Nicotine modulates molecules of the innate immune response in epithelial cells and macrophages during infection with M. tuberculosis.

Smoking increases susceptibility to becoming infected with and developing tuberculosis. Among the components of cigarette smoke, nicotine has been identified as the main immunomodulatory molecule; however, its effect on the innate immune system is unknown. In the present study, the effect of nicotine on molecules of the innate immune system was evaluated. Lung epithelial cells and macrophages were infected with Mycobacterium tuberculosis (Mtb) and/or treated with nicotine. The results show that nicotine alone decreases the expression of the Toll-like receptors (TLR)-2, TLR-4 and NOD-2 in all three cell types, as well as the production of the SP-D surfactant protein in type II pneumocytes. Moreover, it was observed that nicotine decreases the production of interleukin (IL)-6 and C-C chemokine ligand (CCL)5 during Mtb infection in epithelial cells (EpCs), whereas in macrophages derived from human monocytes (MDMs) there is a decrease in IL-8, IL-6, tumor necrosis factor (TNF)-α, IL-10, CCL2, C-X-C chemokine ligand (CXCL)9 and CXCL10 only during infection with Mtb. Although modulation of the expression of cytokines and chemokines appears to be partially mediated by the nicotinic acetylcholine receptor α7, blocking this receptor found no effect on the expression of receptors and SP-D. In summary, it was found that nicotine modulates the expression of innate immunity molecules necessary for the defense against tuberculosis.

The Ginkgo biloba extract (GbE) protects the kidney from damage produced by a single and low dose of carbon tetrachloride in adult male rats.

Gingko biloba leaves have been used as herbal medicine in China for 5000 years, and the standardized leaf extract (GB-STE) has some beneficial effects in the treatment of age-related, cardiovascular, and neurological diseases. The aim of this study was to investigate the renoprotective effects of the Gingko biloba extract (GbE) against the toxicity of a single and relatively low dose of carbon tetrachloride (CCl4). In male adult Wistar rats, we determined the urine flux, the concentration of total proteins in urine, the concentration of glucose in urine, and the concentration of malondialdehyde (MDA) in renal cortex as well as two markers of renal function (clearance of inulin and p-aminohippurate); we also compared the histological lesions caused by CCl4. Carbon tetrachloride increased the urinary concentration of total proteins, and the renal concentration of MDA; however, it did not modify the urine flux, urinary concentration of glucose, nor the inuline or the p-aminohipurate clearances. Morphologically, CCl4 generated some tubular damage that was more intense in the inner cortex of kidneys. The GbE extract counteracted the effects of CCl4 on the concentration of total proteins in urine, the concentration of renal MDA, and the renal histological changes. In conclusion the main toxic effects produced by CCl4 were prevented by the GbE, probably due to their antioxidant properties and the inhibition of the main P450 isoenzyme (CYP2E1) that metabolize CCl4.

Polymorphisms in the GSTT1 and GSTM1 genes are associated with increased risk of preeclampsia in the Mexican mestizo population.

Preeclampsia is a pregnancy-specific disorder in humans and a major cause of maternal and neonatal morbidity and mortality. Increasing evidence suggests that oxidative stress plays an important role in the pathogenesis of preeclampsia. The aim of this study was to investigate the relationship between null alleles of the glutathione S-transferases (GST) M1 and T1 genes and the risk of preeclampsia. This case-control study involved 112 preeclamptic and 233 normoevolutive pregnant women. The null polymorphisms were genotyped by multiplex polymerase chain reaction (PCR). Our results showed an increased risk of preeclampsia in patients with the GSTT1 null genotype [odds ratio (OR) = 2.21; 95% confidence interval (CI) = 1.14-4.27; P = 0.018]. Our data further showed that a combination of deletion genotypes of the GSTM1 and GSTT1 genes conferred an even higher risk of preeclampsia (OR = 4.56, 95%CI = 1.59-13.09; P = 0.005). Our results provide the first evidence suggesting that a GSTT1 null polymorphism might be associated with preeclampsia in the Mexican mestizo population, and that this risk increases with the combination of both GSTT1 and GSTM1 null polymorphisms.

A randomized trial comparing two corticosteroid regimens combined with mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection.

