Reproductibilite interobservateurs des scores de Knodell et Metavir en milieu Camerounais pour les hepatites virales chroniques

Introduction. Plusieurs scores ont ete proposes a l'histopathologie du materiel de biopsie hepatique dans le cadre de la prise en charge des hepatites virales chroniques parmi lesquels le score de Knodell et le score Metavir. L'objectif de notre travail etait de comparer la reproductibilite des scores Metavir et de Knodell pour determiner lequel serait le plus adequat dans les conditions d'exercice des pathologistes locaux. Materiel et methode. Trente blocs de biopsies hepatiques provenant de patients porteurs d'hepatite virale chronique B ou C ont ete retenus pour notre etude. Ceux-ci ont ete recoupes et colores a l'hemateine-eosine et au Trichrome de Masson. Les lames ainsi confectionnees ont ete interpretees independamment par deux pathologistes disposant d'au moins cinq annees d'experience avec etablissement des scores de Knodell et Metavir. Resultats. La concordance entre les deux pathologistes en ce qui concerne les composantes du score Metavir etait elevee pour la fibrose et moyenne pour l'activite. Pour ce qui est du score de Knodell la concordance pour la fibrose etait egalement elevee; elle etait moyenne pour les scores partiels de necrose intralobulaire et de necrose portale tandis que le pourcentage de scores globaux concordants etait faible. Conclusion. Nous avons observe une concordance acceptable pour les differentes composantes des deux scores cependant celle-ci etait meilleure pour le score Metavir. Le score Metavir pourrait donc etre utilise dans nos conditions d'exercice par des pathologistes non specialises en pathologie hepatique

Clinical, ultrasonographic, and pathologic characteristics of patients with chronic right-lower-quadrant abdominal pain that may benefit from appendectomy.

BACKGROUND: Chronic pains of the right lower quadrant of the abdomen (RLQA) remain a challenging problem worldwide, especially in areas with limited technical background; chronic appendicitis is still a subject of controversy. The aim of this study was to analyze the clinical and paraclinical data of patients with chronic pains of RLQA who had an appendectomy performed. METHODS: During a period of 4 years, all patients presenting with a chronic pain of the RLQA were selected for our study and underwent clinical assessment and systematic ultrasonography of the abdomen; these served as a basis of selecting candidates for appendectomy. The intraoperative findings, histology results, and outcome after appendectomy were analyzed. RESULTS: Three hundred nineteen patients presented with chronic pains of the RLQA of which 213 could be finally analyzed; their mean age was 15.3 years; 192 patients were females. They had pains for 2-8 years. Echography showed a heterogeneous lesion in the RLQA in 87% of the cases. The operative findings displayed adhesions and other signs of chronic inflammation in 182 cases. Pathological analysis frequently revealed fibrosis and lymphoplasmocytic infiltration indicative of chronic inflammation. Eighty-seven percent of the patients were cured by appendectomy. CONCLUSIONS: There is a chronic process involving the appendix that occurs in the RLQA of patients with chronic pains, typically the adolescent female. Appendectomy usually solves the problem. The criteria for selection of candidates still need to be identified, but in the absence of laparoscopic facilities, we recommend appendectomy when no other cause for the pain has been identified.

Repeated inhalation exposure to octamethylcyclotetrasiloxane produces hepatomegaly, transient hepatic hyperplasia, and sustained hypertrophy in female Fischer 344 rats in a manner similar to phenobarbital.

