bluuebunny/crossref_metadata_2025 huggingface dataset:
Gut‐Associated Lymphoid Tissues in Ulcerative Colitis
Authors: Asakura Hitoshi , Suzuki Azuma , Ohtsuka Kazuo , Hasegawa Katsuhiko , Sugimura Kazuhito
Published: September 2009

Background: The main feature of ulcerative colitis (UC) is numerous infiltration of not only lymphocytes and plasma cells but also neutrophils and macrophages, indicating acute on chronic inflammation. Recent studies show that apoptosis may play an important role in the regulation of gut‐associated lymphoid tissues (GALT). Therefore, this study was performed to clarify apoptosis of lymphocytes in the peripheral blood and colonic mucosa of UC. Methods: Three‐color flow cytometry was used to clarify apoptosis of lymphocytes in the peripheral blood and colonic mucosa of patients with active and inactive UC compared with controls using fluorescence‐labeled monoclonal and polyclonal antibodies such as Fas (CD95), Fas ligand, CD4, CD8, CD45RO, etc. Results: The ratio of Fas and CD45RO double‐positive cells in the peripheral blood of UC patients was significantly increased in CD8 but not CD4 T cells when compared with controls. The ratio of Fas‐positive and CD45RO‐negative cells was significantly increased in CD4 and CD8 T cells of UC when compared with controls. There was unbalanced immunoregulation between CD4 and CD8 T cells in the colonic mucosa of UC probably due to apoptosis through Fas‐Fas ligand system. Conclusions: Abnormal GALT system was found in UC probably due to dysregulation of T cells through Fas‐Fas ligand system. (Journal of Parenteral and Enteral Nutrition23:S25‐S28, 1999)
Glutamine: The Pivot of Our Nitrogen Economy?
Authors: van Acker Bernadette A. C. , von Meyenfeldt Maarten F. , van der Hulst René R. W. J. , Hulsewé Karel W. E. , Wagenmakers Anton J. M. , Deutz Nicolaas E. P. , de Blaauw Ivo , Dejong Cornelis H. C. , van Kreel Bernard K. , Soeters Peter B.
Published: September 2009

Glutamine serves as a shuttle of useful nontoxic nitrogen, supplying nitrogen from glutamine‐producing (eg, muscle) to glutamine‐consuming tissues. True production rates of glutamine are difficult to measure, but probably are less than 60 to 100 g/d for a 70‐kg man. During catabolic stress increased amounts of glutamine are released from muscle, consisting of protein derived glutamine, newly synthesized glutamine, and glutamine losses from the intramuscular free pool. The large and rapid losses of free muscle glutamine are difficult to restore, presumably as a result of disturbances in the Na+ electrochemical gradient across the cell membrane. Whereas increased amounts of glutamine are released from muscle, glutamine consumption by the immune system (liver, spleen) also is enhanced. Thus, during catabolic stress changes occur in the flow of glutamine between organs. These changes are not necessarily reflected by alterations in the whole‐body appearance rate of glutamine. In contrast with the gut, where glutamine is taken up in a concentration dependent manner, the immune system actively takes up glutamine despite decreased plasma concentrations. Supplementation with glutamine influences uptake by both the gut and the immune system, as evidenced by increased mucosal glutamine concentrations and gut glutathione production. There is evidence suggesting that this improves gut barrier function. Although the benefit of glutamine supplementation is most evident from experimental studies, clinical studies on the effect of glutamine do exist and suggest that glutamine supplementation has beneficial effects with regard to patient outcome. (Journal of Parenteral and Enteral Nutrition23:S45‐S48, 1999)
Glutamine‐Enriched Enteral Feeding in Trauma Patients: Reduced Infectious Morbidity Is not Related to Changes in Endocrine and Metabolic Responses
Authors: Houdijk Alexander P. J. , Nijveldt Robert J. , van Leeuwen Paul A. M.
Published: September 2009

