Exploring the potential of gold(III) cyclometallated compounds as cytotoxic agents: variations on the C

A series of novel (C^N) cyclometallated Au(III) complexes of general formula [Au(py(b)-H)L(1)L(2)](n+) (py(b)-H = C^N cyclometallated 2-benzylpyridine, L(1) and L(2) being chlorido, phosphane or glucosethiolato ligands, n = 0 or 1) have been synthesized and fully characterized using different techniques, including NMR, IR and far-IR, mass spectrometry, as well as elemental analysis. The crystal structure of one compound has been solved using X-ray diffraction methods. All compounds were tested in vitro in five human cancer cell lines including the lung, breast, colon and ovarian cancer cells. For comparison purposes, all compounds were also tested in a model of healthy human cells from the embryonic kidney. Notably, all new compounds were more toxic than their cyclometallated precursor bearing two chlorido ligands, and the derivative bearing one phosphane ligand presented the most promising toxicity profile in our in vitro screening, displaying a p53 dependent activity in colorectal cancer HCT116 cells. Finally, for the first time C^N cyclometallated gold(III) complexes were shown to be potent inhibitors of the zinc finger protein PARP-1, involved in the mechanism of cisplatin resistance.

Gender-dependent specific immune response during chronic human Schistosomiasis haematobia.

The cellular and humoral acquired immune responses to Schistosoma haematobium 28 kD gluthathione S-Transferase (Sh28GST) antigen were evaluated in a Senegalese population chronically infected with S. haematobium parasite. We show a gender-dependent immune response in adult individuals presenting similar intensities of infection. Indeed, the specific IgA response and production of TGF-beta and IL-10 were found significantly higher in females compared to males. In addition, we showed that this profile was combined with a weak production of Th1-related cytokines (TNFalpha and IFNgamma) and was associated with an absence of proliferation to the antigen. A significantly higher Nuclear Matrix Protein 41/7 secretion, an apoptosis marker, was specifically observed in mononuclear blood cell cultures of females suggesting that a specific cell death process was engaged in a gender-dependent manner. This specific profile could be associated with the so-called T helper type-3 (Th3) immune response specifically promoting the production of IgA and would be developed upon the down-regulation of the specific Type-1 response by a probable cell death mechanism. This gender-dependent immune regulation, which may be under the influence of nonimmunological factors like sexual hormones, may be related to the chronicity of the infection.

Cationic ruthenium allenylidene complexes as catalysts for ring closing olefin metathesis

A series of well accessible cationic ruthenium allenylidene complexes of the general type [(eta6-arene)(R3P)RuCl(=C=CR'2)]+ X- is described which constitute a new class of pre-catalysts for ring closing olefin metathesis reactions (RCM) and provide an unprecedented example for the involvement of metal allenylidenes in catalysis. They effect the cyclization of various functionalized dienes and enynes with good to excellent yields and show a great tolerance towards an array of functional groups. Systematic variations of their basic structural motif have provided insights into the essential parameters responsible for catalytic activity which can be enhanced further by addition of Lewis or Bronsted acids, by irradiation with UV light, or by the adequate choice of the "non-coordinating" counterion X-. The latter turned out to play a particularly important role in determining the rate and selectivity of the reaction. A similarly pronounced influence is exerted by remote substituents on the allenylidene residue which indicates that this ligand (or a ligand derived thereof) may remain attached to the metal throughout the catalytic process. X-ray crystal structures of the catalytically active allenylidene complexes 3b.PF6 and 15.OTf as well as of the chelate complex 10 required for the preparation of the latter catalyst are reported.

The epidemiology of a recent focus of mixed Schistosoma haematobium and Schistosoma mansoni infections around the 'Lac de Guiers' in the Senegal River Basin, Senegal.

