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Despite advances in treatment, breast cancer continues to be the second leading cause of cancer mortality in women. Statistics suggest that while focus on treatment should continue, chemopreventive approaches should also be pursued. Previous studies have demonstrated that naturally occurring retinoids such as 9-cis retinoic acid (9cRA) can prevent breast cancer in animal models. However, these studies have also shown that these compounds are too toxic for general use. Work from our laboratory showed that an RXR-selective retinoid LGD1069 prevented tumor development in animal models of cancer with reduced toxicity as compared to an RAR-selective retinoid TTNPB. In the present study, we investigated the mechanisms by which receptor-selective retinoids inhibit the growth of normal and malignant breast cells. Our results demonstrate that the synthetic retinoids tested are as effective as 9cRA in suppressing the growth of normal human mammary epithelial cells (HMECs) and estrogen receptor-positive (ER-positive) breast cancer cells. Although the receptor-selective retinoids induce minimal amounts of apoptosis in T47D breast cancer cells, the predominant factor that leads to growth arrest is G1 cell cycle blockade. Our data indicate that this blockade results from the downregulation of Cyclin D1 and Cyclin D3, which in turn causes Rb hypophosphorylation. Non-toxic retinoids that are potent inducers of cell cycle arrest may be particularly useful for the prevention of breast cancer.

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BACKGROUND: Debate exists about the optimum way to screen for diabetic retinopathy. Cameras produce a permanent record, but offer patients less choice about when and where to be screened. Optometrists offer flexibility but sensitivity and specificity of schemes have varied considerably, perhaps because of variability in screening methodology and that there is frequently no quality assurance programme. AIMS: To audit our district-wide (population 340000) screening programme for diabetic retinopathy against national targets: sensitivity > 80%, specificity > 95% and referral to review < 3 months. METHODS: Trained optometrists performed slit-lamp examination with Volk lenses (78 dioptre) with standardized reporting. Audit was by ophthalmologist with slit-lamp and Volk lenses through dilated pupils. RESULTS: We examined 872 eyes of 439 patients; 64% were normal, 29% background diabetic retinopathy, 7% sight-threatening eye disease (STED). Sixty-three percent of patients were seen within 6 months of the original screen. Of these, sensitivity for any retinopathy was 72%, specificity 77%, positive predictive value (PPV) 53%, negative predictive value (NPV) 88%. For STED, in this group, sensitivity was 87% and specificity 91%, PPV 30%, NPV 99%. Median interval referral to ophthalmological review was 11.5 weeks with 73% reviewed in under the 13-week target. Of those referred 25% received laser therapy. Eleven patients found to have referable eye disease at their initial screen were not referred to an ophthalmologist by their GP. CONCLUSIONS: We conclude that effective district-wide screening for diabetic retinopathy by optometrists using slit-lamp and Volk lenses is possible; however, only 36% of identified people with diabetes in the district were screened over a 4-year period.

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Retinoids are vitamin A-related compounds that have been found to prevent cancer in animals and humans. In this review, we discuss the role of retinoids and their receptors in the treatment and prevention of breast cancer. The retinoid receptors are expressed in normal and malignant breast cells, and are critical for normal development. In breast cells, when bound by retinoid hormones, these proteins regulate proliferation, apoptosis, and differentiation. The mechanism by which retinoids inhibit breast cell growth has not been completely elucidated, however, retinoids have been shown to affect multiple signal transduction pathways, including IGF-, TGFbeta-, and AP-1-dependent pathways. Retinoids have also been shown to suppress the growth and prevent the development of breast cancer in animals. These agents suppress tumorigenesis in carcinogen-treated rats and in transgenic mice, and inhibit the growth of transplanted breast tumors. These promising preclinical results have provided the rationale to test retinoids in clinical trials for the treatment and prevention of breast cancer. Several retinoids, including all trans retinoic acid and 9-cis retinoic acid, have been shown to have modest activity in the treatment of breast cancer, and these agents are now in clinical trials in combination with cytotoxic agents and anti-estrogens. Another retinoid, 4-HPR, is currently being tested in a human cancer prevention trial. Preliminary results suggest that 4-HPR may suppress breast cancer development in premenopausal women. Future clinical trials will focus on testing new synthetic retinoids that have reduced toxicity and enhanced therapeutic and preventive efficacy.

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We assessed the activities of amphotericin B deoxycholate, liposomal amphotericin B, fluconazole, and SCH 39304 against 10 strains of Trichosporon beigelii in mice with hematogenous infections. Cyclophosphamide-immunosuppressed CF1 male mice were challenged intravenously with a lethal inoculum of T. beigelii (5 x 10(6) conidia per mouse) and were assigned to different treatment groups or were left untreated. Amphotericin B deoxycholate (1 mg/kg of body weight and liposomal amphotericin B (1, 5, and 10 mg/kg) were given parenterally once daily. Escalating doses (5, 10, and 20 mg/kg/day) of fluconazole and SCH 39304 were tested. We also compared the activity of amphotericin B deoxycholate plus fluconazole (1 and 10 mg/kg/day, respectively) with that of each agent alone. Fluconazole significantly prolonged the survival of mice infected with each of the 10 strains tested. Amphotericin B deoxycholate achieved various responses, improving the outcomes in mice infected with seven of the strains. Liposomal amphotericin B was not more effective than amphotericin B deoxycholate against the two strains tested. Both fluconazole and SCH 39304 reduced the kidney fungal counts in a dose-dependent pattern, with SCH 39304 being more active than fluconazole against one of the two strains tested. The activity of the combination of amphotericin B deoxycholate plus fluconazole appeared to be superior to that of either agent alone, especially in reducing the kidney fungal burden. Fluconazole is more active than amphotericin B deoxycholate against experimental murine trichosporonosis.