Background : Recently we have shown that glutamine‐enriched enteral nutrition in trauma patients reduced the occurrence of pneumonia, bacteremia, and sepsis. In that study, no clear explanation for these results was found except for lower tumor necrosis factor (TNF)‐soluble receptors, suggesting immunomodulation. Here we present data on the course of endocrine and metabolic plasma mediators that were analyzed to provide more insight into the working mechanism of glutamine. Methods: Endocrine and metabolic mediators were measured in plasma samples taken on admission (day 0) and on days 1, 2, 3, 7, and 10. Glucose, prealbumin, albumin, alanine, C‐reactive protein, α1‐antitrypsin, complement factors, cortisol, glucagon, insulin, and growth hormone were assessed by standard techniques. Results: The rate of feeding, demography, and injury severity did not differ between the glutamine and control group. There was a sustained hyperglycemic response in both groups. Insulin levels rose in the second phase of the period of observation. A moderate cortisol and glucagon response was seen in both groups. There was no alteration in growth hormone levels in either group. C‐reactive protein, α1‐antitrypsin, and complement factors showed similar increases in both groups but levels remained in the normal range. The course of alanine, albumin, and prealbumin also showed no difference between the groups. Conclusions: Glutamine‐enriched enteral nutrition had no influence on the endocrine and metabolic response in trauma patients. Therefore, the reduction in infectious morbidity seen in glutamine‐supplemented trauma patients is most likely not explained by a modulation of the humoral stress response and its metabolic consequences. (Journal of Parenteral and Enteral Nutrition23:S52‐S58, 1999)
Epidermal Growth Factor, Epidermal Growth Factor Receptors, Intestinal Growth, and Adaptation
Authors: Wong Wai‐Man , Wright Nicholas A.
Published: September 2009

Epidermal growth factor (EGF) is an important constituent of several gastrointestinal secretions. Many studies in both animals and humans have shown EGF to have multiple effects upon gut epithelial cells. These include cytoprotection, stimulatory effects on cell proliferation and migration, induction of gene expression such as mucosal enzymes and trefoil proteins, and inhibitory effects on gastric acid secretion. The main conundrum associated with EGF action is the disparity between experimental studies on its luminal and systemic actions. Opinion is sharply divided as to whether or not EGF has any action when given luminally and on the site of the EGF receptors on gut epithelial cells. Most studies agree that the EGF receptors are located on the basolateral surface, in which case EGF should only be active if surface ulceration has occurred—unless there is translocation across the epithelium. There are several clinical situations in which EGF might be useful in cytoprotection and in stimulating repair and regeneration in the gut. These include necrotizing enterocolitis and mucositis, and it is to be hoped that the solid basis of experimental studies on EGF might stimulate work on this topic. (Journal of Parenteral and Enteral Nutrition23:S83‐S88, 1999)
Long‐Term Outcome of Short Bowel Syndrome in Adult and Pediatric Patients
Authors: Wasa Masafumi , Takagi Yoji , Sando Kinya , Harada Tokuzou , Okada Akira
Published: September 2009

We reviewed 12 pediatric and 18 adult patients with short bowel syndrome (SBS) from Osaka University Hospital and compared clinical characteristics between them. The length of the residual small intestine ranged from 0 to 75 cm (mean 47 cm) in pediatric patients and from 0 to 150 cm (mean 47 cm) in adult patients. In all cases, total parenteral nutrition (TPN) was started immediately after surgery and was gradually replaced by enteral nutrition. Eight pediatric patients (67%) and 4 adult patients (22%) were weaned from TPN. Residual intestinal length in these patients ranged from 27 to 75 cm (mean 57 cm) in pediatric patients and 57 to 150 cm (mean 96 cm) in adult patients. Pediatric patients with residual small intestinal lengths of 0, 16, 25, and 45 cm were not weaned from TPN. None of the adult patients with residual small intestinal length less than 40 cm could achieve complete intestinal adaptation. Five adult patients died due to liver failure (2 cases), heart failure (2 cases), or pneumonia (1 case), whereas all pediatric patients survived. The average life span of indwelling central venous catheters was 511 days and 780 days, and the rate of catheter‐related sepsis per 1000 catheter days was 0.73 and 0.48 in pediatric and adult patients, respectively. Plasma levels of arginine and citrulline in patients receiving TPN were significantly decreased compared with those in patients receiving TPN without SBS both in pediatric and adult patients (p <.01). These results indicate that pediatric and adult patients with SBS can survive with TPN and enteral nutrition. The minimum remaining intestinal length necessary for complete bowel adaptation is shorter for pediatric patients than adults, suggesting better bowel adaptation in pediatric patients. (Journal of Parenteral and Enteral Nutrition 23:S110‐S112, 1999)
Interactions Between Nutrients and Peptide Growth Factors in Intestinal Growth, Repair, and Function
Authors: Ziegler Thomas R. , Estivariz Concepción F. , Jonas Carolyn R. , Gu Li H. , Jones Dean P. , Leader Lorraine M.
Published: September 2009

