In vivo efficacies of 5'-methylthioadenosine analogs as trypanocides

5'-Deoxy-5'-(methylthio)adenosine (MTA), a key by-product of polyamine biosynthesis, is cleaved by MTA phosphorylase and is salvaged as adenine and, through conversion of the ribose moiety, methionine. An analog of MTA, 5'-deoxy-5'-(hydroxyethylthio)adenosine (HETA), is a substrate for trypanosome MTA phosphorylase and is active in vitro and in vivo against Trypanosoma brucei brucei, an agent of bovine trypanosomiasis. In this study, HETA and three O-acylated HETA derivatives were examined for their activities against model infections of T. b. brucei and Trypanosoma brucei rhodesiense, the agent of East African sleeping sickness. HETA was curative (>60%) for infections caused by 5 of 11 clinical isolates of T. b. rhodesiense when it was given to mice at 200 mg/kg of body weight for 7 days as a continuous infusion in osmotic pumps. HETA at 150 to 200 mg/kg also extended the life spans of the mice infected with four additional isolates two- to fivefold. Di- and tri-O-acetylated derivatives of HETA also proved curative for the infections, while a tri-O-propionyl derivative, although also curative, was not as effective. This study indicates that substrate analogs of MTA should be given important consideration for development as novel chemotherapies against African trypanosomiasis.     

In vitro antitrypanosomal activity of African plants used in traditional medicine in Uganda to treat sleeping sickness

In Uganda, as in many other African countries, herbal treatment of various diseases is still common. In the present study, 9 plant species collected from Tanzania and Uganda and used by traditional healers in southern-eastern Uganda for the treatment of human African trypanosomiasis (sleeping sickness) were extracted and screened for their in vitro activity against Trypanosoma brucei rhodesiense, one of the two causative agents of sleeping sickness. Eight lipophilic extracts of 5 plants revealed very promising antitrypanosomal activity with IC50 values below 1 microgram/ml; among them were extracts prepared from Albizia gummifera (2), Ehretia amoena (1), Entada abyssinica (2), Securinega virosa (1) and Vernonia subuligera (2). Activity with IC50 values between 1 and 10 micrograms/ml was determined for 15 further extracts. Cytotoxicity of active extracts, tested on a human fibroblast cell line (WI-38), was found to be high, and therefore selectivity indices resulted in less favourable ranges than those for the few commercially available drugs. Nevertheless, the results confirm the potential of ethnobotanically selected plants as remedies against sleeping sickness and call for phytochemical studies.     

Human African trypanosomiasis: an emerging public health crisis

There is a dramatic resurgence of human African trypanosomiasis (HAT) in sub-Saharan Africa. T.b. gambiense is spreading epidemically in large areas of Central Africa, especially the Southern Sudan, Congo-Zaire, Angola, Uganda and the Central African Republic. Devastating epidemics of T.b. rhodesiense have occurred in south-eastern Uganda. The causes of the re-emergence of sleeping sickness as a public health problem include widespread civil disturbance and war, declining economies, reduced health financing and the dismantling of disease control programmes. Despite the inevitably fatal outcome without treatment, HAT is often given low priority by donors and national governments. The advances made in diagnosis, treatment and vector control have not been sufficiently implemented. To limit the human impact in some of the poorest communities in Africa, endemic countries will require external support to implement strategies for disease control. Donor agencies, NGOs and mission organisations could play an important role in supporting control efforts. National authorities will need to control and co-ordinate these efforts with assistance from WHO and the international community.     

Pacemaker therapy in heart failure

The diagnosis of African trypanosomiasis is parasitologic and often can be difficult, especially in patients infected with Trypanosoma brucei gambiense, the cause of West African sleeping sickness. In the United States imported cases of sleeping sickness are rare, and most occur in tourists returning from East African game parks rather than among immigrants. I report here the use of a T. brucei specific PCR assay in a West African immigrant who presented with neurological symptoms more than 12 years after he had last been in Africa. The patient's historical and physical findings, as well as abnormal cerebrospinal fluid (CSF) parameters, suggested a diagnosis of sleeping sickness. The diagnosis was confirmed when the PCR assay demonstrated the presence of parasite DNA in CSF and blood. Several months after curative therapy the CSF continued to be positive by PCR. These findings suggest that the PCR assay may be useful for sensitive and specific diagnosis of sleeping sickness, but that it may not be helpful for assessing the effect of drug treatment.     

