Economic evidence for nonpharmacological asthma management interventions: A systematic review.

Asthma management, education and environmental interventions have been reported as cost-effective in a previous review (Pharm Pract (Granada), 2014;12:493), but methods used to estimate costs and outcomes were not discussed in detail. This review updates the previous review by providing economic evidence on the cost-effectiveness of studies identified after 2012, and a detailed assessment of the methods used in all identified studies. Twelve databases were searched from 1990 to January 2016, and studies included economic evaluations, asthma subjects and nonpharmacological interventions written in English. Sixty-four studies were included. Of these, 15 were found in addition to the earlier review; 53% were rated fair in quality and 47% high. Education and self-management interventions were the most cost-effective, in line with the earlier review. Self-reporting was the most common method used to gather resource-use data, accompanied by bottom-up approaches to estimate costs. Main outcome measures were asthma-related hospitalizations (69%), quality of life (41%) and utility (38%), with AQLQ and the EQ-5D being the most common questionnaires measured prospectively at fixed time points. More rigorous costing methods are needed with a more common quality of life tool to aid greater replicability and comparability amongst asthma studies.

Lower white blood cell counts in elite athletes training for highly aerobic sports.

White cell counts at rest might be lower in athletes participating in selected endurance-type sports. Here, we analysed blood tests of elite athletes collected over a 10-year period. Reference ranges were established for 14 female and 14 male sports involving 3,679 samples from 937 females and 4,654 samples from 1,310 males. Total white blood cell counts and counts of neutrophils, lymphocytes and monocytes were quantified. Each sport was scaled (1-5) for its perceived metabolic stress (aerobic-anaerobic) and mechanical stress (concentric-eccentric) by 13 sports physiologists. Substantially lower total white cell and neutrophil counts were observed in aerobic sports of cycling and triathlon (~16% of test results below the normal reference range) compared with team or skill-based sports such as water polo, cricket and volleyball. Mechanical stress of sports had less effect on the distribution of cell counts. The lower white cell counts in athletes in aerobic sports probably represent an adaptive response, not underlying pathology.

A novel tactile sensation measurement system for qualifying touch perception.

The feel of films, wrapping paper, cardboards, and other packaging materials are important to the commercial success of foods. It is known from people's self-report studies that different surfaces provoke different subjective responses. There are several mechanical parameters, including friction, roughness, compliance, and thermal properties, which are important to the sensory feel. This paper describes the design, construction, and use of a multisensory measurement system for tactile sensation that can be used to evaluate the feel of different packaging materials. The experiments were conducted by sliding or pressing an artificial fingertip with embedded sensors against the surfaces of different samples which were fixed on a force table. The roughness, friction coefficients, compliance, and rate of change in the temperature were obtained. Forty volunteers were asked to touch and rate the samples by filling in questionnaires about how they felt. Strong correlations were found between people's feelings and the physical measurements.

Biomarkers of thrombosis, fibrinolysis, and inflammation in patients with severe sepsis due to community-acquired pneumonia with and without Streptococcus pneumoniae.

BACKGROUND: Severe Streptococcus pneumoniae (S. pneum) pneumonia has historically been associated with an acute presentation and increased mortality. Using data from patients with community-acquired pneumonia (CAP) and severe sepsis, we investigated: (1) the baseline patient characteristics and biomarkers of thrombosis, fibrinolysis, and inflammation in patients with CAP due to S. pneum infection (S. pneum CAP) or CAP due to infection with other or unidentified organisms (non-S. pneum CAP); (2) the behavior of these biomarkers over time and during treatment with drotrecogin alfa (activated) (DrotAA, recombinant activated protein C). PATIENTS AND METHODS: Data from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation on Severe Sepsis) trial were retrospectively analyzed by treatment (DrotAA or placebo) in patients with CAP. RESULTS: Patients with S. pneum CAP (n = 157) tended to be younger and had fewer comorbid conditions than patients with non-S. pneum CAP (n = 445). Overall disease severity (median APACHE II scores) was not significantly different between the two groups at baseline. However, there were significant baseline differences in protein C and markers of coagulation, fibrinolysis, and inflammation. Although thrombosis markers were not different at baseline, D-dimer levels significantly increased from baseline to day 4 in placebo-treated patients with S. pneum compared to those with non-S. pneum. DrotAA treatment was associated with statistically significant improvements in protein C and markers of thrombosis in patients with S. pneum. In addition, the proportion of patients with severe protein C deficiency (

Novel estrogen receptor coregulators and signaling molecules in human diseases.

