Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients

Wilson disease (WD) is a rare inherited autosomal recessive disorder caused by a defect in a metal transporting P-type ATPase, resulting in copper overload in various tissues and cells. The aim was to assess both the phenotype in Brazilian WD patients and the corresponding ATP7B genotype. Sixty subjects belonging to 46 pedigrees diagnosed as WD were included in this study. Direct sequencing of all 21 exons within ATP7B and their flanking introns was performed. Demographic, clinical, laboratory and histopathological data at the time of diagnosis were obtained. We identified twenty-five mutations, twelve of them reported for the first time. The c.3402delC mutation had the highest allelic frequency (30.8%), followed by the c.2123T>C (p.L708P) (16.7%). Exons 8 and 15 were the site of 62.5% of the mutations. The common European mutation c.3207C>A (p.H1069Q) was not present at all. Phenotype varied greatly among individuals with the same ATP7B genotype. Our data confirm the heterogeneity of ATP7B genotype in Brazilian WD patients. The mutational spectrum is compatible with the Brazilian history of Mediterranean immigration; however, new mutations, and different frequencies and phenotype associated with the previously known mutations characterize this population. Exons 8 and 15 should be preferentially screened in WD cases from Brazil. Phenotype variation among subjects with the same ATP7B genotype suggests that modifying factors play an additional role in the pathogenesis of WD.     

Receptors for immunoglobulin isotypes (FcR) on murine T cells. I. Multiple FcR expression on T lymphocytes and hybridoma T cell clones

T cell receptors for the Fc portion of the various isotypes of mouse immunoglobulins (FcR) were examined by rosette formation, using as indicator cells erythrocytes coated with monoclonal antibodies of all known isotypes of serum immunoglobulins. Three populations of mouse T cells were studied: normal thymocytes, activated T cells (ATC), generated by educating thymocytes in lethally irradiated allogeneic hosts, and hybridoma T cells, derived from somatic hybridization of ATC with the FcR-negative thymoma BW.5147. We found that many different FcR could be distinguished by their specificity for a single isotype or for a combination of several isotypes; ATC and hybridoma T cells expressed several such receptors that, at least in cloned cells, could be demonstrated to be borne by individual cells; hybridoma T cells of independent origin bore indistinguishable receptors whereas ATC expressed markedly different FcR and upon overnight incubation at 37 degrees C, immunoglobulins were found to bind onto the cell surface, even though no corresponding constitutive FcR was detected. The same was observed with hybridoma T cells and with thymocytes. It follows that a single T cell can express several FcR. Altogether, these FcR are capable of binding all known isotypes of serum immunoglobulins. They differ from one T cell to another.     

Longitudinal Examination of Prenatal Tobacco Switching Behaviors and Birth Outcomes,Including Electronic Nicotine Delivery System (ENDS) and Dual Use

Maternal and Child Health Journal - In the US, approximately 8% of pregnant women smoke, and 5–11.9% currently use ENDS products. The health effects of ENDS use are debated; however, most...     

Chronic (−)-isoprenaline infusion down-regulates β1- and β2-adrenoceptors but does not transregulate muscarinic cholinoceptors in rat heart

