Dietary components modify the ability of garlic to suppress 7,12-dimethylbenz(a)anthracene-induced mammary DNA adducts

Various dietary components were evaluated as factors influencing garlic's ability to depress rat mammary cell DNA adducts resulting from 7,12-dimethylbenz(a)anthracene (DMBA) treatment. Diets with or without garlic powder (20 g/kg) were provided for 2 wk before DMBA treatment (25 mg/kg body weight). Rats fed diets containing 36 g casein/100 g diet had 31% fewer (P < 0.05) mammary cell DNA adducts than those fed 12 g/100 g. Garlic supplementation significantly (P < 0.05) reduced DNA adducts in rats fed either 12 or 36 g casein/100 g by 35 and 32% respectively. In the absence of dietary garlic, DNA adducts were 23% lower (P < 0.05) in rats provided a diet containing supplemental L-methionine at 0.9 g/100 g than at 0.3 g/100 g. However, adduct inhibition by garlic supplementation was greater in rats fed the lower (P < 0.05) amount of methionine (54 vs. 26% inhibition). Adduct levels in rats fed diets with 20 g corn oil/100 g were twice those occurring in rats fed 5 g/100 g (P < 0.05), regardless of adjustment for energy density. Garlic supplementation prevented the increase in DNA adducts caused by increasing dietary corn oil. Combining dietary supplements of garlic, selenite (0.5 mg/kg diet) and retinyl acetate (328 mg/kg diet) inhibited the occurrence of DNA adducts to a greater degree than when each was supplied individually. These studies demonstrate that while dietary garlic can reduce DNA adduct formation in mammary tissue caused by DMBA, this protection is influenced by several dietary components.     

Repeated dosing with the peroxisome proliferator clofibrate decreases the toxicity of model hepatotoxic agents in male mice

Pretreatment of mice with clofibrate (CFB) has been shown to protect against acetaminophen (APAP) hepatotoxicity. To determine if pretreatment with CFB prevents the toxicity of other model hepatotoxicants, male C57BL6J or CD-1 mice received 500 mg CFB/kg, i.p., daily for 10 days, and then were challenged with either 250 mg bromobenzene (BrB)/kg, 0.025 ml carbon tetrachloride (CCl4)/kg or 0.5 ml chloroform (CHCl3)/kg. Liver and kidney injury was assessed by plasma sorbitol dehydrogenase activity (SDH) and blood urea nitrogen (BUN), respectively and histopathology. Challenge with BrB significantly elevated plasma SDH activity in C57Bl6J mice. This was prevented in CFB pretreated mice receiving the same dose of BrB. Changes in BUN were not detected in either group of BrB treated mice. Similarly, pretreatment of male CD-1 mice with CFB significantly reduced CCl4-induced elevation in plasma SDH activity, with no BUN elevation detected in either group. CFB pretreatment also diminished elevation in plasma SDH activity produced by CHCl3 in CD-1 mice, while BUN was significantly elevated in both groups, indicating that CFB did not protect against CHCl3-induced nephrotoxicity. Histopathological examination of liver and kidney sections confirmed these results. This study shows that mice pretreated with CFB were protected from toxicity at 24 h after challenge with other model hepatotoxic agents besides APAP.     

Black tea and mammary gland carcinogenesis by 7,12-dimethylbenz[a]anthracene in rats fed control or high fat diets

Epidemiological studies suggest that tea may reduce cancer risk, and in laboratory rodents, chemopreventive effects of tea or purified extracts of tea have been demonstrated in lung, gastrointestinal tract and skin. There is some evidence of chemoprevention by tea in the mammary gland, but the data are not conclusive. In order to evaluate more fully the possible influence of black tea on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary gland tumors in the female S-D (Sprague-Dawley) rat, three large studies were performed: experiment 1, tumorigenesis in rats fed AIN-76A diet and given 25 mg/kg DMBA and 1.25 or 2.5% whole tea extract or water to drink; experiment 2, tumorigenesis in rats given 15 mg/kg DMBA and the same diet and fluids as in experiment 1; experiment 3, tumorigenesis in rats fed control or HF (high fat, corn oil) diet and given 15 mg/kg DMBA and 2% tea or water to drink. Tea was given throughout the experiment; DMBA was given by gastric gavage at 8 weeks of age. There was no consistent effect of tea on tumorigenesis in rats fed AIN-76A diet; there was, however, evidence in experiment 3 of a reduction of tumorigenesis by tea in rats fed the HF diet. In experiment 3, rats fed the HF diet and given water showed the expected increase in tumor burden (number and weight) compared with rats fed control diet. However, rats fed the HF diet and given 2% tea showed no increase in tumor burden; their tumor burden was significantly lower than in rats fed the HF diet and given water (P < 0.01) and was not different from rats fed control diet and given water or tea. In addition, in experiment 3, the number of malignant tumors per tumor-bearing rat was increased by the HF diet in water-drinking rats (P < 0.01) but not in tea-drinking rats. Therefore, it appears that tea partially blocked the promotion of DMBA-induced mammary tumorigenesis by the HF diet.     

