Quantitative diffusion tensor imaging detects dopaminergic neuronal degeneration in a murine model of Parkinson's disease.

Early diagnosis of Parkinson's disease (PD) is required to improve therapeutic responses. Indeed, a clinical diagnosis of resting tremor, rigidity, movement and postural deficiencies usually reflect >50% loss of the nigrostriatal system in disease. In a step to address this, quantitative diffusion tensor magnetic resonance imaging (DTI) was used to assess nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication model of dopaminergic nigral degeneration. We now demonstrate increased average diffusion (p<0.005) and decreased fractional anisotropy (p<0.03) in the substantia nigra (SN) of 5- to 7-day MPTP-treated animals when compared to saline controls. Transverse diffusivity demonstrated the most significant differences (p < or = 0.002) and correlated with the numbers of SN dopaminergic neurons (r=-0.75, p=0.012). No differences were found in the striatum, corpus callosum, cerebral cortex, or ventricles. These results demonstrate that DTI may be used as a surrogate biomarker of nigral dopaminergic neuronal degeneration.

Measuring Consumer Satisfaction in Family Preservation Services: Identifying Instrument Domains

Measuring consumer satisfaction in the social services has become an important source of feedback for the improvement of service delivery. Consumer satisfaction has recently been incorporated into family preservation evaluation. This article reviews instruments used to measure consumer satisfaction in family preservation services and other related areas. Trends in current practice are examined and instrument dimensions are identified. Finally, some recommendations are made about the application of consumer satisfaction measurement in family preservation services.

Family Preservation Journal, 1999, Volume 4, Issue 2. (Entire issue)

Entire issue (large pdf file) Articles include: Behavior Problems of Maltreated Children Receiving In-Home Child Welfare Services. Ferol Mennen, William Meezan, Gino Aisenberg, and Jacquelyn McCroskey Measuring Consumer Satisfaction in Family Preservation Services: Identifying Instrument Domains. Stephen A. Kapp and Rebecca H Vela Intensive In-Home Family-Based Services: Reactions from Consumers and Providers Elaine Walton, and Alfred C. Dodini Coordination of Family Preservation Services in a Rural Community: A Case Study. Richard Freer and Kathleen Wells The Effectiveness of Court Mandated Intervention Versus Voluntary Services in Child Protective Services: Abbreviated Version. Loring Jones, Irene Becker, and Krista F alk

Adaptive Molecular Evolution in the Opsin Genes of Rapidly Speciating Cichlid Species

Cichlid fish inhabit a diverse range of environments that vary in the spectral content of light available for vision. These differences should result in adaptive selective pressure on the genes involved in visual sensitivity, the opsin genes. This study examines the evidence for differential adaptive molecular evolution in East African cichlid opsin genes due to gross differences in environmental light conditions. First, we characterize the selective regime experienced by cichlid opsin genes using a likelihood ratio test format, comparing likelihood models with different constraints on the relative rates of amino acid substitution, across sites. Second, we compare turbid and clear lineages to determine if there is evidence of differences in relative rates of substitution. Third, we present evidence of functional diversification and its relationship to the photic environment among cichlid opsin genes. We report statistical evidence of positive selection in all cichlid opsin genes, except short wavelength–sensitive 1 and short wavelength–sensitive 2b. In all genes predicted to be under positive selection, except short wavelength–sensitive 2a, we find differences in selective pressure between turbid and clear lineages. Potential spectral tuning sites are variable among all cichlid opsin genes; however, patterns of substitution consistent with photic environment–driven evolution of opsin genes are observed only for short wavelength–sensitive 1 opsin genes. This study identifies a number of promising candidate-tuning sites for future study by site-directed mutagenesis. This work also begins to demonstrate the molecular evolutionary dynamics of cichlid visual sensitivity and its relationship to the photic environment.

Life-threatening adverse events following therapeutic opioid administration in adults: Is pharmacogenetic analysis useful?

BACKGROUND Systemic approaches are needed to understand how variations in the genes associated with opioid pharmacokinetics and response can be used to predict patient outcome. The application of pharmacogenetic analysis to two cases of life-threatening opioid-induced respiratory depression is presented. The usefulness of genotyping in the context of these cases is discussed. METHODS A panel of 20 functional candidate polymorphisms in genes involved in the opioid biotransformation pathway (CYP2D6, UGT2B7, ABCB1, OPRM1, COMT) were genotyped in these two patients using commercially available genotyping assays. RESULTS In case 1, the patient experienced adverse outcomes when administered codeine and morphine, but not hydromorphone. Genetic test results suggested that this differential response may be due to an inherent propensity to generate active metabolites from both codeine and morphine. These active metabolites are not generated with hydromorphone. In case 2, the patient experienced severe respiratory depression during postoperative recovery following standard doses of morphine. The patient was found to carry genetic variations that result in decreased morphine efflux transporter activity at the blood-brain barrier and increased sensitivity to opioids. CONCLUSIONS Knowledge of the relative contribution of pharmacogenetic biomarkers and their influence on opioid response are continually evolving. Pharmacogenetic analysis, together with clinical history, has the potential to provide mechanistic insight into severe respiratory depressive events in patients who receive opioids at therapeutic doses.

