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Biomedical subjects

W M Haschek

Publications and source records attributed to W M Haschek.

At least 55 records · Page 3Linked to original sources
PubMed1989

Effects of dimethyl sulfoxide (DMSO) on pulmonary fibrosis in rats and mice.

Dimethyl sulfoxide (DMSO), a putative anti-inflammatory agent and free radical scavenger, was shown to protect against acute bleomycin-induced pulmonary fibrosis in the rat (Pepin and Langner, Biochem. Pharmacol., 34 (1985) 2386). We examined the effect of DMSO on bleomycin-induced pulmonary toxicity in Swiss outbred mice and Sprague-Dawley rats, and on butylated hydroxytoluene (BHT)-induced pulmonary toxicity in Swiss outbred mice. Bleomycin (BL)-induced mortality in mice (20% at 0.1 units BL) and rats (50% at 1.5 units BL) was increased to 100% by daily DMSO (5 g/kg 50% in saline). Similar DMSO treatment after lower doses of bleomycin (1 unit BL in rats and 0.075 or 0.050 units in mice) increased lung hydroxyproline content in the rat but had no effect in the mouse. Lung hydroxyproline content in mice 14 days after 400 mg/kg BHT in corn oil was also slightly increased by daily DMSO at 5 g/kg, but not at 1 or 2 g/kg. Daily DMSO (5 g/kg) did not alter cellular proliferation [( 14C]thymidine incorporation into pulmonary DNA) in the lung at 2 or 5 days after BHT. Thus, we found that DMSO potentiated the lethality of bleomycin, and potentiated or had no effect on bleomycin or BHT-induced pulmonary fibrosis in the rat and mouse.

Animals↗
PubMed1989

Nephrotoxicity of para-substituted thiobenzamide derivatives in the rat.

Histological examination, plasma urea nitrogen levels (BUN), and renal cortical slice uptake of paminohippurate (PAH) or tetraethylammonium (TEA) were used to assess the nephrotoxicity of thiobenzamide and its para-substituted derivatives in Sprague-Dawley rats. Intraperitoneal injection of p-methylthiobenzamide (PMTB) to rats resulted in dose-dependent nephrotoxicity as judged by increased BUN levels, decreased TEA uptake and histologic examination of the kidney. Para-methoxythiobenzamide and PMTB were more potent nephrotoxins than thiobenzamide, which was itself minimally nephrotoxic. Para-methylthiobenzamide-S-oxide (PMTBSO) was more nephrotoxic than PMTB. Rats were pretreated with 1-methyl-1-phenylbenzoylthiourea (MPBTU), a non-toxic arylthiourea which inhibits the metabolism and toxicity of thiocarbonyl compounds. The nephrotoxicity and hepatotoxicity of PMTB was reduced by treatment with MPBTU 30 min prior to PMTB. Pretreatment with MPBTU protected against the renal toxicity of PMTBSO. The results indicate that electron donating para-substituted thiobenzamides produce dose-dependent renal injury, dependent upon oxidative biotransformation.

Amides↗
PubMed1989

Toxicity of microcystin LR, a cyclic heptapeptide hepatotoxin from Microcystis aeruginosa, to rats and mice.

Rats (Sprague-Dawley) and mice (Balb/c) were given microcystin LR intraperitoneally and were killed at intervals up to 24 hr (rats) or 90 min (mice) and necropsied. The lowest consistently lethal dose was 160 micrograms/kg in rats and 100 micrograms/kg in mice. Rats that were clinically unaffected had no lesion. All clinically affected rats in all dose groups died (from 20 to 32 hr after toxin) and had similar hepatic lesions. Livers were enlarged and dark red beginning 40 to 60 min after toxin. Mild disassociation and rounding of centrilobular hepatocytes developed within 20 min. By 60 min after toxin, degeneration and necrosis of hepatocytes involved most of the lobules except for small periportal zones. Weights of livers and kidneys were significantly increased. Eosinophilic fibrillar material filled renal glomerular capillaries as early as 9 hr after toxin. At 18 to 24 hr there was moderate vacuolation of proximal tubular epithelium with mild tubular dilatation. Beginning at 1 hr, intact hepatocytes and hepatic debris were present in pulmonary vessels. Analysis of serum revealed an increase in alanine aminotransferase 40 min after toxin; at 6 to 12 hr there were significant increases in alkaline phosphatase, total bilirubin, blood urea nitrogen, and creatinine. Mice survived only 60 to 90 min after toxin. Hepatic lesions were similar to those in rats, but renal and pulmonary lesions were not seen.