Octamethylcyclotetrasiloxane (D4) has been described as a phenobarbital-like inducer of hepatic enzymes. Phenobarbital (PB) and phenobarbital-like chemicals induce transient hepatic and thyroid hyperplasia and sustained hypertrophy in rats and mice. The extent to which these processes are involved with D4-induced hepatomegaly is not known. The present study has evaluated the effects of repeated inhalation exposure to D4 vapors on hepatic and thyroid cell proliferation and hypertrophy with respect to time and exposure concentration. Female Fischer 344 rats were exposed via whole body inhalation to 0 ppm D4, 700 ppm D4 vapors (6 h/day; 5 days/week), or 0.05% PB in drinking water over a 4-week period. Incorporation of 5'-bromo-2-deoxyuridine (BrdU) and the abundance of proliferating cell nuclear antigen were used as indicators of cell proliferation. Designated animals from each treatment group were euthanized on study days 6, 13, and 27. The effect of D4 exposure concentration on hepatic cell proliferation was evaluated at 0, 7, 30, 70, 150, 300, or 700 ppm. Liver-to-body weight ratios in animals exposed to 700 ppm D4 were increased 18, 20, and 22% over controls while PB-treated animals showed increases of 33, 27, and 27% over controls on days 6, 13, and 27 respectively. Hepatic incorporation of BrdU following exposure to D4 was highest on day 6 (labeling index = 15-22%) and was at or below control values by day 27. This pattern of transient hyperplasia was observed in all hepatic lobes examined and was similar to the pattern observed following treatment with PB.

Pentoxifylline attenuates bacterial lipopolysaccharide-induced enhancement of allyl alcohol hepatotoxicity.

Small amounts of exogenous lipopolysaccharide (LPS) (10 ng/kg-100 microg/kg) enhance the hepatotoxicity of allyl alcohol in male Sprague-Dawley rats. This augmentation of allyl alcohol hepatotoxicity appears to be linked to Kupffer cell function, but the mechanism of Kupffer cell involvement is unknown. Since Kupffer cells produce tumor necrosis factor-alpha (TNF alpha) upon exposure to LPS, and this cytokine has been implicated in liver injury from large doses of LPS, we tested the hypothesis that TNF alpha contributes to LPS enhancement of allyl alcohol hepatotoxicity. Rats were treated with LPS (10-100 microg/kg iv) 2 h before allyl alcohol (30 mg/kg ip). Co-treatment with LPS and allyl alcohol caused liver injury as assessed by an increase in activity of alanine aminotransferase in plasma. Treatment with LPS caused an increase in plasma TNF alpha concentration, which was prevented by administration of either pentoxifylline (PTX) (100 mg/kg iv) or anti-TNF alpha serum (1 ml/rat iv) one h prior to LPS. Only PTX protected rats from LPS-induced enhancement of allyl alcohol hepatotoxicity; anti-TNF alpha serum had no effect. Exposure of cultured hepatocytes to LPS (1-10 microg/ml) or to TNF alpha (15-150 ng/ml) for 2 h did not increase the cytotoxicity of allyl alcohol (0.01-200 microM). These data suggest that neither LPS nor TNF alpha alone was sufficient to increase the sensitivity of isolated hepatocytes to allyl alcohol. Furthermore, hepatocytes isolated from rats treated 2 h earlier with LPS (i.e., hepatocytes which were exposed in vivo to TNF alpha and other inflammatory mediators) were no more sensitive to allyl alcohol-induced cytotoxicity than hepatocytes from naïve rats. These data suggest that circulating TNF alpha is not involved in the mechanism by which LPS enhances hepatotoxicity of allyl alcohol and that the protective effect of PTX may be due to another of its biological effects.

Toxicology and humoral immunity assessment of octamethylcyclotetrasiloxane (D4) following a 28-day whole body vapor inhalation exposure in Fischer 344 rats.

