A novel S-nitrosothiol (RIG200) causes prolonged relaxation in dorsal hand veins with damaged endothelium

BACKGROUND: Reduced nitric oxide bioavailability caused by endothelial dysfunction or damage is a contributory factor in the initiation and progression of a number of cardiovascular diseases. Delivery of exogenous nitric oxide is an attractive therapeutic option, but current agents lack selectivity for areas of endothelial damage. We tested the hypothesis that a novel nitric oxide donor drug, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6-tetra-O-acet yl-P-glucopyranose [RIG200], which has selective effects in endothelium-denuded isolated arteries in vitro, would exert similar effects in dorsal hand veins with experimentally damaged endothelium in vivo. METHODS: Venodilator responses to sodium nitroprusside and RIG200 were compared in two groups of healthy volunteers (age range, 18 to 63 years; n = 7 for each group) in norepinephrine 70% maximum effective concentration (EC70) preconstricted hand veins with use of the Aellig technique. In this doubleblind study, subjects were randomly assigned to receive either sodium nitroprusside or RIG200 (infusions of 0.06 and 6 nmol/min into the hand vein) before and 2 days after 15 minutes of local venous irription with distilled water. Endothelial function was assessed in all subjects on both visits with use of the endothelium-dependent vasodilator acetylcholine (1 nmol/min). RESULTS: Irrigation of hand veins with distilled water abolished endothelium-dependent dilatation in response to acetylcholine in both study groups (n = 14) but did not affect the amplitude or duration of responses to the conventional nitric oxide donor sodium nitroprusside (P = .87; n = 7). However, responses to RIG200 were significantly prolonged during the washout phase (30 minutes) in veins after water irrigation (P = .02; n = 7). CONCLUSION: These studies confirm that RIG200 has prolonged effects in veins with damaged endothelium, a characteristic that might be exploited therapeutically to target nitric oxide delivery to damaged blood vessels.     

Use of unconventional methods of therapy by cancer patients in Pakistan

Most of the studies related to the use of unconventional methods of therapy by cancer patients have been carried out in the developed countries. This study was conducted to ascertain the frequency, type, and duration of use of unconventional methods of therapy by cancer patients in Pakistan. We also wanted to identify individuals who are most likely to use these methods and to compare the findings with those reported from the developed countries. Between 1 April and 30 May 1994, all patients with histologically proven cancer who visited the oncology unit were interviewed. A printed questionnaire with questions and options was used as an interview guide. Informed consent was obtained. One hundred and ninety-one patients were interviewed, on average, for 25 minutes each. Use of unconventional methods of therapy by cancer patients was widespread (54.5% of all patients). The majority (83.7%) were influenced by family members to use these methods. Traditional herbal medicines (70.2%) and homeopathy (64.4%) were the most commonly employed methods. Thirty-six percent of the users employed these methods before receiving any conventional therapy. Only 15% used these methods after conventional therapeutic options had been exhausted. Patients generally perceived these methods as useful, non-toxic and inexpensive. Age, marital status, socio-economic background, education level and status of underlying neoplasm did not influence the frequency of use of unconventional methods. The use, however, was influenced by gender, family size, and type of underlying malignancy. Patients aware of their diagnosis were less likely to use these methods. This study suggests that use of unconventional methods by cancer patients in Pakistan is widespread. Unlike western countries, these methods are often employed before receiving any conventional therapy. This probably results in a significant delay which can be expected to adversely influence the subsequent disease management and survival. Public education, reduction of cost and easy availability of conventional therapy may be helpful in reducing the use of methods which otherwise may have no proven value.     

Chemistry of Rain Water in Riyadh, Saudi Arabia

Twenty-three rain water samples were collected from 15 sampling locations in Riyadh during four rain events in 1994 and analyzed for pH, conductivity, TDS, alkalinity, Cl, NO₃, F, SO₄, Na, Mg, Ca, and 12 trace metals. The pH ranged between 6.83 and 8.21. The major cation and anion were Ca and SO₄, contributing with 30.5% and 20.8%, respectively, to TDS. Moderate variation in major ions concentration was found to occur between different sites. The concentrations of different metals varied considerably from one sampling location to another. The dominant trace metal ions in the rain water samples were Zn, Pb, and Al. Samples collected from a site near a cement factory in Riyadh showed maximum concentrations of most of the major ions and metals. The concentrations of various ions in the first rain event were comparatively higher than the concentrations of these ions in the later rain events. Received: 15 September 1999/Accepted: 28 December 1999     

