New active substances authorized in the United Kingdom between 1972 and 1994

Aims Dihydropyrimidine dehydrogenase (DPD) catalyses the reduction of pyrimidines, including the anticancer agent 5-fluorouracil (5FU). Impaired 5FU degradation, through low DPD activity, has led to severe, life-threatening or fatal toxicity after administration of 5FU. Complete DPD deficiency is associated with the inherited metabolic disease thymine uraciluria. Several mutations in the gene encoding DPD have recently been identified, but the phenotype-genotype concordance of these alterations in the general population has not been reported.
Methods Mononuclear cells were isolated from whole blood and DPD activity was determined after ex vivo incubation with ¹⁴C-5FU followed by h.p.l.c. analysis of 5FU metabolites. Analysis of mutations in the DPD gene at an exon splice site, codons 534, 543, and 732, and a deletion at base 1897 (ΔC1897) were performed in 30 subjects with the lowest and 30 subjects with the highest enzyme activity using PCR-RFLP.
Results DPD activity was measured in 226 Caucasian subjects and was highly variable (range 19.1–401.4  pmol  min⁻¹  mg⁻¹ protein). Mutations were frequently observed at codons 543 (allele frequency 28%), 732 (allele frequency 5.8%), and 534 (allele frequency 0.8%), but were not associated with low DPD activity. There were no splice site or ΔC1897 mutations found in this population.
Conclusions The five mutations analysed in this study are insufficient for identification of patients at risk for 5FU toxicity or thymine uraciluria. Both the splice site mutation and ΔC1897 are relatively rare in the general Caucasian population. Therefore, identification of further molecular alterations is required to facilitate the use of DPD analysis in genetic diagnosis and cancer therapeutics.     

Virologic suppression in nevirapine-exposed HIV-infected infants initiating antiretroviral therapy in rural Uganda

We measured virologic suppression among 34 nevirapine (NVP)-exposed HIV-infected children with median age of 8.6 months (range: 3.2-19.9) initiating NVP-based antiretroviral therapy (ART) in rural Uganda. In Kaplan-Meier analysis, the cumulative probability of virologic suppression, defined as having two consecutive HIV-1 RNA <400 copies ml(-1) by 18 months was 56%. In multivariate Cox proportional hazard modeling, the following pre-ART measurements were independently associated with an increased probability of viral suppression: increasing age [hazard ratio (HR) =1.28 per 1 month increase in age, p?=?0.002], lower viral load (HR?=?3.54 for HIV RNA?>?7?50?000 copies ml(-1), p?=?0.03) and high CD4% (HR?=?6.0 for CD4%?>?25, p?=?0.003). These results lend additional support to the 2010 World Health Organization recommendations that protease inhibitors be used to treat NVP-exposed children, but that NVP-based ART should be initiated before the decline of CD4% to optimize outcomes in NVP-exposed children when protease inhibitors are not available.     

Anxiety and Optimism Associated with Gestational Age at Birth and Fetal Growth

Psychosocial factors such as anxiety or optimism may be related to the risk of adverse pregnancy outcomes, but the evidence is conflicting. We investigated the relation between maternal anxiety, optimism, gestational age and infant birth weight in a cohort of 667 nulliparous women from the Prenatal Exposures and Preeclampsia Prevention study, Pittsburgh PA. Women completed the Spielberger Trait Anxiety Inventory and the Life Orientation Test at 18 weeks gestation. Linear and logistic regression models assessed the relation of anxiety and optimism to gestational age, birth weight centile, preterm delivery (<37 weeks) or small for gestational age (<10th percentile) births. After adjustment for age, race, preeclampsia, and smoking, higher anxiety was associated with decreasing gestational age (−1.6 days per SD increase in anxiety score, P = 0.06). This relationship was modified by maternal race (P < 0.01 for interaction). Among African American women, each SD increase in anxiety was associated with gestations that were, on average, 3.7 days shorter (P = 0.03). African American women with anxiety in the highest quartile had gestations that were 8.2 days shorter, and they had increased risk for preterm birth after excluding cases of preeclampsia (OR 1.69, 95% CI 1.08, 2.64). There was no association between anxiety and gestational age among White women. There was also no relation between anxiety, optimism and birth weight centile. Trait anxiety was associated with a reduction in gestational age and increased risk for preterm birth among African American women. Interventions that reduce anxiety among African American pregnant women may improve pregnancy outcomes.     

