Experiences in implementing uHTS--cutting edge technology meets the real world

Driven by growing corporate compound files, the demands of target biology, and attempts to cut cost, the number of solutions to HTS has spiralled. In quick succession new assay technologies and screening platforms are appearing on the market, with the promise of screening faster than ever in low volume high density formats whilst providing high quality data. Within this world of rapid change, Pfizer has applied cutting edge technology to HTS by introducing screening in 1 microl formats utilising single molecule detection technology. Instead of resource intensive in-house development, Pfizer entered into a collaboration with Evotec OAI / Evotec Technologies and introduced their Mark-II EVOscreen platform. In this article we will outline the benefits of the approach taken at Pfizer, Sandwich, and introduce the Mark-II EVOscreen platform, illustrating the potential but also possible pitfalls of HTS miniaturisation.     

Hematological malignancies in the island of Sardinia, 1974-1993: age and sex distributions and temporal changes in incidence

We have collected, by an active retrospective survey, all the cases of hematologic malignancies (HM) newly diagnosed during the time period 1974-1993 in the resident population of Sardinia. Diagnosis was deemed valid, after consultation of clinical records, in more than 90% of the 7264 collected cases. The number of newly diagnosed cases by year more than doubled during the 20-year period investigated. This striking increase can be only partially accounted for by ageing of population. Indeed, age-specific and age-adjusted rates of most of HM increased during this period, although Hodgkin Disease (HD), Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL) were notable exceptions. The observed increase in rates is likely, in a large part, to be fictitious, due to easier access to a health care system, which in the meantime, improved its diagnostic efficiency. This was particularly evident for Chronic Lymphocytic Leukemia (CLL), Multiple Myeloma (MM) and some others myelo- and lympho-proliferative disorders, but its relevance declined after 1984-1989. A likely true increase in occurrence was evidenced for Non-Hodgkin Lymphomas (NHL) and similarly, although to a lesser extent and more doubtful, for Myelodysplasias (MDS) and Acute Myeloid Leukemia (AML). At the end of the studied period each type of HM presented age and sex distributions and age-adjusted rates that show only minor differences from those reported for other western countries. No argument emerged to suggest that any genetic peculiarities of the Sardinian population might have affected the occurrence of HM. The confounding effects of improved diagnostic efficiency have prevented a reliable assessment of influence on incidences of environmental and socio-economic changes that, in relatively recent times, have occurred in Sardinia.     

Application of the model for end-stage liver disease score for transjugular intrahepatic portosystemic shunt in cirrhotic patients with refractory ascites and renal impairment

BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) can manage severe complications of portal hypertension. The Mayo Clinic group proposed a so-called model for end-stage liver disease (MELD) to predict survival in cirrhotic patients. High creatinine levels determine a decrease in calculated survival chances with MELD but functional renal disease can be reversed by TIPS. The aim of this study was to evaluate the efficacy of MELD in predicting survival after TIPS, particularly in patients with refractory ascites associated with functional renal failure. METHODS: This retrospective analysis examines 68 cirrhotic patients who underwent elective TIPS: 48 patients had refractory ascites and 20 patients had recurrent variceal bleeding. Multivariate analysis was used to establish predictive parameters of survival after TIPS. Kaplan-Meier and log-rank tests were used to compare survival rates observed in our patients with those evaluated with the MELD score. RESULTS: The age of patients was the only variable shown to have an independent value in predicting survival after TIPS. In patients undergoing shunting for refractory ascites, the survival rates at 6, 12 and 24 months after the procedure were significantly higher than expected with the MELD score. CONCLUSIONS: The MELD scale may underestimate the efficacy of TIPS in end-stage cirrhotic patients with refractory ascites and functional kidney dysfunction. Further studies are needed to confirm this finding and ultimately to assess a correction factor to better predict survival after TIPS in patients with functional renal impairment.     

