Antiangiogenic treatment with thrombospondin-1 enhances primary tumor radiation response and prevents growth of dormant pulmonary micrometastases after curative radiation therapy in human melanoma xenografts

Thrombospondin-1 (TSP-1) is a potent antiangiogenic factor that has been shown to inhibit tumor growth by preventing endothelial cells from responding to a wide variety of angiogenic stimulators. We have demonstrated previously that D-12 primary tumors (human melanoma xenografts) suppress the growth of their spontaneous pulmonary micrometastases by secreting TSP-1 into the blood circulation. The same tumor model was used in the present work to study antitumor effects of combined radiation therapy and antiangiogenic treatment with TSP-1. Curative radiation treatment of D-12 primary tumors resulted in rapid growth of previously dormant micrometastases. Growth of dormant micrometastases could be prevented by treating the host mice with exogenous TSP-1 after the radiation treatment. Treatment with exogenous TSP-1 after subcurative radiation treatment reduced the growth rate of recurrent primary tumors in addition to suppressing metastatic growth. TSP-1 suppressed tumor growth at both primary and metastatic sites by inducing apoptosis in tumor-associated microvascular endothelial cells. Treatment with exogenous TSP-1 before radiation treatment enhanced the antitumor effect of the radiation treatment. The radiopotentiation by TSP-1 involved at least two distinctly different mechanisms, i.e., TSP-1 reduced the fraction of radiobiologically hypoxic parenchymal tumor cells and increased the radiation sensitivity of the tumor microvasculature by promoting radiation-induced endothelial cell apoptosis. In conclusion, the present preclinical study showed that TSP-1 has antiangiogenic, antimetastatic, and radiopotentiating properties that merit additional investigation in clinical studies.     

Role of arterial smooth muscle tone and geometry in the regulation of peripheral conduit artery mechanics by shear stress

1. Although arterial blood flow is recognized as an important modulator of vascular tone and geometry, the effect of acute changes in shear-stress on conduit artery mechanics has not been fully investigated in humans because of technical limitations. 2. To assess, respectively, the effects of decreases and increases in flow and shear stress on radial artery tone and mechanics, arterial pressure (photoplethysmography), total blood viscosity, radial artery internal diameter, wall thickness (echotracking) and blood flow (Doppler) were measured in healthy volunteers (mean (+/-SEM) age 25 +/- 1 years) during a distal flow arrest (n=12) and hand skin heating (n=18). 3. Radial artery flow decreased from 31 +/- 4 to 7 +/- 1 10(-3) L/min during distal flow arrest (P < 0.001) and increased from 10 +/- 2 to 22 +/- 4 and 69 +/- 6 10(-3) L/min during heating (P < 0.001). At mean arterial pressure, these changes in flow were respectively associated with a parallel flow-dependent reduction and increase in diameter and midwall stress. There was no significant modification in mean elastic modulus. Compliance did not change when flow decreased and only increased at the highest level of flow. Finally, the cross-sectional compliance and incremental modulus were fitted as functions of midwall stress. The decrease in flow was associated with an upward shift of the modulus-midwall stress curve and a downward shift of the compliance-midwall stress curve. The increase in flow was associated with a downward shift of the modulus-midwall stress curve and an upward shift of the compliance-midwall stress curve at each level of wall shear stress. 4. By using two different procedures, we obtained similar results concerning the direct effects of increases and decreases in flow on stiffness of the arterial wall and on arterial compliance and demonstrated the presence of a flow-dependent regulation of arterial smooth muscle tone of peripheral conduit arteries in humans.     