Animals↗
PubMed1989

Comparative response of swine and rats to high-fiber or high-protein diets.

Twenty-four growing swine and 24 growing rats were fed high-protein (34%) diets on an ad libitum basis to determine their effects on body weight, carcass characteristics, intestinal microbiological profile and visceral organ weights. High dietary fiber reduced body weight gain and gain:feed ratio in both swine and rats and decreased body fatness in swine; it increased relative kidney weight (percentage of body weight) in both swine and rats and decreased relative liver weight in rats but increased it in swine. Absolute weights of stomach and large intestine were unaffected by high fiber in either species, but relative weight of small and large intestine was increased in swine and relative weight of stomach was increased in rats. High dietary protein increased absolute and relative weights of kidneys in both species and increased relative liver in swine but not in rats. Absolute weight of large intestine was increased by high dietary protein in rats and tended to be increased in swine; relative large intestine weight was increased in both species. The microbial profile of large intestinal contents of rats showed no effect of diet on Enterobacteriaceae, Campylobacter, Salmonella or total anaerobes and cellulolytic organisms, but coliforms were higher in rats fed high fiber or high protein than in controls. We conclude that dietary levels of fiber and protein influence growth of specific segments of the gastrointestinal tract of growing rats and swine, probably by different mechanisms of action.

Animal Feed↗
PubMed1988

Protection by dimethylsulfoxide against acetaminophen-induced hepatic, but not respiratory toxicity in the mouse.

Dimethylsulfoxide (DMSO) is used as a vehicle for the administration of compounds that are difficult to solubilize. Acetaminophen (AP), typically administered ip in hot basic saline, dissolves readily in DMSO. However, since DMSO acts as a free radical scavenger in vitro, and since AP toxicity may be mediated through oxidative stress, we examined the possibility that DMSO might protect against AP toxicity. Survival of mice 96 hr after AP (900 mg/kg ip) was increased from 10 to 60% by concomitant DMSO administration (4 g/kg sc). Adult female Swiss inbred mice given AP (800 mg/kg ip in hot basic saline) exhibited severe centrilobular hepatic necrosis, pulmonary nonciliated bronchiolar epithelial (Clara cell) necrosis and nasal epithelial necrosis. DMSO (8 g/kg 50% in saline) protected against AP hepatotoxicity, whether administered prophylactically (14.5 and 2.5 hr before AP), concomitantly with AP, or antidotally (30 or 60 min post-AP). No treatment protected against pulmonary Clara cell damage. Nor did pretreatment with DMSO protect against AP-induced necrosis of nasal epithelium. Other treatment regimes were not evaluated for their effect on nasal epithelial toxicity. Since DMSO protection is tissue specific, it does not appear to be mediated by a nonspecific mechanism, such as scavenging of free radicals. Six hours after AP, glutathione (GSH) levels had dropped significantly in liver, but not in lung. AP-induced loss of hepatic GSH was slowed by DMSO even in the presence of BSO, an inhibitor of GSH synthesis. These findings are consistent with decreased utilization of GSH, due to decreased bioactivation of AP or decreased turnover of GSH.

Acetaminophen↗
PubMed1988

Experimental T-2 toxicosis in swine following inhalation exposure: clinical signs and effects on hematology, serum biochemistry, and immune response.

