Inhibitory effect of 1α-hydroxyvitamin D3 on N-nitrosobis(2-oxopropyl)amine-induced cholangiocarcinogenesis in Syrian hamsters

Sixty-three male 5-week-old Syrian hamsters received the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) s.c. in 5 weekly injections (the first, 70 mg/kg body, and the remaining, 20mg/kg each). The hamsters that received BOP were given intragastric administration of 0.2 ml of medium chain triglyceride (MCT) with or without 0.04 μg of 1α-hydroxyvitamin D3 [1α(OH)D3] through a feeding tube for 12 weeks. Thus, 3 groups were assigned:Group 1;BOP alone (n＝20), Group 2;BOP＋MCT (n＝18) and Group 3;BOP＋1α(OH)D3 (n＝25). The mean body weight of Group 3 was lower than those of Groups 1 and 2 at the end of the experiment (p＜0.001,Tukey-Kramer HSD test). At the end of week 12, all surviving hamsters were put to sleep. The incidences of liver tumors were 80%, 72% and 32% in Groups 1, 2 and 3, respectively. The incidence of tumors in Group 3 was significantly lower than in Group 1 and Group 2 (p＜0.05, χ2-test). All tumors were cholangiocarcinoma. These results indicated that BOP-induced cholangiocarcinogenesis was suppressed by the supplemental administration of 1α(OH)D3.     

Ethanol-induced alterations in the morphology and function of the rat ovary

The purpose of this study was to compare the effects of different dosages of ethanol on ovarian morphology and function. Holtzman rats, 20 days old, were divided into groups as follows: The rats in Group I were autopsied at 20 days of age, and those in Group II were placed on ad libitum chow and water diet; the rats in Groups III and V were fed on a liquid diet containing 2.5% or 5% ethanol respectively; Groups IV and VI were pair-fed controls to Groups III and V, respectively. Rats in Groups II, III, IV, and VI were maintained on the diets for 50–55 days and killed at late proestrus-estrus, while the animals in Group V did not exhibit estrous cycles and were killed on day 55 of treatment. The average increase in body weights of rats in Groups II, III, and IV was significantly greater than the increase in body weights of rats given 5% ethanol or their pair-fed controls. In the rats treated with 5% ethanol, vaginal opening was significantly delayed from the controls, estrous cycles were absent, ovarian weights were similar to those of the 20-day-old rats, ovaries contained corpora lutea of only one estrus, uteri weighed less than controls, and histologically, the uteri and vaginae were similar to those of 20-day-old rats. However, in the rats treated with 2.5% ethanol, all of the parameters were similar to those of the controls. The average serum alcohol level for the rats on the 5% ethanol diet was 249 mg%; the serum alcohol levels were at the lower limit of detection for the rats on the 2.5% ethanol diet. The data show that ovarian function was suppressed in the rats that received the 5% ethanol but not in rats on the 2.5% ethanol diet.     

Effect of ethanol treatment on metabolic activation and detoxification of esophagus carcinogenic N-nitrosamines in rat liver

