Flavonol and Flavone Intake and the Risk of Intermittent Claudication in Male Smokers

The objective of this study was to investigate the association between flavonol and flavone intake and the risk of intermittent claudication in male smokers. The study population consisted of participants of the Finnish alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) Study, who were free of intermittent claudication at study entry. These 25,041 male smokers were 50-69 years old at baseline. Participants completed a validated dietary questionnaire at baseline. The occurrence of intermittent claudication was assessed by annual administration of the Rose questionnaire. During the median follow-up of 4.1 years, 2412 new cases of intermittent claudication were observed. Dietary intake of flavonols and flavones was inversely associated with the risk of intermittent claudication when adjusted for cardiovascular risk factors (relative risk, RR in the highest vs. lowest quintile of intake 0.86, 95% confidence interval, CI: 0.75-0.98, p for trend 0.007). However, after further adjustment for intakes of vitamins C and E and total carotenoids, the association was attenuated (RR: 0.93, 95% CI: 0.81-1.08, p for trend 0.12). The risk of intermittent claudication was lower among men in the highest quintile of vegetable consumption (RR: 0.78, 95% CI: 0.69-0.89, p for trend 0.0001) and among wine drinkers (RR: 0.63, 95% CI: 0.41-0.98). Adjustment for flavonol and flavone intake only marginally changed these associations. In conclusion, flavonol and flavone intake was not independently associated with the risk of intermittent claudication.     

Cancer cells as targets for lentivirus-mediated gene transfer and gene therapy

Lentiviruses have been used as gene transfer vectors for almost 10 years and their utility has been demonstrated in a variety of different applications. However, their value in cancer gene therapy has not been studied thoroughly. Here we show that VSV-G pseudotyped HIV-1-based lentiviruses are efficient vectors for human tumor cells in vitro and in vivo. Lentiviral gene transfer efficiency was demonstrated by transducing 42 different cell lines, representing 10 different human tumor types. It was shown that most of the cell lines were good or excellent targets for lentiviral transduction, allowing 50-95% gene transfer efficiency. These results were comparable to those obtained with an E1/E3 deleted, serotype 5 adenovirus vector. Analysis of lentivirus vector structure revealed that virus particles devoid of HIV-1 accessory proteins appeared to be more efficient, but the presence of enhancing elements cPPT and WPRE did not play a major role in transduction efficiency to four different human tumor cell lines. However, their effect on the gene expression level in these cells was apparent. To examine the impact of lentiviral gene expression level on suicide gene therapy approach, human osteosarcoma cells were transduced with lentivirus- or adenovirus vectors carrying the fusion gene HSV-TK-GFP and exposed to ganciclovir. Cell viability analysis after the treatment revealed that both vector types induced similar level of cytotoxicity, suggesting that lentiviral expression of a suicide gene is adequate for tumor cell destruction. Finally, in vivo transduction studies with subcutaneous tumors showed that lentivirus vectors can yield similar gene transfer efficiency than adenovirus vector, despite three orders of magnitude lower titer of the lentiviral preparation. In conclusion, these data show that lentiviruses are efficient gene transfer vehicles for human tumor cells and justify their use in further preclinical cancer gene therapy studies.     

Asphyxia aggravates systemic hypotension but not pulmonary hypertension in piglets with meconium aspiration

Meconium aspiration and birth asphyxia are both separately connected to significant pulmonary and systemic hemodynamic changes in newborns, but, although these insults frequently coexist, their combined effects on the neonatal circulation are still controversial. To determine the pulmonary and systemic circulatory changes induced by pulmonary meconium contamination with concurrent asphyxia, 41 anesthetized and ventilated newborn piglets (10-12 d) were studied for 6 h. Eleven piglets were instilled with a bolus of human meconium intratracheally, and 10 piglets had meconium instillation with immediate induction of an asphyxic insult. Eight piglets had only asphyxia and 12 ventilated piglets served as controls. Meconium instillation (with and without asphyxia) resulted in a sustained decrease in the oxygenation, which remained, however, on the control level in the asphyxic group. Although meconium insufflation (with and without asphyxia) increased pulmonary artery pressure and vascular resistance progressively during the study period, the meconium-induced hypertensive effect was actually diminished by additional asphyxia. Asphyxia alone did not have any effect on these pulmonary hemodynamic parameters. On the other hand, whereas systemic arterial pressure and vascular resistance remained on the control level after meconium instillation alone, asphyxia (with and without pulmonary meconium insult) resulted in a sustained fall in systemic pressure already by 4 h. Our data thus indicate that although the coexisting asphyxia seems to moderate the meconium aspiration-induced pulmonary hypertensive response, this additional asphyxic insult does not affect the associated hypoxemia, but rather significantly exacerbates systemic hypotension.     