Octamethylcyclotetrasiloxane, D4, is a low viscosity, silicone fluid consisting of four dimethyl-siloxy units ((CH3)2SiO)4 in a cyclic structure. It is primarily used as a building block in the industrial synthesis of long chain silicone polymers. The combination of D4 with decamethylcyclopentasiloxane (D5) is commonly referred to as cyclomethicone which has a wide range of applications as a formulation aid in personal care products. To extend the existing database regarding the biological activities of D4, a 28 day whole body vapor inhalation study was conducted using Fischer 344 rats at 0 (room air), 7, 20, 60, 180 and 540 ppm for 6 hours/day, 5 days/week. Parameters measured included body weights, organ weights, gross pathology, histopathology, serum chemistries, and urinalysis. In addition to these standard toxicological endpoints, the ability of D4 exposed animals to mount an IgM antibody response was evaluated by a splenic antibody forming cell (AFC) assay and a serum enzyme-linked immunosorbant assay (ELISA). The results of this 28-day inhalation study indicate that D4 exposure caused no adverse effects on body weight, food consumption, or urinalysis parameters. In addition, there were no exposure related histopathological alterations at any site for any exposure group. A statistically significant increase in liver weight and the liver to body weight ratio was observed in both male (180-540 ppm) and female (20-540 ppm) rats, which was not observed in the 14-day recovery group animals. There were no other significant organ weight changes. Although statistically significant changes were observed in several hematological and serum chemistry parameters in both the terminal and 14-day recovery animals, the changes were marginal and within the normal range of values for the rat. Under these experimental conditions, there were no alterations noted in immune system function at any of the D4 exposure levels.

Bile duct epithelial cells exposed to alpha-naphthylisothiocyanate produce a factor that causes neutrophil-dependent hepatocellular injury in vitro.

The acute hepatotoxicity induced by alpha-naphthylisothiocyanate (ANIT) in rats is manifested as neutrophil-dependent necrosis of bile duct epithelial cells (BDECs) and hepatic parenchymal cells. This hepatotoxicity mirrors that of drug-induced cholangiolitic hepatitis in humans. Since BDECs are primary targets of ANIT-induced toxicity, we hypothesized that after exposure to ANIT, BDECs produce a factor(s) that causes neutrophil chemotaxis and neutrophil-dependent hepatocellular injury. To test this hypothesis BDECs were isolated from male Sprague Dawley rats and incubated with ANIT (6.25, 12.5, 25, or 50 microM) or vehicle for 24 h. The conditioned medium (CM) was collected and placed in the bottom chamber of a two-chambered chemotaxis system, while isolated neutrophils were placed in the top chamber. Chemotaxis was indicated by neutrophil migration through a membrane to the bottom chamber. CM from BDECs exposed to each concentration of ANIT was chemotactic, whereas CM from vehicle-treated BDECs was not. ANIT alone caused a modest degree of chemotaxis at 50 microM. The conditioned media were added to isolated hepatocytes or to hepatocyte-neutrophil cocultures and incubated for 24 h. Hepatocyte toxicity was indicated by alanine aminotransferase release into the culture medium. CM from vehicle-treated BDECs did not cause hepatocyte killing in either hepatocyte-neutrophil cocultures or hepatocyte cultures. In contrast, the addition of CM from ANIT-treated BDECs (CM-BDEC-A) to hepatocyte-neutrophil cocultures resulted in hepatocyte killing. The same CM was not cytotoxic to hepatocyte cultures devoid of neutrophils. The hepatocyte killing could not be explained by residual ANIT in the CM, which was below the limit of detection (< or = 0.5 microM). The addition of antiproteases afforded protection against neutrophil-dependent hepatocellular injury induced by CM-BDEC-A. These results indicate that ANIT causes BDECs to release a factor(s) that attracts neutrophils and stimulates them to injure hepatocytes in vitro.

Cytotoxicity of naphthylisothiocyanates in rat hepatocyte-neutrophil cocultures.