In order to elucidate the mechanism underlying enhancement by ethanol of N-nitrosodiethylamine (DEN)- and N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in rats, hepatic levels of cytochrome P-450 (CYP) enzymes, mutagenic activation of several N-nitrosamines and three kinds of UDP-glucuronyltransferase (UDPGT) activities were assayed in F344 rats. Immunoblot analyses of microsomal CYP proteins revealed induction of CYP2E1 (approximately 2-fold), but not CYP2B1/2, 1A1/2 or 3A2, by treatment with 10% ethanol in the drinking water for 2 weeks. In contrast, s.c. treatment with 0.5 mg/kg NMBA three times per week for 2 weeks produced no significant alterations in the levels of these CYP species. Ethanol treatment also elevated the mutagenic activities of N-nitrosodimethylamine (DMN), DEN and N-nitrosopyrrolidine (NPYR) in strain TA100 up to 2.1-, 1.6- and 2.3-fold above each control, respectively. However, this was not the cases for four N-nitrosamines, including NMBA, in strain TA100 and two heterocyclic amines and aflatoxin B(1) in strain TA98. In addition, ethanol did not affect UDPGT activities towards 4-nitrophenol, bilirubin and testosterone. Hepatic CYP species responsible for mutagenic activation of selected N-nitrosodialkylamines were confirmed by use of specific CYP inducers and inhibitors with the liver from F344 and Wistar rats, indicating that DMN, DEN and NMBA are selectively activated by CYP2E1, predominantly by CYP2E1 with a slight contribution by CYP2B2 and selectively by CYP2B1/2, respectively. These results demonstrate that ethanol exerts an enhancing effect on mutagenic activation by CYP2E1 of DMN, DEN and NPYR, but does not affect that of NMBA and the other carcinogens by CYP2B1/2, 1A1/2 and 3A2 and UDPGT1A1, 1A6 and 2B1 activities. Consequently, this suggests that enhancement by ethanol of DEN-induced esophageal carcinogenesis in F344 rats can be attributed to an increase in hepatic activation during the initiation phase, but that of NMBA-induced tumorigenesis is not attributable to metabolic activation and inactivation via glucuronidation in liver.     

Failure of angiotensin converting enzyme inhibition to affect the course of chronic puromycin aminonucleoside nephropathy.

The effects of the angiotensin converting enzyme (ACE) inhibitor enalapril on the proteinuria and degree of focal glomerular sclerosis hyalinosis (FSH) in chronic puromycin aminonucleoside nephropathy (PAN) were examined. Chronic PAN was induced in male Sprague-Dawley rats by seven subcutaneous injections of puromycin aminonucleoside (20 mg/kg) over 10 weeks (Groups I and II). Group II rats also received enalapril 10 mg/kg/day in the drinking water throughout the study (12 weeks). Group III rats served as age-matched controls. Proteinuria was similar in Groups I and II (35.5 +/- 9.7 versus 29.1 +/- 4.1 mg protein/mg creatinine, mean +/- SEM, P greater than 0.05). Serum creatinine remained unchanged in Group I, but rose from 0.7 +/- 0.04 to 1.2 +/- 0.1 mg/dl (mean +/- SEM, P less than 0.05) in Group II. FSH was 13.8% in Group I, 12.9% in Group II (P greater than 0.05), and 0.6% in Group III. There was no significant difference in glomerular lipid content and in immunofluorescence for rat albumin, fibrinogen, IgM, IgG, and C3 between Groups I and II. ACE activity was inhibited by 94% in serum, 83% in lungs, and 92% in kidneys; and blood pressure response to. Angiotensin I challenge was decreased by 50% in rats similarly treated with enalapril versus controls. In summary, proteinuria and glomerular sclerosis in this model are not affected by ACE inhibition.     

Evaluation of carcinogenic potential of diuron in a rat mammary two-stage carcinogenesis model

This study aimed to evaluate the carcinogenic potential of the herbicide Diuron in a two-stage rat medium-term mammary carcinogenesis model initiated by 7,12-dimethylbenz(a)anthracene (DMBA). Female seven-week-old Sprague-Dawley (SD) rats were allocated to six groups: groups G1 to G4 received intragastrically (i.g.) a single 50 mg/kg dose of DMBA; groups G5 and G6 received single administration of canola oil (vehicle of DMBA). Groups G1 and G5 received a basal diet, and groups G2, G3, G4, and G6 were fed the basal diet with the addition of Diuron at 250, 1250, 2500, and 2500 ppm, respectively. After twenty-five weeks, the animals were euthanized and mammary tumors were histologically confirmed and quantified. Tumor samples were also processed for immunohistochemical evaluation of the expressions of proliferating cell nuclear antigen (PCNA), cleaved caspase-3, estrogen receptor-α (ER-α), p63, bcl-2, and bak. Diuron treatment did not increase the incidence or multiplicity of mammary tumors (groups G2 to G4 versus Group G1). Also, exposure to Diuron did not alter tumor growth (cell proliferation and apoptosis indexes) or immunoreactivity to ER-α, p63 (myoephitelial marker), or bcl-2 and bak (apoptosis regulatory proteins). These findings indicate that Diuron does not have a promoting potential on mammary carcinogenesis in female SD rats initiated with DMBA.     

