The current use of studies on promoters and cocarcinogens in quantitative risk assessment.

Several of the priority pollutants discussed in EPA's Ambient Water Quality Criteria documents have been reported to have promotion or cocarcinogenic activity. For example, phenol appears to have tumor-promoting activity in mice when repeatedly applied after initiation with either 7,12-dimethyl-1,2-benzanthracene (DMBA) or benzo(a)pyrene (BaP). Similarly, it has been reported that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent promoter of liver tumors as well as a cocarcinogen. However, in developing guidelines to derive ambient water quality criteria, it became apparent that satisfactory approaches had not been developed for using promotion/cocarcinogen data in human health risk estimation, nor were available promotion and/or cocarcinogen data on individual chemicals strong enough to permit a defensible quantitative risk estimation, if such approaches had existed. For this reason, the criteria derived for pollutants with reported promotion/cocarcinogenic activities were based on approaches for carcinogenic (e.g., TCDD), toxic (e.g., fluoranthene) or organoleptic effects (e.g., 2,4-dichlorophenol). Nonetheless, with advances in studies on both the biological mechanisms and dose/response patterns of promoters and cocarcinogens, it may be possible to develop a scientifically valid quantitative approach to use this type of data for derivation of ambient water quality criteria or other risk assessments. Some progress toward this goal and the problems associated with this effort are discussed.

Morphine, clonidine coadministration in subanalgesic doses: effective control of tonic pain.

The aim of the present study was to investigate whether clonidine and morphine interact positively to produce analgesia against the low intensity tonic pain represented by the formalin model in rats. Sub-threshold doses of morphine (0.5 mg kg-1) and clonidine (0.025 mg kg-1) were found to elicit marked antinociceptive effects when co-administered intraperitoneally, 15 min prior to formalin challenge. Repeated administration of this combination for eight days did not exhibit any significant decay of this analgesic response, whilst morphine (2 mg kg-1)-induced analgesia, deteriorated after similar administration. Clonidine and morphine thus exhibit a supra-additive effect against low intensity pain with negligible potential for induction of tolerance. This finding may be relevant for the long term control of chronic pain in certain clinical conditions.

Significance of plasma N-terminal pro-brain natriuretic peptide in patients with systemic sclerosis-related pulmonary arterial hypertension.

OBJECTIVES: A single centre pilot study to investigate the role of the plasma N-terminal pro-brain natriuretic peptide (N-T proBNP) assay to risk stratify patients with suspected pulmonary arterial hypertension (PAH) from a background SSc population. METHODS: Out of 49 SSc patients, 23 had and 26 did not have PAH. Right ventricular haemodynamic variables, six-minute walk test and plasma N-T proBNP levels were recorded from patients catheterised for suspected PAH (23 with PAH and 11/26 without PAH). RESULTS: Mean value of N-T proBNP for SSc patients with PAH was 3365 (standard error 1095) pg/ml compared to 347 (174) pg/ml for patients without PAH. There was a statistically significant correlation (P < 0.05) between N-T proBNP values and (i) mean pulmonary artery pressure (r = 0.53), (ii) right ventricular end diastolic pressure (r = 0.59) and (iii) pulmonary vascular resistance (r = 0.49). Receiver operator characteristic curve analysis showed that a cut-off value of 395.34 pg/ml had a sensitivity of 0.69 and specificity of 1.0. CONCLUSIONS: N-T proBNP estimation in systemic sclerosis-related pulmonary hypertension is a potentially useful diagnostic tool with a high specificity and negative predictive value. This test has the potential to have an important role in risk stratification and monitoring of therapy in the future.

Pharmaceutical service delivery by community pharmacies in areas of contrasting medical provision.

The clinical content of community pharmacists' work was studied in a well-doctored and a poorly-doctored area. A total of 315 interactions between clients and pharmacy staff were observed. Some level of clinical work was recorded in approximately one-third of these interaction, with this proportion being significantly higher in the poorly-doctored area. Alternative interpretations of these findings are examined.

Fibrinolytic guidelines in diabetes.

Urokinase and streptokinase are the two fibrinolytics approved for clinical use. Streptokinase has the broader application, being used to treat deep vein thrombosis (DVT), pulmonary embolism (PE), arterial thromboembolism, and occluded arteriovenous shunts in renal dialysis. Bleeding, the most significant complication of fibrinolytic therapy, arises mostly from invaded sites and can be significantly reduced by minimizing venipuncture and other invasive procedures.

Health impact of polychlorinated dibenzo-p-dioxins: a critical review.