Colchicine antimitosis abolishes resiliency of postnatally developing rats to chlordecone-amplified carbon tetrachloride hepatotoxicity and lethality

We have previously reported that rats are resilient to the hepatotoxic and lethal combination of chlordecone (CD) and carbon tetrachloride (CCl4) during early postnatal development. The overall findings pointed to stimulated cell division and tissue repair mechanisms as the underlying cause of resistance. The objective of the current study was to investigate if the antimitotic effect of colchicine (CLC) abolishes this resiliency to CD + CCl4 by inhibiting ongoing and stimulated cell division. We used 45-day-old rats in this study because this age group exhibited partial sensitivity to CD + CCl4 in our previous studies. Male Sprague-Dawley rats were treated with a single low intraperitoneal dose of CCl4 (100 microl/kg) or corn oil after exposure to either 10 ppm CD in the diet or a normal diet (ND) for 15 days. CLC (1 mg/kg) was administered 6 or 30 hr after CCl4 to ND or CD rats, respectively. Administration of CLC resulted in increased CCl4-induced mortality from 25% to 85% in rats pretreated with CD, in contrast to 100% survival in ND rats. Liver injury was assessed by plasma alanine transaminase (ALT) and sorbitol dehydrogenase (SDH) elevations as well as by histopathology. Hepatocellular regeneration was assessed by 3H-thymidine (3H-T) incorporation into hepatonuclear DNA and proliferating cell nuclear antigen (PCNA) studies during 0-96 hr after CCl4. Administration of CLC to ND + CCl4 rats resulted in a slight delay in cell division and tissue repair, as indicated by 3H-T incorporation and PCNA, thereby leading to prolonged liver injury as revealed by elevations in plasma ALT, SDH, and histopathological lesions. In contrast, CLC administration to CD + CCl4-treated rats further delayed and diminished cell division by 80%, which led to unrestrained progression of CCl4-induced liver injury, resulting in 85% mortality. These findings underscore the importance of ongoing and toxicant-stimulated cell division and tissue repair mechanisms in hepatotoxicity, and the need for the inclusion of age factors in risk assessment of exposure to environmental and other chemicals.     

Cytochrome P450 1A-like proteins expressed in the islets of Langerhans and altered pancreatic beta-cell secretory responsiveness

1. The cytochrome P450 (CYP) mixed-function oxidase system is widely distributed in body tissues and plays a key role in the metabolism of endogenous and exogenous compounds. Little attention has been paid to the expression of the system in the islets of Langerhans. The current study has examined the expression and potential role of the CYP1A family within the islets of Langerhans of control and 3-methylcholanthrene (3-MC)-induced Wistar rats. 2. CYP1A expression within pancreatic slices and islets from 3-MC-induced and control rats demonstrated that CYP1A-like protein levels were induced by 3-MC pretreatment (25 mg kg-1 day-1; i.p. for 3 days). 3. Effects of 3-MC-induction on beta-cell secretory responsiveness were investigated by use of rat collagenase-isolated islets. Insulin release from control islets incubated with 3 mM glucose (basal) was 1.4 +/- 0.2 ng/islet h-1 (mean +/- s.e.mean, n = 7). Incubation with 16.7 mM glucose, 25 mM KCl, 100 microM arachidonic acid, or 100 microM carbachol caused a 4.4, 7.0, 4.0 and 4.2 fold, respectively, increase in insulin release (P < 0.001). Forskolin (2 microM), or phorbol 12-myristic 13-acetate (10 nM) potentiated glucose-stimulated insulin release 1.2 and 1.6 fold (P < 0.01) whereas adenalin (1 microM) caused a 76% inhibition (P < 0.01). 4. Islets from 3-MC pretreated animals displayed similar responsiveness to all agents tested except arachidonic acid, carbachol and forskolin. Insulin release in response to arachidonic acid and carbachol was enhanced 5.2 and 5.0 fold, respectively, by 3-MC pretreatment (P < 0.001 compared to control islets incubated with 3 mM glucose); the effect of forskolin on insulin output was significantly decreased (20%; P < 0.01) compared to control islets. 5. 3-MC pretreatment did not cause any significant differences in food intake, plasma glucose or total islet insulin content. Incubation of islets with 3-MC in vitro (1 microM - 10 mM) did not affect basal or glucose-stimulated insulin release. 6. These data suggest that CYP1A-like protein expression within the pancreatic islets of Langerhans is inducible and may have a role in the alteration of pancreatic beta-cell secretory responsiveness.     