Nine- to ten-week-old, male castrated, specific pathogen-free derived pigs, weighing 34 to 42 kg, were exposed to a T-2 toxin aerosol (390 micrograms/liter, 1.5 microM mass median aerodynamic diameter) for a time period which allowed an amount equivalent to 8 mg/kg to be nebulized (six pigs). Control animals (five pigs) were exposed to an equivalent amount of the nebulized vehicle. Pigs were immunized subcutaneously with sheep red blood cells on Days 0 and 21. Whole blood and serum samples were taken periodically for clinical pathologic and immunologic studies. Pigs were closely observed, and daily rectal temperatures and weekly weights were measured. The T-2-treated pigs vomited and exhibited cyanosis, anorexia, lethargy, lateral recumbency, slightly elevated rectal temperature, and depressed body weight gain. The lymphocyte count decreased while the neutrophil count increased. The concentrations of total serum protein and hemoglobin declined. There was a marked increase in serum alkaline phosphatase activity on Day 1, followed by a marked and persistent decrease. Mitogen-induced (Con A, PHA, and PWM) blastogenic responses of peripheral blood mononuclear cells and hemagglutination titers to SRBC were also transiently decreased. Thus, inhalation exposure of pigs to a sublethal dose of T-2 toxin caused clinical signs of toxicity and adverse effects on clinical pathologic parameters and immune responses; however, most of these effects were short-lived. The changes described in our study resemble those reported in pigs given T-2 toxin by intravascular injection.

Administration, Inhalation↗
PubMed1988

The role of intestinal microflora in the metabolism of trichothecene mycotoxins.

The role of faecal and intestinal microflora on the metabolism of trichothecene mycotoxins was examined in this study. Suspensions of microflora obtained from the faeces of horses, cattle, dogs, rats, swine and chickens were incubated anaerobically with the trichothecene mycotoxin, diacetoxyscirpenol (DAS). Micro-organisms from rats, cattle and swine completely biotransformed DAS, primarily to the deacylated deepoxidation products, deepoxy monoacetoxyscirpenol (DE MAS) and deepoxy scirpentriol (DE SCP). By contrast, faecal microflora from chickens, horses and dogs failed to reduce the epoxide group in DAS and yielded only the deacylation products, monoacetoxyscirpenol (MAS) and scirpentriol (SCP), in addition to unmetabolized parent compound. Intestinal microflora obtained from rats completely biotransformed DAS to DE MAS, DE SCP and SCP; and T-2 toxin to the deepoxy products, deepoxy HT-2 (DE HT-2) and deepoxy T-2 triol (DE TRIOL). Rat intestinal microflora also biotransformed the polar trichothecenes, T-2 tetraol and scirpentriol, to their corresponding deepoxy analogues. Deepoxy T-2 toxin (DE T-2) was synthesized from T-2 toxin and demonstrated to be 400 times less toxic than T-2 toxin in the rat skin irritation bioassay and non-toxic to mice given 60 mg/kg ip, demonstrating that epoxide reduction is a significant single step detoxification reaction for trichothecene mycotoxins.

Animals↗
PubMed1988

Mechanism of inhibition of hepatic bioactivation of paracetamol by dimethyl sulfoxide.

Prior work has shown that DMSO inhibits paracetamol hepatotoxicity. In this paper we show that DMSO and its reduced metabolite dimethyl sulfide (DMS) can inhibit in vitro hepatic dimethylnitrosamine N-demethylase. We also show that DMSO can inhibit in vivo production of glutathione conjugates of paracetamol. Glutathione is known to conjugate the bioactivated form of paracetamol. Also, the isozyme of cytochrome P-450 responsible for dimethylnitrosomine N-demethylase, cytochrome P-450j, is thought responsible for paracetamol bioactivation. We therefore propose that DMSO inhibits paracetamol hepatotoxicity due to inhibition of cytochrome P-450j-dependent paracetamol bioactivation by DMSO and its metabolite DMS.

Acetaminophen↗
PubMed1988

Healing of transverse humeral fractures in pigeons treated with ethylene oxide-sterilized, dry-stored, onlay cortical xenografts and allografts.

Transverse humeral fractures were created in adult male pigeons (Columbia livia). They were bridged with an allograft or a xenograft, or they were allowed to heal without treatment. Tissues were examined for wound healing, bony union, infection, and sequestration of the graft at 28, 43, 85, 106, and 168 days after surgery. Neither allografts nor xenografts contributed to nor interfered with bone healing. In nontreated pigeons (controls), bony union with marked callus formation developed between misaligned fragment ends. When onlay grafts were used, bone fragments remained aligned, with minor callus formation. There was a significant (P = 0.0001) increase in the number of wounds opening after surgery and infections of the surgical site (xenograft, P = 0.0026; allograft, P = 0.0021) associated with graft use. A significant (P = 0.0001) frequency of graft sequestration was observed, regardless of graft type. A significant (P = 0.0001) frequency of foreign body reaction also was observed. Under these circumstances, the application of a graft should be considered as an alignment device, rather than a stimulus to healing.