Polychlorinated dibenzo-p-dioxins (PCDDs), commonly known as dioxins, form as unwanted impurities in the manufacturing of chlorophenol and its derivatives--pulp and paper--and in the combustion of municipal, sewage-sludge, hospital, and hazardous waste. Combustion, in presence of a chlorine donor, seems to be a major source of these compounds. High levels of dioxins are also emitted from metallurgical industries including copper smelters, electric furnaces in steel mills, and wire reclamation incinerators. Trace levels are detectable in emissions from motor vehicles using leaded gasoline or diesel fuel, in forest fires, and in residential wood burning. Extremely persistent and widely distributed in the environment, PCDDs have been detected in all three primary and many secondary media. Releases into the air occur mainly from combustor emissions. Atmospheric dispersion, deposition, and subsequent accumulation in the food chain seem to be the major pathways of exposure to the general population. Residues of these chemicals have been detected in soil, sediment, fish, meat, cow's milk, human adipose tissue, and mothers' milk. In general, these chemicals have high lipophilicity. The elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in humans is approximately 7-11 years. Very little human toxicity data from exposure to PCDDs are available. Health-effect data obtained from occupational settings in humans are based on exposure to chemicals contaminated with TCDD. It produces a spectrum of toxic effects in animals and is one of the most toxic chemicals known. Most of the toxicity data available on TCDD are from high-dose oral exposures to animals. Very few percutaneous and no inhalation exposure data are available in the literature. There is a wide range of difference in sensitivity to PCDD lethality in animals. The signs and symptoms of poisoning with chemicals contaminated with TCDD in humans are analogous to those observed in animals. Dioxin exposures to humans are associated with increased risk of severe skin lesions such as chloracne and hyperpigmentation, altered liver function and lipid metabolism, general weakness associated with drastic weight loss, changes in activities of various liver enzymes, depression of the immune system, and endocrine- and nervous-system abnormalities. It is a potent teratogenic and fetotoxic chemical in animals. A very potent promoter in rat liver carcinogenesis, TCDD also causes cancers of the liver and other organs in animals. Populations occupationally or accidentally exposed to chemicals contaminated with dioxin have increased incidences of soft-tissue sarcoma and non-Hodgkin's lymphoma. No comprehensive studies have been conducted to determine any health impact to the general population from environmental exposure to PCDDs. This paper presents a brief review of relevant animal and human data for projecting any possible health effects from environmental exposures to PCDDs.

The effect of isometric graft posterior cruciate ligament reconstruction on anterior tibial translation.

Eight fresh-frozen cadaver knees were studied to evaluate whether an isometrically placed posterior cruciate ligament (PCL) graft restores normal posterior tibial translation without overconstraining anterior tibial translation. Each knee was tested with a three-axis load cell in the intact state, after PCL sectioning, and after PCL reconstruction. After PCL reconstruction, posterior tibial displacement was restored to values observed in the intact state for all flexion angles except 60 degrees and 90 degrees. Anterior tibial translation was not significantly changed for any of the three states. These results indicate isometric reconstruction of the PCL significantly reduces posterior tibial translation without overconstraining anterior tibial translation.

Effect of vitamin "A" on free radical cascade in pregnancy induced hypertension.

The role of vitamin A therapy in pregnancy induced hypertension (P.I.H.) on free radical cascade was studied in P.I.H. patients of third trimester. It was found that vitamin A therapy causes statistically significant decrease in lipid peroxidation. However it has no effect on superoxide dismutase and catalase. This indicates that vitamin A acts as chain breaking antioxidant. The present study opens a future prospective of giving vitamin A for the prophylaxis of P.I.H.

Cardiovascular effects of novel imidazoline congeners.

2-Aryl-4,5-bis(diphenyl)-1-(N-acetyl hydrazide)-1,3-imidazoline (IIb1-4) was prepared by the reaction of ethyl chloro acetate and hydrazine hydrate with 2-Aryl-4,5-bis (diphenyl)-1H-imidazoline (I a1-4), which on further substitution with aryl/heterocyclyl aldheyde gave 2-Aryl-4,5-bis (diphenyl)-1-(4-substituted hydrazone)-1,3-imidazoline (III Ca-i). This was again cyclised to oxadiazole in the presence of ferric chloride and glacial acetic acid yielded 2-Aryl-4,5-bis(diphenyl)-1-(2-substituted-1,3,4-oxadizole)-1,3-imi dazoline (IV da-i). These compounds were screened for hypotensive activity and an attempt were made to get the site of action of these compounds.

Biologically active substituted benzodiazepines and their effect on cardiovascular and central nervous system.

Some substituted 1,5-benzodiazepine derivatives (including a spirocyclopentane moiety) were synthesized (Table I) and evaluated for their hypotensive and CNS activities respectively. The compounds which showed promising cardiovascular activity also exhibited marked anti-depressant action (Table II,III,IV). All the compounds showed higher ALD50 value.

