Sulfation of endogenous compounds and xenobiotics--interactions and function in health and disease

Sulfation is a major detoxication mechanism for endogenous compounds and xenobiotics performed by a family of sulfotransferase isoenzymes. Understanding the normal cellular functions of these different sulfotransferases and the way in which endogenous and exogenous factors are able to influence their activity and expression will provide us with the information necessary to develop novel therapeutic strategies for conditions where sulfation may be implicated. This concept is discussed and is illustrated by examples including adverse drug reactions, fetal development and cancer.     

Ocular and nasal irritation in operatives in Lancashire cotton and synthetic fibre mills

OBJECTIVES: To document the prevalence of work related ocular (eyeWRI) and nasal (noseWRI) irritation in workers in spinning mills of cotton and synthetic textile fibres and to relate the prevalence of symptoms to atopy, byssinotic symptoms, work history, and measured dust concentrations in the personal breathing zone and work area. METHODS: A cross sectional study of 1048 cotton workers and 404 synthetic fibre workers was performed. A respiratory questionnaire was given to 1452 workers (95% of the total available population). Atopy was judged by skin prick tests to three common allergens. Work area cotton dust sampling (WAdust) was carried out according to EH25 guidelines in nine of the 11 spinning mills included in the study. Personal breathing zone dust concentrations were assessed with the IOM sampler to derive total dust exposure (PTdust) and a concentration calculated after the removal of fly (Pless). RESULTS: 3.7% of all operatives complained of symptoms of byssinosis, 253 (17.5%) complained of eyeWRI and 165 (11%) of noseWRI. These symptoms did not relate to atopy or byssinosis, or correlate univariately with any measure of cotton dust exposure (noseWRI v WAdust r = 0.153, PTdust r = 0.118, eyeWRI v WAdust r = 0.029, PTdust r = 0.052). Both of these symptoms on logistic regression analysis were related to being of white origin (P < 0.001), female sex (P < 0.001), and younger age (P < 0.001). With regression analysis, there was a negative relation between dust concentration and prevalence of symptoms. CONCLUSION: Work related ocular and nasal irritation are the most common symptoms complained of by cotton textile workers. There was no relation between these symptoms and atopy, byssinosis, or dust concentration. It is likely that they relate to as yet unidentified agents unrelated to concentration of cotton dust.     

Cardiac transplantation in perspective for the future. Survival, complications, rehabilitation, and cost

Two hundred twenty-seven cardiac transplant procedures have been performed in 206 patients from January, 1968, to April, 1981. Postoperative survival rates, calculated by the actuarial method for program years 1968 to 1973 (66 patients), are 44%, 33%, 27%, 21%, and 18% at 1, 2, 3, 4, and 5 years after transplantation, respectively. Postoperative survival rates for program years 1974 to 1981 (140 patients) are 63%, 55%, 51, 44%, and 39% at 1, 2, 3, 4, and 5 years after transplantation, respectively. This increase results primarily from improvement in survival achieved in the first 3 postoperative months (59% +/- 7%, 1968 to 1973, versus 80% +/- 40%, 1974 to 1980), reflecting improved patient management. Infection remains the primary cause of death following transplantation (76/131 patients, 58%), followed by acute rejection (24/181, 18.3%), graft arteriosclerosis (14/131, 10.7%), and malignancy (6/131, 4.6%). The development of graft arteriosclerosis has been examined in 85 one-year survivors studied by annual coronary arteriograms. Coronary lesions of varying severity have developed in 21 patients. HLA-A2 incompatibility was associated with a higher incidence of graft arteriosclerosis than was apparent for all other A locus incompatibilities (p less than 0.0003). Lymphoma has been shown to be associated with younger recipient age, a primary disease diagnosis of idiopathic cardiomyopathy, and retransplantation. One hundred six patients have survived at least 1 year after transplantation; 97% were in NYHA Class 1 at that time interval and 82% returned to employment or activity of choice. The longest survival time is new 11 years, 3 months. Cardiac transplantation can be considered "reasonable and therapeutic treatment to extend life" in selected individuals.     

Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin

Glycoprotein 330 (gp330) is a member of a family of endocytic receptors related to the low density lipoprotein receptor. gp330 has previously been shown to bind a number of ligands in common with its family member, the low density lipoprotein receptor-related protein (LRP). To identify ligands specific for gp330 and relevant to its localization on epithelia such as in the mammary gland, gp330-Sepharose affinity chromatography was performed. As a result, a 70-kDa protein was selected from human milk and identified by protein sequencing to be apolipoprotein J/clusterin (apoJ). Solid-phase binding assays confirmed that gp330 bound to apoJ with high affinity (Kd = 14.2 nM). Similarly, gp330 bound to apoJ transferred to nitrocellulose after SDS-polyacrylamide gel electrophoresis. LRP, however, showed no binding to apoJ in either type of assay. The binding of gp330 to apoJ could be competitively inhibited with excess apoJ as well as with the gp330 ligands apolipoprotein E, lipoprotein lipase, and the receptor-associated protein, a 39-kDa protein that acts to antagonize binding of all known ligands for gp330 and LRP. Several cultured cell lines that express gp330 and ones that do not express the receptor were examined for their ability to bind and internalize 125I-apoJ. Only cells that expressed gp330 endocytosed and degraded radiolabeled apoJ. Furthermore, F9 cells treated with retinoic acid and dibutyryl cyclic AMP to increase expression levels of gp330 displayed an increased capacity to internalize and degrade apoJ. Cellular internalization and degradation of radiolabeled apoJ could be inhibited with unlabeled apoJ, receptor-associated protein, and gp330 antibodies. The results indicate that gp330 but not LRP can bind to apoJ in vitro and that gp330 expressed by cells can mediate apoJ endocytosis leading to lysosomal degradation.     

