Health-promoting school development in Zhejiang Province, China

In 2003, after three pilot projects successfully implemented WHO's Health-Promoting Schools (HPS) concept, officials in Zhejiang Province, China, expanded to additional 51 schools (93,000 students and their families and 6800 school personnel). Each school identified a health issue to begin HPS development, followed by conceptual orientation, resource mobilization, teacher training, surveys, interventions, outreach and evaluation. This study focused on the extent to which participating schools implemented the HPS concept and improved their psycho-social environments (PSEs). Forty-nine of the 51 schools met China's HPS criteria. Schools with fewer resources and with substantial resources, i.e. schools in both rural and urban areas, met the criteria. Schools' PSEs, as measured by the PSE Profile, improved as they became HPS. Findings from interviews and observations identified strong encouragement and support from officials, school personnel, students, parents and community leaders, and consistency of HPS with the national policy on quality education, as success factors. (AU)

Abnormal regulation of maternal cerebral blood flow under conditions of gestational diabetes mellitus.

AIM: Gestational diabetes mellitus is a prediabetic state leading to endothelial dysfunction and altered organ perfusion. Under normal conditions cerebral blood flow is closely coupled to cortical activity, to which it rapidly adjusts. On the basis of this so-called neurovascular coupling we evaluated the influence of a gestational diabetic state on endothelium-dependent vasoregulative properties of this mechanism. METHOD: A functional transcranial Doppler test performed during visual stimulation was used to measure vascular reactivity. Peak systolic and end-diastolic flow velocity response from 20 non-pregnant (age 27 +/- 6 y), 31 healthy pregnant women (31 +/- 6 y; 31 +/- 4 gestational week) and 30 women with gestational diabetes (32 +/- 5 y; 34 +/- 4) were separately evaluated according to a control system approach. All women did not show any vascular risk factors prior to pregnancy. RESULTS: Comparison of resting blood flow velocity and the control system parameters of gain, attenuation, rate time and natural frequency, showed a consistent and significant difference in the parameter "attenuation" for the peak systolic data (0.55 +/- 0.18 vs. 0.44 +/- 0.1 and 0.45 +/- 0.11, p < 0.01) as well as end-diastolic (0.61 +/- 0.23 vs. 0.49 +/- 0.2 and 0.5 +/- 0.14, p < 0.05) figures (mean +/- SD of value from women with gestational diabetes vs. non-pregnant and healthy pregnant women, significance level). No differences were found between non-pregnant and normal pregnant women for the neurovascular coupling mechanism. CONCLUSIONS: Gestational diabetes mellitus results in endothelial dysfunction which can be measured in a non-invasive, painless and easy manner by a transcranial Doppler test.

Neurovascular coupling remains unaffected during normal aging.

BACKGROUND AND PURPOSE: During normal aging, the cerebral autoregulation mechanism and the CO2-induced cerebral reserve capacity remain unaffected. This led to the suggestion of a wide compensatory range of mechanisms responsible for the cerebral blood flow regulation. The authors investigated the neurovascular coupling mechanism for age-related changes. Because several authors criticized the comparison between higher and younger age groups, the current authors restricted their study on volunteers between 10 and 60 years. METHODS: Twenty healthy volunteers in the age group of 10 to 20, 20 to 40, and 40 to 60 each without cerebrovascular risk factors were enrolled in this study; they were aged 16.3 +/- 3.4 SD years (9 boys), 32.7 +/- 2.3 SD years (9 men), and 53.1 +/- 5.3 SD years (10 men). A functional transcranial Doppler test was performed using a visual stimulation paradigm. The resultant flow velocity changes in the posterior cerebral artery were analyzed using a control system approach. Resting flow velocity and each of the control system parameters, which were time delay, attenuation, natural frequency, rate time, and gain, were compared between groups statistically. RESULTS: Control system parameters remained statistically unchanged between groups, whereas the resting flow velocity decreased significantly by age. CONCLUSIONS: The neurovascular coupling mechanism seems to be unaffected by moderate aging as estimated by Doppler parameters. Vasoregulative dysfunction in patients at vascular risk is more likely to be caused by the risk factor rather than by age.

Comparison of visually evoked peak systolic and end diastolic blood flow velocity using a control system approach.