The steroid hormone estrogen and signaling from its receptors are increasingly recognized as critical mediators of a variety of organ-specific biological processes. Recent advances in the identification and functional characterization of novel estrogen receptor interacting proteins clearly show the complexity of hormonal signaling regulation, but may also contribute to our understanding of the roles of estrogen signaling in normal physiology and the pathobiology of human disease.

Growth factor regulation of the molecular chaperone calnexin.

Heregulin-beta1 (HRG) is a regulatory polypeptide having several distinct biological effects in mammary epithelial cells. To address the hypothesis that HRG selectively regulates gene expression, we performed differential display screening using cells grown in the presence or absence of HRG. One cDNA clone upregulated by HRG was identical to human calnexin, a protein with molecular chaperone function. This is the first demonstration of the regulation of calnexin mRNA and protein expression by a physiologically relevant polypeptide factor in human breast cancer cells. HRG stimulation also caused a rapid redistribution of calnexin from vesicle-like structures in the cell cytoplasm to the perinuclear area and to the cell membrane. Furthermore, HRG induced colocalization and physical interaction of calnexin with the HER2 growth factor receptor. Finally, calnexin protein levels were increased in progressive stages of human breast cancer. These findings suggest that stimulation of calnexin expression by HRG may constitute a mechanism of protein redistribution and facilitate downstream signaling events in growth-factor-activated cells.

The effects of age, sex, and shoulder dominance on range of motion of the shoulder.

To determine the effects of age, sex, and arm dominance on shoulder range of motion, we measured active and passive forward elevation, abduction, internal and external rotation at 90 degrees of abduction, external rotation with the arm adducted, and extension bilaterally in 280 subjects ranging in age from 4 to 70 years. Linear regression analyses were performed for all motions except forward elevation. This motion, which showed a nonlinear pattern of decline with age, was evaluated with 3-way analysis of variance. Shoulder range of motion decreased with age for all measured motions with the exception of internal rotation, which increased with age. Female subjects had a significantly greater range of motion than male subjects for all motions measured. Dominant arms displayed significantly greater external rotation than nondominant, regardless of whether the arm was abducted or adducted at the time of measurement. However, nondominant shoulders demonstrated significantly greater internal rotation and extension than dominant. No significant differences were found between dominant and nondominant sides for forward elevation or abduction.

Ethnic differences in the effect of parenting on gang involvement and gang delinquency: a longitudinal, hierarchical linear modeling perspective.

This study examined the relative influence of peer and parenting behavior on changes in adolescent gang involvement and gang-related delinquency. An ethnically diverse sample of 300 ninth-grade students was recruited and assessed on eight occasions during the school year. Analyses were conducted using hierarchical linear modeling. Results indicated that, in general, adolescents decreased their level of gang involvement over the course of the school year, whereas the average level of gang delinquency remained constant over time. As predicted, adolescent gang involvement and gang-related delinquency were most strongly predicted by peer gang involvement and peer gang delinquency, respectively. Nevertheless, parenting behavior continued to significantly predict change in both gang involvement and gang delinquency, even after controlling for peer behavior. A significant interaction between parenting and ethnic and cultural heritage found the effect of parenting to be particularly salient for Black students, for whom higher levels of behavioral control and lower levels of lax parental control were related to better behavioral outcomes over time, whereas higher levels of psychological control predicted worse behavioral outcomes.

Knuckle pads: does knuckle cracking play an etiologic role?

Very little has been published on knuckle pads and the cosmetic and psychological effects they can have. In children, most knuckle pads are considered to be idiopathic; however, familial cases as well as those caused by trauma have been described. We report a 14-year-old African American girl with a 3-year history of slowly enlarging hyperkeratotic nodules over multiple finger joints and on the lateral aspects of several fingers. These lesions were initially confined to the patient's left hand but subsequently involved the right hand. The patient and her mother denied any unusual hobbies or sports in which the patient's fingers might be traumatized. The patient, however, was noted to crack her knuckles during her clinic visit. To the mother's surprise, the patient admitted to doing this quite frequently on a daily basis. A diagnosis of knuckle pads was made and confirmed histologically. To our knowledge, this is the first reported case of knuckle pads with cracking of the knuckles as the possible etiology.

Inactivation of germline mutant APC alleles by attenuated somatic mutations: a molecular genetic mechanism for attenuated familial adenomatous polyposis.