Relation between diagnoses on severity, sick leave and loss of job among patients with occupational hand eczema

BACKGROUND: Epidemiological studies indicate that occupational hand eczema (OHE) often is associated with persistent dermatitis and prolonged sick leave, which may lead to unemployment. Previous studies suggest that OHE caused by allergic contact dermatitis and atopic dermatitis (AD) carries the worst prognosis. OBJECTIVES: To evaluate and compare the severity and consequences of recognized OHE in different diagnostic and subdiagnostic groups. METHODS: Between October 2001 and November 2002, all new cases of recognized OHE were identified from the Danish National Board of Industrial Injuries Registry (758 cases). Severity was graded from 0 to 2 depending on the intensity of skin response and the frequency of relapse. To supplement the information from the Registry, we surveyed the study population using a postal questionnaire which included questions about disease duration, sick leave, current occupation and loss of job. RESULTS: The overall response rate to the questionnaire was 82%. We observed substantially greater severity among those with occupational irritant contact dermatitis (ICD) and AD than for any other diagnoses. Age above 50 years was also associated with increased severity of OHE. Prolonged sick leave due to OHE was reported by 19.9% and was associated with AD and severe OHE. We found a higher proportion of prolonged sick leave among those in food-related occupations (27.2%) compared with those in wet occupations (20.1%) and other occupations (16.5%). Twenty-three per cent reported that they had lost their job at least once during the past 12 months due to OHE. The only strong association with loss of job was food-related occupations. CONCLUSIONS: Occupational ICD and AD appear to be strongly associated with severity of OHE. AD and severity of OHE were independently associated with prolonged sick leave. Having a food-related occupation appears to be associated with increased risk of loss of job.     

Effects of G-CSF on telomere lengths in PBMCs from human immunodeficiency virus-infected patients: results from a randomized, placebo-controlled trial

Telomeres are unique terminal chromosomal structures, the length of which has been shown to decrease with cell division in vitro and with increased age in vivo for human somatic cells. In human immunodeficiency virus (HIV)‐1 infection, decrease of telomere length is primarily found in CD8⁺ T cells, and not in CD4⁺ T cells. In this double‐blind placebo‐controlled study, we investigated the effect of granulocyte colony stimulating factor (G‐CSF) treatment combined with highly active antiretroviral therapy (HAART) on mean telomere length in peripheral blood mononuclear cells (PBMC). The terminal restriction fragment (TRF) length showed no changes during G‐CSF treatment although the number of lymphocytes increased significantly. The mean TRF length correlated positively (R = 0.552, P = 0.009) and negatively (R = ?0.503, P = 0.02) to the proportion of CD4⁺ memory and naïve cells, respectively. Our data suggest that during G‐CSF treatment lymphocytes are recruited by a combination of central and peripheral proliferation.     

Diabetic patients treated with dialysis: complications and quality of life

Aims/hypothesis The aim of this study was to describe the prevalence of complications, health-related quality of life (HRQOL) and the influence of beliefs about control over health in diabetic dialysis patients. Methods Of 53 eligible diabetic patients on chronic dialysis during January 2004 in our clinic, 38 (76%) completed a kidney-specific (Kidney Disease Quality of Life) and a generic (SF-36) questionnaire and were characterised in terms of cardiovascular diseases and diabetic complications. Matched groups of non-diabetic dialysis patients (n = 40) and diabetic patients with a long duration of diabetes and normal kidney function (n = 38) served as controls. Generic HRQOL was compared with matched data from a survey on the Danish general population (n = 2248). Results Micro- and macrovascular complications were significantly more frequent in diabetic dialysis patients than in diabetic patients without renal disease. Self-rated physical health was significantly worse (p < 0.01) in diabetic dialysis patients (35 ± 9 [mean ± SD]) compared with non-diabetic dialysis patients (41 ± 10), diabetic patients with normal kidney function (45 ± 12) and the matched general population (47 ± 19). The diabetic dialysis patients had similar levels of kidney-specific quality of life and mental health compared with the control groups. Reduced physical health was predicted by the presence of end-stage renal disease, diabetes and short time spent in education. Among the diabetic patients, those who believed more on their own ability to control their diabetes and less on chance reported better mental health and were less likely to be on dialysis. Conclusions/interpretations Diabetic dialysis patients are characterised by a high prevalence of diabetic complications, reduced self-rated physical health but relatively good mental health. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Social Normative Perceptions of Alcohol Use and Episodic Heavy Drinking Among Central and Eastern European Adolescents