Nicotine dependence and health care issues with special emphasis on mental health

The diet and nutritional status dominate a tolerance to environmental xenobiotics. In this study, the cytotoxic action of carbon tetrachloride (CCl4) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), one of the dietary carcinogens, was investigated using primary cultured hepatocytes from rats fed a high-fat (23% corn oil) or high-protein (50% casein) diet for three weeks. Both chemicals showed strong cytotoxicity to hepatocytes, which was judged by measurement with the MTT-test and lactate dehydrogenase leakage test. A dietary effect on cytotoxicity was observed; hepatocytes from rats fed the high-protein diet were more susceptible to cytotoxicity than the cells from rats fed a standard diet. On the other hand, ureogenesis, as a cellular function of hepatocytes, was markedly decreased in the cells from rats fed the high-fat diet. These activities were affected in the CCl4-treated cells but not in the Trp-P-1-treated cells. The same trend of both diet and chemical effects was observed in gluconeogenesis from fructose. We conclude that the hepatocytes from rats fed a high-protein diet have high susceptibility to the cytotoxicity of CCl4 and Trp-P-1, but cytotoxicity was not related to the reduction of cellular functions.     

Penclomedine-induced DNA fragmentation and p53 accumulation correlate with reproductive cell death in colorectal carcinoma cells with altered p53 status

Acarbose reduces the absorption of monosaccharides derived from dietary carbohydrates, which play an important role in the metabolism and toxicity of some chemical compounds. We studied the effects of acarbose on the hepatotoxicity of carbon tetrachloride (CCl4) and acetaminophen (AP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 2E1 (CYP2E1). Male Sprague-Dawley rats were kept on a daily ration (20 g) of powdered chow diet containing 0, 20, 40, or 80 mg/100 g of acarbose, with drinking water containing 0% or 10% of ethanol (vol/vol). Three weeks later, the rats were either killed for an in vitro metabolism study or challenged with 0.50 g/kg CCl4 orally or 0. 75 g/kg AP intraperitoneally. The ethanol increased the hepatic microsomal CYP2E1 level and the rate of dimethylnitrosamine (DMN) demethylation. The 40- or 80-mg/100 g acarbose diet, which alone increased the CYP2E1 level and the rate of DMN demethylation, augmented the enzyme induction by ethanol. The 40- or 80-mg/100 g acarbose diet alone potentiated CCl4 and AP hepatotoxicity, as evidenced by significantly increased levels of both alanine transaminase (ALT) and aspartate transaminase (AST) in the plasma of rats pretreated with acarbose. Ethanol alone also potentiated the toxicity of both chemicals. When the 40- or 80-mg/100 g acarbose diet was combined with ethanol, the ethanol-induced potentiation of CCl4 and AP hepatotoxicity was augmented. Our study demonstrated that high doses of acarbose, alone or in combination with ethanol, can potentiate CCl4 and AP hepatotoxicity in rats by inducing hepatic CYP2E1.     

The influence of high- and low-fibre diets on the activity of piperazine against Oesophagostomum spp. in pigs

An in vivo study evaluated the effect of diet on the efficacy of piperazine against nodular worms of pigs. Twenty pigs, later allocated into five groups, were each infected (and 37 days later re-infected) with 3000 infective larvae of a mixed isolate of Oesophagostomum dentatum and Oesophagostomum quadrispinulatum. Beginning on day 23 post infection (p.i.), pigs in groups 1 and 2 were fed a low-fibre diet consisting of 70% barley flour and 30% protein concentrate, while pigs in groups 3, 4 and 5 were fed a high-fibre diet consisting of 55% barley flour, 21% oat-husk meal and 24% protein concentrate. On day 42 p.i., pigs in groups 1 and 3 were orally dosed with 200 mg piperazine dihydrochloride (Ascarex D, 53%) per kg bodyweight, the recommended dose, while pigs in group 4 were given 100 mg kg-1. Groups 2 and 5 served as non-treated controls for the respective dietary regimens. Eight days after treatment, the pigs were slaughtered and worms recovered from the caecum and large intestine (divided into five sections) and counted. The mean worm count reduction (WCR) in group 1 (full-dose piperazine with low-fibre diet) was 89.8%, while the high-fibre diet in group 3 increased the WCR to 99.4%. In group 4, where the pigs were fed the high-fibre diet and treated with only 100 mg piperazine kg-1, the WCR was 90.9%, identical to the "low fibre" group 1 treated with twice this piperazine dose. There was a zero efficacy recorded against immature worms in all three treated groups. The high-fibre diet improved the efficacy of piperazine against more pathogenic and generally more tolerant O. quadrispinulatum to 99.2% compared with 84.3% at the low-fibre diet.     