Germline mutations of the adenomatous polyposis coli (APC) tumor-suppressor gene result in familial adenomatous polyposis (FAP). Patients with FAP typically develop hundreds to thousands of benign colorectal tumors and early-onset colorectal cancer. A subset of germline APC mutations results in an attenuated FAP (AFAP) phenotype, in which patients develop fewer tumors and develop them at an older age. Although a genotype-phenotype correlation between the locations of APC germline mutations and the development of AFAP has been well documented, the mechanism for AFAP has not been well defined. We investigated the mechanism for AFAP in patients carrying a mutant APC allele (APC(AS9)) that has a mutation in the alternatively spliced region of exon 9. APC(AS9) was found to down-regulate beta-catenin-regulated transcription, the major tumor-suppressor function of APC, as did the wild-type APC. Mutation analysis showed that both APC(AS9) and the wild-type APC alleles were somatically mutated in most colorectal tumors from these patients. Functional analysis showed that 4666insA, a common somatic mutation in APC(AS9) in these tumors, did not inactivate the wild-type APC. Our results indicate that carriers of APC(AS9) develop fewer colorectal tumors than do typical patients with FAP because somatic inactivation of both APC alleles is necessary for colorectal tumorigenesis. However, these patients develop colorectal tumors more frequently than does the general population because APC(AS9) is inactivated by mutations that do not inactivate the wild-type APC.

Effect of aging and dietary restriction on rat testicular germ cell apoptosis.

The purpose of this study was to determine whether apoptotic cell death of rat testicular germ cells varies with increased age or with dietary restriction. Slide-mounted cross-sections of formalin-fixed testis from 4-, 13-, and 23-month-old ad-libitum-fed and 40% dietary-restricted male F344 rats were used in an in situ assay for apoptotic germ cells. Results show that in ad-libitum-fed rats, increased age caused a significant increase in the percentage of seminiferous tubules containing apoptotic cells, but a significant decrease in the number of apoptotic cells per apoptosis-positive tubule. In the 23-month-old rats, dietary restriction significantly increased both the percentage of apoptotic positive tubules and the number of apoptotic cells per apoptosis-positive tubule above ad-libitum-fed values. Both ad-libitum and diet-restricted groups demonstrated a decrease in the percentage of apoptotic spermatogonia concomitant with a significant increase in the percentage of apoptotic primary spermatocytes with advanced age. The significant age-related increase in total numbers of apoptotic germ cells may reflect elimination of defective germ cells, which occurs with increased frequency in advanced age. Dietary restriction may induce enhanced screening against defective germ cells above that seen in the ad-libitum-fed rats. These results have potential implications in aging studies as well as research involving perturbation of normal germ cell homeostasis.

Determination of an optimal dosing regimen for aspirin chemoprevention of 1,2-dimethylhydrazine-induced colon tumours in rats.

In order to establish an optimal timing and duration of aspirin treatment in the chemoprevention of 1,2-dimethylhydrazine (DMH)-induced colon cancer in rats, colon tumours were induced using an established protocol and aspirin was given in the diet at 500 p.p.m. during various stages of colon carcinogenesis. Results indicate that only aspirin treatment throughout the entire carcinogenic period significantly reduced tumour incidence and volume whereas intermittent aspirin dosing increased tumour number and/or volume, suggesting that aspirin must be used for an extended period in order to gain any chemopreventive benefit.

Effect of aspirin on prostaglandin E2 formation and transforming growth factor alpha expression in human rectal mucosa from individuals with a history of adenomatous polyps of the colon.

Colorectal cancer is the second-most frequent cause of cancer mortality in the United States. Human epidemiology and laboratory studies indicate that aspirin may be an effective colorectal cancer chemopreventive agent. This study was designed to determine whether treatment with 81 mg of aspirin per day for 3 months would alter two putative surrogate end point biomarkers of chemoprevention of colorectal cancer [i.e., mucosal prostaglandin E2 (PGE2) formation and transforming growth factor alpha (TGF-alpha) expression] in normal-appearing rectal mucosa from individuals with a history of adenomatous polyps. Rectal biopsies were obtained by flexible sigmoidoscopy at three sequential time points: (a) after a 1-month placebo run-in period (baseline), (b) after 3 months of ingesting 81 mg of aspirin (as a single tablet) once per day, and (c) after 3 months of ingesting a placebo tablet once per day (washout period). Daily aspirin significantly suppressed PGE2 formation, but this significant suppression was completely reversed when aspirin was withdrawn. The extent of TGF-alpha staining in rectal crypts was also reduced significantly (P = 0.039) by daily aspirin. After a 3-month placebo-washout period, however, the mean extent of TGF-alpha staining was not significantly different from either baseline or the aspirin time point. Thus, 81 mg of aspirin daily significantly reduced rectal mucosal PGE2 formation and TGF-alpha expression in patients with a history of adenomatous polyps. These putative surrogate end point biomarkers may be useful intermediate end points in future colorectal cancer chemoprevention trials.