Development and testing of a procedure for systematically assigning gestational age for clinical and research use

A graphing method was developed and tested to estimate gestational ages pre-and postnatally in a consistent manner for epidemiological research and clinical purposes on feti/infants of women with few consistent prenatal estimators of gestational age. Each patient's available data was plotted on a single page graph to give a comprehensive overview of that patient. A hierarchical classification of gestational age determination was then applied in a systematic manner, and reasonable gestational age estimates were produced. The method was tested for validity and reliability on 50 women who had known dates for their last menstrual period or dates of conception, and multiple ultrasound examinations and other gestational age estimating measures. The feasibility of the procedure was then tested on 1223 low income women with few gestational age estimators. The graphing method proved to have high inter- and intrarater reliability. It was quick, easy to use, inexpensive, and did not require special equipment. The graphing method estimate of gestational age for each infant was tested against the last menstrual period gestational age estimate using paired t-Tests, F tests and the Kolmogorov-Smirnov test of similar populations, producing a 98 percent probability or better that the means and data populations were the same. Less than 5 percent of the infants' gestational ages were misclassified using the graphing method, much lower than the amount of misclassification produced by ultrasound or neonatal examination estimates. ^

THE EFFECTS OF STREPTOZOTOCIN DIABETES AND DIETARY IRON INTAKE ON CATALASE, GLUTATHIONE PEROXIDASE, SUPEROXIDE DISMUTASE AND LIPID PEROXIDATION IN CARDIAC AND SKELETAL MUSCLES OF RATS

Catalase, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) prevent oxygen free radical mediated tissue damage. Diabetes increases and a low dietary intake of iron decreases catalase activity in muscle. Therefore, the combined effects of diabetes and iron deficiency on the free radical scavenging enzyme system and lipid peroxidation were studied. Male, weanling rats were injected with streptozotocin (65 mg/kg, IV) and fed diets containing either 35 ppm iron (Db + Fe) or 8 ppm iron (Db $-$ Fe). Sham injected animals served as iron adequate (C + Fe) or iron deficient (C $-$ Fe) controls. Heart, gastrocnemius (GT), soleus and tibialis anterior (TA) muscles were dissected, weighted and analyzed for catalase, GSH-Px and SOD activities after 3, 6 or 9 weeks on the respective diets. The TBA assay was used to assess lipid peroxidation in the GT muscle. Diabetes elevated catalase activity in all muscles while it had a slight lowering effect on SOD and GSH-Px activities in the GT and TA muscles. In the C $-$ Fe rats, catalase activity declined and remained depressed in all muscles except the heart. There was an elevation in GSH-Px and SOD in the GT muscles of these animals after 6 weeks but not after 9 weeks of consuming the low iron diet. The Db $-$ Fe animals were unable to respond to the diabetic state with catalase activity as high as observed in the Db + Fe rats. Treatment with insulin or iron returned catalase to control levels. The C $-$ Fe animals had significantly lower levels of lipid peroxidation than the other groups at 6 and 9 weeks. Refeeding an iron adequate diet resulted in an increase in lipid peroxidation levels. These studies indicate that skeletal muscle free radical scavenging enzymes are sensitive to metabolic states and that dietary iron influences lipid peroxidation in this tissue. ^

Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial

BACKGROUND The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. METHODS For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. FINDINGS Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6-36·8) in the chemotherapy-alone group and 32·0 months (27·5-36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0·87, 95% CI 0·72-1·07; p=0·18). 3-year IDFS was 82·7% (95% CI 80·5-85·0) with chemotherapy alone and 83·7% (81·4-86·0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0·84, 95% CI 0·64-1·12; p=0·23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab (Cox interaction test p=0·029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [<0·5%]), and treatment discontinuation (bevacizumab, chemotherapy, or both; 256 [20%] vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [<0·5%] vs three [<0·5%]). INTERPRETATION Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival.

The Aeolian Flux of Calcium, Chloride and Nitrate to the McMurdo Dry Valleys Landscape: Evidence from Snow Pit Analysis

We have determined the flux of calcium, chloride and nitrate to the McMurdo Dry Valleys region by analysing snow pits for their chemical composition and their snow accumulation using multiple records spanning up to 48 years. The fluxes demonstrate patterns related to elevation and proximity to the ocean. In general, there is a strong relationship between the nitrate flux and snow accumulation, indicating that precipitation rates may have a great influence over the nitrogen concentrations in the soils of the valleys. Aeolian dust transport plays an important role in the deposition of some elements (e.g. C(2+)) into the McMurdo Dry Valleys' soils. Because of the antiquity of some of the soil surfaces in the McMurdo Dry Valleys regions, the accumulated atmospheric flux of salts to the soils has important ecological consequences. Although precipitation may be an important mechanism of salt deposition to the McMurdo Dry Valley surfaces, it is poorly understood because of difficulties in measurement and high losses from sublimation.