INTRODUCTION: The launching of mycophenolate mofetil (MMF) has reduced the incidence of acute rejection episodes. We sought to evaluate the efficacy of decreasing the steroid dose. MATERIALS AND METHODS: This was a quasiexperimental, randomized, prospective trial. We enrolled 150 patients who received de novo renal transplantations from living or cadaveric donors, fulfilling the screening criteria. Patients were randomized to one of the following two arms: (A) MMF at a 2 g/d dose, cyclosporine (CsA) at a dose necessary to achieve target levels, and corticosteroids at the usual doses; (B) MMF at a 2 g/d dose, CsA at a dose necessary to achieve target levels, and corticosteroids at doses 50% lower than those of group A. RESULTS: Group A included 72 (48%) and group B, 78 patients (52%). There were no differences among the variables: leukopenia occurred in 11 patients in group A, and five patients in group B. Complications occurred in 67.4% (56) of group A, but only 32.6% (27) were related to infections. One case of urinary infection occurred in group B, while six occurred in group A. There was one case of acute rejection in group A, and none in group B. One graft loss occurred in group A. There were no differences in the remaining variables under study. DISCUSSION: The results showed an increased complication rate related to receiving usual steroid doses. There was no increase in acute rejection episodes among patients receiving 50% of the usual steroid dose.

Electronic microscopy and EDX characterization of Teotihuacan prehispanic mortar from the cave under the Sun Pyramid.

A cave (102 m long) under the structure of the Sun pyramid of the prehispanic Teotihuacan City indicates the importance of the pyramid. Studies of the cave mortar samples using energy dispersive X-ray (EDX) fluorescence, scanning electron microscopy (SEM) and X-ray diffraction (XRD) showed no difference in the chemical elemental composition. The elements can be distributed in three groups: major, minor and trace elements. The minerals identified were compatible with the origins of the cave and with the magnetic pattern.

The ATP levels in kidneys and blood are mainly decreased by acute ingestion of tullidora (Karwinskia humboldtiana).

Our previous acute toxicity studies with Karwinskia humboldtiana (Kh) in rats showed renal hemodynamic changes with a marked increase in the fractional excretion of sodium and morphological damage. To analyse the effects of Kh or 'tullidora' on energetic metabolism, a single dose of an oral preparation from the seed fruits was given to Wistar rats (1.25 g/kg). In tullidora-treated rats there was 8% mortality. ATP concentrations in renal tissue decreased significantly (control: 53.85+/-3.34, tullidora 38.28+/-5.31 micromol/g fresh tissue, P<0.05). Total blood (54.8+/-0.96, tullidora: 40.2+/-1.55 micromol/dL, P<0.01) and haemoglobin-ATP concentrations (3.69+/-0.12, tullidora: 2.56+/-0.11 micromol/g, P<0.01) were also significantly diminished. Moreover, the total protein in renal cortex from tullidora-treated rats decreased as compared to control group (control: 71.43+/-2.88, tullidora: 55.20+/-4.06 mg/g fresh tissue, P<0.05). In contrast, Na+-K+-ATPase activity in tullidora-treated animals was not different from control rats. These findings might partially explain the acute effects and mortality observed in the Kh treated rats.

Safety assessment of the conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in stable renal transplant recipients.

The immunosuppressant mycophenolate mofetil (MMF; CellCept) has greatly improved transplant recipients' clinical outcomes, but its efficacy may be limited by dose adjustments due to adverse events (AEs). An enteric-coated formulation of mycophenolate sodium (EC-MPS; myfortic), designed to improve gastrointestinal tolerability is now available. This Latin-American, prospective, multicenter, open-label, 6-month trial assessed the safety and tolerability of converting renal transplant recipients from MMF to EC-MPS. In total, 237 renal transplant recipients (stable > or = 3 months' posttransplant) receiving MMF (< or =1000 mg b.i.d.) were enrolled. Adults (n = 218) were converted to EC-MPS 720 mg b.i.d. (equimolar to MMF 1000 mg b.i.d.) even if they were initially receiving <1000 mg MMF b.i.d. (ie, 47 adults received a higher than equimolar dose of EC-MPS). Children (n = 19) were converted to EC-MPS 450 or 432 mg/m2 b.i.d. Patients also received cyclosporine microemulsion (Neoral) and corticosteroids. There were three acute rejections and no graft failures. The incidence of AEs was 59.9% (in those receiving a higher than equimolar EC-MPS dose it was 57.4%). In all, 22% of patients had gastrointestinal AEs, 37% had infections, and 4.8% had hematological AEs. Only 24 patients (10%) had an AE-related dose reduction. Seven of these patients had received higher than equimolar doses of EC-MPS. Patients can be safely converted from different doses of MMF to a standard dose of EC-MPS. The requirement for EC-MPS dose reduction to manage AEs was relatively low. Use of EC-MPS is a valid alternative for renal transplant recipients receiving maintenance MMF treatment.