Regulation of -adrenoceptor (-ar) subtypes and transregulation of muscarinic cholinoceptors (mAchr) was examined in regions of rat heart after chronic infusion of (–)-isoprenaline (450 /kg per hour) for 14 days. Following (–)-isoprenaline infusion systolic blood pressure was reduced for 10 days but then gradually returned to control levels, whereas heart rate was increased for 7 days before declining to a level significantly above control. Heart weight to body weight ratio was increased in (–)-isoprenaline treated rats. -ar subtype densities were measured by quantitative autoradiography with [¹²⁵I]-cyanopindolol (CYP) in sinoatrial node (SA), atrioventricular node (AV), bundle of His (BH), left (LB) and right (RB) bundle branches, interventricular (IVS) and interatrial (IAS) septa, right atria (RA), apex (AX) and mitral valve (MV). ₁-ars were reduced by 59.1–74.2% in the AV conducting regions, 53.4% in the SA node and 43.3–53.4% in myocardial areas. ₂-ars were markedly reduced in myocardial regions (93.2–98.5%) and in pacemaker and conducting regions (87.7–97.8%). No changes in mAchr densities measured using [³H]-N-methyl scopolamine (NMS) occurred in the AV node, BH, LB, RB, IVS and IAS following (–)-isoprenaline infusion.Densities of ₁- and ₂-ars and mAchrs were also measured in ventricular homogenates from control and (–)-isoprenaline treated animals. -ar levels were significantly reduced (P < 0.05) in treated animals and the ratio of ₁- to ₂-ars increased after treatment. mAchr density in ventricular homogenates measured using either [³H]-NMS or [³H]-quinuclidinyl [phenyl-4-³H]benzilate (QNB) was unchanged. Homogenates of left and right ventricle also showed no change using [³H]-NMS.Organ bath studies were used to investigate the effect of (–)-isoprenaline infusion on negative inotropic and chronotropic effects of the non-selective muscarinic receptor agonist bethanechol in left and right atria, respectively. Lower concentrations of bethanechol (3 × 10^–10 to 10^–6 M) produced a negative inotropic response in isolated electrically driven left atria from (–)-isoprenaline treated rats, but not from control rats, with the slope of the curves being significantly different between groups (ANCOVA, P = 0.037). At concentrations of bethanechol from 10^–6 to 3 × 10^–4 M the negative inotropic response was not changed between (–)-isoprenaline treated and control animals. Bethanechol also produced a negative chronotropic response at lower concentrations (10^–10 to 10^–6 M) in (–)-isoprenaline treated rats, but not in controls. A second, steeper phase of the negative chronotropic response occurred at concentrations of bethanechol greater than 10^–6 M and was also seen in control rats.Expression of M₂ (cardiac) mAchrs (m₂Achr) in left and right ventricular tissues measured using a quantitative non-competitive polymerase chain reaction (PCR) assay showed a significant (P = 0.001) 28.5% increase in expression in left ventricle and a significant (P = 0.003) 21.5% decrease in expression in right ventricle after (–)-isoprenaline treatment, compared to controls. There was no significant difference in total ventricular m₂Achr expression between the two groups of rats. The results suggest that chronic -ar stimulation down-regulates both ₁- and ₂-ars, and appears to differentially transregulate m₂Achr expression, but not mAchr protein. Following (–)-isoprenaline infusion, muscarinic receptor mediated responses were sensitised, with no change in receptor densities, suggesting changes occur in the cell signalling system beyond the level of the receptor.     

(5) Feminist theory and pharmacy practice

This is the fifth in a series of articles highlighting the relevance of sociological theory to pharmacy practice research. The article provides an introduction to feminist theory and research as applied to health, illness and health care. The aim is to clarify the contribution made by feminist theory in developing useful conceptual tools and theories in two major areas: the specific experiences of women's health and understanding the role of women as providers of health care. We seek to contribute to a research agenda, informed by feminist thinking, for pharmacy practice. The focus of this article is on feminist theory as developed in the West, with particular emphasis on issues of concern for pharmacy practice research. We begin with a discussion of the historical context of feminism, including the women's movement and the women and health movement. This is followed by an overview of selected feminist theories. Feminist perspectives on the experience of health and illness are discussed in more detail, including issues of reproductive technologies, gender, health and morbidity; gender differences in the medical encounter; and finally the relevance of a feminist approach to pharmacy practice research, including research questions that are relevant today.     

Relations Between Coercive Strategies and MMPI-2 Scale Elevations Among Women Survivors of Childhood Sexual Abuse

The relationship between coercion strategies used by perpetrators of childhood sexual abuse (CSA) and elevations of CSA survivors on the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) was investigated. Participants were 151 women survivors of CSA in outpatient treatment at a university-based community mental health center. Scores on the MMPI-2 clinical scales and the Keane posttraumatic stress disorder (PTSD) scale were examined. Main effects were found for promised or received rewards on several clinical scales and the PTSD scale of the MMPI-2, independent of the presence of force. Specifically, the presence of such rewards was associated with significantly higher levels of symptomatology on Paranoia (Pa), Psychasthenia (Pt), Schizophrenia (Sc), and PTSD (Pk). There were no main or interaction effects noted for the presence of actual or threatened force on any of the scales.     

Validation of a brief screen for cognitive impairment (BSCI) administered by telephone for use in the medicare population.

