Photodynamic therapy inhibits transforming growth factor β activity associated with vascular smooth muscle cell injury

Purpose: The multifunctional cytokine, transforming growth factor β1 (TGF-β), plays an important role in the development of injury-associated intimal hyperplasia (IH). Strategies to suppress local TGF-β activity may have a clinical potential to prevent restenosis caused by IH. Photodynamic therapy (PDT) involves the local generation of cytotoxic free radicals by light activation of photosensitizer dyes and has been shown to inhibit experimental IH. This study investigated whether PDT-generated free radicals can affect TGF-β activity in a biologic system using vascular smooth muscle cells (SMCs).Methods: The release and activation of TGF-β by injured SMCs in culture was compared between mechanical injury and PDT. Mechanical injury was induced with a rubber policeman, and PDT was performed with the photosensitizer chloroaluminum sulfonated phthalocyanine (5 μg/ml) and 675 nm laser light at subtherapeutic 10 J/cm² and the in vivo therapeutic dose of 100 J/cm². Cell viability was assessed by the tetrazolium salt conversion assay, and active and total (active + latent) TGF-β was determined by enzyme-linked immunosorbent assay in the conditioned media of SMCs 24 hours after treatment. Functional TGF-β activity was assessed by inhibition of endothelial cell mitogenesis.Results: Both forms of injury severely reduced (p < 0.0005) SMC viability to less than 15%. In untreated SMC conditioned media, only 14.5% of the total TGF-β was active (27.7 ± 8.7 pg per 1 × 10⁵ cells). However, after mechanical injury and PDT with 10 J/cm², there was a significant increase (p < 0.02) in active TGF-β (60.1 ± 10.1 pg and 48.6 ± 21.0 pg, respectively), despite a total reduction of approximately 50%. In contrast to this result, PDT with 100 J/cm² did not result in increased levels of active TGF-β (8.1 ± 3.5 pg), despite having similar levels of total TGF-β. Consequently, the conditioned media of SMCs that had 100 J/cm² PDT did not inhibit endothelial cell mitogenesis as compared with the conditioned media of SMCs with mechanical injury and 10 J/cm² PDT (p < 0.0002).Conclusions: This report describes two novel findings: (1) injury to SMCs in vitro induces the conversion of biologically latent TGF-β to active TGF-β; and (2) the therapeutic PDT dose interferes with this injury activation process. This study substantiates the concept of local cytokine inhibition by PDT in a biologic system and provides new insights into the mechanisms of PDT-mediated inhibition of experimental IH. (J Vasc Surg 1997;25:1033-43.)     

Cardia: study design, recruitment, and some characteristics of the examined subjects

In 1984, a prospective cohort study, Coronary Artery Risk Development in Young Adults (CARDIA) was initiated to investigate life-style and other factors that influence, favorably and unfavorably, the evolution of coronary heart disease risk factors during young adulthood. After a year of planning and protocol development, 5,116 black and white women and men, age 18-30 years, were recruited and examined in four urban areas: Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota, and Oakland, California. The initial examination included carefully standardized measurements of major risk factors as well as assessments of psychosocial, dietary, and exercise-related characteristics that might influence them, or that might be independent risk factors. This report presents the recruitment and examination methods as well as the mean levels of blood pressure, total plasma cholesterol, height, weight and body mass index, and the prevalence of cigarette smoking by age, sex, race and educational level. Compared to recent national samples, smoking is less prevalent in CARDIA participants, and weight tends to be greater. Cholesterol levels are representative and somewhat lower blood pressures in CARDIA are probably, at least in part, due to differences in measurement methods. Especially noteworthy among several differences in risk factor levels by demographic subgroup, were a higher body mass index among black than white women and much higher prevalence of cigarette smoking among persons with no more than a high school education than among those with more education.     

Amyotrophic lateral sclerosis patient antibodies label Ca2+ channel α1 subunit

Sporadic amyotrophic lateral sclerosis is an idiopathic human degenerative disease of spinal cord and brain motor neurons. Prior studies demonstrated that most patients with amyotrophic lateral sclerosis posses immunoglobulins that bind to purified L-type voltage-gated calcium channels, that titers of anti–voltage-gated calcium channel antibodies correlate with disease progression rates, and that amyotrophic lateral sclerosis patient-derived antibodies (ALS IgG) produce electrophysiological changes in the function of voltage-gated calcium channels. Using Western transfer immunoblots and enzyme-linked immunosorbent assays, the calcium ionophore–forming α₁ subunig of the voltage-gated calcium channel is now identified as the major voltage-gated calcium channel antigen to which ALS IgG binds. Additionally, the binding of an L-type voltage-gated calcium channel α₁ subunit–directed monoclonal antibody, which itself mimics the effects of ALS IgG on skeletal muscle voltage-gated calcium channel currents, is selectively prevented by preaddition of ALS IgG. Voltage-gated calcium channel–binding IgG from patients with Lambert-Eaton myasthenic syndrome appears to be differentiated from ALS IgG by the reactivity of the former to both α₁ and β subunits of the calcium channel. These assays provide further evidence linking amyotrophic lateral sclerosis to an autoimmune process, and suggest one means to differentiate immunoglobulins from patients with amyotrophic lateral sclerosis from those of patients with another autoimmune disease expressing calcium channel antibodies.     