Coronary artery ectasia in a patient with myocardial infarction.

We report on a case of triple-vessel coronary artery ectasia (CAE) in a young patient. This patient presented with anterior wall myocardial infarction (MI) with post-infarct angina. His coronary angiogram revealed coronary artery ectasia involving the left anterior descending, circumflex and right coronary arteries.

Top of the pops: a comparative look at China and India's demographic growth.

PIP: At the turn of this century, the number of women of childbearing age, according to 1980 UN projections, will be about 40% higher in China than India, but the same projections show that the present difference between their respective populations -- about 310 million in 1980 -- will continue to narrow. By 2000, the gap may be 4% smaller. Extrapolated indefinitely, the Indians may overtake the Chinese, yet this is unlikely. Until now, India has been only about 10 years behind China in the rate at which population growth is declining. In 1965-70 Chinese women in the reproductive age bracket 15-49 were giving birth to 149 children/1000. In those years the Indian rate was 186/1000. In 1975-80, the Chinese rate had moved down to 90/1000 and India's to 151/1000, or about the same as China's a decade earlier. In India official spending on family planning programs is still among the highest in the less developed countries, but the drive has slackened because of a weakened consensus. China is in a much better position to make headway. Monetary incentives can be decided at the local level according to what the factories and farms can afford. India is at a disadvantage in many ways. Overall literacy is lower as is the status of women. The end result is that India will add 276 million people over the last 2 decades of this century to reach 961 million. The numbers in China will grow a shade less by 262 million to reach 1.26 billion. For the 1st time, India will take over from China as the biggest absolute contributor to crowding this already overcrowded planet.^ieng

Evidence for a role of inhibition of sympathetic neurotransmission in the cardiovascular effects of intravenously administered verapamil.

The effects of intravenous administration of verapamil, nifedipine and diltiazem on sympathetic stimulation-induced increase in heart rate (HR) and blood pressure (BP) have been investigated in chloralose-anaesthetized and artificially-ventilated cats. Verapamil (300 micrograms kg(-1) i.v.) produced a significant inhibition of sympathetically-induced tachycardia and pressor responses. The same dose of verapamil did not significantly alter adrenaline (2 micrograms kg(-1) i.v.) induced increase in HR and BP. In contrast, neither the sympathetically-induced nor the adrenaline-induced pressor and tachycardiac responses were significantly affected by nifedipine or diltiazem. These results demonstrate that peripherally administered verapamil but not nifedipine and diltiazem can inhibit cardiovascular sympathetic neurotransmission and this can possibly contribute to its effects on HR and BP.

A study of the health assessment questionnaire to evaluate functional status in polymyalgia rheumatica.

OBJECTIVE: To evaluate the Health Assessment Questionnaire (HAQ) in the assessment of functional status, its responsiveness to change with treatment and its correlation with conventional disease activity indices in polymyalgia rheumatica (PMR). METHODS: Newly diagnosed patients with PMR, satisfying modified Jones and Hazleman criteria, were recruited to the study. The clinical assessments, including early morning stiffness (EMS), pain measured on a horizontal 10 cm visual analogue scale (VAS), C-reactive protein (CRP) and the HAQ, were carried out 0, 6, 12 and 24 weeks after treatment had been started. Any comorbid condition likely to affect the HAQ was noted. RESULTS: Eighteen patients completed the 6-month assessment period. These included four males and 14 females, with a mean age of 68.5 years. Pretreatment mean disease activity showed EMS of 68 min, VAS pain of 69 mm, CRP of 46 mg/l and a HAQ score of 1.57. At 6 months, mean EMS had declined to 4 min, VAS pain to 11 mm, CRP to 9 mg/l and the HAQ score to 0.14. Linear regression analysis of HAQ vs EMS, VAS and CRP showed correlation coefficients of 0.72, 0.66 and 0.63, respectively. Standardized response means (SRM), a measure of responsiveness, for HAQ, EMS, VAS and CRP were 3, 1.7, 1. 8 and 1.6, respectively. We assessed each section of the HAQ individually to see if any particular daily activity was more responsive to change. Questions on dressing and grooming, rising and eating were more responsive to change (SRM 2.5, 2.7 and 1.8, respectively) than questions about walking, hygiene, reach, grip and activities (SRM 0.8, 1.4, 1.2, 1.1 and 1.1, respectively). CONCLUSION: The HAQ is useful in the assessment of functional status in PMR, is responsive to change and correlates well with conventional indices of disease activity. However, fixed disabilities like osteoarthritis, shoulder capsulitis and systemic diseases may affect its interpretation. The sections of the HAQ measuring disability related to inflammatory stiffness/proximal involvement showed greater responsiveness to change than other sections, and hence may have a greater role in evaluating disease activity in PMR.