Transcranial Doppler sonography measures blood flow velocity in basal cerebral vessels with high accuracy. For quantification, time averaged mean blood flow velocities are used most because the peak systolic and end diastolic blood flow velocities mark the velocity extremes of one heart cycle. It is known, from hemodynamic measurements of the neurovascular coupling mechanism, that the end diastolic velocity is more sensitive for change in hemodynamics than the peak systolic velocity. Thus, we used a recently introduced control system approach to compare both indices for their use in functional transcranial Doppler tests focusing on hemodynamics of blood flow velocity change. We enrolled 65 healthy young volunteers without a medical history of cardiovascular risk factors, and performed a visual stimulation test. Peak systolic and end diastolic maximal blood flow velocities were used after transformation to relative data for control-system analysis. Due to Doppler artefacts, 95% of peak systolic and 86% of end diastolic data sets were analyzed. Results showed statistically significant differences for resting blood flow velocity and the control system parameter gain, attenuation and rate time, whereas the parameters' natural frequency and time delay were equal. Increase in relative blood flow velocity in the posterior cerebral artery due to visual-cortical stimulation was higher in end diastolic values than peak systolic data. Using a complex visual stimulation paradigm, the higher sensitivity of the end diastolic index is of no practical use. Being less influenced by Doppler artefacts, the peak systolic velocity index is more feasible for control-system analysis of dynamic blood flow regulation.

High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1.

Recently, the human ATP-binding cassette transporter-1 (ABC1) gene has been demonstrated to be mutated in patients with Tangier disease. To investigate the role of the ABC1 protein in an experimental in vivo model, we used gene targeting in DBA-1J embryonic stem cells to produce an ABC1-deficient mouse. Expression of the murine Abc1 gene was ablated by using a nonisogenic targeting construct that deletes six exons coding for the first nucleotide-binding fold. Lipid profiles from Abc1 knockout (-/-) mice revealed an approximately 70% reduction in cholesterol, markedly reduced plasma phospholipids, and an almost complete lack of high density lipoproteins (HDL) when compared with wild-type littermates (+/+). Fractionation of lipoproteins by FPLC demonstrated dramatic alterations in HDL cholesterol (HDL-C), including the near absence of apolipoprotein AI. Low density lipoprotein (LDL) cholesterol (LDL-C) and apolipoprotein B were also significantly reduced in +/- and -/- compared with their littermate controls. The inactivation of the Abc1 gene led to an increase in the absorption of cholesterol in mice fed a chow or a high-fat and -cholesterol diet. Histopathologic examination of Abc1-/- mice at ages 7, 12, and 18 mo demonstrated a striking accumulation of lipid-laden macrophages and type II pneumocytes in the lungs. Taken together, these findings demonstrate that Abc1-/- mice display pathophysiologic hallmarks similar to human Tangier disease and highlight the capacity of ABC1 transporters to participate in the regulation of dietary cholesterol absorption.

An E-mail assessment of undergraduates' attitudes toward smoking.

Responses from 513 of 1,000 randomly selected undergraduate students who were sent an e-mail questionnaire, about cigarette smoking were analyzed. Thirteen percent of the respondents identified themselves as smokers. No statistically significant differences were observed between smokers and nonsmokers and year in college, sex, age, race, or having attended public or private high schools. Ninety-eight percent of the respondents considered themselves knowledgeable about adverse health consequences of smoking, yet 39.1% of current smokers seriously considered stopping smoking, and 11.5% of current nonsmokers intended to start smoking. The preferred quitting method of smokers and ex-smokers was stopping all at once ("cold turkey"). Fifty-two percent of the smokers did not want professional assistance to stop smoking; 40% of the nonsmokers wanted information on second-hand smoke.

Orally active aldose reductase inhibitors: indazoleacetic, oxopyridazineacetic, and oxopyridopyridazineacetic acid derivatives.

Benzothiazole side chains featured in zopolrestat (1a) and its congeners were incorporated into oxophthalazineacetic acid replacements, including indazole, pyridazinone, and pyridopyridazinone with a pendant acetic acid moiety. Potent aldose reductase inhibition activity among resulting compounds is as widespread as it is in the earlier zopolrestat series, thus lending further support to our hypothesis that there is a binding site on the aldose reductase enzyme with strong affinity for benzothiazoles. Representative new compounds 1-[(5,7-difluoro-2-benzothiazolyl)-methyl]-1H-indazoleacetic acid (62), [6-[[5-(trifluoromethyl)benzothiazol-2-yl]methyl]-8-oxo- 6H-pyrido[2,3-d]-pyridazin-5-yl]acetic acid (70), 3,4-dihydro-4-oxo-5,6-dimethyl-3-[(5,7-difluorobenzothiazol-2-yl) methyl]-1-pyridazineacetic acid (79), and 3,4-dihydro-4-oxo-5,6-cyclohexano-3-[[5-(trifluoromethyl) benzothiazol-2-yl]-methyl]-1-pyridazineacetic acid (82) are potent aldose reductase inhibitors with IC50s of 30, 2.1, 5, and 52.2 nM, respectively. The best of these compounds, 79 and 82, also inhibit accumulation of sorbitol in rat sciatic nerve in a model of diabetic complications, when administered orally at 10 mg/kg. The inhibition values are 76 and 61%, respectively. In addition to benzothiazole, we have examined its surrogates effective in potentiating aldose reductase inhibition activity, including benzoxazole and aryl[1,2,4]oxadiazole. Structure-activity relationships emerging from this program are also discussed.