Stable renal transplant recipients can be safely converted from MMF to enteric-coated mycophenolate sodium tablets: Interim results of a multicenter Latin American study.

Enteric-coated mycophenolate sodium (EC-MPS) is designed to reduce mycophenolate acid (MPA)-related upper gastrointestinal (GI) adverse events (AEs). A multicenter, open-label, Latin American study in stable renal transplant patients is ongoing to assess the safety of the conversion from mycophenolate mofetil (MMF) to EC-MPS. An interim analysis was performed when 93 patients had completed 3 months. Prior to conversion, they had received MMF at a dose of 2 g/d, with the exception of eight adult patients who were receiving an average daily dose of 1.25 g. All adult patients were converted to EC-MPS (1.44 g/d; 0.450 g/m(2) bid for children). After conversion, the reported total incidence of AEs was 40.9%, including 28% infections, 1.1% hematologic, 19.4% GI, including 10.8% upper-GI AE (all mild) and 5.4% diarrhea. No patient discontinued the study medication due to adverse events. Only six patients (6%) required a dose adjustment. There were no episodes of acute rejection, death, or graft loss. During the period of analysis, the conversion from MMF to EC-MPS was safe, the enteric-coated tablet formulation prevented release of MPA in the upper GI tract, and only one patient had to reduce the dose due to an upper GI AE, concomitant with diarrhea. EC-MPS offers transplant physicians and their patients an alternative MPA therapy that is as effective and safe as MMF, but in a formulation that may provide GI tolerability benefits.

Glutathione S-transferases and esterases in placenta after normal and pre-eclamptic pregnancies.

Severe pre-eclampsia reduced significantly (P<0.05) by 68+/-6 per cent (mean+/-sem, n=10) the maximal velocity (V(max)) and, consequently, reduced significantly by 60+/-7 per cent the catalytic efficiency (C(E)) of placental glutathione transferase pi, assayed with ethacrynic acid. Mild and severe pre-eclampsia reduced significantly by 82+/-5 per cent (mean+/-sem, n=5) and by 41+/-5 per cent (mean+/-sem, n=10), respectively, the V(max)and, consequently, reduced significantly by 72+/-7 and by 33+/-13 per cent, respectively, the C(E)of esterase, assayed with p-nitrophenyl acetate. Furthermore, severe pre-eclampsia increased significantly by 296+/-78 per cent the Michaelis-Menten constant (K(m)) of total GST, assayed with chlorodinitrobenzene and, consequently, decreased significantly the C(E)by 83+/-3 per cent. On the other hand, the concentrations of total and non-protein thiols did not change significantly in placental homogenates from patients with mild or severe pre-eclampsia compared to normal pregnancies. These findings would indicate a decreased capacity of the glutathione transferases and esterase detoxification systems to protect the fetus from drugs prescribed to pregnant women suffering pre-eclampsia, mainly in the severe phase.

Temporal secretion of a multicellulolytic system in Myxobacter sp. AL-1. Molecular cloning and heterologous expression of cel9 encoding a modular endocellulase clustered in an operon with cel48, an exocellobiohydrolase gene.

The Gram-negative soil micro-organism Myxobacter sp. AL-1 possesses at least five extracellular cellulases, the production of which is regulated by the growth cycle. We cloned the complete gene for one of these cellulases, termed cel9, which encoded a 67-kDa modular family 9 endoglycohydrolase, which was produced during the stationary phase of growth and was strongly enhanced by avicel. The predicted product of cel9 matches the structural architecture of family 9 cellulases such as Thermonospora fusca endo/exocellulase E4. Cel9 protein was synthesized in Escherichia coli from a multicopy plasmid and in Bacillus subtilis from the isopropyl thiogalactoside-inducible Pspac promoter and was purified from the culture medium. Thermal stability, optimum pH and temperature dependence of Cel9 were similar when expressed from either source, and were indistinguishable from related cellulases produced by thermophilic bacteria. Downstream from cel9 was found a partial ORF, designated cel48, the deduced product of which was highly similar to bacterial exocellobiohydrolases and processive endoglucanases belonging to family 48 of the glycosyl hydrolases. The cel9 and cel48 genes appear to be arranged as part of an operon.