Antifibrotic and hemodynamic effects of the early and chronic administration of octreotide in two models of liver fibrosis in rats

The aim of this study was to assess the effect of the early and chronic administration of octreotide in the prevention of hepatic fibrosis and portal hypertension (PHT). Two experimental models of liver fibrosis caused by bile duct ligation (BDL) or CCl4 were divided into 4 rat groups: sham, placebo, and octreotide (10 and 100 micrograms/kg twice daily, subcutaneously). Liver fibrosis was assessed by the area of fibrosis (image analysis), liver hydroxyproline and fibronectin mRNA contents, and serum hyaluronate. Systemic and splanchnic hemodynamic changes were also evaluated, including the splenorenal shunt blood flow by the transit-time ultrasound (TTU) technique. In both models, splenorenal shunt blood flow was significantly lower in the octreotide groups than in the placebo group (P <.05), while portal pressure was not significantly decreased. There was a significant decrease in fibrosis by octreotide in the CCl4 model only: area of fibrosis: 13.9% +/- 3.7% vs. 9.8% +/- 2.5% (P <.01), hydroxyproline: 1.8 +/- 0.6 vs. 1.3 +/- 0.4 mg/g wet liver (P <.05), respectively, placebo vs. octreotide 10 micrograms/kg. There was a significant correlation between the area of fibrosis and hydroxyproline liver content (r =.87 in the biliary model and r =.91 in the CCl4 model; P <.0001). The early and chronic administration of octreotide prevents the development of portocollateral blood flow without reducing portal pressure in two models of liver fibrosis and the development of liver fibrosis in the CCl4 model.     

Effects of high fat diet and cholecystokinin receptor blockade on pancreatic growth and tumor initiation in the hamster

The mechanism by which high-fat diet potentiates pancreatic cancer is not known, but trophic hormones may be involved. In preliminary growth studies, hamsters fed a high fat diet (17.5% lard, 17.5% corn oil) for 14 days showed a 16.3% increase (P < 0.01) in pancreatic weight compared to controls on low fat diet (2.5% lard, 2.5% corn oil). A significant increase was also seen at 28 days. Similar increases were seen in pancreatic DNA (29%, P < 0.01) and pancreatic RNA (22%, P < 0.05) at 14 days. Plasma cholecystokinin (CCK) levels at 14 days were 2.5 fold higher in the animals fed high fat (P < 0.01). Infusion of the CCK antagonist MK329 (25 nmol/kg/h) completely abolished the increase in pancreatic weight, pancreatic DNA and pancreatic RNA. The effect of CCK receptor blockade during the initiation period of carcinogenesis was investigated in hamsters fed the same diets used in the growth studies. One hundred animals received a single injection of N-nitrosobis(2-oxopropyl)amine, (BOP, 20 mg/kg). Half of the hamsters in each diet group received a 2 week infusion of MK329 (25 nmol/kg/h), beginning 8 days before carcinogen administration. At the time of death, 55 weeks after carcinogen administration, non-fasting plasma CCK levels were 31% higher in the high fat fed hamsters than in the low fat fed animals (P < 0.01). The high-fat diet group had a 3-fold increase in total cancer incidence and a 5-fold increase in advanced lesions (adenocarcinomas). Tumor incidence and yield were not changed in either diet group by CCK-receptor blockade during the initiation period. Cholecystokinin appears to mediate the short-term trophic effect that high-fat feeding has on the pancreas. However, potentiation of pancreatic cancer by high-fat diet in the hamster cancer model does not appear to be influenced by endogenous cholecystokinin at the time of tumor induction.     