1-Naphthylisothiocyanate (ANIT) produces cholangiolitic hepatitis in rats. This injury is characterized by periportal bile duct and hepatic parenchymal cell necrosis with inflammatory cell involvement. In contrast, 2-naphthylisothiocyanate (BNIT) does not induce cholangiolitic hepatitis. The mechanism(s) involved in ANIT-induced hepatic injury remain to be elucidated. To investigate this difference in toxicity further, we examined the cytotoxicity of ANIT and BNIT in primary rat hepatocyte cultures. Since neutrophils (PMNs) are required for the development of ANIT-induced cholangiolitic hepatitis in vivo, we also examined the potential for PMNs to modulate ANIT and BNIT cytotoxicity in rat hepatocyte-PMN cocultures. Both ANIT and BNIT injured rat hepatocytes within the range of concentrations examined (0-100 microM); however, BNIT was more potent. The presence of PMNs did not significantly influence the hepatocellular injury produced by either naphthylisothiocyanate (NIT). In an attempt to clarify the disparity between these results in vitro and observations reported in vivo, we examined, in hepatocyte PMN cocultures, the cytotoxic potential of bile collected from NIT-treated rats. Bile from BNIT-treated rats was markedly more cytotoxic to hepatocytes than was bile from ANIT-treated rats. As was observed in earlier experiments, the inclusion of PMNs had no effect on the hepatocellular toxicity of bile from NIT-treated rats. These findings prompted evaluation of the effect of NITs on rat PMNs. ANIT (1 and 10 microM) had no effect on phorbal myristate acetate (PMA)-induced superoxide production by PMNs, whereas BNIT (1 and 10 microM) markedly inhibited PMA-induced superoxide production. In contrast, ANIT and BNIT were equally effective at inhibiting f-met-leu-phe (fMLP)-induced PMN degranulation (beta-glucuronidase release). Altogether, the relative NIT toxicity observed in hepatocyte primary cultures is contrary to reports of hepatotoxic potential of these NITs in vivo. The PMN-dependence of ANIT hepatotoxicity in vivo was not reproduced in hepatocyte-PMN cocultures exposed to ANIT, suggesting that the PMN dependence in vivo involves factors not present in hepatocyte PMN cocultures. The greater PMN inhibitory effect of BNIT may, in part, underlie its inability to elicit the PMN-dependent liver injury in vivo that characterizes ANIT-induced cholangiolitic hepatitis.

Naphthylisothiocyanate disposition in bile and its relationship to liver glutathione and toxicity.

1-Naphthylisothiocyanate (ANIT), but not 2-naphthylisothiocyanate (BNIT), produces cholangiolitic hepatitis in rats after a single, oral administration. The mechanisms responsible for the disparate toxic outcomes for these closely related structural isomers are not fully understood. Recent reports suggest that ANIT-induced hepatotoxicity is dependent upon the formation and biliary excretion of a reversible glutathione-ANIT conjugate. To understand better the relationship between hepatic glutathione, secretion into bile and hepatotoxicity, the bile concentrations and hepatotoxicities of ANIT and BNIT were examined in rats with and without pretreatment with buthionine sulfoximine (BSO). ANIT (100 mg/kg, p.o.) caused a 3-fold elevation of plasma alanine aminotransferase activity (ALT), a 6-fold elevation of total plasma bilirubin, and a > 90% reduction in bile flow 24 hr after administration. BNIT, at this same dose and route of administration, did not alter significantly these markers of liver injury. Accumulation of ANIT and BNIT in bile occurred with the same temporal characteristics; however, BNIT accumulated to markedly larger concentrations (292 +/- 83 and 235 +/- 100 microM BNIT and 78 +/- 19 and 29 +/- 13 microM ANIT at 1 and 4 hr, respectively). The accumulation of ANIT and BNIT in bile was coincident with a > 2-fold elevation of reduced glutathione in bile. Pretreatment of rats with BSO decreased hepatic glutathione concentration and reduced the concentration of naphthylisothiocyanates in bile by 85%. Associated with this reduction was an attenuation of ANIT hepatotoxicity. Altogether, these findings indicate that both ANIT and BNIT accumulate in bile in a glutathione-dependent manner, yet they yield different hepatotoxic outcomes. Therefore, the disparity in hepatotoxicities observed with these isomers is not related to a difference in ability to enter bile. Other differences, such as in metabolism, chemical reactivity, conjugate stability and/or cytotoxic potential to bile duct epithelial cells may be more important determinants of hepatotoxicity.