Spermatic granulomas of ischemic origin in the rat epididymis

Trypanosoma (Trypanozoon) brucei includes three morphologically identical subspecies which are poorly defined by clinical behaviour; T. b. brucei does not infect man, whereas T. b. rhodesiense causes an acute, and T. b gambiense a chronic, disease. Thirty-three isolates of the complex, each of which had previously been identified on clinical or other criteria, were compared by the electrophoretic patterns of two trypanosomal enzymes, alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT). One particular ALAT pattern clearly segregated a group of human pathogens of which all except one were labelled T. b. gambiense. The exception was labelled T. b. rhodesiense, and in addition three putative T. b. gambiense isolates did not have this pattern; it is suggested that only one presents a serious anomaly. The T. b. gambiense group could also be subdivided by three ASAT patterns which coincided with known groupings based on serological criteria.     

In vitro and in vivo activities of trybizine hydrochloride against various pathogenic trypanosome species

Trybizine hydrochloride [O,O'-bis(4,6-diamino-1,2-dihydro-2, 2-tetramethylene-s-triazine-1-yl)-1,6-hexanediol dihydrochloride] was active in vitro against the sleeping sickness-causing agents Trypanosoma brucei subsp. rhodesiense and T. brucei subsp. gambiense; against a multidrug-resistant organism, T. brucei subsp. brucei; and against animal-pathogenic organisms Trypanosoma evansi, Trypanosoma equiperdum, and Trypanosoma congolense; but not against the intracellular parasites Trypanosoma cruzi and Leishmania donovani. Cytotoxic effects against mammalian cells were observed at approximately 10(6)-fold higher concentrations than those necessary to inhibit T. brucei subsp. rhodesiense. Trybizine hydrochloride was able to eliminate T. brucei subsp. rhodesiense and T. brucei subsp. gambiense in an acute rodent model with four intraperitoneal doses of 0.25 mg kg of body weight-1 or four doses of 1 mg kg-1, respectively, or with four oral doses of 20 mg kg-1. The compound expressed activity against suramin-resistant T. evansi strains in mice. However, these concentrations were not sufficient to cure mice infected with multidrug-resistant T. brucei subsp. brucei. A late-stage rodent model with central nervous system involvement could not be cured, indicating that trybizine may not pass the blood-brain barrier in sufficient quantities.     

(+)-7-Deaza-5''-noraristeromycin as an anti-trypanosomal agent

The (+)-enantiomer of 7-deaza-5'-noraristeromycin (4) has been found to show IC50 values ranging from 0.16 to 5.3 microM against four strains of African trypanosomes, one Trypanosoma brucei brucei isolate, and several clinical isolates of Trypanosoma brucei rhodesiense (agent of east African sleeping sickness), including a multidrug resistant clone of one isolate. While this compound was originally designed to inhibit S-adenosyl-L-homocysteine hydrolase, it has been found to have no effect on this enzyme.     

The susceptibility of chickens to Trypanosoma brucei subspecies

Chickens were susceptible to infection with three different stocks of the subgenus Trypanozoon: two of presumptive Trypanosoma b. brucei and one of T. b. rhodesiense. Two groups of chickens were used: the first hatched following inoculation with either T. b. brucei or T. b. rhodesiense during embryonic development, and the second were infected as adult birds. In both experimental groups, parasitaemia persisted for prolonged periods, but was mostly subpatent and detectable only by subinoculation of blood into mice. In chickens infected as embryos, parasitaemias were patent for five weeks after hatching, but subpatent thereafter (to weeks 13 to 17). Quantitative estimations of the parasitaemias of seven of the birds hatched from embryos inoculated with T. b. brucei revealed fluctuations in the number of circulating trypanosomes, with an initial peak between days 2 to 9 after hatching. Between weeks 13 to 17 after hatching the chickens appeared to have recovered spontaneously from the trypanosome infections. Homologous challenge at week 20 failed to produce a recrudescence of parasitaemia, indicative of a possible acquired immunity. The infections of ten chickens inoculated with either T. b. brucei or T. b. rhodesiense as adult birds were microscopically subpatent throughout the observation period of six weeks, but subinoculation of blood into mice showed the chickens were parasitaemic from week one and thereafter. Different aspects of infection of avian hosts by the Trypanozoon subspecies are discussed.     