Effect of 2 types of diet changes on dietary habits, body weight and cholesterol levels in high risk cardiovascular patients

Several non-pharmacological interventions such as weight reduction in obese subjects or diet alteration in subjects having hypercholesterolemia have been shown to be effective in therapeutic trials. Our aim was to test the value of two different ways of teaching patients about their diet. From March 1, 1993, to May 30, 1994, 300 consecutive patients seen in a one-day care hospital were randomised into two groups. The 2 inclusion criteria were: 1) body mass index > 27 kg/m2 in men and > to 25 kg/m2 in women and/or 2) presence of a hypercholesterolemia defined by a total cholesterol > 6.5 mmol/l. Patients in the first group (C) were educated in a 20 to 50 minutes consultation tailored to their needs. Patients in the second group (CC) were given in addition a one-hour course about diet. The goal of the diet was to loss at least 3 kg of body weight and/or to have a cholesterol value below 6.5 mmol/l without treatment. All Patients were followed-up by the same 3 dietician nurses. An out-patient visit was planned at 3 months, and a recall letter was sent to the patients who missed their appointments. Among the 300 patients, 169 (55%) were seen at the 3-month outpatient visit. This proportion did not differ between the 2 groups. Knowledge on diet was assessed by the same 33-item self-administered questionnaire. At baseline scores were comparable between groups (16 vs 17). Scores improved more in the CC than in the C group both at the end of the teaching question (27 vs 23 in the CC and C group respectively, p < 0.001), and at 3 months (25 vs 23 in the CC and C group respectively; p < 0.001). Total cholesterol decreased below 6.5 mmol/l in 28% of the patients with dyslipidemia and a weight loss > 3 kg was observed in 32% of the obese subjects, but improvement did not differ between the 2 groups. We conclude that a specific one-hour course on diet is able to improve knowledge of patients more than a consultation alone, but that better knowledge did not result in improved alteration of risk factors at 3 months.     

Tropical pasture hay utilization with slaframine and cottonseed meal: ruminal characteristics and digesta passage in wethers

Sixteen mature, ruminally cannulated wethers (average BW = 41 +/- 1 kg) were fed a low-quality hay diet with or without a cottonseed meal (CSM) supplement and the parasympathomimetic agonist slaframine (SF). Treatments were basal diet (Mitchell grass hay, 4.8% CP, 46.8% ADF) available on an ad libitum basis, basal diet plus SF (8 micrograms/kg BW, 2 x daily i.m. injection), basal diet plus CSM (41.0% CP; 100 g/d), or basal diet plus SF and CSM. Treatments were arranged as a 2 x 2 factorial within a replicated 4 x 4 Latin square with 20-d periods followed by a 10-d adjustment during which only the basal diet was fed. All measurements were performed within the final 10 d of each period. Slaframine increased salivary flow by 10 to 35% (P < .07), ruminal fluid dilution rate by 8 to 11% (P < .10), and pH by 3 to 4% (P < .001). A twofold increase (P < .05) in ruminal cellulolytic bacteria numbers occurred in SF-treated wethers. Despite these SF-induced changes in the ruminal environment, whole-tract apparent nutrient digestibility, N and mineral balance, and ruminal VFA concentrations were not changed. Cottonseed meal increased forage intake by 34 to 54% (P < .001) and DM digestibility by 30% (P < .001). Cottonseed meal supplementation of a Mitchell grass hay diet improved nutritional status and attenuated live weight loss.     

Dietary supplementation at home improves the regain of lean body mass after surgery

Little is known about nutritional intake after discharge though it takes months to regain preoperative weight after gastrointestinal surgery. We studied whether a 4-mo intervention with dietary advice and protein-rich supplements would increase nutritional intake and gain in lean body mass (LBM) in patients who had undergone gastrointestinal surgery. Patients admitted for gastrointestinal surgery were randomized at discharge to serve as control patients (n = 47) or to receive intervention (n = 40). One month after discharge, the control patients had a nutritional intake (3-d diet record) comparable with the intake of the general population that did not increase further. During the 4 m, the intervention patients had an increased intake of protein (+22%) and energy (+16%), and an enhanced gain of LBM after 2 mo (control 0.8 kg versus intervention 2.1 kg; P = 0.009). After the 4-mo intervention, both LBM and fat were gained (control 1.7 kg LBM and 0.2 kg fat versus intervention 3.1 kg LBM and 1.5 kg fat; LBM: P = 0.029 and fat: P = 0.056). At discharge patients should increase protein intake to 1.5 g.kg-1.d-1 for 2 mo, e.g., by taking protein-rich liquid supplements.     