A village with mixed Schistosoma mansoni and S. haematobium infections (probably in a early endemic phase) was identified around the Lac de Guiers in the Senegal River Basin. In documenting the epidemiology of both schistosomes, we focused on prevalence and intensity of infection, transmission patterns and the impact of treatment. S. mansoni prevalences (near 100%) and egg counts (overall geometric mean eggs per gram of faeces (epg) of 589 were high in all age groups, with 35% of individuals excreting > 1000 epg, and showing a slow decline in egg output only after the age of 30 years. The overall prevalence (28%) and egg counts (2% > 50 eggs/10 ml) of S. haematobium were low, with mean counts of 6.3 eggs/10 ml. Maximal mean S. mansoni egg counts were found in 5-9 year-old boys and in 15-19 year-old girls; S. haematobium maximal counts in 1-4 year-old boys and in girls aged 5-9. Extremely high Biomphalaria pfeifferi infection ratios were recorded over the whole year. Following a single treatment, re-infection was rapid with prevalences and mean egg counts of both Schistosoma species reaching pretreatment levels within 7 months.

Rift valley fever surveillance in the lower Senegal river basin: update 10 years after the epidemic.

After the Rift valley fever (RVF) epidemic of 1987 in the Senegal River Basin, RVF surveillance based on serosurveys has been conducted for 10 years. Serum samples were obtained from 1336 persons and from sheep and goats in selected areas, and these were tested for IgG/IgM RVF antibodies by ELISA. After a period of regular decrease in RVF prevalence in domestic animals until 1993, an epizootic was observed in all herds in 1994-95 with increases in IgM levels and abortions. During the same period, no human cases or RVF IgM were detected. The RVF IgG prevalence significantly correlated with date of birth: children born after 1987 have a low prevalence (5%) in clear contrast to the older population (25.3%) in Podor district. A retrospective analysis of rainfall and RVF prevalence in small domestic animals over the last 10 years showed that the re-emergence correlated with heavy rainfall. A general analysis of the risk of re-emergence and the efficiency of this RVF surveillance system are presented.

The effect of different treatment regimens on the epidemiology of seasonally transmitted Schistosoma haematobium infections in four villages in the Senegal River Basin, Senegal.

This paper describes the present epidemiological situation of Schistosoma haematobium in 4 villages in the middle valley of the Senegal River Basin, in terms of level and intensity of infection, seasonality of transmission, and intermediate hosts, and the effect of different treatment schedules with praziquantel on the overall infection levels and re-infection rates. The longitudinal study involving 7 surveys was carried out between June 1995 and March 1997 in Diatar, Guia, Donaye and Niandane. The prevalence and intensity of infection remained low throughout the survey (< 55% and < 12 eggs/10 mL urine), and there were no systematic differences in the prevalence or intensity of infection between men and women. Before treatment, infections were highly aggregated in individuals and were concentrated in children (aged < 15 years) with 85% of the potential contamination; no individual aged > 24 years produced > 50 eggs/10 mL urine. Using WHO guidelines mass treatment was given to all Diatar and Guia villagers in December 1995, whereas in Donaye and Niandane only individuals positive for eggs were treated. Six weeks post-treatment cure rates in all villages were > 80%, with marked declines in levels of infection (< 20% and < 4.5 eggs/10 mL). By March 1997 infection levels in Donaye and Niandane had returned to pre-treatment levels, whereas in the 2 mass-treated villages (Diatar and Guia) infection levels were still markedly reduced compared to pre-treatment levels. Rates of conversion were very low between all surveys; however, there was an apparent high level of reversion (> 20%), due to the alternation of individuals apparently positive and negative between surveys. Water and infected snails were present from June to March. Therefore, owing to the high aggregation of infections in children, the low overall infection levels and the transmission period, it is suggested that in this area the best treatment schedule would be selective treatment of school-aged children in March/April, probably on an annual basis.

Efficacy of praziquantel against Schistosoma mansoni in northern Senegal.

Two treatments with praziquantel (PZQ) 40 mg/kg, 40 d apart, were given to individuals in a recently established (< 6 years) Schistosoma mansoni focus in the Senegal River Basin (SRB). Efficacy of treatment was evaluated 4 weeks after each treatment. Among 130 individuals who provided stool samples on days 0, 118 and 153 and were treated on days 85 and 125, 113 (87%) were infected with S. mansoni before treatment. The overall geometric mean faecal egg count of the infected individuals was 478 eggs/g. Four weeks after the first treatment (day 118), the overall cure rate was only 42.5% and the overall reduction in intensity of infection was 70.7%. However, 4 weeks after the second treatment (day 153), the overall cure rate rose to 76.1% and the overall reduction in intensity was 88.1%. The greatest increase in cure rate between the 2 treatments was in those individuals who were initially the most heavily infected (> 1000 eggs/g). There was no apparent difference in cure rate between younger (< 20 years) and older individuals (> 20 years). No evidence for the existence of a PZQ tolerant strain of S. mansoni was found. Two treatments of PZQ 40 mg/kg, 40 d apart, were sufficient to give an adequate cure rate and high reductions in the intensity of infection. As there was insufficient time for reinfection between treatment and follow-up to result in egg production, the low cure rate observed after one treatment was probably the result of a combination of high infection intensity and the maturation of pre-existing prepatents S. mansoni infections.

