ADAM proteases, ErbB pathways and cancer

A disintegrin and metalloproteases (ADAMs) are zinc-dependent trans-membrane metalloproteases that shed the extracellular domains of membrane-bound growth factors, cytokines and receptors. Key functions of ADAMs have emerged in ErbB signalling pathways as being sheddases for multiple ErbB ligands. As the ErbB pathway is a validated target for anti-cancer drugs, the upstream activators of ErbB ligands, their sheddases, now enter the spotlight as new drug targets in the ErbB pathway. ADAMs are involved not only in tumour cell proliferation but also in angiogenesis and metastasis. Therefore, strategies targeting ADAMs might be an important complement to existing anti-ErbB approaches.     

Evaluation of the traveling vision examiner program in the submacular surgery trials pilot study

PURPOSE: To describe methods and results and to assess the value of a Traveling Vision Examiner (TVE) Program designed to provide masked vision measurements by expert vision examiners who were independent of, and traveled to, local clinical centers. METHODS: The Submacular Surgery Trials (SST) Pilot Study was conducted to refine the design and methods for a set of multicenter, randomized clinical trials to evaluate submacular surgery in patients with subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) or ocular histoplasmosis (OHS), or idiopathic CNV in which the primary study outcome would be change in 2-year best-corrected vision from baseline. As part of the SST Pilot Study, the feasibility and value of a TVE Program was assessed. The goal of the program was to obtain unbiased vision measurements, according to a standard protocol, of best-corrected visual acuity, reading speed, and contrast threshold, of each patient at 2 and 4 years after enrollment. RESULTS: Eighty-three visits by TVEs were made to 16 centers participating in the SST Pilot Study; 239 patients had at least one masked vision examination. Comparison of pairs of vision measurements of the traveling vision examiners and local vision examiners for 71 patients made on the same day showed good agreement overall (intraclass correlation coefficient > or = 0.81). CONCLUSIONS: The proposed TVE Program was judged to be a feasible and useful method of providing standardized, unbiased, masked vision measurements. This approach was incorporated into the larger clinical trials conducted by the SST Research Group.     

Methods of pain assessment in residents of long-term care facilities: a pilot study

OBJECTIVES: Structured programs for routine pain assessment and treatment are necessary to optimize care for residents of long-term care facilities (LTCFs). A pilot study was designed to develop, implement, and evaluate a system for pain assessment and monitoring in a LTCF. Additional goals were to determine whether a verbal and/or non-verbal tool adequately assess pain in residents of LTCFs and whether the pharmacologic therapy for pain changes with the implementation of a pain assessment and monitoring system. DESIGN: Quantitative, nonexperimental design using two pain assessment tools. SETTING: The study was conducted at a LTCF in a rural midwestern setting. PARTICIPANTS: The study population for phase I included residents on any pain medication (regularly scheduled or as needed) on the secure dementia unit. The target population for phase II consisted of residents on any pain medication on an open unit. INTERVENTION: Training was provided to the nursing staff on how to use two pain assessment tools, one verbal (colored visual analog scale) and one nonverbal (observed pain target behaviors), and documentation. In addition, a continuing education program on pain assessment and management in elderly residents and barriers to pain management in LTCFs was offered to medical providers. MEASUREMENTS: Evaluation with the colored visual analog scale (CVAS) occurred twice daily. Pain target behaviors were monitored throughout the day and recorded by nursing staff at the end of each shift. All residents in the study population were monitored daily for six months. RESULTS: Most of the residents on both units were unable to use the verbal tool; however, the nonverbal tool was used successfully for all residents studied. On the dementia unit, the use of pain medications increased, and pain target behaviors decreased during the study period; on the open unit, the use of pain medications remained stable, and pain target behaviors decreased. CONCLUSION: These data suggest that an increase in awareness of pain may facilitate an improvement in the assessment and management of pain in residents of LTCFs. The feasibility of the nonverbal pain monitoring method shown in this study has positive implications on quality of care issues if generalizable to a larger population.     

Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease

Few population-based case-control studies have assessed etiologic factors for penile cancer. Past infection with high-risk human papillomavirus (HPV) is a known risk factor for penile cancer; however, few previous studies have related the HPV DNA status of the tumor to potential demographic and behavioral risk factors for the disease or evaluated whether in situ and invasive penile cancer share risk factors. Little information is available on the role and timing of circumcision in the etiology of penile cancer. We conducted a population-based case-control study in western Washington state that included 137 men diagnosed with in situ (n = 75) or invasive (n = 62) penile cancer between January 1, 1979, and December 31, 1998, and 671 control men identified through random digit dialing. Cases and controls were interviewed in person and provided peripheral blood samples. Case and control blood samples were tested for antibodies to HPV16 and HSV-2, and tumor specimens from cases were tested for HPV DNA. Men not circumcised during childhood were at increased risk of invasive (OR = 2.3, 95% CI 1.3-4.1) but not in situ (OR = 1.1, 95% CI 0.6-1.8) penile cancer. Approximately 35% of men with penile cancer who had not been circumcised in childhood reported a history of phimosis compared to 7.6% of controls (OR = 7.4, 95% CI 3.7-15.0). Penile conditions such as tear, rash and injury were associated with increased risk of disease. Among men not circumcised in childhood, phimosis was strongly associated with development of invasive penile cancer (OR = 11.4, 95% CI 5.0-25.9). When we restricted our analysis to men who did not have phimosis, the risk of invasive penile cancer associated with not having been circumcised in childhood was not elevated (OR = 0.5, 95% CI 0.1-2.5). Cigarette smoking was associated with a 4.5-fold risk (95% CI 2.0-10.1) of invasive penile cancer. HPV DNA was detected in 79.8% of tumor specimens, and 69.1% of tumors were HPV16-positive. The proportion of HPV DNA-positive tumors did not vary by any risk factors evaluated. Many risk factors were common for both in situ and invasive disease. However, 3 factors that did not increase the risk for in situ cancer proved significant risk factors for invasive penile cancer: lack of circumcision during childhood, phimosis and cigarette smoking. The high percentage of HPV DNA-positive tumors in our study is consistent with a strong association between HPV infection and the development of penile cancer regardless of circumcision status. Circumcision in early childhood may help prevent penile cancer by eliminating phimosis, a significant risk factor for the disease.     

Adolescent anorexia nervosa patients have a discrepancy between neurophysiological responses and self-reported emotional arousal to psychosocial stress

In both clinical practice and research, eating disorder patients are reported to have difficulties in identifying and describing their feelings. They are often described as being unaware of the linkage between their feelings and their behavior. The present study experimentally induced emotions in adolescent anorexia nervosa (AN) patients to examine both self-reported emotional arousal and neurophysiological responses. A group of 10 AN patients and a group of 22 healthy controls (HC) were compared with respect to changes in self-reported emotional arousal and neurophysiological responses, heart rate (HR) and HPA-axis response (cortisol in saliva) during a public speaking test inducing anxious stress. The AN group reported higher levels of anxiety, as a result of stress, but this was not reflected in their HR or cortisol response. By contrast, in the HC group higher levels of self-reported anxiety coincided with clear increases in HR and cortisol. The data indicate that AN patients, in contrast to healthy individuals, show a discordance between self-reported emotional and neurophysiological arousal during psychosocial stress.     

Mitogen- and stress-activated protein kinase 1: convergence of the ERK and p38 pathways in Alzheimer's disease

Two of the earliest manifestations of the selective neurodegeneration that occurs in Alzheimer's disease (AD) involve the oxidative modification of various biomacromolecules and the reexpression of a multitude of cell cycle-related proteins. Taken together with the proximal and ectopic increases in activated components of the ERK and p38 pathways, involved in mitotic and cellular stress signaling, respectively, there is a clear and important role for mitotic and oxidative insults in the pathogenesis of AD. Despite the mounting evidence, however, for the causal role of mitogenic abnormalities and oxidative stress in AD pathogenesis, the effect of the converging relevant pathways due to chronic stimulation in AD remains largely unknown. To delineate further the mechanism by which mitogenic and stress signaling cascades converge, we focused on one of the downstream effectors of activated ERK and p38, mitogen- and stress-activated kinase 1 (MSK1). Activated MSK1, phosphorylated at residues Ser376 and Thr581, was upregulated in vulnerable neurons in AD when compared to that in age-matched controls, whereas MSK1 phosphorylated at residue Ser360 was not increased in AD. Furthermore, activated MSK1 phosphorylated at Thr581 colocalized strongly with activated p38 but only weakly with activated ERK, whereas MSK1 phosphorylated at Ser376 colocalized strongly with activated ERK but only weakly with activated p38, suggesting potential preferential phosphorylation sites for the two upstream effectors.