Presence of well-differentiated distal, but not poorly differentiated proximal, rat colon carcinomas is correlated with increased cell proliferation in and lengthening of colon crypts.

To determine whether colon crypt proliferative parameters were significantly altered by the stage of colon carcinogenesis or the type or location of colon tumors in rats, male Sprague-Dawley rats received an injection of the carcinogen 1,2-dimethylhydrazine (12 mg DMH base/kg body weight) or DMH vehicle once a week for 8 weeks, then were killed 24 weeks later. Three hours before sacrifice, rats were injected with 1 mg/kg body weight colchicine to arrest mitotic cells at metaphase. Transverse sections of the colon mucosa were taken 6 cm from the anus and at least 3 cm from any tumor, fixed in formalin, then stained with hematoxylin & eosin (H&E) for analyses of proliferative parameters. Only complete, mid-axial crypts were scored for mitotic count (MC), crypt proliferative zone (PZ) height and crypt height (CH). Serial tumor sections were stained with H&E for histological evaluation or used in immunohistochemical detection of transforming growth factor alpha (TGF alpha). DMH treatment significantly increased MC, PZ and CH regardless of tumor status. The PZ and CH of rats with a carcinoma located in the distal colon were significantly increased compared with DMH-treated rats without an adenocarcinoma (AC) or with rats which had a tumor located in the proximal colon. Distal colon ACs were found to be well differentiated and to have greater TGF alpha immunoreactivity than the generally less differentiated proximal colon carcinomas. Distal colon AC production and systemic circulation of a soluble colon crypt stimulating factor such as TGF alpha may explain the significant increase in PZ and CH in histologically normal colonic mucosa located away from the tumor.

Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin.

BACKGROUND & AIMS: Colorectal cancer is a significant source of morbidity and mortality in the United States and other Western countries. Epidemiological and experimental data indicate that regular use of aspirin reduces colon cancer risk. This study was designed to determine if aspirin would significantly inhibit gastrointestinal tumor formation in a mouse model of familial adenomatous polyposis. METHODS: Six-week-old male and female C57BL/6J +/+ (control) and C57BL/6J ApcMin/+ (Min) mice were fed either a control AIN-76A diet or one supplemented with 250 or 500 parts per million (ppm) aspirin (n = 6 per group) for 7 weeks. RESULTS: All of the Min mice, but no control mice, developed gastrointestinal tumors. Aspirin significantly reduced tumor multiplicity (number of tumors per mouse) in the small intestine, but not the colon, from an average of 35.8 tumors per mouse (control diet) to 16 and 18.5 tumors per mouse with 250 and 500 ppm aspirin, respectively. Total tumor load (sum of tumor diameters per mouse) was also significantly reduced, from 93.2 mm in total diameter to 40. 4 and 45.0 mm with 250 and 500 ppm aspirin, respectively. Results were not significantly different because of sex or aspirin dose. CONCLUSIONS: High doses of aspirin are effective chemopreventive agents in a mouse model of spontaneous intestinal tumor formation.

Non-steroidol anti-inflammatory drug effect on crypt cell proliferation and apoptosis during initiation of rat colon carcinogenesis.

Sustained use of non-steroidal anti-inflammatory drugs (NSAIDs) may prevent colorectal cancer. However, the optimal drug, period of efficacy and mechanism(s) of action are unknown. Experiments were undertaken to determine which of several NSAIDs would modulate colon crypt cell proliferation or apoptosis when given during the initiation phase of 1,2-dimethylhydrazine (DMH)-induced rat colon cancer. Colon crypts located both away from and over an aggregate of lymphoid nodules (ALN) were examined. Rats were injected with aspirin, indomethacin, nabumetone, sodium salicylate, 16,16-dimethyl prostaglandin E2 or saline for 3 days and DMH or DMH vehicle on day 4 of each week for 8 weeks, then killed 3 days after the last DMH injection. At the time of killing, DMH had significantly increased crypt cell proliferation but not apoptosis. There was significantly more cell proliferation and apoptosis in crypts over the ALN than away from the ALN. Aspirin and salicylate increased proliferation and apoptosis in crypts over the ALN. Finally, the distributional peaks of cell proliferation and apoptosis were shifted significantly closer together after DMH. Thus, DMH increases proliferation and alters the distribution of proliferating and apoptotic cells in colon crypts early in carcinogenesis. Aspirin may suppress tumour incidence via salicylate by enhancing apoptosis in carcinogen-initiated cells.