A systemic type I 5 alpha-reductase inhibitor is ineffective in the treatment of acne vulgaris

Excessive sebum production is a central aspect of the pathophysiology of acne vulgaris. Sebaceous gland function is under androgen control and it is hypothesized that dihydrotestosterone is formed by the action of 5 alpha-reductase. Type I is the controlling isoenzyme. This study describes a 3-month, multicenter, randomized, placebo-controlled clinical trial with a potent, selective inhibitor of type I 5 alpha-reductase used alone and in combination with systemic minocycline. Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function.     

Young adults’ recollections of parental bonds

Abstract. Background: Recollections of cold and overprotective behaviors from parents have been hypothesized to lead to the presence of mental disorders in young adulthood through their detrimental effects on individuals satisfaction in later partner relationships. Previous studies have not explicitly tested, however, whether partner relationship satisfaction mediates the longitudinal relationship from parental bonds to DSMIII-R disorders in young adults. Methods: We examined: (1) whether recollections of parental bonds in the first 16 years of life were related to the prevalence of DSMIII-R mental disorders in young adulthood, and (2) whether young adults satisfaction with current partner relationships mediated these links. Data were used from 1,581 Dutch young adults aged 18–34 years, who were interviewed in three waves (1996, 1997, and 1999) of a nationwide epidemiological study Results: Structural Equation Models demonstrated that recollections of caring, non-intrusive parenting behaviors were significantly, negatively associated with the prevalence of mood and anxiety disorders (but not substance disorders) in young adulthood. The satisfaction with current partner relationships did not mediate these negative associations. Conclusion: Results replicate and extend earlier findings from the National Comorbidity Survey (Enns et al. 2002), demonstrating that mental disorders are directly related to peoples recollections of parental care and overprotection. Low-quality parental bonds were only related to internalizing types of psychopathology, however, and were of a modest strength. Results may indicate that there is relatively little cross-relationship continuity in the experience of intimacy between relationships with parents and with partners.     

Psychosocial disability before, during, and after a major depressive episode: a 3-wave population-based study of state, scar, and trait effects

BACKGROUND: Psychosocial disability after remission from a unipolar major depressive episode (MDE) can be due to (1) residual symptoms (state effect), (2) the continuation of premorbid disability (trait effect), and/or (3) disability that developed during the MDE and persisted beyond recovery (scar effect). METHODS: Data came from the Netherlands Mental Health Survey and Incidence Study (NEMESIS), a prospective Dutch psychiatric population-based survey. We obtained psychiatric data (Composite International Diagnostic Interview) and information on psychosocial functioning (work, housekeeping, spouse/partner, and leisure-time domains) from 4796 respondents in 1996 (T1), 1997 (T2), and 1999 (T3). We evaluated trait effects using between-subject comparisons, and state and scar effects using within-subject comparisons. RESULTS: In 216 and 118 respondents, a first and a recurrent MDE developed, respectively, after T1 that remitted before T3. Compared with never-MDE individuals, first-MDE subjects had higher disability scores long before their episode (effect size, 0.42-0.57 U). During the MDE, disability further increased in first- and recurrent-MDE subjects (effect size, 0.44-0.79 U), but returned to its premorbid level after MDE remission, except in subjects who experienced a severe recurrent episode. If the premorbid period (T1 to MDE onset) was longer than the postmorbid period (MDE remission to T3), disability at T3 was higher than at T1, misleadingly suggesting scar effects. The reverse occurred if the premorbid period was shorter than the postmorbid period. CONCLUSIONS: Postmorbid psychosocial disability reflects largely the continuation of premorbid psychosocial disability. Scarring does not occur routinely, but may occur in a severe recurrent episode. Within-subject premorbid-postmorbid comparisons are sensitive to state effects of prodromal and residual symptoms. These findings point at the following 2 independent processes: (1) the ongoing expression of trait vulnerability to depression in mild psychosocial dysfunctioning; and (2) synchrony of change between severity of depressive symptoms and psychosocial disability.     