Morbidity induced by Schistosoma haematobium infections, as assessed by ultrasound before and after treatment with praziquantel, in a recently expanded focus (Senegal River basin).

Seven years after the completion of two dams in the Senegal River basin, 203 individuals from four villages around Podor in the middle valley, where Schistosoma haematobium infections were present, were examined in June 1995. In December 1995 a single dose of praziquantel (40 mg/kg) was given to each of these subjects, who were re-examined in April 1996. Clinical and parasitological signs of infection were investigated at both examinations, and ultrasonography was performed to check for lesions of the urinary tract induced by S. haematobium. As uninfected controls, 200 people from four villages where S. haematobium was absent were similarly examined, in November 1995. Prior to treatment, bladder irregularities were observed in 43% of the subjects from Podor but only 6% of the uninfected controls. The severity of the bladder lesions visible by ultrasonography was significantly associated with intensity of infection, despite the generally low levels of infection in the subjects mean = 13.1 eggs/10 ml urine). Four months after treatment, however, the frequency of bladder irregularities among the subjects (11%) was similar to that in the uninfected controls and intensities of infection and other clinical signs of disease had also significantly declined. The prevalence of haematuria, for example, fell from 35% pre-treatment to 10% post-treatment. The results indicate that the onset of S. haematobium morbidity can be relatively rapid even in areas with seasonal and low levels of transmission, and demonstrate that treatment to reduce morbidity in such areas is important and could be relatively simple and very effective.

Seasonality, malaria, and impact of prophylaxis in a West African village I. Effect of anemia in pregnancy.

The importance of malaria as a cause of anemia in pregnancy in endemic areas remains controversial. The prevalence of anemia in pregnant women following the dry (May) and the rainy (November) seasons was compared in two successive years in Bougoula village (region of Sikasso, Mali). Phase I (1992) was observational and included 172 pregnant women and 208 controls. In Phase II (1993, 174 pregnant women and 206 controls), malaria prophylaxis with proguanil (200 mg/day) and chloroquine (300 mg/week) was offered to pregnant women. A strong seasonal variation in the prevalence of moderate to severe anemia in pregnant women (hematocrit < 30%) occurred in Phase I (dry season = 8.7%, rainy season = 41.2%). This variation was present only in women of parity lower than five, and paralleled variation in parasitemia. In Phase II, the seasonal variation of anemia was suppressed in women under malaria prophylaxis (presence of antimalarial metabolites in urine), and the overall prevalence of moderate to severe anemia in pregnancy decreased by 55.5% (22.8-74.3%). We conclude that malaria is the major cause of anemia in pregnancy in this region. A high priority should be given to prevention of malaria in pregnancy.

Seasonality, malaria, and impact of prophylaxis in a West African village. II. Effect on birthweight.

The impact of malaria on low birthweight was investigated in Bougoula village (Sikasso region, Mali). In two successive years, pregnant women were followed until delivery. Phase I (1992) was observational, with 135 complete observations. Phase II (1993) included 126 participants, who were offered malaria prophylaxis with proguanil (200 mg/day) and chloroquine (300 mg/week). The results show that 1) infants of first and second pregnancies had lower birth weights (-382.7 +/- 62.6 g; P < 0.0001) compared with higher rank pregnancies; 2) strong seasonal variation in birthweight was observed in Phase I, with an annual cycle, a nadir in January, and an amplitude of 372.4 g (P = 0.0002); 3) parasitemia measured during pregnancy was associated with lower birthweight in infants from first and second pregnancies, but not from higher parity mothers; and 4) malaria prophylaxis taken for 20 weeks or more in Phase II suppressed the seasonal variation of birthweight and the effect of low parity (+423.4 +/- 118.8 g; P = 0.0004). We conclude that malaria in pregnancy has an important negative impact on birthweight in first and second pregnancies. Prophylaxis with proguanil and chloroquine is an effective prophylaxis when taken for 20 weeks or more.