[Genetic determinant factors of resistance to HIV infection and of control of progression to AIDS: implications on pathogenesis and therapeutic approaches for the eradication of HIV. A review]. / Los factores genéticos determinantes de la resistencia a la infección por VIH y del control de la progresión al SIDA: implicaciones sobre la patogénesis y las estrategias terapéuticas para la erradicación del VIH. Una revisión.

In this review, we describe and discuss the genetic factors that, up to some point, determine resistance to the infection and control the progression of the disease in HIV-infected individuals. Genetic factors may account for non-progression or slow progression of the disease in some of so called long-term non progressors HIV-infected individuals. In general, this group shows no symptoms for more than 10 years, while their circulating T CD4+ cells levels remain stable and they usually have a low virus load. Even though non-progression and rapid progression phenomenon are still not fully understood, there probability exists that some class I and class II MHC alleles are associated with a greater or smaller risk to develop AIDS. Class I HLA-B*35 and Cw*04 alleles are the ones commonly associated with the rapid transition of the infection into AIDS. In contrast, heterozygosity for class I HLA alleles and, particularly, the absence of HLA-B*35 and Cw*04 may contribute to non-progression. Studies which set forward other HLA alleles as possibly taking part of the pathogenic mechanism of non-progression are also described; although, relevant methodological problems can be noticed. Furthermore, this review explains and discusses allelic variations for some of the components of the chemokine receptors family, particularly the genes which codify for CCR5 and CCR2 and other genetic factors such as the SDF1-3'. A variant of the alpha SDF1 chemokine gene that have been associated with AIDS' slow progression or non-progression in HIV-infected individuals. As a whole, the factors described in this review are those that influence the natural history of the disease due to HIV and give an example of what genetic or multigenetic influence can have over the pattern of evolution of HIV infection. Finally, we mention the possible implications that the identification of the genetic markers has in the pathogenesis of HIV disease and in the development of the new therapeutic strategies to control or eliminate HIV.

Acidosis and weight loss are induced by cyclosporin A in uninephrectomized rats.

The effects of cyclosporin A (CyA, 50 mg/kg body weight) or its commercial vehicle (cremophor) on the acid-base regulation of uninephrectomized rats were assessed for 7 days and in non-nephrectomized rats for 15 days. CyA induced a marked systemic acidosis, accompanied by decreases in blood PCO(2) and plasma bicarbonate. Untreated uninephrectomized rats did not show the acidosis. In CyA-treated rats the urine pH decreased (control 6. 65+/-0.06 vs. CyA 6.18+/-0.08; P<0.01) as well as urinary bicarbonate (non-nephrectomized rats 7.50+/-1.88 mM vs. uninephrectomy plus CyA 0.75+/- 0.06 mM; P<0.01), suggesting partial renal compensation of systemic acidosis. Titratable acidity increased in CyA-treated rats (control 21.6+/-1.2 vs. CyA 63.3+/-12.0 microEq/l; P<0.001). Phosphate, glucose, and osmolar clearances were not significantly altered in non-nephrectomized rats treated with CyA for 15 days. There was a striking decrease in body weight in CyA-treated rats (control 274.0+/-3.8 vs. CyA 225.0+/-5.1 g; P<0. 01), but compensatory growth of the remaining kidney was not prevented by this drug or by its vehicle. In summary, CyA induced a severe metabolic acidosis in uninephrectomized rats that was not compensated by the remaining kidney, in spite of the well-preserved compensatory weight gain of this organ. Loss of body weight was significant in CyA-treated animals.

Structural improvement of higher education in environmental toxicology in Latin America and Europe.

Industrial development has resulted in an increased release of chemicals and other agents into the environment, resulting in damage to the environment as well as increasing the risk of adverse effects on human health. Environmental toxicology (ET) is the discipline responsible for assessing the risks to human health and the environment from the effects of new chemicals and those already present in the environment. The development of human resources in toxicology is therefore a priority in both Latin America (LA) and the European Union (EU), although LA professionals are more involved in risk evaluation than in risk assessment compared to their EU colleagues. A solid background in general toxicology will enable those interested in environmental issues to tackle local problems. Moreover, the increasing globalization of markets and, therefore, of the necessary regulations, requires harmonisation of postgraduate programmes to ensure that risk assessment and management related to the environment are dealt with uniformly and by highly qualified scientists. The Inaugural Meeting of the ALFA-OMET Toxicology', a 2-year programme supported by the European Commission, offered the opportunity to discuss a number of these issues. The present status of existing ET courses in the EU and LA and the corresponding professional profiles in the two regions were examined, and a harmonized academic curriculum for a postgraduate professional profiles in the two regions were examined, and a harmonized academic curriculum for a postgraduate course in environmental toxicology was developed. Finally, a course programme for toxicology and a specialization in environmental toxicology designed by a panel of experts was discussed, and its relevance as a model for other specialisation programmes was analysed. Exercises such as those performed by ALFA-OMET may be useful not only in promoting discussion for the implementation of national and international professional registers in LA, but also in encouraging the same, ongoing process in the EU.