Hydantoin bioisosteres. In vivo active spiro hydroxy acetic acid aldose reductase inhibitors.

The hypothesis that clinical side effects of the aldose reductase inhibitor (ARI) sorbinil were related to its hydantoin ring led to a bioisosteric analysis and replacement of the hydantoin by a spiro hydroxy acetic acid moiety as in 40. These hydroxy acids, compared to hydantoins, showed a similar potency increase on chroman 2-methyl substitution, a similar orthogonal relationship of acidic to aromatic moieties, and similar ARI enantioselectivity. In this series the six-membered spiro hydroxy acetic acid anion array is a bioisostere for a spiro hydantoin anion and leads to ARIs with excellent in vivo activity. In vitro and in vivo activity was improved over 40 by chroman cis 2-methylation as in 4 and by aromatic 6,7-halogen substitution. Compounds with the best acute in vivo activity in rats were compared for chronic in vivo activity. The highest tissue levels and best chronic in vivo activities were found in the racemic 6,7-dichloro and 6-fluoro-7-chloro analogues 18 and 23. ARI activity was enantioselective for 58 and 60, the 2R,4R-enantiomers of 18 and 23. 7-Chloro-6-fluoro-cis-4-hydroxy-2(R)-methyl-chroman-4-acetic acid (60) was selected for phase 1 clinical trials and did not exhibit sorbinil-like hypersensitivity side effects.

Potent, orally active aldose reductase inhibitors related to zopolrestat: surrogates for benzothiazole side chain.

A broad structure-activity program was undertaken in search of effective surrogates for the key benzothiazole side chain of the potent aldose reductase inhibitor, zopolrestat (1). A structure-driven approach was pursued, which spanned exploration of three areas: (1) 5/6 fused heterocycles such as benzoxazole, benzothiophene, benzofuran, and imidazopyridine; (2) 5-membered heterocycles, including oxadiazole, oxazole, thiazole, and thiadiazole, with pendant aryl groups, and (3) thioanilide as a formal equivalent of benzothiazole. Several benzoxazole- and 1,2,4-oxadiazole-derived analogues were found to be potent inhibitors of aldose reductase from human placenta and were orally active in preventing sorbitol accumulation in rat sciatic nerve, in an acute test of diabetic complications. 3,4-Dihydro-4-oxo-3-[(5,7-difluoro-2-benzoxazolyl)methyl]-1- phthalazineacetic acid (124) was the best of the benzoxazole series (IC50 = 3.2 x 10(-9) M); it suppressed accumulation of sorbitol in rat sciatic nerve by 78% at an oral dose of 10 mg/kg. Compound 139, 3,4-dihydro-4-oxo-3-[[(2-fluorophenyl)-1,2,4- oxadiazol-5-yl]methyl]-1-phthalazineacetic acid, with IC50 less than 1.0 x 10(-8) M, caused a 69% reduction in sorbitol accumulation in rat sciatic nerve at an oral dose of 25 mg/kg. The thioanilide side chain featured in 3-[2-[[3-(trifluoromethyl)phenyl]amino]-2-thioxoethyl]-3,4-dihydro - 4-oxo-1-phthalazineacetic acid (195) proved to be an effective surrogate for benzothiazole. Compound 195 was highly potent in vitro (IC50 = 5.2 x 10(-8) M) but did not show oral activity when tested at 100 mg/kg. Additional structure-activity relationships encompassing a variety of heterocyclic side chains are discussed.

Novel, potent aldose reductase inhibitors: 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl] methyl]-1-phthalazineacetic acid (zopolrestat) and congeners.

A new working hypothesis that there is a hitherto unrecognized binding site on the aldose reductase (AR) enzyme with strong affinity for benzothiazoles was pursued for the design of novel, potent aldose reductase inhibitors (ARIs). The first application of this hypothesis led to a novel series of 3,4-dihydro-4-oxo-3-(benzothiazolylmethyl)-1-phthalazineacetic+ + + acids. The parent of this series (207) was a potent inhibitor of AR from human placenta (IC50 = 1.9 x 10(-8) M) and was orally active in preventing sorbitol accumulation in rat sciatic nerve, in an acute test of diabetic complications (ED50 = 18.5 mg/kg). Optimization of this lead through medicinal chemical rationale, including analogy from other drug series, led to more potent congeners of 207 and culminated in the design of 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl] methyl]-1-phthalazineacetic acid (216, CP-73,850, zopolrestat). Zopolrestat was found to be more potent than 207, both in vitro and in vivo. Its IC50 against AR and ED50 in the acute test were 3.1 x 10(-9)M and 3.6 mg/kg, respectively. Its ED50s in reversing already elevated sorbitol accumulation in rat sciatic nerve, retina, and lens in a chronic test were 1.9, 17.6, and 18.4 mg/kg, respectively. It was well absorbed in diabetic patients, resulting in high blood level, showed a highly favorable plasma half-life (27.5 h), and is undergoing further clinical evaluation. An assortment of synthetic methods used for the construction of benzothiazoles, including an efficient synthesis of zopolrestat, is described. Structure-activity relationships in the new series are discussed.