Seasonality of growth and the relationship between weight and height gain in children under three years of age in rural Malawi

AIM: To describe the seasonal pattern of growth and analyse the relationship between weight and height gain in children under 3 y of age. METHODS: A population-based cohort of 767 children was prospectively followed from birth until 36 mo of age in rural Malawi, southeast Africa. Weight and height measurements were collected at monthly intervals until 18 mo of age and quarterly thereafter. Gains in weight and height and prevalence of malnutrition in different seasons were calculated. The relationship between weight and height gain was analysed using a series of correlation analyses. RESULTS: Both weight gain and linear growth velocity showed an age-dependent seasonal pattern. After infancy, periods of maximal or minimal height increments systematically occurred 3 mo after those for weight gain. The prevalence of malnutrition also followed a seasonal pattern, peaking a few months after periods of reduced growth. Despite the overall pattern, weight gain and subsequent linear growth were not correlated on an individual level. At any point, however, a child's weight for height was directly, albeit weakly, correlated to height gain in the subsequent 3-mo interval. CONCLUSION: Growth of children under 3 y of age followed an age-dependent seasonal pattern. The poor correlation between children's weight and height increments suggests that seasonality affected weight gain and linear growth through different mechanisms.     

Determinants of linear growth and predictors of severe stunting during infancy in rural Malawi

Stunting is common among children under 5 y of age in sub-Saharan Africa. Several risk factors have been associated with poor growth but few studies have prospectively addressed the development of linear growth faltering and stunting during the first year of life. The present study was designed to analyse typical growth among rural Malawian infants, focusing particularly on the impact of birth size, adherence to feeding guidelines and morbidity in the development of severe stunting during infancy. A community-based cohort of 613 singleton newborns was prospectively followed by monthly home visits. Data were collected on the children's socioeconomic background, maternal size and weight gain during pregnancy, birth events, morbidity, breastfeeding and complementary feeding, growth and mortality. Univariate and multivariate analyses were used to determine associations between predictor variables and poor linear growth. The proportions of stunted infants (Height-for-age Z-score 3 32) at 3, 6 and 9 mo of age were 27%, 51%, and 63%, respectively. At 1 y of age, over two-thirds (71%) of the infants were at least moderately (HAZ 3 32) and 31% severely stunted (HAZ 3 33). Conclusion: The strongest predictor of severe stunting at 12 mo of age was small birth size. Other variables independently associated with this outcome included inappropriate complementary feeding, high morbidity, maternal short stature, male gender, and home delivery. Faltering of linear growth started soon after birth and continued throughout infancy. Interventions increasing birth size could have a significant role in the prevention of early childhood stunting. The ideal strategy should also emphasize the importance of appropriate infant feeding and decreasing the number of illness episodes amongst the infants.     

Prediabetes in children: natural history,diagnosis, and preventive strategies

The clinical manifestation of type 1 diabetes mellitus is preceded by an asymptomatic prodromal period called prediabetes or preclinical diabetes. It may last from a few months to several years, during which the autoimmune destruction of the insulin-producing beta-cells in the pancreas progresses. The genes on the human leukocyte antigen (HLA) and insulin gene region are major genetic determinants for genetic disease susceptibility, while dietary compounds and viral infections are the most likely environmental factors contributing to the etiopathogenesis. T cells are thought to be the effector cells for the beta-cell destruction, and glutamic acid decarboxylase, insulinoma-associated protein 2 and insulin represent the three major autoantigens. Autoantibodies are early detectable markers of an ongoing disease process and are used to diagnose prediabetes. Among first-degree relatives of patients with type 1 diabetes, the risk for clinical disease can be graded from <5% in those with one or no antibodies to >90% in individuals who carry the HLA-DQB1*02/0302 risk genotype and are positive for multiple autoantibodies. beta-Cell function may also be tested in autoantibody-positive individuals and low first-phase insulin response is highly predictive for rapid progression to the clinical disease. However, dynamic course and individual variation of the disease process complicates the disease prediction, and it is not known whether all individuals with signs of prediabetes will inevitably progress to clinical type 1 diabetes. Until clinically applicable prevention for the condition exists, the screening for the risk markers of type 1 diabetes should actively be undertaken only in the context of research projects. Several major national and international multicenter studies are ongoing to test the potential of various agents (e.g. insulin and nicotinamide) or early elimination of dietary compounds (e.g. cow's milk proteins) to delay or prevent the onset of clinical type 1 diabetes.     