Age-dependent sensitization to oxidative stress by dietary fatty acids.

Experiments were designed to test the hypothesis that short-term feeding of a high polyunsaturated fatty acid (PUFA) diet would increase susceptibility to lipid peroxidation in an age-dependent manner. Young (6 month) and old (24 month) male B6C3F1 mice were fed modified AIN-76 diets containing either 5% corn oil (CO, N = 5 per age group) or 19% fish oil plus 1% corn oil (FO, N = 20 per age group) for two weeks. Five CO and five FO diet mice per age received an intraperitoneal injection of normal saline and were sacrificed one hour later; the remaining FO diet mice (N = 15 per age) were challenged with an acute systemic oxidative stress by intraperitoneal injection of 125 mg iron/kg body weight as iron dextran, and were sacrificed 1, 5, and 24 hours post-injection. Microsomal membrane fatty acid analysis revealed that increased age and a FO diet significantly increased membrane PUFA content. Serum iron levels increased significantly following iron treatment, peaking at 5 hours in both age groups. Formation of microsomal malondialdehyde (MDA), a product of lipid peroxidation, was significantly greater in the livers of the young mice. The temporal patterns of serum iron and microsomal MDA concentrations were significantly correlated in young mice, but not in old mice. Histochemical examination showed that liver iron accumulation following iron injection was similar in both age groups, but was associated with a significant temporal increase in liver apoptotic cells in young mice, but not in old mice. Thus, both age groups had similar iron exposure and iron accumulation, and the liver microsomal membranes of old mice were more unsaturated, yet there was significantly greater peroxidative damage (MDA formation) and cell death (apoptosis) in the young mouse livers. These findings suggest that the older animals have upregulated antioxidant defenses.

Effect of aging on spontaneous and induced mouse testicular germ cell apoptosis.

The purpose of this study was to determine whether apoptotic cell death of mouse testicular germ cells varies with increased age, or with exposure to an acute systemic oxidative stress. Results show that the percent of seminiferous tubules with apoptotic cells, and the number of apoptotic cells/tubule cross section were not significantly altered with age. However, there were significantly more apoptotic metaphase spermatocytes at tubule stage XIV in 24-month-old mice than in 6-month-old mice. Oxidative stress significantly increased apoptotic metaphase spermatocytes in young mice, and severely reduced testicular apoptosis in old mice. Our results have potential clinical relevance to changes with increased age in human sperm aneuploidies.

Age alters expression and inducibility of heme oxygenase isozymes in mice.

Heme oxygenase (HO) performs the rate limiting step in heme degradation and is induced by cell injury or stress. We wished to determine if dietary fatty acid composition, increased age and/or an induced oxidative stress would alter the expression of HO-1 (constitutive and inducible isozyme) or of HO-2 (constitutive isozyme), in mouse liver, spleen and brain. Six-and 24-month-old male B6C3F1 mice were fed AIN-76A diets containing either 5% corn oil (CO, moderately unsaturated, n=5 per age group) or 19% menhaden fish oil plus 1% corn oil (FO, highly polyunsaturated, n=20 per age group). After 2 weeks, 5 CO and 5 FO fed mice in each age group were sacrificed. The remaining FO diet mice (n=15 per age group) were then challenged with a systemic oxidative stress by intraperitoneal injection of 125 mg iron/kg body weight as iron dextran. Five stressed mice from each age group were sacrificed 1, 5, and 24 hours post injection; liver, spleen and brain were removed. Part of each tissue was fixed in formalin, and microsomal protein isolated from the remaining tissue. HO-1 and HO-2 were detected by immunoblot of microsomal protein and by immunohistochemical staining of fixed tissue in the liver and spleen, but only HO-2 was detected in the brain. There was no significant difference in HO-1 or HO-2 expression due to diet. The liver of old unstressed mice had significantly more HO-1 than young mice. However, HO-1 was significantly induced in the livers of young mice, but not of old mice, following oxidative stress. Spleen HO-1 expression was not significantly altered by age or oxidative stress. HO-2 expression was not significantly altered by age or induced oxidative stress in any tissue examined. Age-related alterations in liver HO-1 isozyme expression and inducibility may contribute to increased susceptibility to exogenous stress and disease.