肝硬化大鼠模型肝细胞移植途径的筛选

目的 通过比较4种同种异体肝细胞移植方法治疗肝硬化大鼠模型的疗效,筛选出较好的细胞移植途径.方法 50只经证实成模的肝硬化大鼠模型动物被完全随机分为5组:肝动脉移植组(G1)、门静脉移植组(G2)、脾动脉移植组(G3)、尾静脉移植组(G4)及对照组(G5).前4组分别自肝动脉、门静脉、脾动脉及尾静脉注射肝细胞悬液2 ml(细胞数量为2×106),对照组(G5)不作干预.移植前后对各组大鼠行肝功能检测及术后处死大鼠取肝脏作病理评分.结果 G1、G2组移植后前3周血清白蛋白水平逐渐下降,第5周后逐渐回升,到第7周达到峰值[(15.4±2.3)g/L,(15.4±2.1)g/L].G1、G2组移植后前3周血清总胆红素水平逐渐上升,到第5周后逐渐回落,到第7周达到移植前的水平[(13.62±2.32)μmol/L].G5组移植前后血清总胆红素水平变化不明显;术后病理G3组改善最为明显,G1、G2组次之,G4组再次之,G5改善情况最差.结论 在针对肝硬化大鼠模型不同的移植途径中,经脾动脉途径移植肝细胞,术后病死率较低,能更有效地改善肝脏功能及减轻肝细胞的变性和坏死.     

Effects of ginger (Zingiber officinale Roscoe) on DNA damage and development of urothelial tumors in a mouse bladder carcinogenesis model

Extracts of the spice ginger (Zingiber officinale Roscoe) are rich in gingerols and shogaols, which exhibit antioxidant, anti-inflammatory, antifungal, antimycobacterial, and anticarcinogenic proprieties. The present study evaluated the chemoprotective effects of a ginger extract on the DNA damage and the development of bladder cancer induced by N-butyl-N-(4-hydroxibutyl) nitrosamine (BBN)/N-methyl-N-nitrosourea (MNU) in male Swiss mice. Groups G1-G3 were given 0.05% BBN in drinking water for 18 weeks and four i.p. injections of 30 mg/kg body weight MNU at 1, 3, 10, and 18 weeks. Group G4 and G5 received only the BBN or MNU treatments, respectively, and groups G6 and G7 were not treated with BBN or MNU. Additionally, Groups G2, G3, and G6 were fed diets containing 1, 2, and 2% ginger extract, respectively, while Groups G1, G4, G5, and G7 were fed basal diet. Samples of peripheral blood were collected during the experiment for genotoxicity analysis; blood collected 4 hr after each MNU dose was used for the analysis of DNA damage with the Comet assay (assay performed on leukocytes from all groups), while reticulocytes collected 24 hr after the last MNU treatment of Groups G5-G7 were used for the micronucleus assay. At the end of the experiment, the urinary bladder was removed, fixed, and prepared for histopathological, cell proliferation, and apoptosis evaluations. Ginger by itself was not genotoxic, and it did not alter the DNA damage levels induced by the BBN/MNU treatment during the course of the exposure. The incidence and multiplicity of simple and nodular hyperplasia and transitional cell carcinoma (TCC) were increased by the BBN/MNU treatment, but dietary ginger had no significant effect on these responses. However, in Group G2 (BBN/MNU/2% ginger-treated group), there was an increased incidence of Grade 2 TCC. The results suggest that ginger extract does not inhibit the development of BBN-induced mouse bladder tumors.     

