PEG1/MEST and IGF2 DNA methylation un CIN and in cervical cancer

INTRODUCTION: Although most invasive cervical cancer (ICC) harbor <20 human papillomavirus (HPV) genotypes, use of HPV screening to predict ICC from HPV has low specificity, resulting in multiple and costly follow-up visits and overtreatment. We examined DNA methylation at regulatory regions of imprinted genes in relation to ICC and its precursor lesions to determine if methylation profiles are associated with progression of HPV-positive lesions to ICC. MATERIALS AND METHODS: We enrolled 148 controls, 38 CIN and 48 ICC cases at Kilimanjaro Christian Medical Centre from 2008 to 2009. HPV was genotyped by linear array and HIV-1 serostatus was tested by two rapid HIV tests. DNA methylation was measured by bisulfite pyrosequencing at regions regulating eight imprinted domains. Logistic regression models were used to estimate odd ratios. RESULTS: After adjusting for age, HPV infection, parity, hormonal contraceptive use, and HIV-1 serostatus, a 10 % decrease in methylation levels at an intragenic region of IGF2 was associated with higher risk of ICC (OR 2.00, 95 % CI 1.14-3.44) and cervical intraepithelial neoplasia (CIN) (OR 1.51, 95 % CI 1.00-2.50). Methylation levels at the H19 DMR and PEG1/MEST were also associated with ICC risk (OR 1.51, 95 % CI 0.90-2.53, and OR 1.44, 95 % CI 0.90-2.35, respectively). Restricting analyses to women >30 years further strengthened these associations. CONCLUSIONS: While the small sample size limits inference, these findings show that altered DNA methylation at imprinted domains including IGF2/H19 and PEG1/MEST may mediate the association between HPV and ICC risk (AU)

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PEG1/MEST and IGF2 DNA methylation in CIN and in cervical cancer.

INTRODUCTION: Although most invasive cervical cancer (ICC) harbor <20 human papillomavirus (HPV) genotypes, use of HPV screening to predict ICC from HPV has low specificity, resulting in multiple and costly follow-up visits and overtreatment. We examined DNA methylation at regulatory regions of imprinted genes in relation to ICC and its precursor lesions to determine if methylation profiles are associated with progression of HPV-positive lesions to ICC. MATERIALS AND METHODS: We enrolled 148 controls, 38 CIN and 48 ICC cases at Kilimanjaro Christian Medical Centre from 2008 to 2009. HPV was genotyped by linear array and HIV-1 serostatus was tested by two rapid HIV tests. DNA methylation was measured by bisulfite pyrosequencing at regions regulating eight imprinted domains. Logistic regression models were used to estimate odd ratios. RESULTS: After adjusting for age, HPV infection, parity, hormonal contraceptive use, and HIV-1 serostatus, a 10 % decrease in methylation levels at an intragenic region of IGF2 was associated with higher risk of ICC (OR 2.00, 95 % CI 1.14-3.44) and cervical intraepithelial neoplasia (CIN) (OR 1.51, 95 % CI 1.00-2.50). Methylation levels at the H19 DMR and PEG1/MEST were also associated with ICC risk (OR 1.51, 95 % CI 0.90-2.53, and OR 1.44, 95 % CI 0.90-2.35, respectively). Restricting analyses to women >30 years further strengthened these associations. CONCLUSIONS: While the small sample size limits inference, these findings show that altered DNA methylation at imprinted domains including IGF2/H19 and PEG1/MEST may mediate the association between HPV and ICC risk.

Vibrio cholerae H-NS silences virulence gene expression at multiple steps in the ToxR regulatory cascade.

H-NS is an abundant nucleoid-associated protein involved in the maintenance of chromosomal architecture in bacteria. H-NS also has a role in silencing the expression of a variety of environmentally regulated genes during growth under nonpermissive conditions. In this study we demonstrate a role for H-NS in the negative modulation of expression of several genes within the ToxR virulence regulon of Vibrio cholerae. Deletion of hns resulted in high, nearly constitutive levels of expression of the genes encoding cholera toxin, toxin-coregulated pilus, and the ToxT virulence gene regulatory protein. For the cholera toxin- and ToxT-encoding genes, elevated expression in an hns mutant was found to occur in the absence of the cognate activator proteins, suggesting that H-NS functions directly at these promoters to decrease gene expression. Deletion analysis of the region upstream of toxT suggests that an extensive region located far upstream of the transcriptional start site is required for complete H-NS-mediated repression of gene expression. These data indicate that H-NS negatively influences multiple levels of gene expression within the V. cholerae virulence cascade and raise the possibility that the transcriptional activator proteins in the ToxR regulon function to counteract the repressive effects of H-NS at the various promoters as well as to recruit RNA polymerase.

What price politics? Scientists and political controversy.

There is a long tradition within scientific communities that encourages governments, patrons and citizens to enlist scientific expertise in the service of the public good. However, since the 17th century, scientists who have engaged in public political controversy have often been judged harshly by scientific colleagues, as well as by political adversaries. Some prominent scientists were politically active in Germany, France and England during the 1920s and 1930s; controversial stands were taken by the British physicist P.M.S. Blackett and the American chemist Linus C. Pauling against their countries' nuclear weapons policy following the Second World War.

The Kaiser Permanente/USC Patient Consultation Study: change in use and cost of health care services.