The aim of this research was to examine the validity of a brief screen for cognitive impairment (BSCI) consisting of three questions administered by telephone (delayed recall, frequency of help with planning trips for errands, and frequency of help remembering to take medications). The study design was an age and gender matched case-control study. Seventy managed care members, 35 with dementia (cases) and 35 without dementia (controls), were assessed using BSCI embedded within a longer health assessment questionnaire commonly used in Medicare-managed care. A number of measures were used to examine validity of BSCI, including comparisons of the differences between cases and controls in BSCI scores, comparisons of the correlations between patient scores on BSCI and the Mini Mental Status Exam (MMSE, a common screening test for dementia) and the Alzheimer's Disease Assessment Scale (ADAS, a common dementia assessment test), and comparisons of the areas under the receiver operating characteristic (ROC) curves for the three instruments. BSCI scores for cases and controls were significantly different, as were their scores for the MMSE and ADAS. Scores on BSCI were significantly correlated with scores for the MMSE and ADAS using both the Kendall's tau-b and Spearman rank-order correlation; correlations ranged from 0.654 between BSCI and ADAS to -0.83 for the correlation between BSCI and the MMSE (p < 0.001 for both). The areas under the ROC curves ranged from 0.94 to 0.96 for the three tests, meaning that they were equally accurate in discriminating between demented and nondemented patients. BSCI, a brief telephone screen for cognitive impairment due to dementia, discriminates between demented patients and normal controls as well as two standard tests of dementia, and may be considered a valid screen for dementia. Compared to existing screening tests, it has the additional advantages of extreme brevity, and ease of administration and scoring by lay interviewers via telephone. The use of brief screening instruments for dementia, such as the one validated here, will be increasingly important for the effective management of dementia and other chronic diseases where dementia is a coexisting condition.     

Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists.

PURPOSE: To investigate the relationships between biomarker changes in breast cancer during neoadjuvant (preoperative) endocrine therapy. PATIENTS AND METHODS: The IMPACT trial compared the preoperative use of tamoxifen with anastrozole alone or in combination in postmenopausal women (n = 330) with primary breast cancer. Biomarkers were measured in tumor biopsy specimens taken at baseline, and after 2 and 12 weeks of treatment. RESULTS: 52 (93%) of 56, 46 (85%) of 54, and 37 (84%) of 44 patients in the anastrozole, tamoxifen, and combination groups, respectively. There was a significantly greater suppression of Ki67 in the anastrozole-treated group than in the tamoxifen- or combination-treated groups, which is parallel to the greater efficacy seen for anastrozole over these two treatments in the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial. A positive relationship was noted between estrogen-receptor level and Ki67 suppression in all patients. Ki67 was reduced to a greater extent in progesterone receptor-positive tumors compared with progesterone receptor-negative tumors. HER-2-negative tumors tended to show a greater reduction in Ki67 compared with HER-2-positive tumors, but the difference was only significant in the tamoxifen group after 2 weeks, and in the anastrozole group after 12 weeks. CONCLUSION: These results confirm the value of Ki67 as a molecular marker, and provide information regarding the relationships between treatment-induced changes in Ki67 and other important biomarkers. Studies such as this should help integrate agents targeted at growth factor signaling with endocrine agents in breast cancer.     

Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer.

PURPOSE: To evaluate the effect of BLP25 liposome vaccine (L-BLP25) on survival and toxicity in patients with stage IIIB and IV non-small-cell lung cancer (NSCLC). Secondary objectives included health-related quality of life (QOL) and immune responses elicited by L-BLP25. PATIENTS AND METHODS: Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and stable or responding stage IIIB or IV NSCLC after any first-line chemotherapy were prestratified by stage and randomly assigned to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received a single intravenous dose of cyclophosphamide 300 mg/m2 followed by eight weekly subcutaneous immunizations with L-BLP25 (1,000 microg). Subsequent immunizations were administered at 6-week intervals. RESULTS: The survival results indicate a median survival time of 4.4 months longer for patients randomly assigned to the L-BLP25 arm (88 patients) compared with patients assigned to the BSC arm (83 patients; adjusted hazard ratio [HR] = 0.739; 95% CI, 0.509 to 1.073; P = .112). The greatest effect was observed in stage IIIB locoregional (LR) patients, for whom the median survival time for the L-BLP25 arm has not yet been reached compared with 13.3 months for the BSC arm (adjusted HR = 0.524; 95% CI, 0.261 to 1.052; P = .069). No significant toxicity was observed. QOL was maintained longer in patients on the L-BLP25 arm. CONCLUSION: L-BLP25 maintenance therapy in patients with advanced NSCLC is feasible with minimal toxicity. The survival difference of 4.4 months observed with the vaccine did not reach statistical significance. In the subgroup of patients with stage IIIB LR disease, a strong trend in 2-year survival in favor of L-BLP25 was observed.