Several lines of evidence demonstrate that general nutritional status, specific nutrients (eg, zinc, glutamine), and certain trophic growth factors (eg, growth hormone, insulin‐like growth factor I, keratinocyte growth factor, and glucagon‐like peptide‐2) have important interactions relevant for intestinal growth and function. Adequate nutritional status is critical for endogenous growth factor synthesis in the gut and other tissues and is an important mediator of organ responsiveness to exogenous growth factor administration. Both endogenously synthesized and exogenously administered growth factors upregulate nutrient uptake and utilization by gut mucosa, skeletal muscle, and other organs. Emerging data from both animal and human studies indicate that combinations of selected growth factors and specific nutrients may improve the growth, adaptation, and repair of the intestinal mucosa. Additional studies to determine basic mechanisms of nutrient—growth factor interactions and the safety and efficacy of treatment with combinations of specific nutrients and recombinant growth factors are needed. Results of these investigations should define new methods for support of the intestinal tract during short bowel syndrome (SBS), catabolic illness, and malnutrition. (Journal of Parenteral and Enteral Nutrition23:S174‐S183, 1999)
Effects of Insulin‐Like Growth Factor‐I and Growth Hormone in Models of Parenteral Nutrition
Authors: Ney Denise M.
Published: September 2009

Background: Administration of growth factors such as growth hormone (GH) and insulin‐like growth factor‐I (IGF‐I) is being investigated as a strategy to promote nitrogen accretion in catabolic patients who may require total parenteral nutrition (TPN). IGF‐I has advantages compared with GH because IGF‐I enhances insulin sensitivity, is effective in conditions of GH resistance, and selectively stimulates the gastrointestinal and immune systems. Methods: Experiments were conducted to evaluate the anabolic and metabolic effects associated with administration of recombinant human GH or IGF‐I in rats subjected to clinically relevant stress and maintained with TPN. Results: Administration of IGF‐I, but not GH, attenuates dexamethasone‐induced protein catabolism and increases insulin sensitivity. Simultaneous treatment with GH and IGF‐I additively increases the serum concentration of IGF‐I, whole‐body anabolism, and lipid oxidation. GH or IGF‐I when given alone produces similar increases in the serum concentration of IGF‐I. However, GH selectively increases skeletal muscle mass whereas IGF‐I selectively attenuates the intestinal atrophy and abnormal intestinal ion transport induced by TPN. These tissue‐selective anabolic effects of GH and IGF‐I are associated with differential increases in protein synthesis in skeletal muscle and jejunum, respectively. Conclusions: Simultaneous treatment with GH and IGF‐I may offer the greatest clinical efficacy because of improved nitrogen retention in association with enhanced lipid oxidation and stimulation of protein synthesis in multiple tissue types. (Journal of Parenteral and Enteral Nutrition23:S184‐S189, 1999)
Use of Growth Hormone and Other Anabolic Agents in AIDS Wasting
Authors: Mulligan Kathleen , Tai Viva W. , Schambelan Morris
Published: September 2009

Body wasting and loss of lean body mass (LBM) have been associated with increased mortality and disease progression, and reduced quality of life, in patients with human immunodeficiency virus (HIV) infection. The failure of nutritional therapies and, more recently, of effective viral suppression, to consistently restore LBM has prompted investigation of the pharmacologic use of a number of specific protein anabolic agents, including recombinant human growth hormone (rhGH), insulinlike growth factor I (rhIGF‐I), and synthetic testosterone derivatives, such as nandrolone decanoate, oxandrolone, and oxymetholone. In a placebo‐controlled trial, treatment with rhGH resulted in a significant and sustained increase in weight that was accompanied by an even greater increase in LBM and a decrease in fat, and improvement in treadmill work output. Preliminary data suggest that short‐term rhGH treatment may be effective in mitigating weight loss in patients with secondary infections. Open‐label studies of nandrolone decanoate suggest that this injectable agent also can increase weight and LBM. Two oral agents, oxandrolone and oxymetholone, can increase weight, but their effects on LBM in placebo‐controlled trials have not been reported. Taken together, these studies demonstrate that HIV‐infected individuals can regain weight and LBM under the proper therapeutic circumstances. The effects of reversal of wasting on survival and disease progression, long‐term safety, and the potential value of these therapies in the treatment of fat redistribution remain to be determined. (Journal of Parenteral and Enteral Nutrition23:S202‐S209, 1999)
Chronic Progressive Nephropathy in Aging Rats
Authors: Barthold Stephen W.
Published: September 2009

