.6, 95% confidence interval [CI] 2.0–78.8, p = 0.0005) and asymptomatic controls (OR 16.6, 95% CI 2.5–111.5, p = 0.0005). Persons with severe malaria were more likely to have a CD4 count <350/µL than were asymptomatic controls (OR 23.0, 95% CI 3.35–158.00, p<0.0001).     

Capture-recapture for estimating the size of the female sex worker population in three cities in Côte d'Ivoire and in Kisumu, western Kenya

Objective To estimate the female sex worker population size in three cities in Côte d’Ivoire and in Kisumu, Kenya. Methods Capture–recapture was used, calculating size estimates by first ‘tagging’ a number of individuals and, through an independent recapture, calculating the proportion of overlap. The same procedures were used in all four cities. In the first phase, members of the target population were ‘captured’ and ‘marked’ by giving them a capture card. Six days later, in the same places and at the same time, a second sample was ‘captured’, which comprised a certain number of people who were captured in the first round. During the exercise, questions were asked to estimate the coverage of the sex worker clinics. Results Using capture–recapture, the estimated number of female sex workers was 1160 in Yamoussoukro (95% CI 1053–1287), 1202 in Bouaké (95% CI 1128–1279), 1916 in San Pedro (95% CI 1809–2030) and 1350 in Kisumu (95% CI 1261–1443). The proportion of female sex workers in Côte d’Ivoire who had visited the clinic ranged from 15% in Yamoussoukro to 30% in San Pedro and was 34% in Kisumu. Conclusions Capture–recapture was successfully applied to estimate the population size of female sex workers. These estimations were urgently needed to help mobilize an increased response to HIV, to assess programme coverage and to estimate potential impact of the targeted intervention.