Acute mountain sickness in the Southern Alps of New Zealand

AIM: To assess the incidence and impact of acute mountain sickness in the Southern Alps of New Zealand. METHODS: Over a 22 month period, mountaineers in the Mount Cook region were asked to complete a questionnaire at the completion of their climbing excursions. The questionnaire recorded demographic data and incorporated the Lake Louise scoring system to assess the presence of acute mountain sickness. RESULTS: Of the 114 subjects who completed the questionnaire, 30 (26%) developed acute mountain sickness. The incidence was higher amongst those who slept above 2500 m (50%). Of those with acute mountain sickness, 33% reported that their symptoms resulted in no reduction in activity, while 13% reported a moderate or severe reduction in activity. CONCLUSION: Mountaineers climbing in New Zealand's Southern Alps should be aware of the risk of acute mountain sickness, especially for those sleeping above 2500 m.     

Fluorescent estimation of H2O2-induced changes in cell viability and cellular nonprotein thiol level of dissociated rat thymocytes

Vector control and the detection (followed by treatment) of infected individual are the two methods currently available for the control of sleeping sickness. The basic reproduction rate of a compartmental model (Kermack and McKendrick) is used to analyze and compare the two strategies. The model shows that when there is a long first stage characteristic of an endemic situation, the detection of sick individuals is more efficient than vector control. This higher efficiency of detection decreases in a epidemic situation. In this case vector control in the form of a decrease in vector density and/or an increase in vector mortality is relatively more efficient than detection. Because it is squared in the basic reproduction rate, the probability of a tsetse blood meal on humans is an important and sensitive parameter in the study of control strategies. This sensitivity has been observed previously and empirically by field workers. When the probability of a tsetse blood meal on humans is above a certain value, vector control becomes warranted or even necessary.     

Acute myocardial infarction case fatality, incidence and mortality rates in a population registry in Gerona, Spain, 1990-1992. REGICOR Investigators

BACKGROUND: Community-based registries provide the best approach to assessing the impact of myocardial infarction (MI) in a population. The objective of the present study was to determine MI mortality, incidence, attack rate and 28-day case fatality in the province of Gerona, Spain from 1990 to 1992. METHODS: Standardized methods were used to find, register and classify MI cases in that population (509628 inhabitants) as definite, possible and insufficient-data MI. RESULTS: Of the 1456 cases fulfilling eligibility criteria, 850 (58.4%) were classified as definite MI, 162 (11.1%) as fatal possible MI, 232 (15.9%) as no MI and 160 (11.0%) as fatal insufficient data. The 1990-1992 age-standardized incidence rates (first MI cases only) for definite and fatal possible MI were 140.8 per 100000 men and 20.4 per 100000 women, all aged 35-64 years; attack rates (first and recurrent MI cases) were 182.9 and 24.5, and mortality rates 46.4 and 5.8, respectively. Case fatality at 28 days was 27.4% and 19.9% in men and women, respectively, but women died later over that period. With respect to men, the age-adjusted risk among women of dying within 28 days post-MI was 1.26 (95% confidence interval [CI]: 0.94-1.69). CONCLUSIONS: Myocardial infarction, incidence, mortality rates and case fatality in Gerona are among the lowest in the world. Age-adjusted case fatality within 28 days is only marginally higher in women than in men, but fatal cases occur later within this period in women.     

Trends in mortality from tuberculosis in England and Wales: effect of age on deaths from non-respiratory disease

BACKGROUND: Although mortality from tuberculosis has continued to fall in recent years, there has been little change in the case fatality rate for tuberculosis over the same period. This has previously been shown to be due to the increasing proportion of cases of tuberculosis occurring in the elderly. Tuberculosis mortality and case fatality were therefore analysed to determine if this disappointing trend in case fatality rate has occurred from disease in all or only certain sites. METHODS: A retrospective analysis of the tuberculosis mortality and case fatality rates in England and Wales for the period 1972-92 was carried out. The average annual percentage change in tuberculosis was calculated for each disease site and by age group and the results were compared. RESULTS: The analysis showed that, although the mortality rate fell steadily by 5.6% per annum, the case fatality rate decreased by only 0.9% (95% CI -1.7 to -0.1) per annum. The case fatality rate for respiratory and central nervous system disease declined, but no decline in tuberculosis at "other" sites was observed (1.01% (+2.2 to -0.2) for all age groups combined). In the group aged 75 and over, however, the proportion of deaths due to disease at other sites increased by 3.2% (2.2 to 4.3) per annum whilst in the other age groups the mortality rate declined. CONCLUSIONS: This analysis suggests that clinicians may be becoming less able to recognise non-respiratory presentations of tuberculosis, particularly in the elderly, and underlines the need to consider tuberculosis as a diagnosis to avoid delay in treatment.     