Hepatotoxicity of carbon tetrachloride after chronic ethanol consumption

Hepatotoxicity of carbon tetrachloride after chronic ethanol consumption was examined in rats fed a standard pellet diet and a 5 or 20% ethanol solution as a sole source of fluid for 1-100 weeks. Carbon tetrachloride hepatotoxicity in rats fed 5 and 20% ethanol (4.0 and 8.8 g of ethanol/kg body weight, respectively) for 1-100 weeks was markedly greater than that in control rats given water instead of ethanol, and the hepatotoxicity in rats fed 20% ethanol was more severe as compared with that in rats fed 5% ethanol at any time during a period of 100 weeks. The degree of the enhanced hepatotoxicity in rats fed both 5 and 20% ethanol did not change significantly during a period of 100 weeks. Moreover, the enhanced hepatotoxicity in the rats fed both 5 and 20% ethanol for 1-100 weeks is of the same degree as that in the rats that received 4.0 and 8.8 g of ethanol/kg body weight as a single dose, respectively. These experimental findings suggest that the effect of ethanol on the carbon tetrachloride hepatotoxicity is dependent on the daily amount of alcohol intake and is not affected by the duration of alcohol consumption.     

Effect of N-nitrosomethylbenzylamine on nasal mucosa in rats.

N-nitrosomethylbenzylamine (NMBA) is one of the most potent organ-specific carcinogens routinely used in rat esophageal tumorigenesis. The aim of the study was to evaluate NMBA effect on nasal mucosa, one of the non-target organs. NMBA was administered subcutaneously to 20 male albino rats of Wistar strain for 5 weeks (0.5mg/kg/dose; three doses/week). The experiment was terminated on week 22. In each case, seven standard frontal sections of the nose were taken after fixation for assessment of all the parts of the nasal mucosa. Microscopic examination revealed one small squamous cell papilloma located on the ventro-lateral surface of the left superior nasal concha, one focus on simple hyperplasia and two foci of squamous epithelium dysplasia within the mucosa covering nasal vestibule near the respiratory part of the nasal cavity. Furthermore, statistically significant increase of proliferation activity in both lesional and non-lesional nasal squamous epithelium in NMBA-exposed animals was also found. These phenomena could be potentially induced by carcinogen exposure.     

The effect of L-dopa and carbidopa treatment on the survival of rat fetal dopamine grafts assessed by tyrosine hydroxylase immunohistochemistry and [3H]mazindol autoradiography.

The effect of treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) and carbidopa for five weeks on the survival of rat fetal dopaminergic ventral mesencephalon cells implanted into the denervated striatum of rats with unilateral 6-hydroxydopamine nigrostriatal lesions was assessed. Rats receiving unilateral nigral 6-hydroxydopamine lesions followed by sham striatal grafts (Groups A and B) showed no recovery of (+)-amphetamine- or apomorphine-induced motor asymmetry. Rats in Group B (receiving treatment with L-DOPA and carbidopa) showed an increase in apomorphine-induced contralateral rotation and stereotypy. Animals receiving unilateral nigral 6-hydroxydopamine lesions followed by fetal striatal dopamine grafts (Groups C and D) showed complete recovery of (+)-amphetamine-induced rotation and a decrease of apomorphine-induced contralateral rotation. Treatment of animals in Groups B and D with L-DOPA (200 mg/kg per 24 h) and carbidopa (25 mg/kg per 24 h) by mouth for five weeks had no effect on the behavioural response to (+)-amphetamine. In the 6-hydroxydopamine-lesioned animals there was loss of tyrosine hydroxylase-immunoreactive cells in substantia nigra and ventral tegmental area of greater than 97% and to 66%, respectively, compared to the intact side. The number and morphology of tyrosine hydroxylase-immunoreactive cells in the intact substantia nigra and ventral tegmental area was not altered by treatment with L-DOPA and carbidopa. In the 6-hydroxydopamine-lesioned striatum of rats receiving a sham graft (Group A) or a sham graft and treatment with L-DOPA and carbidopa (Group B) there were no tyrosine hydroxylase-positive cells or fibres visible.(ABSTRACT TRUNCATED AT 250 WORDS)     

Expression of laminin-5-gamma-2 chain in intraductal papillary-mucinous and invasive ductal tumors of the pancreas.