Factors associated with hypertension in Nigerian civil servants

BACKGROUND. Study of hypertension in segments of West African populations in transition toward Westernization may lead to better understanding of the high risk for hypertension among Westernized blacks. METHODS. Five hundred fifty-nine urban civil servants, ages 25-54, were recruited from six ministries of Bendel State, Nigeria. Blood pressure, physical measurements, urinary protein and glucose, fasting blood glucose, and demographic data were collected at the workplace. Subjects were classified as senior staff (professionals or administrators) or junior staff (non-administrators). RESULTS. Among 172 male senior staff, the age-adjusted rate of hypertension (diastolic blood pressure > or = 90 mm Hg, systolic blood pressure > or = 140 mm Hg, or on an antihypertensive medication) was 43% and occurrence rose dramatically from 21 to 63% across age groups 25-34 to 45-54, respectively. Among 266 male junior staff, the age-adjusted rate of hypertension was 23%, and occurrence did not rise with age. Logistic regression showed that body mass index (kg/m2), age, alcohol drinking, and being senior staff were all independently related to hypertension in men. On the other hand, the age-adjusted rate of hypertension in 121 women was 20% and was significantly related only to body mass index. CONCLUSION. Male urban civil servants appeared to have a risk for hypertension similar to that of U.S. black males. Age, body mass index, alcohol drinking, and other unidentified factors related to higher socioeconomic status were strong determinants of hypertension in this population.     

SPROUT,HIPPO and CAESA: Tools for de novo structure generation and estimation of synthetic accessibility

Summary Several components of a system for structure generation are now well developed. HIPPO is a program that characterises a receptor binding site for potential target sites within the cavity that can be used in de novo design. The target sites include simple and complex hydrogen bonds, covalent bonds and bonds to metal ions. The SPROUT program for structure generation consists of two main components: the first is skeleton generation, followed by atom substitution to convert the solution skeletons to molecules. A new method of skeleton generation is presented here, where part skeletons are grown outwards from each target site. The part skeletons are then connected together to form solution skeletons. Finally the CAESA program is described, that ranks the output from SPROUT according to ease of synthesis.     

MESENTERIC CYST

Mesenteric cyst is one of the rarest abdominal tumours, with approximately 820 cases reported since 1507. The incidence varies from 1 per 100000 to 250000 admissions. The lack of characteristic clinical features and radiological signs may present great diagnostic difficulties. The cyst may present in one of three ways: (i) non-specific abdominal features; (ii) an incidental finding; or (iii) an acute abdomen. Abdominal pain is the major presenting symptom. Abdominal mass is found in more than 50% of cases and 40% of cases are discovered incidentally. More than one aetiological mechanism is probably involved in the development of mesenteric cysts. Mesenteric cysts have been reported from the duodenum to the rectal mesentery but are most commonly located in the ileal mesentery. Malignant cysts occur in less than 3% of cases. Enucleation of the cyst is the treatment of choice. Knowledge of these tumours is important due to the various complications associated with suboptimal surgical management. Two cases of mesenteric cysts are presented including a recurrent mesenteric cyst in a post-partum woman demonstrating the inferior technique of internal marsupialization. The association of mesenteric cyst with pregnancy is discussed.     

Is the apparent U-shape of well-being over the life course a result of inappropriate use of control variables? A commentary on Blanchflower and Oswald (66: 8, 2008, 1733–1749)

In their article in this journal “Is well-being U-shaped over the life cycle?” Blanchflower and Oswald (Blanchflower, D.G., & Oswald, A.J. (2008). Is well-being U-shaped over the life cycle? Social Science & Medicine, 66, 1733–1749) report the results of an ambitious cross-national study of age and well-being and conclude that in most societies studied the well-being of adults tends to be high in young adulthood and old age and lowest around age 40. I argue that the appearance of this U-shaped curve of well-being is the result of the use of inappropriate and questionable control variables. The most clearly inappropriate control variable is marital status, the control of which to a large extent accounts for the U-shaped curve. Most researchers who have studied the relationship between being married and being happy believe that happiness affects marital status (happier people are more likely to marry and stay married), and of course a variable that is affected by the dependent variable should not be included as a control variable in a simple recursive model. Such control variables as income and education are suspect because the relationship between them and well-being is likely to be partially spurious, and such variables as race and whether or not persons lived with both parents at age 16 should not be controlled, because they cannot affect or be affected by age. Finally, year of survey should not be controlled because of the age-period-cohort conundrum, which makes including age, period, and cohort all as predictor variables in a regression inappropriate (and impossible if the three variables are measured precisely and comparably). The only clearly appropriate control variable is birth cohort, and when only it is controlled, the regression data become estimates of how the well-being of persons has actually changed as they have gone through the life course. I argue that such estimates are much more useful than the counterfactual abstractions provided by Blanchflower and Oswald (Blanchflower, D.G., & Oswald, A.J. (2008). Is well-being U-shaped over the life cycle? Social Science & Medicine, 66, 1733–1749), and I conclude that those authors (or someone else) could make a very important contribution by redoing their analyses with birth cohort as the only control variable. I do that with the American happiness data and find that the results do not come close to the U-shaped pattern.