Animals↗
PubMed1987

Experimental T-2 toxicosis in swine. III. Morphologic changes following intravascular administration of T-2 toxin.

The gross and microscopic changes in swine following a single intravascular (iv) dose of T-2 toxin are described and evaluated quantitatively. T-2 toxin, in 70% ethanol, was given iv at 0 (5 pigs), 0.6 (5 pigs), 1.2 (1 pig), 4.8 (5 pigs), or 5.4 (2 pigs) mg/kg to 40 to 60 kg female crossbred pigs. The 4.8 and 5.4 mg/kg group pigs died between 5 and 10.5 hr after treatment, while the 0, 0.6, and 1.2 mg/kg pigs were killed at 24, 24, and 12 hrs after treatment, respectively. Morphologic examination was performed at the gross and light microscopic levels. In addition, a quantitative evaluation of microscopic changes present in lymphoid tissues and intestinal tract was performed using a semiquantitative scoring system. Gross lesions in the T-2-treated pigs consisted of edema, congestion, and hemorrhage of the lymph nodes and pancreas; congestion and hemorrhage of the gastrointestinal mucosa, subendocardium, adrenal gland, and meninges; and edema of the gall bladder. Histologic examination confirmed the gross observations. Additional microscopic lesions included widespread degeneration and necrosis of the lymphoid tissues as well as of the surface and crypt epithelium of the gastrointestinal mucosa; mild scattered necrosis of pancreatic acinar cells, myocardium, bone marrow cells, adrenal cortical cells, and tubular epithelium of renal medulla; and mild interstitial pneumonia. A dose-dependent increase in lesion severity was observed except for the pancreatic lesion which was slightly more apparent in the pigs from the 0.6 mg/kg group. These findings indicate that T-2 toxin-induced lesions in the lymphoid tissues and gastrointestinal tract of pigs are similar to those of other species the pancreas and heart should be considered as additional target organs in the pig, and both rapidly dividing cells and those with little or no turnover are damaged by T-2 toxin.

Animals↗
PubMed1987

The toxicity of T-2 toxin in swine following topical application. I. Clinical signs, pathology, and residue concentrations.

T-2 toxin at 0 or 15 mg/kg in 0.75 ml dimethyl sulfoxide was topically applied to 11- to 12-week-old specific-pathogen-free derived crossbred female pigs. Animals were killed on Days 1, 3, 7, or 14 after treatment. Clinical signs and morphologic changes in the skin and internal organs, as well as the residual concentrations of T-2 toxin and its metabolites in plasma, bile, urine, skin, and subcutaneous tissue, were examined. The T-2-treated pigs had signs of lethargy, anorexia, posterior weakness or paresis, and persistent fever. The skin at the site of application was red and swollen initially and progressively became dark red and then purple. By Day 7, at the margin of the exposed area, clefts had formed and were covered by serosanguinous exudate. By Day 14, the affected skin was focally separated from the underlying tissue and covered by a thick scab. The initial skin lesions were characterized as a spongiotic dermatitis and were located mainly in the dermal papillae and stratum germinativum of the epidermis. These lesions progressed to a locally extensive necrotizing dermatitis between Days 3 and 7 that was still evident at Day 14. Healing began on Day 7 and was more prominent on Day 14. Morphologic changes in the internal organs were minimal. They consisted of necrosis of single cells in the follicles of lymphoid tissues and in the exocrine pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1987

The toxicity of T-2 toxin in swine following topical application. II. Effects on hematology, serum biochemistry, and immune response.