The laminin-5-gamma-2 chain is expressed in various invasive carcinoma cells. To clarify the relationship between laminin-5 expression and the development of intraductal papillary-mucinous tumors (IPMTs), we performed an immunohistochemical study of 26 IPMTs and 30 invasive ductal adenocarcinomas. Cases were classified into five groups: intraductal papillary-mucinous adenoma (Group A; n = 8), adenocarcinoma without invasion (Group B; n = 3), adenocarcinoma with minimal invasion (Group C; n = 5), adenocarcinoma with macroscopically evident invasion (Group D; n = 10), and invasive ductal adenocarcinoma (conventional type; Group E; n = 30). In the invasive components of Groups D and E, laminin-5 was expressed in 80% and 100% of cases, respectively. In the intraductal components of IPMTs, expression of laminin-5 was not seen in Groups A and B, whereas they were seen in one case in Group C (20%) and in seven in Group D (70%). Most of the staining patterns of the intraductal components were focal and scattered. Laminin-5-gamma-2 expression in the intraductal components of IPMTs tends to increase as tumors develop and may be a indicator of the potential invasiveness of the tumor cells.     

The oxidant and antioxidant effects of 25-hydroxyvitamin D3 in liver, kidney and heart tissues of diabetic rats

Previous studies have implicated protective effects of vitamin D on insulin secretion and pancreas beta cell function. The goal of the present study is to determine if a combination therapy of 25-hydroxyvitamin D3 and insulin had any advantage over insulin therapy alone on lipid peroxidation and antioxidant activity in the streptozotocin (STZ)-induced diabetic rat. The lipid peroxidation product, thiobarbituric acid-reacting substances (TBARS), was measured to assess free radical activity in the heart, kidney and liver tissues. The enzymatic activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) were measured as indicators of antioxidation in these tissues. Sprague-Dawley rats were made diabetic with a single injection of STZ (75 mg/kg i.p.). Rats were separated into three groups, each containing 10 animals: Group 1, non-diabetic and no drug treatment was given; Group 2, diabetic rats were treated with 3 IU/day subcutaneous (s.c.) insulin; and Group 3, diabetic rats were treated with 3 IU/day (s.c.) insulin plus 1 mg/kg/day per oral (p.o.) 25-hydroxyvitamin D3 for a period of 4 weeks. At the end of the study, TBARS contents of the liver, kidney and heart tissues in Groups 2 and 3 were found to be significantly increased as compared to Group 1 (P<0.05) and kidney MDA levels in Group 3 were also significantly increased as compared to Group 2 (P<0.05). The SOD and CAT contents of the heart in Group 2 were significantly increased as compared to Groups 1 and 3 (P<0.05). GSH-Px activity was unaltered in all groups (P>0.05). We suggest that a combination of insulin with 25-hydroxyvitamin D3 treatment would not be more beneficial than the use of insulin alone in antioxidant defence of diabetic liver and kidney tissues.     

Different modifying responses of capsaicin in a wide-spectrum initiation model of F344 rat

The modifying potential of capsaicin (CAP) on lesion development was examined in a rat multiorgan carcinogenesis model. Groups 1 and 2 were treated sequentially with diethylnitrosamine (DEN) (100 mg/kg, ip, single dose at commencement), N-methylnitrosourea (MNU) (20 mg/kg, ip, 4 doses at days 2, 5, 8, and 11), and N,N-dibutylnitrosamine (DBN) (0.05% in drinking water during weeks 3 and 4). Group 3 received vehicles without carcinogens during the initiation period. Group 4 served as the untreated control. After this initiating procedure, Groups 2 and 3 were administered a diet containing 0.01% CAP. All surviving animals were killed 20 weeks after the beginning of the experiment and the target organs examined histopathologically. The induction of GST-P+ hepatic foci in rats treated with carcinogens was significantly inhibited by treatment with CAP. CAP treatment significantly decreased the incidence of adenoma of the lung but increased the incidence of papillary or nodular (PN) hyperplasia of the urinary bladder. The tumor incidence of other organs, such as the kidney and thyroid, was not significantly different from the corresponding controls. These results demonstrated that concurrent treatment with CAP not only can inhibit carcinogenesis but can also enhance it depending on the organ. Thus, this wide-spectrum initiation model could be used to confirm organ-specific modification potential and, in addition, demonstrate different modifying effects of CAP on liver, lung, and bladder carcinogenesis.     