Vulnerability before, during, and after a major depressive episode: a 3-wave population-based study

BACKGROUND: Vulnerability as defined by high levels of neuroticism, low self-esteem, and poor coping skills characterizes individuals with a history of major depressive episodes (MDEs). OBJECTIVE: To separate postmorbid vulnerability into (1) trait effects (ie, the continuation of premorbid vulnerability); (2) state effects of subthreshold (residual) symptoms on personality or its perception; and/or (3) scar effects (ie, negative personality change that develops during an MDE and persists beyond MDE remission). METHODS: Data come from the Netherlands Mental Health Survey and Incidence Study, a prospective Dutch psychiatric population-based survey. We obtained psychiatric (Composite International Diagnostic Interview) and personality data on neuroticism, depressive coping style, self-esteem, and mastery from 4796 respondents at 3 time points (T1, T2, and T3), 12 and 24 months apart. Between- and within-subjects differences were tested with repeated-measures analysis of variance and adjusted for sex, age, and time. RESULTS: After T1, 409 respondents developed an MDE, of whom 334 were MDE-free at T3. In comparison with individuals without any lifetime MDE, the 262 subjects with a first MDE had higher premorbid T1 vulnerability scores on each personality measure (0.38-0.83 effect size units). During the MDE, vulnerability scores further increased (0.33-0.52 effect size units) but returned to premorbid levels after MDE remission. We found no scar effects among subgroups with severe or long-lasting MDEs. Subthreshold residual symptoms at T3 biased comparisons between T1 and T3 if the premorbid period of T1 to MDE onset was longer than the postmorbid period of MDE remission to T3, misleadingly suggesting scar effects. We obtained similar results in the 147 subjects with recurrent MDEs. CONCLUSIONS: There was no evidence of a negative change from premorbid to postmorbid assessment for any of the personality traits. Postmorbid vulnerability reflected the continuation of premorbid vulnerability. Pre-post MDE comparisons are sensitive to prodromal and residual symptoms. Our findings suggest 2 independent simultaneous processes: (1) the ongoing expression of vulnerability as a personality deviance; and (2) synchrony of change between severity of depressive symptoms and personality deviance.     

HLA DR13 and HCV vertical infection

Risk factors affecting vertical hepatitis C virus (HCV) transmission are not completely known, if we exclude maternal HIV coinfection. We hypothesized that immunogenetic factors related to maternal or neonatal HLA profiles may affect HCV vertical transmission. HLA typing (microcytotoxicity assay on blood samples) was performed in 18 infants affected by vertically transmitted HCV infection and in 17 serum-reverted infants. (Serum-reversion is defined as antibody negative by 1 year of age and persistently HCV-RNA negative.) Moreover, HLA typing was performed in 20 mothers. Logistic regression analysis showed a significant negative association between children's HLA-DR13 antigens and risk of HCV vertical transmission (p < 0.01). This association persisted in a model including the maternal HIV status: HLA DR13 and maternal HIV coinfection showed a separate, opposite effect on vertical HCV infection (p < 0.01 and p < 0.001, respectively). The relative risk estimate for the ratio of not-infected to infected children in the presence of DR13 was 8.4 (95% confidence bounds, 1.1-60.8). Breast-feeding did not affect the risk of vertical HCV transmission. Maternal HLA profile did not relate to vertical infection. The present study reveals a significant association between HLA-DR13 and the likelihood of seroreversion in infants born to HCV-infected mothers. The findings of the present study could help in better understanding the pathogenesis of vertical HCV infection and in better identifying the cases at higher risk, which would be useful for the development of prevention strategies. It is possible that DR13 modulates the immune response to viruses, enhancing their clearance and, thus, in the case of HCV, exerting a protective role against the development of vertical infection.     

Verification of expected death by district nurses

Pressures on a local out-of-hours GP deputizing service led to lengthy delays before a doctor could visit to verify the (expected) death of patients under the care of the district nursing service. This resulted in distress to the relatives and delayed transfer of the body to a funeral home. This article explores an initiative to enable community nursing staff to verify those expected deaths and to provide more effective support to relatives at a difficult time. The article highlights the benefits of multidisciplinary collaboration in the development of an appropriate protocol and provides an overview of its implementation in one area. The initiative contributes to the Government's agenda to improve access to primary care and to create more patient-friendly services.