Rash as a surrogate marker for efficacy of epidermal growth factor receptor inhibitors in lung cancer

Rash and other cutaneous adverse events are class-effect toxicities seen with therapeutic agents such as the small-molecule tyrosine kinase inhibitors erlotinib and gefitinib and monoclonal antibodies cetuximab and panitumumab, targeting the epidermal growth factor receptor (EGFR) in the treatment of cancer. Rash has been reported in approximately two thirds of patients treated with these agents in phase II/III clinical trials in different tumor types. The rash that occurs with EGFR-targeted agents is generally mild to moderate; severe (grade 3/4) rash is rare (< 15% in non-small-cell lung carcinoma trials). In a number of clinical trials, the association of the incidence and severity of rash with response and survival after treatment with erlotinib or gefitinib has been analyzed. Although the significance of the association is yet to be determined, in most studies, a positive correlation between rash and clinical outcomes with EGFR-targeted therapy has been demonstrated. Therefore, the potential of using rash as a surrogate marker for efficacy of EGFR inhibitors in lung cancer therapy exists and needs to be further explored. This article provides a review of the data evaluating the association between rash and treatment outcomes and summarizes the current knowledge regarding the significance of this association. Understanding the biology/etiology of the rash resulting from EGFR inhibitors and assessing its correlation with treatment outcomes in large, prospective trials will help define the role of rash as a surrogate marker for efficacy of EGFR-targeted therapy.     

A Life Course Perspective on Depressive Symptoms in Mid-Pregnancy

Objective: To examine the prevalence of depressive symptoms in mid-pregnancy and their relation to life circumstances across the life course in a community-based sample. Methods: The Pregnancy Outcomes and Community Health (POUCH) Study enrolled women at 16–26 weeks' gestation from 52 clinics in five Michigan communities. At enrollment women completed a screening instrument for depressive symptoms (CES-D) and questions about life circumstances covering three “periods,” i.e. previous 6 months, adulthood, and childhood. Questions were grouped into sub-constructs (e.g., abuse, economic, substance use, loss, and legal) for each “period” and evaluated in relation to CES-D scores. Analyses included 1321 POUCH participants divided into three subgroups: teens; women ≥20 years insured by Medicaid (disadvantaged); and women ≥20 years not insured by Medicaid (advantaged). Results: A positive CES-D screen (≥16) was more common in teens (46%) and disadvantaged women (47%) than in advantaged women (23%). Recent problems (previous 6 months) with abuse, economics, and substance use in someone close were each associated with higher adjusted mean CES-D scores (2.3–7.5 increase) in the three subgroups of women. In life course analyses, abuse and substance use in teens, and abuse and economic problems in disadvantaged and advantaged women were strongly linked to higher adjusted mean CES-D scores when these problems occurred both in childhood and adulthood (range 2.2–7.1 increase), whereas the associations were more modest when problems were confined to childhood. Conclusions: Strategies for addressing the public health problem of depressive symptoms in mid-pregnancy will benefit from a life course perspective.     

"Condoms are reliable but I am not": A qualitative analysis of AIDS-related beliefs and attitudes of young heterosexual adults in Budapest, Hungary, and St. Petersburg, Russia

HIV and STD prevention is an essential component of public health initiatives in countries throughout Central and Eastern Europe. Liberalization in sexual values, declining age at first sex, higher levels of sexual activity, and inconsistent condom use have been well-documented among young people in the region following the political, economic, and cultural transitions after the end of the state socialism era. Less well-understood are the reasons for high-risk sexual behavior and psychosocial factors that must be addressed in the development of effective HIV/STD prevention programs. This study recruited members of 12 high-risk social networks of young adult men and women (n= 66 participants) in two cities, St. Petersburg, Russia, and Budapest, Hungary. In-depth focus groups were conducted with all members of each network, and qualitatively analyzed to examine factors surrounding high-risk sexual behavior. Main themes that emerged were that STDs are less known and less feared than AIDS, HIV risk factors were relatively well known among young adults in both countries but vulnerability is perceived differently, pregnancy prevention is a more immediate concern than protection from HIV or STDs, condom use declines quickly following first sex with a new partner, reintroducing condom use in a relationship is very difficult, and young adults report many barriers to condom use including those related to alcohol or other substance use. HIV/STD prevention programs are needed that extend beyond risk education alone and that also address critical psychological, social, and relationship factors related to sexual risk behavior.     

Patterns of organization and management in private and public substance abuse treatment programs

As an organizational field, substance abuse treatment clearly includes a remarkable range of organizations. Yet only in the past two decades has there been research interest in the organizational context in which treatment is delivered. The goal of this article is to promote the concept of organizational field by summarizing findings from an ongoing research program and by examining the organizational structure, service delivery, and patterns of innovation adoption in two large samples of substance abuse treatment programs in the United States. Among highlighted findings, there are notable differences between the public and private sectors in structural and staffing characteristics, as well as in the characteristics of clients receiving substance abuse treatment. With regard to the use of evidence-based practices, our findings suggest that pharmacotherapies are more likely to be adopted in private centers, whereas notably effective voucher approaches are more common in public centers. Future research directions are discussed.     

Dose-incidence relationships derived from superposition of distributions of individual susceptibility on mechanism-based dose responses for biological effects.