Time courses of hepatic injuries induced by chloroform and by carbon tetrachloride: comparison of biochemical and histopathological changes

The relationship was investigated between biochemical and morphological changes in chloroform (CHCl3)- and carbon tetrachloride (CCl4)-induced liver damage. The time courses of hepatic microsomal cytochrome P450 (CYP) content, hepatic microsomal CYP2E1 activity, hepatic reduced glutathione (GSH) content, plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were examined in relation to the liver morphology in rats orally treated with CHCl3 or CCl4 (3.35 mmol/kg). The CYP content and the activity of CYP2E1 markedly decreased in the CCl4-treated rats 3 h after treatment compared to much lower decreases in the CHCl3-treated rats. The hepatic GSH content was decreased to a similar extent in both groups of rats at 3 h after treatment; in the CCl4-treated rats, the GSH content continued to decrease, reaching a minimum at 24 h and without attaining the normal level at 72 h after treatment. By contrast, hepatic GSH content in the CHCl3-treated rats began to increase from 6 h, attaining complete recovery 48 h after treatment. Plasma ALT and AST activities were significantly elevated by CCl4 as early as 3 h after treatment, while the activities in the CHCl3-treated rats did not increase until 6 h after treatment. In both groups of rats, ALT and AST activities reached a maximum at 24 h, and gradually decreased, remaining at abnormal levels at 72 h. Hepatic cells in the CCl4-treated rats were found to be necrotic as early as 3 h post-treatment, whereas few or no morphological changes appeared in the liver of CHCl3-treated rats. The extent of necrosis was at a maximum 24 h after treatment in both CHCl3- and CCl4-treated rats. In addition, some necrotic cells remained in the liver of CCl4-treated rats 72 h after treatment, while the necrosis in the CHCl3-treated rats was almost negligible. The present results indicate that almost the same time-courses of biochemical and morphological changes were followed in rats of both the CHCl3- and CCl4-treated groups.     

Docetaxel chronopharmacology in mice

Docetaxel tolerance and antitumor efficacy could be enhanced if drug administration was adapted to circadian rhythms. This hypothesis was investigated in seven experiments involving a total of 626 male B6D2F1 mice, synchronized with an alternation of 12 h of light and 12 h of darkness (12:12), after i.v. administration of docetaxel. In experiment (Exp) 1, the drug was given once a week (wk) for 6 wks (20 mg/kg/wk) or for 5 wks (30 mg/kg/wk) at one of six circadian times, during light when mice were resting [3, 7, or 11 hours after light onset (HALO)], or during darkness, when mice were active (15, 19, or 23 HALO). Endpoints were survival and body weight change. In Exp 2 and 3, docetaxel (30 mg/kg/wk) was administered twice, 1 wk apart, at one of four circadian stages (7, 11, 19, or 23 HALO). Endpoints were hematological and intestinal toxicities. In Exp 4, circadian changes in cell cycle phase distribution and BCL-2 immunofluorescence were investigated in bone marrow as possible mechanisms of docetaxel tolerability rhythm. In Exp 5 to 7, docetaxel was administered to mice bearing measurable P03 pancreatic adenocarcinoma (270-370 mg), with tumor weight and survival as endpoints. Mice from Exp 5 and 6 received a weekly schedule of docetaxel at one of six circadian stages (20 or 30 mg/kg/wk at 3, 7, 11, 15, 19, or 23 HALO). In Exp 7, docetaxel (30 mg/kg) was given every 2 days (day 1, 3, 5 schedule) at 7, 11, 19, or 23 HALO. Docetaxel dosing in the second half of darkness (19 or 23 HALO) resulted in significantly worse toxicity than its administration during the light span (3, 7, or 11 HALO). The survival rate ranged from 56.3% in the mice treated at 23 HALO to 93.8 or 87.5% in those injected at 3 or 11 HALO, respectively (Exp 1, P < 0.01). Granulocytopenia at nadir was -49 +/- 14% at 7 HALO compared with -84 +/- 3% at 19 HALO (Exp 2 and 3, P < 0.029), and severe jejunal mucosa necrosis occurred in 5 of 8 mice treated at 23 HALO as opposed to 2 of 18 receiving docetaxel at 7, 11, or 19 HALO (Exp 2 and 3, P < 0.02). The time of least docetaxel toxicity corresponded to the circadian nadir in S or G2-M phase and to the circadian maximum in BCL-2 immunofluorescence in bone marrow. Docetaxel increased the median survival of tumor-bearing mice in a dose-dependent manner (controls: 24 days; 20 mg/kg weekly, 33 days; 30 mg/kg weekly or day 1, 3, 5 schedule, 44 or 46 days, respectively; Exp 5-7). Survival curves of treated mice differed significantly according to dosing time for each dose and schedule (P from log rank <0.003 to P < 0.03). In Exp 5 and 6, the percentage of increase in life span was largest if docetaxel was administered weekly at 7 HALO (20 mg/kg, 220%; 30 mg/kg, 372%) and lowest after docetaxel dosing at 19 HALO (80% with 20 mg/kg) or at 15 HALO (78% with 30 mg/kg). In Exp 7, (day 1, 3, 5 schedule), docetaxel was most active at 11 HALO (percentage increase in life span, 390%) and least active at 23 HALO (210%). Docetaxel tolerability and antitumor efficacy were simultaneously enhanced by drug dosing in the light span, when mice were resting. Mechanisms underlying the tolerability rhythm likely involved the circadian organization of cell cycle regulation. Docetaxel therapeutic index may be improved with an administration at night in cancer patients, when fewest bone marrow cells are in S or G2-M phase.     