Posterior chorioretinal atrophy and vitreous phenotype in a family with Stickler syndrome from a mutation in the COL2A1 gene

PURPOSE: To report posterior chorioretinal atrophy (PCRA) and correlate the vitreous phenotype with inheritance of the disease mutation in a family with vitreoretinal dystrophy. DESIGN: Prospective observational case series. METHODS: Twenty-four members of a family with 14 affected individuals were examined, and genetic linkage analysis was performed at the COL2A1, COL11A1, and Wagner disease loci. The vitreous phenotype was prospectively graded as optically empty with retrolenticular membrane, fibrillar, or normal. Ocular ultrasonography and optical coherence tomography (OCT) were performed on selected individuals to study the vitreous structure and vitreoretinal interface. RESULTS: The 6-year-old proband had PCRA and optically empty vitreous without systemic features, suggestive of Wagner disease. The family history was negative for systemic disease, except for one cousin with cleft palate. However, when examined, clinical features of the 14 affected subjects included 5 with small chin, 4 with at least submucosal cleft palate, and 9 with a myopic refractive error greater than 5 diopters. Lens opacity or previous cataract extraction was found in 13 family members. All affected individuals in whom the vitreous could be examined had an optically empty vitreous with retrolental membrane. Posterior chorioretinal atrophy was found in eight of the affected subjects. The finding was not limited to highly myopic subjects, nor did all the high myopes have PCRA. Ultrasonography and OCT revealed vitreous adherent to the retina, but without apparent retinal distortion or edema of the macula. Significant linkage was established to the COL2A1 locus; the other loci were excluded. A single nucleotide insertion mutation (c.2012 2013insC) was identified in exon 34, leading to a downstream premature stop codon in the COL2A1 gene. CONCLUSIONS: Although posterior chorioretinal atrophy and vitreoretinal degeneration have been classically associated with Wagner disease, we demonstrate its presence in a family with typical Stickler syndrome. On the basis of clinical, ultrasonographic, and OCT studies, the etiology of PCRA in this family does not seem to be attributable to vitreomacular traction or myopia. The vitreous findings in this large family confirm reports that mutations in the COL2A1 gene lead to the optically empty vitreous with retrolenticular membrane phenotype.     

Production of an EGFR targeting molecule from a conditionally replicating adenovirus impairs its oncolytic potential

Oncolytic virotherapy with conditionally replicating viruses is a promising approach for treating advanced cancers. Promiscuous tropism and low tumor transduction have represented limiting issues, which targeting approaches seek to overcome. An approach utilizing a secretory targeting molecule for the epidermal growth factor pathway (sCAR-EGF) has previously been shown to be compatible with replicating adenoviruses, when an E1-deleted vector was used in a dual-virus system in conjunction with a replication-competent agent. Here, we constructed a virus that replicates in cancer cells and codes for sCAR-EGF. Interestingly, the oncolytic potency of the novel agent was not improved over nontargeted controls in vitro or in vivo. These results suggest that the expression of biologically active proteins can be counterproductive to virus replication.     

Sex hormones and sexual function in obese men losing weight

OBJECTIVE: To study the impact of a weight-loss program on sex hormones and sexual function among 38 middle-aged obese men (BMI >or=35 kg/m(2)). RESEARCH METHODS AND PROCEDURES: A randomized controlled clinical trial was conducted. The treatment group (n = 19) participated in a 4-month weight-loss program including 10 weeks on a very-low-energy diet (VLED) and 17 behavior modification visits. There was no intervention in the control group (n = 19). Both groups were followed for 8 months, i.e., 22 weeks after the active weight loss in the treatment group. The outcome measures (weight, sex hormones, sexual function, leptin, and metabolic variables) were obtained at baseline and at three time-points during follow-up. RESULTS: The mean weight loss in the treatment group was 21 kg at the end of the 10-week VLED. At the end of follow-up, the maintained weight loss was 17 kg of baseline weight. The control group was weight stable throughout the study. In the treatment group, increases in sex hormone-binding globulin, testosterone, and high-density lipoprotein-cholesterol, as well as decreases in insulin and leptin, were maintained until the end of follow-up, although with VLED, the level of several hormones and metabolic variables improved transiently during the rapid weight loss. There were no significant changes in the questionnaire scores on sexual function in either group. DISCUSSION: We conclude that obese men lose weight and increase their serum testosterone level on a weight-loss program with VLED and behavior modification. However, they do not change their sexual function scores.