Effects of aflatoxin B(1) on the liver and kidney of broiler chickens during development.

Aflatoxin B(1) (AFB(1)) negatively affects chicken (Gallus domesticus) growth. This effect is more severe during development. We studied the influence of age on the toxic effects of AFB(1) on plasma, renal and hepatic enzymes, under two protocols, in adult and in developing Arbor-Acres chickens. Protocol A: 100 male 4-week-old chickens (640 g), received AFB(1), 0.5, 1.0, or 2.0 microg/g of feed (daily p.o.), a fourth group received an aflatoxin-free diet. Five birds/group were slaughtered at 7, 14, 21 and 28 days of treatment. Body, hepatic and renal weights, succinate-dehydrogenase (SDH) and glutamate-dehydrogenase (GluDH) in plasma and liver were measured. Hepatic SDH and GluDH decreased (P<0.05). Protocol B: two groups of 24 male 1-week-old chickens (106 g) received either aflatoxin-free feed (n=24) or AFB(1) feed (2.0 microg/g). At days 7, 14, 21 and 28, the same parameters of Protocol A were measured. AFB(1) markedly reduced body weight gain (20-30%), plasma proteins, albumin, renal and hepatic protein content (P<0.05) and increased absolute and relative weights of the kidney (P<0.05). SDH and GluDH were reduced (P<0.05), while total renal gamma-glutamyltranspeptidase (GGT) increased (P<0.05). Results suggest that serum proteins, SDH and GluDH are sensitive early indicators of this toxicity that was more severe in developing chickens. Decrease in serum albumin might be used as an early and suitable indicator of the deleterious effect of this mycotoxin in developing chickens.

Heat-shock protein (HSP70-2) allelic frequencies in three distinct Mexican populations.

The major histocompatibility complex (MHC) genes are highly polymorphic and therefore have been useful in population genetics and disease association studies. We analyzed restriction fragment length polymorphism of HSP70-2 alleles in healthy unrelated Mestizo, Mazatecan and Nahua populations. Both Indian groups, Mazatecans and Nahuas, were in Hardy-Weinberg equilibrium, while Mestizos were in disequilibrium (chi 2 = 0.399; P < 0.05). The Mazatecan Indians presented a high frequency of BB homozygosity (17.35%) compared to Mestizos (5%) (P = 0.01). Mexican ethnic groups present differences in distribution of BB genotype. The low frequency of BB genotype in Mestizos may be the result of a negative selection process.

Increase in the renal damage induced by paracetamol in rats exposed to ethanol translactationally.

Administration of ethanol (8%) or acetone (1%) to nursing dams in the drinking water, for 10 days, increased the nephrotoxicity of paracetamol (APAP) in the 14-day-old lactating offspring. The percentage of proximal tubular cells with evidence of necrotic damage in male rats was higher in those animals that received APAP (500 mg/kg, i.p.) and whose nursing rats were exposed to ethanol (25. 0 +/- 8.4%) or acetone (17.2 +/- 1.2%), than in the group treated with APAP alone (10.6 +/- 1.6%). The activity of urinary N-acetylglucuronidase was also significantly higher in the rats exposed translactationally to ethanol or acetone than in animals treated with the APAP alone. Nephrotoxicity showed a sexual dimorphic pattern with a higher toxicity in male than in female rats. The percentage of necrotic tubules in the male rats not exposed to inductor was 10.6 +/- 1.6%, and in female rats 5.0 +/- 1.4% (p < 0. 05). Animals exposed to ethanol or acetone and treated with APAP showed less weight gain than the group treated only with APAP. Our results suggest that renal toxicity is enhanced in the nursing animals that were exposed, via maternal milk, to ethanol or acetone (inductors of cytochrome P4502E1), than in the control animals. This circumstance may be relevant in alcoholic women while they are lactating.