School-based mental health services in the United States: history, current models and needs

The prevalence of ruminant trypanosomosis and tsetse flies was investigated in Katsina-Ala Local Government Area--a sleeping sickness endemic area--between the valleys of River Benue, Katsina-Ala and Donga in Central Nigeria. Analysis of three hundred and twenty blood samples showed that among semi-nomadic animals, about one cattle (21.3%; 0.213, confidence interval C1 +/- 0.06) and two sheep (38.0%; 0.380, C1 +/- 0.10) out of five carried mature trypanosome infections. Significantly lower (P < 0.05) values (12.5%; 0.125, C1 +/- 0.08) were recorded among peri-domestic West African Cross Red Sokoto (WAD x RS) goats. Trypanosoma vivax was the most prevalent species encountered; it was diagnosed in 10.3% of the ruminant population and responsible for 42.8% of the infections in all animals. Corresponding figures for T. congolense were 5.9% and 24.6%, respectively. T. brucei infections were low in cattle (1.8%) and absent in goats. Males and young stock had lower infection but the difference was not significant (P > 0.05) except between the ages in cattle. Glossina tachinoides was the only tsetse species encountered and responded to acetone odour attractant in biconical traps.     

An ecological study of the effectiveness of mammography in reducing breast cancer mortality

OBJECTIVES: The purpose of this study was to determine the relation of screening mammography to breast cancer incidence and case fatality. METHODS: In a sample of White female Medicare beneficiaries hospitalized in 1990-1991, age-adjusted breast cancer incidence and 2-year case fatality rates were estimated and compared with the frequency of mammographic screening from a population-based survey. RESULTS: The average rates for incidence, case fatality, and mammography within 5 years in 29 states were 414/100,000, 18.8%, and 59.2%, respectively. There was a positive state-level correlation between mammography rates and incidence and an inverse correlation between mammography and case fatality. CONCLUSIONS: High screening mammography rates in some states are associated with reduced breast cancer case fatality rates, presumably as a result of diagnosis of earlier stage cancers.     

Epidemiologic data of stroke. Data of the WHO-MONICA Project in Germany

Analyses of stroke morbidity or mortality are usually based on official statistics. A reduction in stroke mortality rates has been shown for many countries. It is not clear, however, whether this is due to declining morbidity or case fatality (or both). For this purposes population-based register data are required. Using the standardized methodology of the WHO-MONICA Project, stroke cases were also registered in Germany from 1984 to 1993 (7,435 first-ever and recurrent stroke cases). The data collection was almost restricted to East Germany. The age-specific stroke rates in males/females showed an increase from 9/11 per 100,000 population in the youngest age group (25-34) to 1,005/779 cases per year in the oldest group under study (65-74). If one tries to classify stroke types, which is not always possible in a population-based register, the best estimate for men (women) would be: 63(62%) thromboembolic stroke, 25(22)% intracerebral hemorrhage, and 12(17)% subarachnoid hemorrhage. The 28-day case fatality of the 25-74 year old stroke patients was found to be about 40%. Neither for stroke attacks nor for case fatality was a convincing time trend over the 10-year period found. The very small changes observed over 10 years time should lead to increased attention to strokes, particularly primary and secondary prevention, and this not only in East Germany. This applies also for treatment in the acute phase, because the case fatality before admission in the hospital and during the first few days is still very high. Population-based studies of the long-term prognosis of stroke patients in Germany are also missing, i.e., including the effectiveness of various forms of treatment and rehabilitation. Systematic monitoring of the development in this field is an important part of the assessment of the quality and effectiveness of the health care service.     