Vitamin K Treatment Reduces Undercarboxylated Osteocalcin but Does Not Alter Bone Turnover,Density, or Geometry in Healthy Postmenopausal North American Women

Low vitamin K status is associated with low BMD and increased fracture risk. Additionally, a specific menaquinone, menatetrenone (MK4), may reduce fracture risk. However, whether vitamin K plays a role in the skeletal health of North American women remains unclear. Moreover, various K vitamers (e.g., phylloquinone and MK4) may have differing skeletal effects. The objective of this study was to evaluate the impact of phylloquinone or MK4 treatment on markers of skeletal turnover and BMD in nonosteoporotic, postmenopausal, North American women. In this double‐blind, placebo‐controlled study, 381 postmenopausal women received phylloquinone (1 mg daily), MK4 (45 mg daily), or placebo for 12 mo. All participants received daily calcium and vitamin D₃ supplementation. Serum bone‐specific alkaline phosphatase (BSALP) and n‐telopeptide of type 1 collagen (NTX) were measured at baseline and 1, 3, 6, and 12 mo. Lumbar spine and proximal femur BMD and proximal femur geometry were measured by DXA at baseline and 6 and 12 mo. At baseline, the three treatment groups did not differ in demographics or study endpoints. Compliance with calcium, phylloquinone, and MK4 treatment was 93%, 93%, and 87%, respectively. Phylloquinone and MK4 treatment reduced serum undercarboxylated osteocalcin but did not alter BSALP or NTX. No effect of phylloquinone or MK4 on lumbar spine or proximal femur BMD or proximal femur geometric parameters was observed. This study does not support a role for vitamin K supplementation in osteoporosis prevention among healthy, postmenopausal, North American women receiving calcium and vitamin D supplementation.     

Girls' calcium intake is associated with bone mineral content during middle childhood

We examined longitudinally the association between calcium intake and total body bone mineral content (TBBMC) in 151 non-Hispanic white girls. Intakes of dairy, energy, and calcium were assessed using three 24-h dietary recalls in girls at ages 5, 7, 9, and 11 y. We assessed their total-body bone mineral content with dual-energy X-ray absorptiometry at ages 9 and 11 y. Dairy foods comprised the major contributor (70%) to calcium intake over the 6-y period; 28% of calcium came from other foods, and 2% from supplements. By age 9 and 11 y, the majority of girls did not meet calcium recommendations. Higher calcium intake at ages 7 and 9 y was associated with higher TBBMC at age 11 y. Calcium intake at age 9 y was also positively associated with TBBMC gained from age 9 to 11 y. Calcium intake at age 11 y was not correlated with TBBMC at the same age. Relations between calcium intake and TBBMC did not differ for total calcium and for calcium from dairy sources, likely reflecting the fact that dairy products were the major source of calcium in this sample. Results from the present study provide new longitudinal evidence that calcium intake, especially calcium from dairy foods, can have a favorable effect on girls' TBBMC during middle childhood.     

Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum

Objective

To determine whether hormonal therapies have efficacy in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum.

Methods

We searched departmental databases for patients with histologically-confirmed, evaluable, recurrent low-grade serous ovarian or peritoneal carcinoma who received hormonal therapy at our institution between 1989 and 2009. We retrospectively reviewed patients' medical records for demographic, disease, hormonal therapy, and estrogen receptor and progesterone receptor expression data. We used the Response Evaluation Criteria in Solid Tumors version 1.1 to determine patients' responses to hormonal therapy. Because patients could have received more than one evaluable hormonal therapy regimen, we chose to define the outcome metric as “patient-regimens.” Median time to disease progression (TTP) and overall survival (OS) were also calculated. Regression analysis was also performed.

Results

We identified 64 patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. Patients' median TTP and median OS were 7.4 and 78.2 months, respectively. Patients received 89 separate hormonal patient-regimens, which produced an overall response rate of 9% (6 complete responses and 2 partial responses). Sixty-one percent of the patient-regimens resulted in a progression-free survival duration of at least 6 months. Patient-regimens involving ER +/PR + disease produced a longer median TTP (8.9 months) than patient-regimens involving ER +/PR − disease did (6.2 months; p = 0.053). This difference approached but did not reach statistical significance.

Conclusions

Hormonal therapies have moderate anti-tumor activity in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. Further study to determine whether ER/PR expression status is a predictive biomarker for this rare cancer subtype is warranted.     

Best practice interprofessional stroke care collaboration and simulation: The student perspective

Interprofessional practice (IPP) is the accepted standard of care for clients following a stroke. A brief, embedded and evidence-based IPP team simulation was designed to address stroke care knowledge and IPP competencies for students within limited curriculum space. Each team was required to construct a collaborative care plan for their patient during the simulation and submit the care plan for evaluation of best practice stroke care knowledge and implementation with evidence of interprofessional collaboration (IPC). A total of 302 students (274 on-site, 28 by distance technology) representing four professions comprised of 55 teams took part in this experience. Post-simulation, voluntary and anonymous programme evaluations were completed using the standardised interprofessional collaborative competency assessment scale (ICCAS) and open-ended free-text responses to five questions. There was a significant improvement for all pre–post ratings on the ICCAS regardless of profession or previous interprofessional experience. Additionally, the open-ended responses indicated perceived changes to role clarification, communication, and teamwork. The combined interpretation of the programme evaluation results supports interprofessional team simulation as an effective and efficient learning experience for students regardless of previous interprofessional experience, and demonstrated positive changes in stroke best-practice knowledge and IPC competencies.     