Vitamin A or zymosan pretreatment attenuates alpha-naphthylisothiocyanate-induced liver injury.

alpha-Naphthylisothiocyanate (ANIT) is a cholangiolitic hepatotoxicant that causes periportal hepatic injury in the rat that is neutrophil- and platelet-dependent. Since macrophages have recently been implicated as participants in some chemically induced hepatotoxicities, we evaluated the role of these cells in ANIT-induced hepatic injury. Rats were treated with gadolinium chloride (GdCl3), an agent which decreases hepatic macrophage numbers and activity, zymosan, an agent which increases hepatic macrophage numbers, or vitamin A, which increases hepatic macrophage activity. GdCl3 did not ameliorate ANIT-induced hepatotoxicity, as demonstrated by a lack of attenuation of any of the markers of hepatic insult evaluated. In contrast, pretreatment with either zymosan or vitamin A decreased ANIT hepatotoxicity. Zymosan administration reduced blood neutrophil numbers and influx of neutrophils into the peritoneum after intraperitoneal glycogen administration but did not affect hepatic neutrophil accumulation in ANIT-treated rats. To determine if macrophages were important in the protection by vitamin A, rats were cotreated with GdCl3 and vitamin A. GdCl3 did not alter the protection from ANIT hepatotoxicity afforded by vitamin A. Vitamin A treatment decreased ANIT and glutathione concentrations in bile at 1 and 4 hr after ANIT administration but had a minimal effect on plasma ANIT concentration. In summary, pretreatment of rats with zymosan or vitamin A but not GdCl3 attenuated ANIT-induced liver injury. The protection afforded by zymosan may derive from its effects on neutrophils or platelets. The protection by vitamin A appears to result from its effect on the transport of ANIT into bile. The results suggest that hepatic macrophages are not required for the manifestation of ANIT hepatotoxicity.

Platelet participation in liver injury from gram-negative bacterial lipopolysaccharide in the rat.

Intravenous administration of lipopolysaccharide (LPS) to rats results in multifocal, primarily midzonal hepatic necrosis. The hepatic injury is associated with inflammation and is dependent on neutrophils and the coagulation system. After LPS injection into rats, plasma fibrinogen concentration and numbers of blood platelets and leukocytes decrease. Results of our studies, using immunocytochemistry for the detection of neutrophils and 111indium-labeling to identify platelets, indicate that both neutrophils and platelets accumulate within the liver early after administration of LPS to rats. The accumulation of platelets in the liver before the onset of injury suggested that platelets contribute to the manifestation of LPS-induced hepatotoxicity. To test this hypothesis, the number of circulating blood platelets was decreased by the administration of an anti-rat platelet serum (APS) before LPS administration. The consequent thrombocytopenia by APS administration was associated with an attenuation of both LPS-induced liver injury and the activation of the coagulation system. However, the APS treatment did not prevent the hepatic neutrophil accumulation. These results suggest that platelets contribute to the pathogenesis of liver injury after LPS administration, perhaps through their integral role in coagulation and/or interaction with neutrophils, but they do not appear to contribute to hepatic neutrophil accumulation.

1-naphthylisothiocyanate-induced elevation of biliary glutathione.

1-Naphthylisothiocyanate (ANIT) has been used for many years to study cholangiolitic hepatotoxicity in laboratory animals. Hallmarks of ANIT hepatotoxicity include portal edema and inflammation with bile duct epithelial and hepatic parenchymal cell necrosis. In rats, ANIT hepatotoxicity is dependent upon hepatic glutathione. Studies in vitro have demonstrated that ANIT combines reversibly with glutathione and suggest that intracellular formation and secretion of this glutathione-ANIT conjugate from hepatic parenchymal cells may be responsible for the efflux of glutathione observed upon exposure to ANIT. In vivo, glutathione conjugates produced within hepatic parenchymal cells are typically transported into bile for elimination. Therefore, large concentrations of ANIT in bile may result from hepatic parenchymal cell secretion of a reversible glutathione-ANIT conjugate. To investigate this hypothesis, bile and plasma concentrations of ANIT were determined in rats 1, 4, 8, 12 and 24 hr after administration (100 mg/kg, p.o.). Liver and bile glutathione concentrations were also evaluated. Plasma ANIT concentrations ranged between 2 and 5 microM at 1, 4, 8 and 12 hr and were 0.9 microM at 24 hr after administration. ANIT concentrations in bile at 1, 4, 8 and 12 hr were 60, 28, 21 and 22 microM, respectively. Thus, ANIT was concentrated in bile. Hepatic glutathione was not affected by ANIT during the first 12 hr after administration; however, a moderate elevation occurred by 24 hr. In contrast, a marked elevation in bile glutathione concentration (two times control) occurred 1, 4 and 8 hr after ANIT administration. Thus, the early accumulation of ANIT in bile was coincident with an elevation in bile glutathione. These findings support the hypothesis that glutathione functions to concentrate ANIT in bile. The large concentration of this toxicant in bile may be injurious to bile epithelium, a primary cellular target in ANIT hepatotoxicity.