Effects of fasting and intermittent fasting on rat hepatocarcinogenesis induced by diethylnitrosamine

The influences of fasting on DEN-initiation and of intermittent fasting (IF) on the rat liver chemical carcinogenesis process were evaluated in a 52-week long assay. Three groups of adult male Wistar rats were used: Groups 1 to 3 were treated with a single i.p. injection of 200 mg/kg of diethylnitrosamine (DEN). Group 2 was submitted to 48 h fasting prior to DEN treatment. After the 4th week, Group 3 was submitted to IF, established as 48 h weekly fasting during 48 weeks, while Groups 1 and 2 were fed ad libitum until the 52nd week. All animals were submitted to 70% partial hepatectomy and sacrificed at the 3rd and 52nd weeks, respectively. Fasting prior to DEN-initiation did not influence the development of altered foci of hepatocytes (AFHs) and of hepatic nodules (Group 2 vs. Group G1). IF inhibited the development of preneoplastic lesions, since this dietary regimen decreased the number and the size of glutathione S-transferase (GST-P) positive foci and the number and size of liver nodules (Group G3 vs. Group G1). The inhibitory effect of IF was also reflected in the development of clear and basophilic cell foci. These results indicate that long-term IF regimen exerts an anti-promoting effect on rat hepatocarcinogenesis induced by DEN.     

不同方法注射乙肝免疫球蛋白阻断HBsAg、HBeAg双阳性孕妇母婴传播的研究

目的研究不同方法注射乙肝免疫球蛋白(HBIG)对HBsAg伴HBeAg双阳性孕妇的乙肝病毒(HBV)宫内感染阻断作用。方法将137例双阳性孕妇分为4组:A组从孕16周起注射HBIG,B组从孕20周起注射HBIG,C组从孕28周起注射HBIG,A、B、C 3组孕妇每次均注射HBIG200IU,并间隔4周1次,直至临产;D组作为对照组,不注射HBIG;出生后4组所有新生儿均于16h内和生后2周注射HBIG200IU,满月起按1、2、7月龄分别接种乙肝疫苗,并定期随访。结果新生儿出生时外周血测得HBsAg,A组与B组无显著性差别(P>0.05),A、B 2组与C组、D组以及C组与D组均有显著性差别(P均<0.05);经随访A、B、C、D 4组HBV宫内感染率分别为5.6%、5.3%、19.4%和48.5%,母婴传播阻断率A组与B组无显著差异(P>0.05),A组和B组均显著高于C组和D组、C组显著高于D组(P均<0.05)。结论对HBsAg伴HBeAg双阳性孕妇,选择孕20周开始注射HBIG比较合适,阻断率最高,能有效减少HBV宫内感染的发生率。     

Conditioned aversion to an intraperitoneally injected odor CS in rats]

Two experiments were conducted to specify an CS property of intraperitoneally injected odor substance in conditioned odor aversion formation. In experiment 1, three groups of water-restricted rats received one trial of conditioning with intraperitoneal injections of orange-extract (CS) and LiCl(UCS). The CS-UCS intervals of experimental groups were 30 minutes (Group IE-30) and 120 minutes (Group IE-120). In the test trial, Group IE-30 rats showed aversion to the test solution (0.5% orange extract), whereas no significant difference was observed between the control group and Group IE-120. In experiment 2, three groups of rats received one or two or three conditioning trials (Groups E1, E2 and E3, respectively). The CS-UCS interval of all groups was 30 minutes. In the test trial, rats in Groups E2 and E3 consumed less amount of test solution (0.5% orange extract) than the control rats, whereas no significant difference was observed between Group E1 and the control group. These results suggest that the intraperitoneally injected odor substance have CS property on conditioned odor aversion.     