Chronic progressive nephropathy (CPN) is a commonly encountered lesion in aging laboratory rats. CPN has been given a variety of names, based upon its complex nature. It is a lesion that occurs primarily in albino strains and is influenced not only by genetics but also by sex, age, hormones, diet, and microflora, among other factors. Affected kidneys are enlarged, pale and finely indented. The lesion begins with progressive thickening of glomerular, Bowman's capsular and proximal tubular basement membranes. Mesangial matrix increases with deposition of IgM and, to a lesser extent, other serum components. Tubular atrophy and degenerative changes occur as the lesion progresses. The disease is manifested by increasingly non-selective proteinuria, consisting mainly of albumin. Serum chemical changes include elevations in α globulins and cholesterol and a decrease in albumin. Creatinine and urea remain unchanged until late in the course of CPN. Renal secondary hyperparathyroidism may occasionally be seen.
Immunopathology of the Rat Kidney: A Review
Authors: Robertson John L.
Published: September 2009

The rat has been used extensively as a model for human and animal renal diseases. Three types of model systems have been especially well researched.

Autologous immune-complex (AIC) nephritis (Heymann nephritis) is induced in rats by the intraperitoneal injection of the tubular brush border antigen RTEα5 and complete Freund's adjuvant. Rats develop proteinuria and proliferation of glomerular endocapillary cells as complexes of antigen and antibody lodge in glomerular basement membrane.

Nephrotoxic serum nephritis (NTS), also called Masugi nephritis, is induced in rats by administration of antiserum to rat renal structural proteins. Binding of this antiserum to glomerular basement membranes (and other proteins) causes proteinuria. As the rat produces its own antibody to the injected “foreign” antiserum, a secondary phase of damage occurs with inflammation and cellular proliferation.

Recently, there has been extensive work on anti-basement membrane nephritis in Brown-Norway rats. These rats, when immunized against heterologous glomerular and tubular basement membranes, develop florid tubulointerstitial and glomerulonephritis, with proteinuria and azotemia.

These models may be used to research basic pathogenesis of renal disease and test treatment strategies.
Measurement of 14 Blood Components in Rats, Dogs, and Mice Using CentrifichemR Analyzer
Authors: Chin B. H. , Kozbelt S. J. , Sullivan L. J.
Published: September 2009

Methods for determining 14 blood chemistry parameters in dogs, mice, and rats were established using an automated centrifugal analyzer methodologies for human samples. The precision of each method was determined to be satisfactory with the exception of the following; albumin and alanine aminotransferase in mice and creatinine in dogs. Based on these methods, normal values for 14 tests in these species were compiled.
Spontaneous Bladder and Kidney Lesions in Young Rats
Authors: Robertson John L.
Published: September 2009

Spontaneous hyperplastic and inflammatory lesions were found in the bladders and kidneys of female rats and their offspring being observed as part of a reproduction study.

Bladder lesions consisted of hyperplasia of the mucosal epithelium, mucosal erosion and ulceration, and infiltration of the bladder mucosa with polymorpho-nuclear neutrophils.

Kidney lesions included dilation of the renal pelvis, hyperplasia of the pelvic epithelium and inflammation of the renal pelvis (pyelitis).

The incidence of these lesions is presented. Spontaneous lesions of this type may affect the interpretation of chemically-induced changes in these organs.
Degenerative Cardiomyopathy in Experimental Beagles Following Parvovirus Exposure
Authors: Cimprich R. E. , Robertson J. L. , Kutz S. A. , Struve P. S. , Detweiler D. K. , DeBaecke P. J. , Streett C. S.
Published: September 2009

Three apparently healthy beagle dogs (6-8 months old) from a commercial supplier were found to have electrocardiographic abnormalities on routine screening. At postmortem, areas of ventricular myocardial thinning and/or fine gray streaks were present in both ventricles. Histologically, areas of multifocal fibrosis, degenerating myocytes, and sparse mononuclear cell infiltrates were present. Serum titers from these dogs were indicative of natural infection with parvovirus. These findings are significant in drug safety studies where underlying disease must be differentiated from compound-induced lesions.
Practical Applications of Morphometric Analysis in Toxicology
Authors: Visscher George E. , Stifano Toni M.
Published: September 2009