Relationship between tumor necrosis factor-alpha and neutrophils in endotoxin-induced liver injury.

Tumor necrosis factor-alpha (TNF-alpha) and blood neutrophils (polymorphonuclear leukocytes; PMNs) have been implicated in the pathogenesis of endotoxin (lipopolysaccharide, LPS) hepatotoxicity. However, the mechanism by which these factors mediate liver injury during LPS exposure is uncertain. The objective of this study was to test the hypothesis that TNF-alpha contributes to LPS hepatotoxicity by an indirect, PMN-dependent mechanism. Pretreatment of rats with an antiserum to TNF-alpha afforded protection against liver injury 6 h after LPS exposure. Pretreatment with pentoxifylline (100 mg/kg i.v.), which attenuated the increase in circulating TNF-alpha concentration 1.5 h after administration of LPS, also afforded protection against liver injury. Neither antiserum to TNF-alpha nor pentoxifylline affected hepatic PMN accumulation 1.5 h after LPS exposure. Depletion of circulating PMNs, which protects against LPS hepatotoxicity, enhanced circulating TNF-alpha concentration compared with control rats 1.5 h after LPS exposure. These results suggest that TNF-alpha contributes to liver injury after LPS exposure, but in the absence of circulating PMNs it is insufficient for full manifestation of liver injury. TNF-alpha apparently contributes to the pathogenesis of LPS-induced liver injury by an indirect, PMN-dependent mechanism.

Utilization of glutathione during 1,2-dihaloethane metabolism in rat hepatocytes.

The metabolism of 1,2-dihaloethanes (DHEs) to glutathione-containing metabolites by freshly isolated rat hepatocytes was investigated. 1,2-Dichloroethane (DCE), 1,2-dibromoethane (DBE), and 1-bromo-2-chloroethane (BCE) were metabolized to S-(2-hydroxyethyl)glutathione (HEG), S-(carboxymethyl)glutathione (CMG), and S,S'-(1,2-ethanediyl)bis(glutathione) (GEG). The formation of these glutathione-containing metabolites was concomitant with the depletion of intracellular glutathione (GSH) and accounted for 58%, 84%, and 71% of the DCE-, BCE-, and DBE-induced loss of intracellular GSH, respectively. The covalent binding of [14C]DBE to hepatocyte protein reached 18.7 nmol/mL of cell suspension (7.8 nmol/mg of protein) within 2.0 h of incubation. Half of this covalent binding occurred within 0.5 h of incubation (4.0 nmol/mg of protein) in the presence of high levels of intracellular GSH (30% of initial GSH level at 0.5 h). Hepatocyte metabolism of 2-chloroacetic acid produced only CMG. 2-Chloroethanol metabolism gave rise to CMG and HEG in a 11.5:1.0 ratio; 2-chloroacetaldehyde produced almost equal amounts of CMG and HEG. GEG formation was increased significantly for DBE and BCE when GSH was added to the medium during treatment, suggesting that the GSH conjugates S-(2-haloethyl)glutathione are exported from the hepatocytes. These results indicate that the glutathione S-transferase-catalyzed conjugation of GSH with the DHEs is responsible for the majority of the DHE-induced GSH depletion. The S-(2-haloethyl)glutathione conjugates appear responsible for the extensive covalent binding to protein observed during [14C]DBE metabolism.

Involvement of glutathione in 1-naphthylisothiocyanate (ANIT) metabolism and toxicity to isolated hepatocytes.