Magnesium sulphate in the treatment of eclampsia and pre-eclampsia: an overview of the evidence from randomised trials

Objective To evaluate the effectiveness of magnesium sulphate in the treatment of eclampsia and pre-eclampsia by a systematic quantitative overview of controlled clinical trials.
Design Online searching of the MEDLINE database between 1966 and 1995, and scanning of the bibliography of known primary studies and review articles on the use of magnesium sulphate in eclampsia and pre-eclampsia. Study selection, study quality assessment and data extraction were performed independently by two reviewers under masked conditions. Where possible outcome data from trials were pooled and summarised using the Mantel-Haenszel method.
Participants One thousand seven hundred and forty-three women with eclampsia and 2390 with pre-eclampsia included in nine randomised trials that evaluated the effects of magnesium sulphate.
Main outcome measures Seizure activity and maternal death.
Results In eclampsia, recurrence of seizures was less common with magnesium sulphate therapy compared with phenytoin (odds ratio [OR] 0.27, 95% CI 0.17.0.45,   P = 0.00  ) and diazepam (OR 0–41, 95% CI 0.30–0.57,   P = 0.00  ). As indicated by the point estimate, there was a trend towards a reduction in maternal mortality with magnesium sulphate in eclampsia (OR 0.51,95% CI 0.24–1.07,   P = 0.10  versus phenytoin; OR 0.78, 95% CI 0.41–1.45,   P = 0.52  versus diazepam). When used for seizure prophylaxis in pre-eclampsia, magnesium sulphate was found to be more effective than phenytoin (OR 0.15, 95% CI 0.03–0.72,   P = 0.01  ).
Conclusion Magnesium sulphate is a superior drug in preventing the recurrence of seizures in eclampsia and in seizure prophylaxis in pre-eclampsia.     

Effect of alcohol consumption on the progression of hepatitis C virus infection and risk of hepatocellular carcinoma in Japanese patients

Chronic hepatitis C virus (HCV) infection is associated with a spectrum of liver diseases and a proportion of chronic cases progress through cirrhosis to hepatocellular carcinoma (HCC). The viral and host factors that are important in the clinical and histological progression of HCV infection are unclear. We investigated the effect of moderate (<80 g/day) and heavy (>80 g/day) alcohol intake on the histological and clinical progression of HCV infection and their associated risk of hepatic cancer in a group of Japanese patients. A number of other variables were assessed to evaluate their impact on disease progression. We recruited 120 patients with HCV infection and categorized them into four groups, based on alcohol consumption pattern. All clinical and biochemical profiles were collected from recorded files. Liver biopsies were analysed for the degree of fibrosis, presence of cirrhosis and histological activity of necroinflammation. Hepatic tumours were detected by the follow-up imaging analysis. There was no difference in the age, length of exposure to HCV infection and HCV RNA serum levels in the alcohol and alcohol-free groups. The histological grading of necroinflammation, serum levels of alanine aminotransferase and HCV RNA did not have any correlation with each other in the alcohol and alcohol-free group. There was a 1.5-2. 5-fold greater risk of liver cirrhosis and hepatocellular carcinoma in the alcohol intake group compared to the alcohol-free group. Kruskal-Wallis analysis among four groups demonstrated a significant transition to fibrosis (P < 0.05) for alcoholics with HCV infection. The increased risk of liver cancer in the alcohol group is independent of size and growth of tumours. The clinical manifestations of gastro-oesophageal variceal bleeding, ascites, and encephalopathy were also higher in the alcohol intake group. Alcohol consumption is an important risk factor in the histological and clinical progression of HCV infection and has no relation with HCV replication. Chronic HCV carriers should avoid excessive alcohol intake to reduce the acceleration of liver disease and risk of liver cancer.     

Cocaine use in pregnancy in Amsterdam

To study the effects of cocaine use in pregnancy in Amsterdam, clinical data on cocaine-using pregnant women ( n = 21) and their offspring ( n = 23) were obtained retrospectively (1987–1994) at the Academic Medical Center, Amsterdam. Infants exposed to cocaine had a median gestational age of 39 weeks and a median birth weight of 3090 g. There were six preterm infants, two small-for-gestational-age infants and five infants with a small head circumference. Three infants had a congenital malformation. One infant (Potter's syndrome) died shortly before birth. One infant had congenital syphilis, four had intracerebral abnormalities on ultrasound and four had abnormal neurologic symptoms in the neonatal period. One infant died after 21 days of life. At follow-up four infants showed abnormal development. In 12 of the 23 infants (52%), one or more possible effects of cocaine were found.     