The efficacy of an enzymic cocktail and a fungal mycelium in dephosphorylating corn-soybean meal-based feeds fed to growing turkeys

A study was conducted to determine the efficacy of phytase, an enzymic cocktail, and a waste Aspergillus niger mycelium to hydrolyze phytate present in corn-soybean meal diets. One hundred turkey poults were assigned to dietary treatments for 2 wk (days 7 to 21). Dietary treatments included: 1) NRC (1994) diet (NRC), with recommended concentration of 0.6% available P (aP) and 1.2% Ca; 2) Phytase diet (PHYT), 1,000 units phytase/kg diet, 0.16% aP, and 0.84% Ca; 3) cocktail diet (COC), 1,000 units of phytase/kg diet plus acid phosphatase (100 units/g of diet), acid protease (42 units/g of diet), pectinase (2.94%), 0.16% aP, and 0.84% Ca; 4) Fungal mycelium diet (MYC), 5% mycelium, 0.16% aP, and 0.84% Ca; and 5) a positive control diet (CTRL+), 0.42% aP, and 0.84% Ca. Turkeys fed the PHYT diet consumed less feed and gained less weight but retained more P than poults fed the CTRL+ or NRC diets. Poults fed the COC diet performed as well as poults fed CTRL+ or NRC diets but retained more P (77%) and Ca (68%). Poults fed the MYC diet retained 79% P, gained the most weight, and were more efficient than poults fed any other dietary treatment. In vitro P release from experimental diets correlated well (R = 0.906) with P retention as observed in the feeding trial. Compared with the diet containing phytase as the sole supplemental enzyme, both the enzymic cocktail and fungal mycelium enhanced performance, bone mineralization, and retention of P and Ca in growing turkeys.     

Effect of initial breeding weight and management system using a high-producing sow genotype on resulting reproductive performance over three parities

A study was conducted with sows of a high-producing genotype to evaluate their reproductive performance using three breeding weights over a three-parity period in two management systems. A total of 114 F1 gilts (Landrace x Yorkshire) were used in a split-plot, randomized, complete block experiment conducted as a 3 x 2 factorial arrangement of treatments in two replicates. Three gilt breeding weights of 120, 135, and 150 kg were achieved by feeding 1.8, 2.3, or 3.2 kg/d of a .73% lysine corn-soybean meal (C-SBM) diet, respectively, from 5 to 8 mo of age. Two locations, each with different management systems, were considered the main plot and consisted of 1) outside, concrete-floored gestation lots and indoor farrowing pens or 2) indoor gestation pens and farrowing crates. All sows were fed 1.8 (Parity 1) or 2.1 (Parity 2 and 3) kg/d of a .73% lysine C-SBM diet during the breeding and gestation periods, whereas a .82% lysine C-SBM diet with 5% added fat was available ad libitum during lactation. All sows lost weight during the first lactation; larger weight losses occurred as breeding weight increased (P < .01). During the second and third lactations the 135- and 150-kg sow breeding groups had less lactation weight change, whereas the 120-kg group lost more weight, resulting in a breeding weight x parity interaction (P < .01). The 120-kg breeding weight group consumed less feed (P < .05) for the three lactation periods than did the heavier weight groups. Initial breeding weight had no effect on number of pigs born (total, live) or pig and litter weights at birth. Pig mortality increased with increasing breeding weight (P < .01) and parity (P < .05), a response that was exacerbated when sows farrowed in pens vs crates. Postweaning breeding intervals and sow removal from the experiment were not significantly affected by initial breeding weight, but a numerically higher percentage of sows in the 120-kg group were anestrous or failed to conceive than the percentage of such sows in the heavier weight groups. These data suggest that an initial breeding weight of approximately 135 kg at 8 mo of age may be best when sows farrow in crates, whereas when sows farrow in pens a lower breeding weight may be more desirable.     