The principles of morphometry permit the determination of volume fraction ratio, surface volume and numerical density of structures, as well as other parameters, to be accurately measured. Mathematical formulae and modern instrumentation allow for reliable and reproducible quantification of biological structures. The measurements obtained from structures which are quantitated can be statistically tested thus leading to the precise analysis of obvious or subtle changes. To the toxicologist or pathologist the quantification of structural change can often aid in the understanding of the cellular mechanisms of toxicity, the interpretation of structure function relationships, and in determining whether a drug induced change has indeed occurred.
Optimization and Standardization of Male Gonad Weight Determinations in Rats
Authors: Adkins A. G. , Alden C. L. , Kanerva R. L.
Published: September 2009

In order to develop an optimal method for measuring male gonad weight, one that is both statistically dependable (i.e. not subject to wide fluctuations within similarly treated groups) and appropriate with respect to end uses of data, testis, epididymis, and epididymal fat pad weights were obtained from normal adult male rats and subjected to statistical analyses. The results underscore the necessity for omitting the epididymal fat pad from “gonad” weight measurements since there appeared to be no relationship between its weight and the weight of either the testis or epididymis. Furthermore, the inclusion of epididymal fat resulted in large variation in total unit weight. An interdependent relationship was shown for testis and epididymis weights, indicating it may be appropriate to report a combined value for these entities, though this decision should be based on the intent of the study. A significant saving in time was effected by obtaining the weight of the testis alone. In studies which require male gonad weight assessment, therefore, the testis, excluding epididymis and epididymal fat, should be weighed to maximize the combined factors of time/cost effectiveness and scientific validity.
A Method For The Demonstration of Small Numbers of Ectoparasites From Laboratory Rodents
Authors: Coleman Gerald L. , Chapman Pauline
Published: September 2009

Examining rats and mice for small numbers of external parasites can be accomplished by washing the anesthetized animal in a detergent-disinfectant bath. The sediment is concentrated by centrifugation and examined microscopically for parasites, their parts or eggs. This method was successfully used to demonstrate mites of the genus Radfordia on six of seven rodents for which skin scrapings had failed to contain evidence of mite infestation.
Initiation/promotion bioassay in rat liver: use of gamma glutamyltranspeptidase-positive foci to indicate carcinogenic activity
Authors: Pereira Michael A. , Herren Sydna L. , Britt Alfred L. , Khoury Marlene M.
Published: September 2009

Gamma Glutamyltranspeptidase (GGTase)-positive foci have been used to indicate activity in an initiation/promotion bioassay in rat liver. This rat liver foci bioassay has been proposed for inclusion in tier 2 of a three tier decision tree approach to carcinogenesis testing where it would function to confirm carcinogenic activity. The assay was sensitive to hepatocarcinogens and some non-hepatocarcinogens and was able to distinguish between tumor initiators and tumor promoters. The induction of GGTase-positive foci by methylating agents was associated with the formation of O6-methylguanine and not N-7 methylguanine, which would indicate a mutagenic origin for the foci. The foci once induced did not regress over the life time of the animal. Zonal induction of GGTase activity was induced by some promoters which confounded the scoring of foci incidence. The results to date indicate that the rat liver foci bioassay warrants further validation for inclusion in tier 2 and emphasizes the need to demonstrate the predictive and precursor relationship of GGTase-positive foci to cancer.
The Epidemiology of Human Liver Tumors
Authors: Higginson John
Published: September 2009

The epidemiology of primary liver cancer is reviewed in relation to associated lesions, e.g., cirrhosis, chronic hepatitis. Little data are available to permit evaluation of the frequency of many preneoplastic and precirrhotic lesions which per se carry a low mortality. The proportion of cirrhotic livers in which primary cancer develops varies between countries due to etiological differences. The major factors suspected of causing cirrhosis and cancer in man are: i) hepatitis B, ii) aflatoxin, and iii) alcohol. There is a miscellaneous group of hepatoproliferative disorders due to a wide range of agents which form a small proportion of the total liver problem in industrial and non-industrial states. In contrast to rodents, few liver carcinomas are related to industrial or occupational factors, apart from an association with alcoholism and low socioeconomic class. Data on benign hepatocellular proliferative lesions are inadequate, apart from steroid-induced adenomas. In contrast to rodent studies, primary liver cancers have not been associated in man with enzyme inducers, such as pesticides or drugs. In conclusion, apart from aflatoxin and hepatitis B, it has proven difficult to make valid comparisons between experimental models and human liver cancer and disease except in relation to morphological pathogenetic pathways. This discrepancy between high frequency or experimental carcinogens identified in rodents and the rarity of demonstrating similar effects due to chemical exposures in man merits further consideration.
Sequential Morphological Changes in Aflatoxin B1-Induced Liver Tumors During Chronic Administration of Glutathione
Authors: Novi Anna M. , Boschnakova Tzanka , Hort Waldemar
Published: September 2009