This study examined alcohol use and related social normative perceptions among a sample of 1,886 Central-Eastern European high school students. The youth represented in the study averaged 16.5 years of age and were from several localities in the countries of Hungary, Slovakia, Czech Republic, and Romania. Data for the study were collected through a school-based alcohol use survey that was completed in June 2005. Our results support the hypothesis that drinking was related to perception of the prevalence of alcohol use by schoolmates and by the number of friends who drink and/or engage in episodic heavy drinking. Specific implications of findings in terms of substance use prevention are discussed. In addition, the need for future research and the limitations of the current research are discussed. This study was largely financially supported through an international grant from the College of Health and Human Performance, Brigham Young University.     

The role of hypertension in the development of nephropathy in type 1 (insulin-dependent) diabetes mellitus

Summary Which comes first when developing clinical diabetic nephropathy, the blood pressure rise or the increasing urinary albumin excretion? This issue is discussed based on recent literature of studies in humans with Type 1 (insulin-dependent) diabetes mellitus. We conclude that hypertension has a central role in the progression of diabetic nephropathy and has deleterious effects on the life expectancy of patients who already have signs of diabetic renal disease in terms of elevated urinary albumin excretion. However, blood pressure is preceded by small increments of urinary albumin excretion rates, an indicator of a universally increased vascular leakiness, and thus does not seem to be the cause of diabetic nephropathy.     

Carrier rate of resistant enterococci in a tertiary care hospital in Norway.

The prevalence of resistant enterococci varies geographically. In the present study we looked at the carrier rate of resistant enterococci in the hematology and gastrointestinal surgery units of a tertiary care hospital in Norway. Anal swabs were taken from all 82 hospitalized patients on 4 different dates, at least 4 weeks apart, in 1995. 51% had positive cultures for enterococci. 6% of all patients carried enterococci resistant to ampicillin. 7% carried enterococci with high-level gentamicin resistance. Two strains resistant to vancomycin were found, including the first vanA Enterococcus faecium isolated in a Norwegian hospital. There was a correlation between use of antibiotics and being a carrier of enterococci per se, but the correlation with resistant enterococci did not reach statistical significance owing to the small number of isolates. The carrier rates both for presence of enterococci and for resistant enterococci were generally lower than those found in other studies.     

HLA or HLA-linked genes reduce birthweight in families affected by idiopathc recurrent abortion

HLA typing was performed in 49 families, each containing at least one woman with a history of unexplained recurrent spontaneous abortion (RSA), and reproductive histories were recorded for the siblings. Abortion rate in sisters sharing two HLA haplotypes with the proband was significantly (p less than 0.01) increased, whereas abortion rates of brothers' wives seemed independent of the brothers' degree of HLA sharing with the proband. Birthweights of offspring of both the sisters and the brothers decreased with increasing HLA haplotype identity between the sibling and the proband (p = 0.05). The mean birthweight of infants of siblings sharing both parental haplotypes with the proband was 3158 g which was significantly (p less than 0.02) less than the average birthweight in Denmark (3417 g). Significantly (p less than 0.05) decreased mean birthweight in infants of brothers who were HLA-identical with the proband suggested that the disposition to growth retardation could be inherited with HLA also through the male gametes. It has been shown that, in their few successful pregnancies, women with RSA bear infants with a birthweight which is approximately 300 g less than normal. The present study demonstrated that the two obstetrical conditions, RSA and retarded fetal growth, share common genetic markers: HLA. It is suggested that HLA or HLA-linked genes causing growth retardation in fetuses are part of the putative complex of genes involved in the pathogenesis of recurrent abortion.