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Hematogenous infections caused by Candida krusei have been noted with increasing frequency, particularly in cancer patients receiving prophylaxis with antifungal triazoles. Progress in understanding the pathogenesis of this emerging infection has been limited by the lack of an animal model. We developed a CF1 mouse intravenous inoculation model of candidiasis to evaluate the pathogenicity of C. krusei in normal and immunosuppressed mice and to compare it with that of Candida albicans. Several inocula (10(6) to 10(8) CFU per animal) of two clinical strains of C. krusei and three American Type Culture Collection strains of C. albicans were tested. Groups of 20 mice each were injected with a single intravenous dose of one inoculum. Animals randomized to receive C. krusei were immunosuppressed by intraperitoneal injection of cyclophosphamide or the combination of cyclophosphamide plus cortisone acetate or they did not receive immunosuppressive agents (normal mice). One hundred percent mortality was observed in normal mice injected with 10(6) CFU of C. albicans per mouse compared with no mortality in normal mice that received 10(8) CFU of C. krusei per mouse (P < 0.01). Resistance to C. krusei infection was markedly lowered by immunosuppression, particularly by the combination of cyclophosphamide plus cortisone acetate, with a significantly shorter survival and a higher organ fungal burden in immunosuppressed than in normal animals (P < 0.01). Tissue infection was documented by culture and histopathologic findings in all examined organs.

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One hundred and eight male adults (mean age 33 +/- 1.7 years) presenting with watery diarrhoea of less than 48 hours duration at home prior to hospitalization and with clinically evident (grade II, severe) dehydration were admitted into a randomized double-blind clinical trial; 54 were treated with standard oral rehydration solution (ORS)--WHO formulation containing citrate--and 54 with an improved ORS formulation which contained, in addition to the standard formula, maltodextrin 20 g (instead of glucose), glycine 4 g and glycyl-glycine 4 g. Patients with clinical cholera were given tetracycline 500 mg q.i.d. Vibrio cholerae was detected in 85 patients. The clinical characteristics of patients in the two groups were comparable. The improved ORS did not reduce the volume of diarrhoeic stools in cholera; indeed, patients with cholera who were treated with improved ORS had larger diarrhoea stool volumes. However, those cholera patients given improved ORS showed significantly greater weight gains during the first six-hour period, at the end of the second day, and at discharge. On the other hand, non-cholera patients treated with improved ORS had significantly smaller diarrhoeic stool volumes during the six to 24-hour significantly smaller diarrhoeic stool volumes during the six to 24-hour period (i.e. during the commencement of maintenance rehydration therapy).

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A study in the dry-zone township of Ayadaw, Burma, has shown that the success of health development activities is largely attributable to collective leadership, viable community organization, balance between local and central priorities, the use of appropriate interventions and technology, community participation, and the maintenance of a proper community financing system. The ayadaw township People's Health Plan Committee was awarded the 1986 Sasakawa Health Prize at the Thirthy-ninth World Health Organization

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Forty-eight children, aged 2-5 years, presenting with watery diarrhoea of less than 48 h duration at home prior to hospitalization, were admitted into a randomized controlled clinical trial, 24 children being treated during the first 24 h of admission with oral rehydration solution (ORS) alone and 24 children being given 'ORS plus boiled-rice feeding'. The latter group received boiled-rice to supply at least 55 kcal/kg/d (about 150 g boiled-rice per feed, given four times daily). Vibrio cholerae were isolated by stool culture on admission from all children. No antibiotics were given. Clinical characteristics of children in the two treatment groups were comparable. Among children given 'ORS plus boiled rice', there was a significant increase in volume of diarrhoea stools (P less than 0.05), duration of diarrhoea in hospital (P less than 0.01), and more frequent diarrhoea motions (not significant statistically). However, the children fed boiled rice absorbed and retained 176 ml more fluid, and had gain in body weight comparable to that observed in children who were not fed during the first 24 h of hospitalization.

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Four hundred adults presenting with acute watery diarrhoea were entered into a randomised, placebo controlled, double blind clinical trial of berberine, tetracycline, and tetracycline and berberine to study the antisecretory and vibriostatic effects of berberine. Of 185 patients with cholera, those given tetracycline or tetracycline and berberine had considerably reduced volume and frequency of diarrhoeal stools, duration of diarrhoea, and volumes of required intravenous and oral rehydration fluid. Berberine did not produce an antisecretory effect. Analysis by factorial design equations, however, showed a reduction in diarrhoeal stools by one litre and a reduction in cyclic adenosine monophosphate concentrations in stools by 77% in the groups given berberine. Considerably fewer patients given tetracycline or tetracycline and berberine excreted vibrios in stools after 24 hours than those given berberine alone. Neither tetracycline nor berberine had any benefit over placebo in 215 patients with non-cholera diarrhoea.

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The effects of oral rehydration fluid alone and of oral rehydration fluid plus breast feeding on the course and outcome of acute diarrhoea were assessed in two groups of 26 children aged under 2 years. Children who continued to be breast fed during treatment with oral rehydration solutions passed significantly fewer diarrhoeal stools. They also passed, on average, a smaller volume of diarrhoeal stools and recovered from diarrhoea sooner after the start of treatment. Their requirement for oral rehydration fluid was significantly reduced. Breast feeding exerts a beneficial effect on the course and outcome of acute diarrhoea by reducing the number and volume of diarrhoeal stools.

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