A monocyte chemoattractant protein-1 gene polymorphism is associated with occult ischemia in a high-risk asymptomatic population

Monocyte chemoattractant protein-1 (MCP-1) recruits monocytes into atherosclerotic plaques. A single nucleotide polymorphism in the MCP-1 gene promoter (-2578A>G) results in greater production of MCP-1 protein. We examined the association of this polymorphism with occult coronary artery disease (CAD) and its interaction with CAD risk factor burden, as assessed by the Framingham risk score (FRS) for hard events. We genotyped 679 apparently healthy 24-59-year-old siblings (SIBS) of people with premature CAD, tested for occult ischemia with exercise treadmill tests and thallium-201 single photon emission computed tomography, and assessed CAD risk factors to calculate the FRS. Occult ischemia occurred in 18% of SIBS and overall was somewhat more prevalent in those with the G allele (20.6%) compared to those without (15.6%), p=0.095. In SIBS at higher risk (highest quartile of FRS, >or=6.8%), occult ischemia occurred significantly more frequently in those with the G allele (44.4% versus 26.1%, p=0.017), while there was no significant difference in SIBS with lower FRS. After adjusting for individual risk factors included in the FRS, multivariate logistic regression modeling demonstrated that the G allele independently predicted occult ischemia in the entire study population (p=0.014, OR=1.86, 95% CI=1.14-3.04). This study demonstrates for the first time that the MCP-1 gene -2578A>G polymorphism is associated with an excess risk of coronary atherosclerosis in an asymptomatic population and demonstrates an apparent interaction with CAD risk factor burden.     

Primary care-based interventions are associated with increases in hepatitis C virus testing for patients at risk

BackgroundAn estimated 3.2 million persons are chronically infected with the hepatitis C virus (HCV) in the U.S. Effective treatment is available, but approximately 50% of patients are not aware that they are infected. Optimal testing strategies have not been described.MethodsThe Hepatitis C Assessment and Testing Project (HepCAT) was a serial cross-sectional evaluation of two community-based interventions designed to increase HCV testing in urban primary care clinics in comparison with a baseline period. The first intervention (risk-based screener) prompted physicians to order HCV tests based on the presence of HCV-related risks. The second intervention (birth cohort) prompted physicians to order HCV tests on all patients born within a high-prevalence birth cohort (1945–1964). The study was conducted at three primary care clinics in the Bronx, New York.ResultsBoth interventions were associated with an increased proportion of patients tested for HCV from 6.0% at baseline to 13.1% during the risk-based screener period (P < 0.001) and 9.9% during the birth cohort period (P < 0.001).ConclusionsTwo simple clinical reminder interventions were associated with significantly increased HCV testing rates. Our findings suggest that HCV screening programs, using either a risk-based or birth cohort strategy, should be adopted in primary care settings so that HCV-infected patients may benefit from antiviral treatment.     

Validation of the Decreased Sexual Desire Screener (DSDS): A Brief Diagnostic Instrument for Generalized Acquired Female Hypoactive Sexual Desire Disorder (HSDD)

IntroductionAn accurate diagnosis of Hypoactive Sexual Desire Disorder (HSDD) currently relies on a time-consuming interview with an expert clinician. Limited access to such expertise means that many women with HSDD remain undiagnosed. The Decreased Sexual Desire Screener (DSDS) was developed to provide clinicians who are neither trained nor specialized in Female Sexual Dysfunction (FSD) with a brief diagnostic procedure for the diagnosis of generalized acquired HSDD in women.MethodsA prospective non-treatment multicenter study enrolled 263 women at 27 centers in North America in order to test the validity of the DSDS for diagnosing generalized acquired HSDD in women. Subjects completed the DSDS at the screening visit and their answers were reviewed with a clinician who was not an expert in FSD (“non-expert clinician”). Separately and while being unaware of the non-expert clinician's diagnosis, an expert clinician conducted a standard diagnostic interview.Main Outcome MeasuresDiagnostic outcomes (generalized acquired HSDD or not) were compared. Primary endpoints included the sensitivity and specificity of the DSDS relative to the standard diagnostic interview. Subject and non-expert clinician debriefing were obtained via a written, structured interview. This ensured that a large sample could be tested under uniform conditions across multiple sites.ResultsDiagnostic assessment by DSDS and standard diagnostic interview were in agreement in 85.2% (224/263) of cases, with the sensitivity and specificity of the DSDS 83.6% and 87.8%, respectively. Debriefing showed that the five DSDS questions were well understood by 85.4% (76/89) of subjects included in the debriefing exercise, while non-expert clinicians considered the DSDS questions adequate to diagnose HSDD in 92.9% (235/253) of cases.ConclusionsThe DSDS is a sensitive and specific brief diagnostic instrument for generalized acquired HSDD in women that is quick and easy to use. Clayton AH, Goldfischer ER, Goldstein I, DeRogatis L, Lewis-D'Agostino DJ, and Pyke R. Validation of the Decreased Sexual Desire Screener (DSDS): A brief diagnostic instrument for generalized acquired female Hypoactive Sexual Desire Disorder (HSDD). J Sex Med 2009;6:730–738.