A comparative study of respiratory syncytial virus (RSV) prophylaxis in premature infants within the Canadian Registry of Palivizumab (CARESS)

We examined the dosing regimens, compliance, and outcomes of premature infants who received palivizumab within the Canadian Registry of Palivizumab (CARESS). Infants receiving ≥1 dose of palivizumab during the 2006-2011 respiratory syncytial virus (RSV) seasons were recruited across 30 sites. Respiratory illness events were captured monthly. Infants ≤32 completed weeks gestational age (GA) (Group 1) were compared to 33-35 completed weeks GA infants (Group 2) following prophylaxis. In total, 6,654 patients were analyzed (Group 1, n?=?5,183; Group 2, n?=?1,471). The mean GA was 29.9?±?2.9 versus 34.2?±?2.2?weeks for Groups 1 and 2, respectively. Group differences were significant (all p-values <0.05) for the following: proportion of males, Caucasians, siblings, multiple births, maternal smoking, smoking during pregnancy, household smokers, >5 household individuals, birth weight, and enrolment age. Overall, infants received 92.6?% of expected injections. Group 1 received significantly more injections, but a greater proportion of Group 2 received injections within recommended intervals. The hospitalization rates were similar for Groups 1 and 2 for respiratory illness (4.7?% vs. 3.7?%, p?=?0.1) and RSV (1.5?% vs. 1.4?%, p?=?0.3). Neither the time to first respiratory illness [hazard ratio?=?0.9, 95 % confidence interval (CI) 0.7-1.2, p?=?0.5] nor to first RSV hospitalization (hazard ratio?=?1.3, 95 % CI 0.8-2.2, p?=?0.3) were different. Compliance with RSV prophylaxis is high. Despite the higher number of palivizumab doses in infants ≤32 completed weeks GA, the two groups' respiratory illness and RSV-positive hospitalization rates were similar.     

Protective Effects of Annona Muricata Linn. (Annonaceae) Leaf Aqueous Extract on Serum Lipid Profiles and Oxidative Stress in Hepatocytes of Streptozotocin-Treated Diabetic Rats

Extracts from various morphological parts of Annona muricata Linn. (Annonaceae) are widely used medicinally in many parts of the world for the management, control and/or treatment of a plethora of human ailments, including diabetes mellitus (DM). The present study was undertaken to investigate the possible protective effects of A. muricata leaf aqueous extract (AME) in rat experimental paradigms of DM. The animals used were broadly divided into four (A, B, C and D) experimental groups. Group A rats served as ‘control’ animals and received distilled water in quantities equivalent to the administered volumes of AME and reference drugs'' solutions intraperitoneally. Diabetes mellitus was induced in Groups B and C rats by intraperitoneal injections of streptozotocin (STZ, 70 mg kg⁻¹). Group C rats were additionally treated with AME (100 mg kg⁻¹ day⁻¹, p.o.) as from day 3 post STZ injection, for four consecutive weeks. Group D rats received AME (100 mg kg⁻¹ day⁻¹ p.o.) only for four weeks. Post-euthanization, hepatic tissues were excised and processed biochemically for antioxidant enzymes and lipid profiles, such as catalase (CAT), reactive oxygen species (ROS), glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), thiobarbituric acid reactive substances (TBARS), triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL) and low density lipoprotein (LDL), respectively. Treatment of Groups B and C rats with STZ (70 mg kg⁻¹ i. p.) resulted in hyperglycaemia, hypoinsulinaemia, and increased TBARS, ROS, TC, TG and LDL levels. STZ treatment also significantly decreased (p<0.05) CAT, GSH, SOD, GSH-Px activities, and HDL levels. AME-treated Groups C and D rats showed significant decrease (p<0.05) in elevated blood glucose, ROS, TBARS, TC, TG and LDL. Furthermore, AME treatment significantly increased (p<0.05) antioxidant enzymes'' activities, as well as serum insulin levels. The findings of this laboratory animal study suggest that A. muricata extract has a protective, beneficial effect on hepatic tissues subjected to STZ-induced oxidative stress, possibly by decreasing lipid peroxidation and indirectly enhancing production of insulin and endogenous antioxidants.     