The impacts of three alternative models of pharmacist consultation on the use and cost of health care services were studied. Two studies were conducted concurrently in an HMO over two years. In one, 6000 patients were randomly assigned to one of three consultation models; in the other, the three models were implemented in six geographic regions of California (4600 patients). The models were (1) consultation about new or changed prescriptions as mandated by state law (state model), (2) consultation focused on selected high-risk ambulatory care patients (Kaiser Permanente [KP] model), and (3) a control model. The patients were surveyed three times about their health status and satisfaction, and computerized data on health care use and cost were collected. The effect of the consultation models on the use and cost of health care services was examined across five risk groups that were based on drug-use profiles. An additional 37,750 patients (10% of the patients residing in the areawide study sites) were included in a supplemental analysis of the use and cost of health care services. There was no indication in the random-assignment study that pharmacist consultations affected either drug costs or the cost of office visits. Similar results were found in the areawide study, with the exception that the KP model was associated with lower drug costs than the control model. In the 10% sample, the KP model appeared to be associated with lower office visit costs but higher drug costs. Both models were associated with a lower likelihood of a hospital admission and with lower total health care costs for some high-risk patients compared with the control model. Counseling patients about their medications may be unlikely to reduce medication costs or the cost of office visits but may reduce the likelihood of hospital admissions and the overall costs of health care services; a combination of counseling patients at high risk for drug-related problems and counseling all patients about any new or changed prescription should be considered.

Measuring the impact of patient counseling in the outpatient pharmacy setting: the research design of the Kaiser Permanente/USC patient consultation study.

This article describes the research method used to measure the impact of three alternative models of patient counseling in the outpatient pharmacy setting. The study was conducted in pharmacies operated by the Southern California region Kaiser Permanente Medical Care Program. Both random assignment and large-scale geographic area research designs were used. The presentation of the research design includes discussions of data collection and patient sampling methods; the measurement of patient outcomes, including measures of health care costs and utilization, patient functional status, and quality of life. Demographic data are presented for the study population, including an analysis of potential biased selection of patients electing to participate in random assignment. Data are also presented documenting potential selection bias across geographically determined treatment groups in the geographic area design arm. Finally, the article presents the analysis plan for the study and discusses study limitations.

Measuring of impact of patient counseling in the outpatient pharmacy setting: development and implementation of the counseling models for the Kaiser Permanente/USC Patient Consultation Study.

The Southern California region Kaiser Permanente Medical Care Program, which serves 2.2 million patients, and the University of Southern California School of Pharmacy have designed and implemented a patient consultation study to determine the cost-effectiveness of three different approaches to providing pharmacist consultation to outpatients. This paper describes the development and implementation of these three models. A total of 107 pharmacies (approximately 600 pharmacists) participated in the study and were assigned to provide one of the models of patient consultation, designated the Kaiser Permanente (KP) model, the state model, and the control model. The KP model (20 pharmacies) provided targeted pharmaceutical care services to high-risk patients based on drug use. The state model (67 pharmacies) provided California-mandated patient consultation to patients with new or changed prescriptions, instructions for use, relevant warnings and precautions, storage requirements, and the importance of compliance. The control model (20 pharmacies) provided consultation when deemed necessary by the pharmacist and provided care similar to that provided before mandatory consultation in California. The KP and state models used the same pharmacist/technician/clerk resources, but the control pharmacies limited personnel resources to those existing before the mandatory consultation law was passed in California. The paper describes the KP model in detail and provides a literature-based rationale for targeting particular high-risk patients for expanded services. The paper also describes the training process, gives an example of a high-risk patient intervention, provides information on documenting pharmacist interventions in all models, and explains the method used for monitoring implementation of the models.

Long-term follow-up of patients with uterine fibroids after treatment with the LHRH agonist buserelin.

Ten patients with uterine fibroids palpable abdominally were treated with the luteinizing hormone-releasing hormone (LHRH) agonist buserelin, administered intransally, 300 micrograms three times daily, for 6 months, and were then followed for a further 12 months. Oestrogen levels were markedly reduced in all patients during treatment. At the end of treatment the mean volume reductions were 44.4% (SEM 3.5) for total uterine volume and 57.3% (SEM 7.4) for volume of discrete fibroids as assessed ultrasonically. There was also marked improvement in associated symptoms. After buserelin therapy was stopped, the total uterine and discrete fibroid volumes returned to, or slightly exceeded, pretreatment volumes within 6 months in five patients, and by 12 months in two patients. Three other patients who underwent surgery for their fibroids during the first 4 months after treatment showed regrowth of fibroids to pretreatment size. Four comparable asymptomatic untreated patients showed no significant change in the total uterine or fibroid volume during six monthly ultrasonic assessments. Buserelin therapy may facilitate rather than replace surgery in the management of uterine fibroids.

Droperidol stability in intravenous admixtures.

The stability and compatibility of droperidol in small-volume i.v. admixtures was assessed. Droperidol was diluted to a nominal concentration of 1 mg/50 ml in 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringer's injection in type I glass bottles and polyvinyl chloride bags. Triplicate samples of each admixture were stored under continuous illumination at 27 +/- 2 degrees C. Specimens from each sample were tested by spectrophotometric assay at intervals during storage periods of up to 272 hours for admixtures containing 5% dextrose injection and 0.9% sodium chloride injection and up to 168 hours for admixtures containing lactated Ringer's injection. Between 48 and 168 hours of storage, a 7% increase was observed in droperidol concentration in 0.9% sodium chloride admixtures in polyvinyl chloride bags. A 24% decrease in droperidol concentration in lactated Ringer's admixtures in polyvinyl chloride bags between 24 and 168 hours was attributed to sorption of droperidol by the plastic container. In all admixtures except those containing lactated Ringer's injection in polyvinyl chloride bags, droperidol concentrations throughout the storage period were within 10% of initial concentrations. Droperidol is stable in the admixtures studied for 7 to 10 days in glass bottles. In polyvinyl chloride bags, concentrations in admixtures containing 5% dextrose injection and 0.9% sodium chloride injection are stable for seven days, but concentrations decrease significantly in lactated Ringer's admixtures.