Cancer incidence and mortality around the Pan Britannica Industries pesticide factory, Waltham Abbey.

OBJECTIVES: To examine the incidence and mortality of cancer near the Pan Britannica Industries factory, Waltham Abbey, after reports of a possible cluster of all cancers and brain cancer in the vicinity. METHOD: Small area study of cancer incidence 1977-89, and mortality 1981-92, within a 7.5 km radius of the factory site. Postcoded cancer registrations and deaths in the study area were extracted from national data sets held by the Small Area Health Statistics Unit and compared with expected numbers computed by applying national rates stratified for age, sex, and deprivation to the local population (1981 and 1991 censuses). Observed/ expected (O/E) ratios were examined from 0-1 km and 0-7.5 km of the plant, and tests applied for a decline in relative risk with distance up to 7.5 km. RESULTS: There were 12,859 incidence cancers (1977-89) from 0-7.5 km (O/E ratio 1.04; 95% confidence interval (95% CI) 1.02 to 1.06) and 385 from 0-1 km (O/E 1.10; 1.00 to 1.22). There was an excess of skin melanoma from 0-1 km based on 11 cases (O/E 2.13; 1.06 to 3.80), and an excess from 0-7.5 km of cancer of the lung, stomach and pancreas combined, and prostate (O/Es ranged from 1.09 to 1.13). Only the findings from lung cancer were suggestive of a decline in risk with distance, especially in the later period (1982-9). There were 9196 cancer deaths (1981-92) from 0-7.5 km (O/E 1.04; 95% CI 1.02 to 1.06) and 308 from 0-1 km (O/E 1.24; 1.11 to 1.39); and 25507 non-cancer deaths (O/E 1.02; 1.01 to 1.04) from 0-7.5 km and 745 (O/E 1.14; 1.06 to 1.22) from 0-1 km. There was evidence of a decline in mortality with distance for all cancers combined, lung cancer (P = 0.001 for each), and colorectal cancer (P < 0.05), and also for non-cancers (P = 0.001). Proportional mortality analyses suggested a decline in risk with distance for lung cancer (P = 0.003) but not for all cancers or the site specific cancers examined. There was no evidence of an excess in the incidence or mortality from brain cancer. For cancer mortality in the inner-most wards, the findings were, for the most part, well within the range of variation across the region as a whole. CONCLUSIONS: The study provides limited and inconsistent evidence for a localised excess of cancer in the vicinity of the PBI plant. At present, further investigation does not seem warranted other than continued surveillance of mortality and cancer incidence in the locality.     

A preliminary, clinical pharmacological assessment of L-659,066, a novel alpha 2-adrenoceptor antagonist.

1. The alpha 2-adrenoceptor antagonist activity of L-659,066 has been investigated in studies of healthy normotensive males to whom doses of up to 8 mg were administered by short intravenous infusion. 2. L-659,066 had no effect on basal levels of glucose or insulin and no significant effect on the plasma glucose and plasma insulin time profiles following an intravenous glucose load. 3. There was a non-significant trend for plasma noradrenaline concentrations to be higher after L-659,066. 4. L-659,066 had no significant effects on mood changes or on physical symptom scores. 5. There were no significant effects on supine blood pressure but there were consistent increases in heart rate both supine (non-significant) and erect (P < 0.01). 6. Ex vivo platelet aggregation studies confirmed alpha 2-adrenoceptor antagonist activity with L-659,066 but with an approximately 9-fold lesser potency than yohimbine. 7. While L-659,066 has alpha 2-adrenoceptor antagonist activity these results suggest that it is unlikely to present a new therapeutic approach for improving insulin release.     

Anti-peptide antibodies to cathepsins B, L and D and type IV collagenase. Specific recognition and inhibition of the enzymes.

Anti-peptide antibodies were raised against synthetic peptides selected from the sequences of human cathepsins B and L, porcine cathepsin D and human type IV collagenase. Sequences were selected from the active site clefts of the cathepsins in the expectation that these would elicit immunoinhibitory antibodies. In the case of type IV collagenase a sequence unique to this metalloproteinase subclass and suitable for immunoaffinity purification, was chosen. Antibodies against the chosen cathepsin B sequence were able to recognize the peptide but were apparently unable to recognise the whole enzyme. Antibodies against the chosen cathepsin L sequence were found to recognise and inhibit the native enzyme and were also able to discriminate between denatured cathepsins L and B on Western blots. Antibodies against the chosen cathepsin D sequence recognised native cathepsin D in a competition ELISA, but did not inhibit the enzyme. Native type IV collagenase was purified from human leukocytes by immuno-affinity purification with the corresponding anti-peptide antibodies.     

Trehalose dimycolate enhances resistance to infection in neutropenic animals.

Bacterial infections are lethal complications of neutropenia, and antibiotics alone are inadequate therapy for these infections. Irradiated mice become severely neutropenic and remain susceptible to infection for 2 to 3 weeks, depending on the dose and quality of radiation. Some bacterial cell wall derivatives stimulate nonspecific host defense mechanisms against a variety of microbes which might cause postirradiation infection. In this study we determined if the cell wall glycolipid trehalose dimycolate (TDM), derived from Mycobacterium phlei, or a synthetic preparation of TDM was able to (i) enhance survival in mice when given before or after lethal doses of 60Co radiation and (ii) increase nonspecific resistance to postirradiation infection. Treatment with TDM oil-in-water emulsions and with synthetic TDM significantly enhanced survival before and after lethal doses of 60Co irradiation. This result correlated with the ability of TDM to reduce the translocation of intestinal bacteria and to stimulate hematopoiesis. With respect to nonspecific resistance to infection, TDM injected 1 h after sublethal irradiation increased resistance to a lethal Klebsiella pneumoniae challenge (10 50% lethal doses of K. pneumoniae in 30 days [LD50/30]) 4 or 14 days later. Increasing the dose of K. pneumoniae to 5,000 LD50/30 on day 4 overwhelmed the ability of TDM-treated mice to overcome infection. However, TDM treatment 1 h postirradiation combined with ceftriaxone antibiotic therapy (days 5 through 14) enhanced survival, even when the higher dose of bacteria (5,000 LD50/30) was used. These results indicate that in irradiated mice, TDM can be used to enhance survival and, as a potent stimulant of nonspecific resistance to infection in neutropenic mice, can act synergistically with antibiotic therapy to reduce sepsis and mortality.     

Synthesis and anthelmintic activity of a series of pyrazino[2,1-a][2]benzazepine derivatives

A series of 1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-alpha][2] benzazepine derivatives was prepared and the cestocidal activity of the compounds evaluated in an in vitro Taenia crassiceps screen. Many of these derivatives proved to be highly active, and 2-(cyclohexylcarbonyl)-4-oxo-1,2,3,4,6,7,8,12b- octahydropyrazino[2,1-alpha][2]benzazepine, epsiprantel (BAN) (22), was selected for further development. The structure-activity relationships are discussed.