Antitrypanosomal activity of a new triazine derivative, SIPI 1029, In vitro and in model infections

A recently developed diaminotriazine derivative [O,O'-bis(1, 2-dihydro-2,2-tetramethylene-4,6-diamino-S-triazin-1-yl)-1, 6-hexanediol dihydrochloride; T-46; SIPI 1029] was examined for activity against African trypanosomes in in vitro and in vivo model systems. In vitro, SIPI 1029 was 50% inhibitory for growth of bloodstream trypomastigotes of four strains of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense at 0.15 to 2.15 nM (50% inhibitory concentrations). In in vivo mouse laboratory models of T. b. rhodesiense clinical isolate infections, SIPI 1029 was curative for 12 of 13 isolates at /=60% curative, and in six of these, a dose of /=60% cure rates. A number of these isolates were resistant to the standard trypanocide melarsoprol (Arsobal) and/or the diamidines diminazene aceturate (Berenil) and pentamidine. SIPI 1029 was also curative in combination with DL-alpha-difluoromethylornithine (Ornidyl) in a T. b. brucei central nervous system model infection. Some evidence of toxicity was found in dosage regimens of 10 mg/kg/day for 2 or 3 days in which deaths were observed in 6 of 65 animals given this dosage regimen. The activity of SIPI 1029 in this study indicates that this class of compounds (diaminotriazines) should be explored as leads for new human and veterinary trypanocides.     

Preinfarction blood pressure and smoking are determinants for a fatal outcome of myocardial infarction: a prospective analysis from the Finnmark Study

BACKGROUND: Serum cholesterol levels, blood pressure, and smoking are the classic coronary risk factors, but what determines whether a myocardial infarction will be fatal or not? OBJECTIVE: To investigate cardiovascular risk factors that may influence survival in subjects with coronary heart disease (myocardial infarction and sudden death). SUBJECTS AND METHODS: All inhabitants aged 35 to 52 years in Finnmark County, Norway, were invited to a cardiovascular survey in 1974-1975 and/or 1977-1978. Attendance rate was 90.5%. A total of 6995 men and 6320 women were followed up for 14 years with regard to incident myocardial infarction and sudden death. Predictors for 28-day case fatality rate after first myocardial infarction were analyzed. RESULTS: During 186 643 person-years, 635 events among men and 125 events among women were registered. The case fatality rate was 31.6% in men and 28.0% in women (P =.50). Among men (women) with baseline systolic blood pressure lower than 140 mm Hg, the 28-day case fatality rate was 24.5% (22.6%), among those with systolic blood pressure of 140 through 159 mm Hg, the case fatality rate was 35.6% (28.2%), and among those with systolic blood pressure of 160 mm Hg or higher, the case fatality rate was 48.2% (41.7%). Of the 760 subjects with myocardial infarction, 348 died during follow-up. In Cox regression analysis, systolic blood pressure at baseline was strongly related to death (relative risk per 15 mm Hg, 1.22; 95% confidence interval, 1.13-1.31). Daily smoking at baseline (relative risk, 1.40; 95% confidence interval, 1.07-1.85) and age at time of event (relative risk per 5 years, 1.12; 95% confidence interval, 1.01-1.24) were additional significant risk factors, while total serum and high-density lipoprotein cholesterol levels were unrelated to survival. Similar results were obtained with diastolic blood pressure in the model. CONCLUSIONS: Preinfarction blood pressure was an important predictor of case fatality rate in myocardial infarction. Daily smoking and age were additional significant predictors.     

Falling hospital mortality for acute myocardial infarction in Quebec hospitals

OBJECTIVE: To present in-hospital mortality trends for acute myocardial infarction (AMI). DESIGN: Observational study using the Quebec administrative hospital database, which records all hospitalizations for AMI, for the period 1986 to 1996. RESULTS: From 1986 to 1996, the case fatality rate for AMI decreased from 18.4% to 12.7% despite an increase in the total number of admissions, due to an ageing population. Men and women have had similar yearly mortality reductions--7.6% versus 7.4%, respectively--although the absolute case fatality rate remains significantly higher for women. The mortality reduction for men was constant over the decade, while the decline for women was more pronounced over the last five years. Improving case fatality rates were also observed in the elderly and again were most evident from 1991 to 1996. CONCLUSIONS: These data show a sharp decline in case fatality rates for AMI patients treated in Quebec hospitals from 1986 to 1996, suggesting that treatment advances observed in clinical trials are being applied at a population level. While improved survival has been observed in all patient groups, the data suggest that the part of the decline in mortality may be due to increased penetration of proven treatment strategies in women and the elderly.