Subchronic effects following a single sarin exposure on blood-brain and blood-testes barrier permeability, acetylcholinesterase, and acetylcholine receptors in the central nervous system of rat: a dose-response study

Subchronic neurotoxic effects of sarin (O-isopropyl methylphosphonofluoridate) treatment at various doses in male Sprague Dawley rats were studied. The animals were treated with a single intramuscular (im) injection of 0.01, 0.1, 0.5, or 1 x LD50 (100 microg/kg). The animals were maintained for 90 d thereafter. [3H]Hexamethonium iodide was used to monitor the changes in blood-brain barrier (BBB) permeability in cortex, brainstem, midbrain, and cerebellum. Brainstem exhibited a significant decrease (approximately 58% of control) in uptake of [3H]hexamethonium iodide at 1 x LD50 dose. No significant changes were observed in BBB permeability in cortex, midbrain, and cerebellum at any dose. Plasma butyrylcholinesterase (BChE) activity remained unchanged, reflecting recovery of the enzyme activity from the initial inhibition following single exposure of 1 x LD50 sarin. Acetylcholinesterase (AChE) activity in the cortex remained inhibited (approximately 29%), whereas in the brainstem there was an increase (approximately 20%) at 1 x LD50 dose of sarin. The m2-selective muscarinic acetylcholine receptor (m2-mAChR) ligand binding was inhibited significantly at 1 x LD50 in the cortex, whereas brainstem showed significantly increased (approximately 45%) ligand binding at 1 x LD50 dose. Nicotinic acetylcholine receptor (nAChR), on the other hand, showed a biphasic response in ligand binding in the cortex with a decrease (approximately 30%) at 0.01 x LD50 but an increase (approximately 40%) at 1 x LD5O. Brainstem did not show any significant change in nAChR ligand binding. These results suggest that single exposure of sarin could lead to changes that may play an important role in neuropathological abnormalities in the central nervous system.     

Three novel monotetrahydrofuran annonaceous acetogenins from Annona montana

Three new monotetrahydrofuran (mono-THF) acetogenins, anmontanins A-C (1-3) were isolated from the leaves of Annona montana. Anmontanin C (3) is the first stereochemically pure acetogenin reported to have a gamma-hydroxymethyl-gamma-lactone moiety. Two known mono-THF acetogenins, murisolin and annonacin, were isolated from the seeds of the plant. The structures of compounds 1-3 were elucidated by spectral methods and chemical derivatization.     

Taraxacin, a new guaianolide from Taraxacum wallichii

A new guaianolide, taraxacin (1), and a known sesquiterpene ketolactone (2) have been isolated from an ethyl acetate-soluble part of a methanolic extract of Taraxacum wallichii. The structure of 1 was established using NMR, MS, and X-ray crystallographic methods. The (13)C NMR data of 2 is also being reported for the first time.     

Cooperativity of Staphylococcal aureus enterotoxin B superantigen, major histocompatibility complex class II, and CD80 for immunotherapy of advanced spontaneous metastases in a clinically relevant postoperative mouse breast cancer model

One of the leading causes of death for women is metastatic breast cancer. Because most animal tumors do not accurately model clinical metastatic disease, the development of effective therapies has progressed slowly. In this study, we establish the poorly immunogenic mouse 4T1 mammary carcinoma as a postsurgical animal model. 4T1 growth characteristics parallel highly invasive human metastatic mammary carcinoma and, at the time of surgery, the extent of disease is comparable with human stage IV breast cancer. Progress in understanding the immune response has led to innovative immune-based anticancer therapies. Here, we test in this postsurgical model, a novel cell-based vaccine, combining MHC class II, CD80(B7.1), and SEB superantigen. Effective treatment of tumor-bearing mice with this immunotherapy requires expression of all three molecules. Mean survival time is extended from 5-7.5 weeks for control-treated mice to 6-10.5 weeks for therapy-treated mice. Increased survival is accompanied by a maximum of 100-fold decrease in clonogenic lung metastases. These therapeutic effects are particularly noteworthy because: (a) the postoperative model demonstrates that early metastases responsible for morbidity are established by 2 weeks after tumor inoculation with 7 x 10(3) parental 4T1 cells into the mammary gland; (b) the immunotherapy is started 4 weeks after tumor inoculation when the mice contain extensive, pre-established, disseminated metastases; and (c) CD4+ and CD8+ T cells are required for the effect.