Arousal, numbing, and intrusion: symptom structure of PTSD following assault

OBJECTIVE: This study investigated hypotheses concerning the importance of symptoms of numbing in posttraumatic stress disorder (PTSD). METHODS: Symptoms of PTSD were assessed in 72 female rape victims and 86 female victims of nonsexual assault approximately 3 months after the crimes occurred. A principal-components factor analysis of subjects' symptoms was then undertaken. RESULTS: The analysis yielded three factors: arousal/avoidance, numbing, and intrusion. These were somewhat different from the symptom clusters in DSM-III-R, since effortful avoidance and numbing symptoms did not load on the same factor. Numbing symptoms appeared to be particularly important in identifying individuals with PTSD. CONCLUSIONS: The results imply that there are two patterns of posttrauma symptoms, one characterizing PTSD and the second characterizing a phobic reaction.     

Particle clearance and histopathology in lungs of F344/N rats and B6C3F1 mice inhaling nickel oxide or nickel sulfate

The goals of this study were to (1) determine the effects of repeated inhalation of relatively insoluble nickel oxide (NiO) and highly soluble nickel sulfate hexahydrate (NiSO4.6H2O) on lung particle clearance, (2) investigate the effects of repeated inhalation of NiO or NiSO4 on the pulmonary clearance of subsequently inhaled 85Sr-labeled microspheres, (3) correlate the observed effects on clearance with accumulated Ni lung burden and associated pathological changes in the lung, and (4) compare responses in F344 rats and B6C3F1 mice. Male F344/N rats and B6C3F1 mice were exposed whole-body to either NiO or NiSO4.6H2O 6 hr/day, 5 days/week for up to 6 months. NiO exposure concentrations were 0, 0.62, and 2.5 mg NiO/m3 for rats and 0, 1.25, and 5.0 mg NiO/m3 for mice. NiSO4.6H2O exposure concentrations were 0, 0.12, and 0.5 mg NiSO4.6H2O/m3 for rats and 0, 0.25, and 1.0 mg NiSO4.6H2O/m3 for mice. After 2 and 6 months of whole-body exposure, groups of rats and mice were acutely exposed nose-only to 63NiO (NiO-exposed animals only), 63NiSO4.6H2O (NiSO4.6H2O-exposed animals only), or to 85Sr-labeled polystyrene latex (PSL) microspheres (both NiO- and NiSO4.6H2O-exposed animals) to evaluate lung clearance. In addition, groups of rats and mice were euthanized after 2 and 6 months of exposure and at 2 and 4 months after the whole-body exposures were completed to evaluate histopathological changes in the left lung and to quantitate Ni in the right lung. Repeated inhalation of NiO results in accumulation of Ni in lungs of both rats and mice, but to a greater extent in lungs of rats. During the 4 months after the end of the whole-body exposures, some clearance of the accumulated Ni burden occurred from the lungs of rats and mice exposed to the lower, but not the higher NiO exposure concentrations. Clearance of acutely inhaled 63NiO was also impaired in both rats and mice, with the extent of impairment related to both exposure concentration and duration. However, the clearance of acutely inhaled 85Sr PSL microspheres was not impaired. The repeated inhalation of NiO resulted in alveolar macrophage (AM) hyperplasia with accumulation of NiO particles in both rats and mice, chronic alveolitis in rats, and interstitial pneumonia in mice. These lesions persisted throughout the 4-month recovery period after the NiO whole-body exposures were terminated. In contrast, repeated inhalation of NiSO4.6H2O did not result in accumulation of Ni in lungs of either rats or mice and did not affect the clearance of 63NiSO4.6H2O inhaled after either 2 or 6 months of NiSO4.6H2O exposure. Clearance of the 85Sr-labeled microspheres was significantly impaired only in rats exposed to the microspheres after 2 months of exposure to NiSO4.6H2O. Histopathological changes in rats were qualitatively similar to those seen in NiO-exposed rats. Only minimal histopathological changes were observed in NiSO4.6H2O-exposed mice. These results suggest that repeated inhalation of NiO at levels resulting in AM hyperplasia and alveolitis may impair clearance of subsequently inhaled NiO. The potential effects of repeated inhalation of soluble NiSO4.6H2O on the clearance of subsequently inhaled poorly soluble particles are less clear.     