Applicability of red blood cell sorbitol measurements to monitor the clinical activity of sorbinil.

Increased flux of glucose through the polyol pathway with resultant resultant accumulation of tissue sorbitol is implicated in the pathogenesis of the chronic complications of diabetes. Sorbinil is a potent inhibitor of aldose reductase (the first enzyme in the polyol pathway) and has been shown to normalize sorbitol levels in relevant tissues (eg, nerve, kidney, lens) of experimentally-induced diabetic animals. The purpose of this study was to identify a relatively noninvasive method of monitoring the intrinsic (or biochemical) efficacy of sorbinil in diabetic man. Specifically, the objective was to identify a readily accessible tissue that would be reflective of polyol pathway activity and the activity of sorbinil in clinically relevant but less accessible tissues. Based on several previous studies, which demonstrated that sorbitol accumulation in human red blood cells (RBCs) was a function of ambient glucose concentrations, either in vitro or in vivo, our investigations were conducted to determine if RBC sorbitol accumulation would correlate with sorbitol accumulation in lens and nerve tissue of diabetic rats; the effect of sorbinil in reducing sorbitol levels in lens and nerve tissue of diabetic rats would be reflected by changes in RBC sorbitol; and sorbinil would reduce RBC sorbitol in diabetic man.

Red blood cell sorbitol as an indicator of polyol pathway activity. Inhibition by sorbinil in insulin-dependent diabetic subjects.

In a double-blind crossover study of 15 diabetic patients, elevated red blood cell (RBC) sorbitol levels were reduced by oral doses of the potent aldose reductase inhibitor, sorbinil (250 mg o.d.), to near-normal ranges. In diabetic rats with severe hyperglycemia, oral sorbinil (5 mg/kg) dramatically reduced (80-90%) sorbitol levels in tissues without affecting blood glucose; the RBC dose-response curve was similar to that in lens and sciatic nerve. In streptozotocin-treated rats with varying degrees of diabetes sorbitol levels in the lens, sciatic nerve, and RBC were elevated in proportion to the degree of hyperglycemia. RBC sorbitol levels in these animals were positively correlated with the levels in lens and sciatic nerve. These results establish that orally administered sorbinil is effective in lowering elevated sorbitol levels, and strongly suggest that the reduction seen in RBC sorbitol levels in human diabetic subjects is likely to reflect comparable effects of the drug in less accessible tissues associated with the long-term complications of diabetes.

CP-45,634: a novel aldose reductase inhibitor that inhibits polyol pathway activity in diabetic and galactosemic rats.

In some tissues containing aldose reductase, increased flux through the polyol pathway has been implicated as being causative in diabetic complications (e.g., cataracts, peripheral neuropathy). We have found CP-45,634 (d-6-fluoro-spiro[chroman-4,4'-imidazolidine]-2',5'-dione) to be a highly potent, structurally novel, uncompetitive inhibitor of calf lens aldose reductase (IC50 approximately 5 X 10(-7)M). In a system in which sorbitol accumulation in isolated rat sciatic nerves was monitored in the presence of high (50 mM) glucose concentrations, CP-45,634 produced inhibition of polyol accumulation at levels as low as 1 X 10(-6)M. To determine if in vitro activity would translate to in vivo models, sorbitol accumulation in rat sciatic nerves was measured 27 hr after induction of diabetes with streptozotocin. Orally administered CP-45,634 was effective at dose levels as low as 0.25 mg/kg, t.i.d., and at 0.75 mg/kg produced an 85% inhibition of sorbitol accumulation. Two weeks after induction of diabetes by streptozotocin, sorbitol levels in rat lens and the sciatic nerve rose to 21,203 nmole/gm and 1,161 nmole/gm, respectively. Subsequent oral administration of CP-45,634 (2.5 mg/kg, b.i.d.) for 1 wk reduced these levels by 92% in nerves and 90% in lenses. In galactosemic rats, CP-45,634 inhibited the rise in lens galactitol and effectively delayed cataract formation at oral doses as low as 5 mg/kg/day. These high levels of in vivo activity suggest that CP-45,634 has potential for assessing the role of the polyol pathway in diabetic complications.