Modification of pancreatic carcinogenesis in the hamster model. 2. The effect of partial pancreatectomy.

The effect of partial pancreatectomy (PP) on the pancreatic carcinogenicity of N-nitrosobis (2-oxopropyl)amine (BOP) was investigated in Syrian golden hamsters by subcutaneous injection of a single dose of BOP (20 mg/kg, body weight) given 30 minutes after (Group 1), 1 week after (Group 2), or 1 week before 70% PP (Group 3). Additional groups consisted of animals with PP alone (Group 4), sham operation (laparotomy) followed 30 minutes later by BOP treatment (Group 5), and BOP treatment only (Group 6). The experiment was terminated 46 weeks after BOP administration in each group. The pancreas and extrahepatic bile ducts, including the common duct and gallbladder, were examined histologically. Tumor patterns were compared in hamsters with PP and in the corresponding segments of the pancreas in BOP-treated control groups. The pancreatic cancer incidence was highest (31%) in Group 2 and lowest in Group 1 (3%), a difference that was statistically significant (P less than 0.01). Also, a statistically highly significant larger number of tumors occurred in Group 2, compared with group 1, 3, or 5 (P less than 0.0005). In a comparison of the number of carcinomas per tumor-bearing hamster, there were greater numbers of carcinomas in Group 2 (2.6 carcinomas) than in Groups 1, 3, 5, and 6 (1.0, 1.0, 1.3, and 2.6 tumors, respectively). Moreover, pancreatic tumors in Group 2 hamsters were larger (average diameter, 10 mm) than in Group 1 (4 mm), Group 3 (3.5 mm), Group 5 (4 mm), and Group 6 (average, 9mm). The incidence of extrapancreatic tumors did not vary among the PP groups but was equally lower than those in BOP-treated control groups. The data indicated BOP carcinogenesis was inhibited by surgery (regardless of whether PP was per formed) when the carcinogen was given 30 minutes after the surgery but was significantly enhanced when BOP was administered 1 week after PP. The possible reasons for these conflicting results are discussed. Morphologically all tumors were of ductular, ductal, and mixed ductular-insular patterns and most developed at the resected margins, where proliferation of islets, ducts, and ductules, but not of acinar cells, occurred. The results confirm our view that the ductal and ductular cells are the progenitor cells for BOP-induced pancreatic tumors in hamsters.     

Induction of pancreatic islet cell tumors in rats by repeated intravenous administration of 4-hydroxyaminoquinoline 1-oxide.

The inducibility of pancreatic islet cell tumors by administration of 4-hydroxyaminoquinoline 1-oxide (4HAQO) was investigated in male 6-week-old Sprague-Dawley rats. Rats were given 4HAQO intravenously at a weekly dose of 5 mg/kg 4 times (group 1) or a single dose of 10 mg/kg (group 2). Control rats received the vehicle alone (group 3). Fifty-six weeks after the first 4HAQO administration, all surviving animals were killed and the pancreas was examined histopathologically, immunohistochemically and ultrastructurally. The incidences and multiplicities of islet cell tumors in groups 1, 2, and 3 were 52.3% (p < 0.05 vs group 2, p < 0.01 vs group 3), 19.2% and 0%, and 0.70/animal (p < 0.05 vs group 2, p < 0.01 vs group 3), 0.23 and 0, respectively. Islet cell carcinomas were induced only in group 1, accounting for 6/44 (26%) tumors. Islet cell hyperplasias were found in 61.4% (p < 0.05 vs group 3), 42.3% and 10.0% of groups 1, 2, and 3, with multiplicities of 0.95 (p < 0.05 vs groups 2 and 3), 0.54 and 0.20, respectively. As compared with normal islets from control subjects, islet cell tumors showed an increase in the number of insulin positive cells associated with cytological features indicative of enhanced insulin synthesis and secretion, and a decrease in the number of glucagon positive cells without ultrastructural signs of modified secretory activity. Thus our results indicate that repeated intravenous administration of 4HAQO to rats is useful for the induction of islet cell tumors at high incidence.