Increased height gain of children fed a high-protein diet during convalescence from shigellosis: a six-month follow-Up study

The impact of dietary supplementation on catch-up growth was evaluated in 69 malnourished children ages 24-60 mo after recovery from shigellosis. They were fed either a high-protein (HP) diet with 15% of energy as protein, or a standard-protein (SP) diet with 7.5% energy as protein, for 3 wk in a metabolic study ward. Children were followed up bi-weekly for 6 mo by trained health assistants when anthropometric measurements and information of any illness were collected. Thirty-one children in the HP group and 28 children in the SP group completed 6-mo follow-up. The increase in height (mean +/- SD) was 5.3 +/- 1.0 cm vs. 4.1 +/- 1.1 cm for HP and SP groups, respectively (P < 0.001), whereas increase in body weight was 1.39 +/- 0.58 and 1.29 +/- 0.72 kg for children fed HP and SP, respectively (P = 0.59). The proportion of children who were severely stunted (< -2 SD height-for-age) decreased from 45 to 29% in the HP group compared to 50 to 46% in the SP group (P < 0.05) at 6-mo follow-up. The number of diarrheal episodes per child tended to be lower in the HP vs. SP than in the SP group (1.9 vs. 2.3, P = 0.41). These results demonstrate that feeding an HP diet to the malnourished children during recovery from shigellosis enhanced linear growth with a modest reduction in diarrheal morbidity during the 6-mo follow-up period.     

Body composition at farrowing and nutrition during lactation affect the performance of primiparous sows: II. Milk composition, milk yield, and pig growth

We used 35 primiparous sows to investigate the link between body fatness at farrowing and voluntary feed intake (VFI) during lactation. Two groups of sows were fed differently throughout gestation (either 2.3 kg/d of a diet containing 5.8% CP and 14.6 MJ DE/kg as fed or 1.7 kg/d of a diet containing 15.6% CP and 14.5 MJ DE/kg as fed) so that they commenced lactation at a similar body weight (158 to 152 kg) but with different body compositions: either 340 (fat) or 280 (lean) g of body fat/kg BW (P < .001). During lactation, sows were offered either a low-protein diet (7.9% CP and 15.5 MJ DE/kg as fed) or a high-protein diet (19.0% CP and 15.6 MJ DE/kg as fed) on an ad libitum basis. During lactation, VFI was measured daily, and sow body weight and backfat were measured weekly. Blood samples were collected from sows on d 110 of gestation and d 14 and 28 of lactation, and plasma was analyzed for NEFA, glycerol, insulin, glucose, and beta-hydroxybutyrate. Fat sows ate 30% less than their lean counterparts during lactation (P < .001), which corresponded to a 70% higher concentration of NEFA in plasma (P = .01) and a 30% higher concentration of glycerol (P = .15). The VFI during the first 2 wk of lactation was affected only by body fatness and not by the protein content of the lactation diet. The dietary supply of protein influenced VFI during wk 3 and 4 of lactation, possibly by affecting milk production and hence the drive to consume feed. Weight loss, particularly lean tissue loss, was minimized by feeding the high-protein diet during lactation (P < .002).     

Chronic fatigue syndrome

The hepatoprotective activity of crude extract of artemisia scoparia (aerial parts) was investigated against experimentally produced hepatic damage using carbon tetrachloride (CCl4) as a model hepatotoxin. CCl4 at the dose of 1.5 ml/kg, produced liver damage in rats as manifested by the rise in serum levels of AST and ALT to 395 +/- 110 and 258 +/- 61 IU/l (mean +/- SEM; n = 10) respectively, compared to control values of 106 +/- 15 and 26 +/- 04. Pretreatment of rats with plant extract (150 mg/kg) significantly lowered (P < 0.01), the respective serum GOT and GPT levels to 93 +/- 05 and 27 +/- 03 IU/l, indicating hepatoprotective action. Pentobarbital sodium (75 mg/kg)-induced sleeping time in mice was found to be 140.8 +/- 1.5 min (n = 10) which was similar (P > 0.05) to that obtained in the group of animals pretreated with the plant extract (139.9 +/- 1.8 min). CCl4 treatment extended the pentobarbital sleeping time to 212.2 +/- 19.1 min and pretreatment of animals with plant extract reversed the CCl4-induced prolongation in pentobarbital sleeping time to 143.9 +/- 5.5 min (P < 0.001) which further confirms the protective action of the plant extract against CCl4-induced liver damage. These data indicate that the plant artemisia scoparia is hepatoprotective and validate the folkloric use of this plant in liver damage.