Environmental Effects and Aquatic Organisms: Investigations of Molecular Mechanisms of Carcinogenesis

Cancers of the reproductive system are among the leading causes of mortality in women in the United States. While both genetic and environmental factors have been implicated in their etiology, the extent of the contribution of environmental factors to human diseases remains controversial. To better address the role of environmental exposures in cancer etiology, there has been an increasing focus on the development of nontraditional, environmentally relevant models. Our research involves the development of one such model, Gonadal tumors have been described in the softshell clam (Mya arenaria) in Maine and the hardshell clam (Mercenaria spp.) from Florida. Prevalence of these tumors is as high as 40% in some populations in eastern Maine and 60% in Some areas along the Indian River in Florida. The average tumor prevalence in Maine and Florida is approximately 20 and 11%, respectively. An association has been suggested between the use of herbicides and the incidence of gonadal tumors in the softshell clam in Maine. The role of environmental exposures in the development of the tumors in Mercenaria in Florida is unknown, however, there is evidence that genetic factors may contribute to its etiology. Epidemiologic studies of human populations in these same areas show a higher than average mortality rate due to cancers of the reproductive system in women, including both ovarian and breast career. The relationship, if any, among these observations is unknown, Our studies on the molecular basis of this disease in clams may provide additional information on environmental exposures and their possible link to cancer in clams and other organisms, including humans.

Between anxiety and hope: the experiences of women with vulval intraepithelial neoplasia during their illness trajectory - a qualitative approach

The vulvar intraepithelial neoplasia (VIN) is a rare chronic skin condition that may progress to an invasive carcinoma of the vulva. Major issues affecting women's health were occurring symptoms, negative influences on sexuality, uncertainty concerning the illness progression and changes in the body image. Despite this, there is little known about the lived experiences of the illness trajectory. Therefore, the aim of this study was to describe the experiences of women with VIN during the illness trajectory. In a secondary data analysis of the foregoing qualitative study we analysed eight narrative interviews with women with VIN by using thematic analysis in combination with critical hermeneutics. Central for these women during their course of illness was a sense of "Hope and Fear". This constitutive pattern reflects the fear of recurrence but also the trust in healing. The eight narratives showed women's experiences during their course of illness occurred in five phases: "there is something unknown"; "one knows, what IT is"; "IT is treated and should heal"; "IT has effects on daily life"; "meanwhile it works". Women's experiences were particularly influenced by the feeling of "embarrassment" and by "dealing with professionals". Current care seems to lack adequate support for women with VIN to manage these phases. We suggest, based on our study and the international literature, that new models of counselling and providing information need to be developed and evaluated.

A patient-reported outcome measure to identify occurrence and distress of post-surgery symptoms of WOMen with vulvAr Neoplasia (WOMAN-PRO) - a cross sectional study.

OBJECTIVE The aim of the study was to describe the (a) symptom experience of women with vulvar intraepithelial neoplasia and vulvar cancer (vulvar neoplasia) during the first week after hospital discharge, and (b) associations between age, type of disease, stage of disease, the extent of surgical treatment and symptom experience. METHODS This cross-sectional study was conducted in eight hospitals in Germany and Switzerland (Clinical Trial ID: NCT01300663). Symptom experience after surgical treatment in women with vulvar neoplasia was measured with our newly developed WOMAN-PRO instrument. Outpatients (n=65) rated 31 items. We used descriptive statistics and regression analysis. RESULTS The average number of symptoms reported per patient was 20.2 (SD 5.77) with a range of 5 to 31 symptoms. The three most prevalent wound-related symptoms were 'swelling' (n=56), 'drainage' (n=54) and 'pain' (n=52). The three most prevalent difficulties in daily life were 'sitting' (n=63), 'wearing clothes' (n=56) and 'carrying out my daily activities' (n=51). 'Tiredness' (n=62), 'insecurity' (n=54) and 'feeling that my body has changed' (n=50) were the three most prevalent psychosocial symptoms/issues. The most distressing symptoms were 'sitting' (Mean 2.03, SD 0.88), 'open spot (e.g. opening of skin or suture)' (Mean 1.91, SD 0.93), and 'carrying out my daily activities' (Mean 1.86, SD 0.87), which were on average reported as 'quite a bit' distressing. Negative associations were found between psychosocial symptom experience and age. CONCLUSIONS WOMAN-PRO data showed a high symptom prevalence and distress, call for a comprehensive symptom assessment, and may allow identification of relevant areas in symptom management.

Great Britain, Palestine, Russia, and the Jews

Canon Edward Hoare