T-2 toxin at 0 (6 pigs) or 15 mg/kg (8 pigs) in 0.75 ml of dimethyl sulfoxide was topically applied to 9- to 10-week-old, male castrated, specific-pathogen-free derived pigs which were immunized subcutaneously with sheep red blood cells (SRBC) on Days 0 and 21. Whole blood and serum samples were taken periodically for clinical pathologic and immunologic evaluations. The pigs were observed daily and weighed weekly; their rectal temperatures were measured periodically. The T-2-treated pigs displayed anorexia, lethargy, posterior weakness and paresis, persistent high fever, and reduced body weight gain. Prominent neutrophilia, decreased serum glucose, albumin, and alkaline phosphatase activity, and increased serum globulin were seen in the T-2-treated group. The responses of enriched peripheral blood mononuclear cells to mitogens concanavalin A, phytohemagglutinin, and pokeweed mitogen of the T-2-treated group were significantly lower than those of the control group both at early (3 to 5 days) and late (20 to 28 days) postdosing intervals. No significant effects were noted in the hemagglutination titer to SRBC. Thus, in addition to the severe local dermal injury reported previously, topical exposure of swine to a sublethal dose of T-2 toxin, 15 mg/kg, can cause significant systemic effects on parameters such as body weight gain, rectal temperature, hematology, serum biochemistry, and cellular immune response.

Administration, Topical↗
PubMed1987

Experimental T-2 toxicosis in swine following inhalation exposure: effects on pulmonary and systemic immunity, and morphologic changes.

Thirty-four, 9- to 11-week-old, male castrated, crossbred, specific pathogen-free derived pigs were exposed to a T-2 toxin aerosol at a nebulized dose of 0 or 9 mg/kg in pairs, each pair consisting of 1 control and 1 T-2 treated pig which were exposed on the same day. Twenty to 30% of the toxin (1.8 to 2.7 mg/kg) was retained by the pigs. Five pairs were killed on each of 1, 3 and 7 days after dosing. Two pairs of pigs were designated as a 0.33-day group when one T-2 treated pig died and the other was killed in a moribund state at 8 to 10 hours after dosing. The pulmonary and systemic immunity and morphologic changes of the lungs and other organs were examined. Bronchoalveolar lavage was performed to obtain alveolar macrophages (AM) and pulmonary lymphocytes (PL). The phagocytic ability of AM and mitogen-induced blastogenic responses of enriched PL and peripheral blood lymphocytes were evaluated. Clinically, all of the T-2 treated pigs vomited and were cyanotic, anorexic, lethargic and laterally recumbent. In the 0.33-, 1-, and 3-day T-2 treated pigs, there was a marked reduction in AM phagocytosis and mitogen-induced blastogenic responses of PL but not of peripheral blood lymphocytes. Mild to moderate, multifocal interstitial pneumonia was seen in the majority of the T-2 treated pigs. In pigs dying following inhalation of T-2 toxin, there was a more severe pneumonia, as well as marked necrosis of lymphoid tissues, severe necrohemorrhagic gastroenteritis and edema of the gall bladder wall, and multifocal necrosis of the heart and pancreas. Thus, inhalation exposure to T-2 toxin can result in clinical signs and morphologic changes resembling those reported previously in pigs given T-2 toxin intravascularly (iv) at a dose of 1.2 mg/kg (approximate LD50) or greater, as well as death. Mild pulmonary injury as well as transient impairment of pulmonary immunity was present in pigs surviving inhalation exposure.

Administration, Inhalation↗
PubMed1987

Blue-green algae (Microcystis aeruginosa) hepatotoxicosis in dairy cows.

Twenty cows from a dairy herd consisting of 60 healthy, lactating Holsteins developed clinical signs of anorexia, mental derangement, dehydration, recumbency, and ruminal atony after ingesting water containing blue-green algae. Of the 20 cows, 9 died. The algal bloom, which developed in a stagnant pond during hot, dry weather, was identified as the cyanobacterium Microcystis aeruginosa, a potentially hepatotoxic algae. One week after the onset of toxicosis, affected cows seemed healthy, although liver-associated enzyme activities (alkaline phosphatase, gamma-glutamyl transferase, aspartate transaminase, and lactate dehydrogenase) were increased. Intraruminal administration of the intact wet bloom to a healthy 125-kg Angus heifer was followed by hepatic necrosis and death. The liver was large, friable, and gun-metal blue, with microscopically evident hepatocyte dissociation, degeneration, and necrosis. The ingesta of the heifer contained typical clumps of cells that were identified as M aeruginosa. The intraperitoneal administration of lyophilized cell material from that bloom to 18 mice caused marked hepatic enlargement. The intraperitoneal median lethal dose of the dried bloom was estimated to be 10 mg/kg of body weight. A cyclic peptide toxin purified from the algae seems to be similar structurally to toxins from other characterized hepatotoxic blooms of M aeruginosa.