1-Naphthylisothiocyanate (ANIT) is a model compound which causes cholestasis in laboratory animals. Various biochemical and morphological changes including biliary epithelial and parenchymal cell necrosis occur in the liver of animals treated with ANIT. Although the mechanism(s) for these effects is not understood, a role for glutathione (GSH) in toxicity has been implicated. The possible role of GSH in hepatocellular toxicity caused by ANIT was investigated in this study. Treatment of freshly isolated rat hepatocytes with ANIT caused a concentration- and time-dependent depletion of cellular GSH that preceded lactate dehydrogenase (LDH) leakage. Analysis of the incubation medium indicated that the majority of the cellular GSH which was lost was present extracellularly as GSH or as a GSH-releasing compound. Mixing ANIT with GSH at pH 7.5 yielded a compound that was characterized by HPLC and fast atom bombardment-mass spectrometry (FAB-MS) S-(N-naphthyl-thiocarbamoyl)-L-glutathione (GS-ANIT). When dissolved in aqueous solutions at neutral pH, 95% of GS-ANIT dissociated to yield free ANIT and GSH. Under conditions designed to maximize formation and stability of GS-ANIT, GS-ANIT was found in the extracellular medium of hepatocytes treated with ANIT. Treatment of hepatocytes with the GS-ANIT caused GSH depletion and LDH leakage similar to that observed with equimolar amounts of ANIT. These data suggest that ANIT depletes hepatocytes of GSH through a reversible conjugation process. Such a process may play a role in the toxicity of ANIT.

HIV-2 and HIV-1 AIDS cases in Senegal: clinical patterns and immunological perturbations.

The serological and immunological parameters, disease patterns, and social characteristics of 39 human immunodeficiency virus type 2 (HIV-2) seropositive CDCIV cases seen in Dakar, Senegal were studied. These data were compared with those obtained from 48 HIV-1 seropositive CDC stage IV patients. Social characteristics of populations infected with HIV-1 or HIV-2 were clearly different. A patient sex ratio of three men to one woman was found for both viruses. In addition, the immune status of nonsymptomatic HIV-1 and HIV-2 seropositive people was evaluated. The correlation between abnormalities of the immune system and clinical status was similar for the two infections. Clinical symptoms of both diseases were the same, but this cross-sectional study could not address the questions of differences between the two infections in latency and development of disease or specific manifestations of HIV-2 infection. This study suggests that HIV-2 infection may contribute to the present AIDS epidemic in West Africa.

In vitro dipeptide, nucleoside, and glutathione alkylation by S-(2-chloroethyl)glutathione and S-(2-chloroethyl)-L-cysteine.

S-(2-Chloroethyl)glutathione (CEG) and S-(2-chloroethyl)-L-cysteine (CEC) are putative glutathione-dependent metabolites of 1,2-dichloroethane bioactivation and have been shown to be direct-acting alkylating agents. A group of dipeptides, nucleosides, and glutathione were used as model compounds to investigate CEG and CEC alkylation events. The extent of glutathione and cysteinyltyrosine alkylation was much greater than histidyltyrosine greater than lysyltyrosine, glycyltyrosine, glycyltryptophan, and 2'-deoxyguanosine greater than 2'-deoxyadenosine, 2'-deoxycytidine, and thymidine for both CEG and CEC. The rate of S-alkylation of cysteinyltyrosine by CEG and CEC occurred at rates 54 and 72 times that for the N7 position of 2'-deoxyguanosine and 16 and 10 times that for histidyltyrosine imidazole nitrogen, respectively. The rate of S-alkylation of glutathione by CEG was found to be 27% faster than that for S-alkylation of cysteinyltyrosine whereas S-alkylation of glutathione by CEC was 22% slower than that for cysteinyltyrosine. Both CEG and CEC demonstrated a selectivity for cysteinyl thiol alkylation over a wide variety of other nucleophilic sites. These findings demonstrate a wide range of functional group reactivity that should be taken into consideration when assessing the alkylation of cellular macromolecules by such glutathione-derived metabolites of the 1,2-dihaloethanes in vivo.