Dose-response relationships for incidence are based on quantal response measures. A defined effect is either present or not present in an individual. The dose-incidence curve therefore reflects differences in individual susceptibility (the "tolerance distribution"). At low dose, only the more susceptible individuals manifest the effect, while higher doses are required for more resistant individuals to be recruited into the affected fraction of the group. Here, we analyze how such dose-incidence relationships are related to mechanism-based dose-response relationships for biological effects described on a continuous scale. As an example, we use the quantal effect "cell division" triggered by occupancy of growth factor receptors (R) by a hormone or mitogenic ligand (L). The biologically effective dose (BED) is receptor occupancy (RL). The dose-BED relationship is described by the hyperbolic Michaelis-Menten function, RL/Rtot = L / (L + K(D)). For the conversion of the dose-BED relationship to a dose-cell division relationship, the dose-BED curve has to be combined with a function that describes the distribution of susceptibilities among the cells to be triggered into mitosis. We assumed a symmetrical sigmoid curve for this function, approximated by a truncated normal distribution. Because of the supralinear dose-BED relationship due to the asymptotic saturation of the Michaelis-Menten function, the composite curve that describes cell division (incidence) as a function of dose becomes skewed to the right. Logarithmic transformation of the dose axis reverses this skewing and provides a nearly perfect fit to a normal distribution in the central 95% incidence range. This observation may explain why dose-incidence relationships can often be described by a cumulative normal curve using the logarithm of the administered dose. The dominant role of the tolerance distribution for dose-incidence relationships is also illustrated with the example of a linear dose-BED relationship, using adducts to protein or DNA as the BED. Superimposed by a sigmoid distribution of individual susceptibilities, a sigmoid dose-incidence curve results. Linearity is no longer observed. We conclude that differences in susceptibility should always be considered for toxicological risk assessment and extrapolation to low dose.     

Reading ability with 3 multifocal intraocular lens models

PURPOSE: To prospectively evaluate reading performance with of 3 types of multifocal intraocular lenses (IOLs) under different lighting conditions based on reading acuity and reading speed tests. SETTING: Augenklinik, Bad Hersfeld, Germany. METHODS: This randomized study comprised 60 cataract patients (120 eyes) randomly assigned to receive an SA40N IOL (AMO) (Group 1, 20 patients), Tecnis ZM001 IOL (AMO) (Group 2, 20 patients), or AcrySof ReSTOR SA60D3 IOL (Alcon) (Group 3, 20 patients). Pupil size and reading ability at near (visual acuity, reading speed) without correction, with best distance correction, and with best near correction were assessed 6 weeks postoperatively under low-light conditions (6 cd/m(2)) and bright-light conditions (100 cd/m(2)) using the Radner Reading Charts. RESULTS: Six weeks postoperatively, there was no significant difference between groups in pupil size measured under low-light (6 cd/m(2)) or bright-light (100 cd/m(2)) conditions. When assessed under low-light conditions, near visual acuity and reading speed with or without correction were generally better in Group 2 than in Groups 1 and 3; there were no significant difference between Groups 1 and 3. Under bright-light conditions, Groups 2 and 3 performed significantly better than Group 1 and Group 2 performed better than Group 3. CONCLUSIONS: Under bright-light conditions, second-generation multifocal IOLs provided better reading performance than the Array SA40N IOL. However, when tested under low-light conditions, patients with the Tecnis ZM001 IOL had the best reading acuity and reading speed.     

Pphysical ageing of amorphous polymeric excipients II. Tracking possibilities

In the course of physical ageing of amorphous polymers, both macro- and microstructural changes occur in the materials. Volume and enthalpy relaxation can be considered as macrostructural aspects of ageing, and can be tracked by dilatometry and calorimetry, respectively. In dilatometric measurements, volume changes are usually traced back to the changes in the length of the examined materials. Among calorimetric methods, differential scanning calorimetry (DSC) is the most widely used technique for monitoring enthalpy changes. Considering microstructural aspects of polymer ageing, free volume plays a critical role in the interpretation of the experimental results. Changes in the size and distribution of the free volume holes can be tracked by spectroscopic methods like positron annihilation lifetime spectroscopy (PALS), electron spin resonance spectroscopy (ESR) and fluorescence spectroscopy. Other techniques, as the use of photochromic probes and labels or small angle X-ray scattering (SAXS) can be informative, as well. The morphological aspects of ageing, on the other hand, can be studied by scanning electron microscopy (SEM).     

The influence of staphylococcin T (StT) on the mouse fibroblasts (3T3) viability, an in vitro experiment

Staphylococcin T (StT) is a bacteriocin, which can serve as an antibiotic. The influence of StT on the mammalian cells viability should be examined before its possible applications. The aim of this work was to study the influence of StT on mouse fibroblasts viability in vitro. StT was delivered as a deposit in agar. 3T3 fibroblasts were used in viability tests. Cells were incubated with StT for 24 and 48 h. In the first controls, cells grew without the agar block, in the second controls, the agar block contained no StT. Trypan blue exclusion test was performed. Growth inhibition of sensitive strain SAU-209P was observed after 24 h incubation with cell culture medium containing StT. Antimicrobial activity of StT in culture medium was confirmed even after 2 months. The viability of 3T3 cells in the second control group was 50% lower than in the first and 25% higher than in StT treated group during the first day. It was noticed mechanical damage of growing cells caused by agar blocks. The number of cells cultured with StT was similar to that of second control group after 2 days. There were no changes in morphology of cells in all groups. It follows that StT had unimportant influence on the fibroblasts (3T3) viability in culture. StT may be considered for future animal trails.