Dosing-induced stress causes hepatocyte apoptosis in rats primed by the rodent nongenotoxic hepatocarcinogen cyproterone acetate

It has been proposed that several nongenotoxic compounds act as hepatocarcinogens by suppressing the apoptosis that would normally act to remove damaged or potentially initiated cells from the liver. During our investigations of this hypothesis using a widely applied protocol, we have found that the stress induced by the process of gavage dosing can induce massive apoptosis in livers uniquely primed by withdrawal of the hepatomitogen cyproterone acetate from the hyperplastic rat liver. This effect of gavage dosing was not seen in livers of naive animals. Apoptosis was measured by both in situ end labeling (ISEL) of the DNA damage associated with programmed cell death and conventional hematoxylin and eosin (H&E) staining of apoptotic morphology. Apoptotic rates measured by H&E increased significantly from 0.005 +/- 0.010% on Day 11 to 0.657 +/- 0.315% of hepatocytes on Day 15, 4 days after cessation of 10 days dosing with CPA (120 mg/kg). The readministration of CPA suppressed > 89% of this Day 15 apoptosis. However, the readministration of vehicle alone (corn oil) caused a 390% increase in apoptosis to 2.56 +/- 1.31% of hepatocytes. Similar results were obtained using ISEL. Measurements of liver to body weight ratios and total DNA per liver reflected these changes in cell loss by apoptosis. In a second experiment, CPA was administered for 10 days as before then animals were subjected to readministration of CPA in corn oil, CPA in saline, corn oil, saline, or sham dosed. Again, apoptosis was dramatically suppressed by the readministration of CPA in either vehicle but was dramatically increased to around 2% of hepatocytes in all other groups, including the sham dosed group. Data on food consumption provided no evidence for a reduction in food intake as a causative agent but rather pointed to a less efficient usage of food in the stressed animals. The ability of stress to induce liver apoptosis should be borne in mind in the design and interpretation of future toxicological studies aimed at understanding the putative suppression of apoptosis by liver nongenotoxic carcinogens and other toxicants.     

Pseudomonas aeruginosa as a cause of infectious diarrhea successfully treated with oral ciprofloxacin

OBJECTIVE: To describe an immunocompromised patient (without AIDS) with nosocomial infectious diarrhea caused by Pseudomonas aeruginosa. Oral ciprofloxacin therapy proved to be effective. CASE SUMMARY: An 80-year-old woman with type II diabetes mellitus and hypertension developed progressive renal insufficiency, was hospitalized because of uremia, and underwent hemodialysis. When the patient developed hematochezia, Duke's C sigmoid colon cancer was detected and successfully resected. She received broad-spectrum antibiotics in the perioperative period. The patient then developed profuse diarrhea associated with abdominal cramping, a low-grade fever, prostration, and headache. The patient then started to received vancomycin 500 mg po qid empirically. Four days later, the diarrhea continued unabated, the Clostridium difficile titer was negative, and the vancomycin therapy was stopped. However, the stool culture was positive for heavy growth of P. aeruginosa sensitive to ciprofloxacin. The patient then began to receive ciprofloxacin 500 mg po bid. Within 3 days the diarrhea stopped. Oral ciprofloxacin therapy was continued for 10 days and the patient remained free of symptoms with formed stools thereafter. DISCUSSION: Diarrhea following the use of broad-spectrum antibiotics implicates pseudomembranous colitis as the cause. The patient did not respond to oral vancomycin therapy and had a negative stool assay for C. difficile toxin. This patient was believed to have Pseudomonas enteritis, which was confirmed by 2 positive stool cultures. The administration of oral ciprofloxacin therapy stopped her diarrhea with a rapid resolution of symptoms. CONCLUSIONS: P. aeruginosa as a cause of infectious diarrhea is unusual. When it occurs, it usually represents a nosocomial infection in an immunocompromised host. This report illustrates that oral ciprofloxacin therapy is effective for Pseudomonas enteritis, with rapid resolution of symptoms.     

Determination of ceftiofur and its desfuroylceftiofur-related metabolites in swine tissues by high-performance liquid chromatography

2- and 4-Nitrophenyl beta-D-xylopyranosides (4 and 5) were transformed, via dibutyltin oxidemediated acylation, into the corresponding 2,3-di-O-benzoyl derivatives 11 and 15. Xylobiose and xylotriose were easily isolated by charcoal column chromatography from a commercially available material and converted into the di- and trisaccharide methyl 1-thio-beta-glycosides 36 and 37. The 2-and 4-nitrophenyl beta-glycosides of the beta-(1-->4)-D-xylo-oligosaccharides of dp 2-4 were synthesized by N-iodosuccinimide-silver triflate-promoted condensation using 11 and 15 as the glycosyl acceptors and ethyl 1-thio-beta-D-xylopyranoside triacetate 16, 36, and 37 as the glycosyl donors. Also described are an improved preparation of 4 and 5, and the synthesis of 1-naphthyl beta-D-xylopyranoside, as well as an alternative approach to the 2- and 4-nitrophenyl beta-xylobiosides.