Royal Society of Tropical Medicine and Hygiene meeting at Manson House, London, 18 May 1995. The epidemiology of human schistosomiasis in the Senegal river basin.

Extensive water development has taken place in the north of Senegal over the last decade, resulting in a large increase in the amount of fresh water for irrigation. The objectives of the present study were to determine the prevalence and intensity of Schistosoma mansoni and S. haematobium in the Senegal river basin (SRB), and to ascertain the distribution of the snail species acting as intermediate hosts for both species of schistosomes. The schistosomiasis survey started in January 1994 and was completed in March 1995. Compared to studies before the construction of the Diama dam, there was a significant increase in both the prevalence and intensity of urinary and intestinal schistosomiasis in the human population in parts of the SRB. From the 9014 people who were registered from 180 villages and 4 towns (10 districts), 7750 were examined. S. mansoni was found in the lower valley (lower delta-Senegal river, lower delta-Lampsar river, upper delta, and diéré) but not in the middle valley. The mean prevalence ranged from 4.4% in the lower delta-Senegal River to 71.8% in the zone of Lac de Guiers, where prevalence and intensity of infection were higher on the eastern side of the lake (81.3% with a mean number of 2088 eggs/g of faeces) compared with the western side (50.3% with a mean 1111 eggs/g). S. haematobium was recorded throughout the area of study, ranging from a mean prevalence of 0.37% in diére (lower valley) to 41.5% in the lower valley (Lampsar river), where the mean egg count was 313/10 mL of urine. Physical and chemical changes to the environment have favoured the spread and increase in the populations of freshwater snails. The only snail involved in the transmission of S. mansoni was Biomphalaria pfeifferi. Five species of bulinid snails were present--Bulinus globosus, Bu. umbilicatus, Bu. senegalensis, Bu. forskalii and Bu. truncatus--but only the first 3 species were involved in the transmission of S. haematobium in the lower and middle valleys.

Malnutrition of children in Sikasso (Mali): prevalence and socio-economic determinants.

BACKGROUND: Malnutrition of children is a major public health problem in many African countries. Despite a relatively favourable geographical situation, the prevalence of malnutrition is high in the Sikasso region (Mali). METHODS: Survey repeated annually during 5 years, to a sample of 491 families living in Sikasso. The determinants of wasting and stunting were analysed using logistic regression. RESULTS: The prevalence of stunting was about 25%. Prevalence of wasting was about 12%, which is very high, and had been increasing in the past years. No strong associations with socio-economic factors were observed for wasting. Stunting was strongly associated with the education level of both parents, and with the family assets.

PIP: There is a high prevalence of malnutrition in the Sikasso region of Mali. The authors report their findings from a study of the determinants of wasting and stunting in the region using logistic regression. A survey was repeated annually over the course of five years in a sample of 491 families living in Sikasso. This group of families was randomly drawn from the administrative census of 1986 and represents 11% of the total number of families in the municipality. The overall prevalence of stunting was 27.2% at the first survey round and 23.2% at the fifth round, with no significant variations between the yearly rounds. The prevalence of wasting, however, was 6.5% on the first round and 12.5% on the fifth round, peaking at 17.9% on the fourth round. These differences were statistically significant. There were no statistically significant differences of malnutrition prevalence between the sexes. No strong association with socioeconomic factors was found for wasting, although stunting was strongly associated with the education level of both parents and with family assets.

[Cities and oil. Historical and prospective aspects of the urban population of Venezuela]. / Ciudades y petroleo. Aspectos historicos y prospectivos de la poblacion urbana de Venezuela.

PIP: The authors present a historical overview of urbanization in Venezuela. The impact of the oil economy on population change and spatial distribution is emphasized. A typology of cities based on socioeconomic function and on a demographic classification of urban centers is devised. Future trends in urbanization are also considered. (SUMMARY IN ENG)^ieng