Animals↗
PubMed1986

Comparative effects of dietary protein and cholesterol-fat content on genetically lean and obese pigs.

Interactions of a high fat-high cholesterol diet with low and high dietary protein levels were tested in genetically obese and lean growing pigs. Sixty-four growing swine (32 obese and 32 lean) were utilized in a 9-wk experiment in which four diets were fed in a 2 X 2 factorial arrangement with two levels of plant protein (8 and 16%) and two levels of fat and cholesterol (0 added or 11% beef tallow-3% dried egg yolk added). Daily gain and gain-to-feed ratio were significantly reduced by low protein (P less than 0.01) and increased by high fat-high cholesterol. Obese pigs gained weight faster than lean pigs but were less efficient in feed utilization (P less than 0.02) except when consuming low protein diets (P less than 0.001). Plasma cholesterol was increased by low protein (P less than 0.01) and by high fat-high cholesterol (P less than 0.02); highest values were in pigs fed low protein-high fat-high cholesterol. Lean pigs showed a greater rise than obese pigs in plasma cholesterol when fed low protein diets, reflecting a higher dietary protein requirement for lean pigs as indicated by plasma total protein, albumin and urea nitrogen (urea-N) responses to diet. Percentage of aortic surface area stained by Sudan IV tended to be higher in lean than in obese pigs but the difference was not statistically significant (P less than 0.25). The data show the hypercholesterolemic effect of dietary protein restriction in growing swine and establish that genetic differences related to body composition and quantitative protein requirement affect the response.

Animals↗
PubMed1986

Myocardial and pancreatic lesions induced by T-2 toxin, a trichothecene mycotoxin, in swine.

Myocardial and pancreatic lesions induced by sublethal doses of T-2 toxin in swine were characterized by light and electron microscopy. Toxin was given intravenously to six 17- to 18-week-old pigs. Pigs were killed 24 or 48 hours after treatment. Grossly, subendocardial hemorrhages, multifocal pinpoint white foci in myocardium, and pancreatic edema occurred in one treated pig. Histologic changes in myocardium of treated pigs consisted of multifocal edema, mononuclear cell infiltration, myofiber hyalinization, vacuolation, and contraction bands with nuclear pyknosis. Ultrastructurally, there were areas of edema, myofibrillar disorganization, dilation of sarcoplasmic reticulum, and formation of hypercontraction bands. Myocardial mineralization was seen in the pig with gross lesions. Pancreatic changes in treated pigs consisted of multifocal acinar degeneration and necrosis. Ultrastructural changes included irregular dilation of rough endoplasmic reticulum and abnormal zymogen granules. Thus, in addition to radiomimetic lesions of the gastrointestinal tract and lymphoid organs, heart and pancreas are target organs of T-2 toxin in swine.

Animals↗
PubMed1985

Pulmonary toxicity of cyclophosphamide: a 1-year study.

The development of cyclophosphamide-induced pulmonary lesions over a 1-year period was studied in mice. Male BALB/c mice received a single intraperitoneal injection of 100 mg/kg of cyclophosphamide. Within 3 weeks there were scattered foci of intraalveolar foamy macrophages. With time, these foci increased in size and, 1 year later, occupied large areas in all lung lobes. There was also diffuse interstitial fibrosis. Chemical determination done 3, 12, 24, and 52 weeks after cyclophosphamide showed that lungs of animals treated with cyclophosphamide had significantly more hydroxyproline per lung than controls. One year after cyclophosphamide pressure-volume curves measured in vivo were shifted down and to the right and total lung volumes were decreased. A single injection of cyclophosphamide produced an irreversible and progressive pulmonary lesion.

Animals↗