The sequential light microscopic changes in aflatoxin B1-induced liver tumors during chronic administration of glutathione were studied. The results suggest that necrosis of neoplastic hepatocytes plays an important role during the regression of tumor growth induced by glutathione.
The Use ofIn vivoHepatic Initiation-Promotion Systems in Understanding the Hepatocarcinogenesis of Technical Grade Dinitrotoluene
Authors: Popp James A. , Leonard Thomas B.
Published: September 2009

A 2 year bioassay sponsored by the Chemical Industry Institute of Toxicology demonstrated the potent hepatocarcinogenicity of technical grade dinitrotoluene (DNT) which contains 76% 2,4-DNT, 18% 2,6-DNT and less than 3% of each 2,3; 2,5; 3,4 and 3,5-DNT isomers. In contrast, a 2 year bioassay of 2,4-DNT sponsored by the National Cancer Institute did not result in the appearance of hepatic neoplasms above the spontaneous incidence. Using previously described in vivo hepatic initiation-promotion systems, an evaluation of the initiating and promoting activity of individual DNT isomers was undertaken to provide an understanding for the differences between the two bioassays. Weak hepatocyte initiating activity was identified in technical grade DNT and purified 2,6-DNT. In contrast, 2,3; 2,4; 2,5; 3,4 and 3,5 isomers had no detectable initiating activity. When fed following a diethylnitrosamine initiating regimen, technical grade DNT, purified 2,4 and 2,6-DNT isomers had demonstrable promoting activity. Therefore, the hepatic neoplasms resulting from technical grade DNT feeding apparently resulted from the initiating activity of 2,6-DNT followed by the promoting effect of both the 2,4 and 2,6-DNT isomers. The lack of hepatic neoplasms following chronic feeding of 2,4-DNT was apparently due to the lack of hepatic initiating activity.
The Biology of Carcinogen-Induced Hepatocyte Nodules and Related Liver Lesions in the Rats
Authors: Farber Emmanuel
Published: September 2009

The only known sequence of tissue changes seen during liver cancer development involves microscopic foci or islands of altered hepatocytes, hepatocyte nodules, a subset of these nodules, the persistent nodules, nodules in nodules and ultimately hepatocellular carcinoma. The nodules show an array of architectural, fine ultrastructural, vascular, biochemical and physiological properties characteristic of this new population of hepatocytes. Despite their origin following initiation with a chemical carcinogen, the vast majority (98-99%) of nodules undergo a complex process of remodeling or redifferentiation to normal looking mature liver. A very small minority persist, continue to grow slowly and ultimately may act as a site of origin for new later precancerous nodules and metastasizing hepatocellular carcinoma. The basis for the different behaviour patterns, remodelling of the majority and persistence of the minority is not understood. Even though the vast majority of nodules do undergo remodelling and “disappear”, it would be unwise at this time to ignore this key role of nodules in general in cancer development.
Lindane Bioassay Studies and Human Cancer Risk Assessment
Authors: Vesselinovitch Stan D. , Carlborg Frank W.
Published: September 2009

Benzene hexachloride or hexachtorocyclohexane comes in eight isomeric forms which differ in the spatial positions of the chlorine atoms on the boat and chair forms. Only one, however, γ-isomer (lindane) possesses relevant insecticidal activity. The majority of studies on the potential carcinogenicity of benzene hexachloride, however, did not discriminate between the various isomers because they assumed that carcinogenicity is independent of steric structure. Also, proper differentiation between morphologic endpoints was not duly carried out and considered.

The present evaluation of lindane's biologic activity was restricted to the lifelong studies in which pure lindane (>99.5%) was utilized and the morphology of the observed lesions, mainly in the liver, were classified according to their biologic behavior into hyperplastic, benign neoplastic, and malignant entities. None of the studies gave evidence that lindane was carcinogenic in mice and rats. An enhancement of benign liver tumors (tumorigenic effect) was observed only in CF1male mice (17/56 at the only tested dose: 400 ppm vs. 3/89 observed in the nontreated controls). Dose-response function of this tumor response in conjunction with two other lifetime studies (80 and 160 ppm in B6C3F1and 50, 25, and 12.5 ppm in NMRI mice) were best described by the Weibull model, giving a relatively high estimate of its shape parameter (m = 2.5). Assuming similar susceptibility of humans to lindane and considering maximal occupational exposure to this agent (professional applicators), the probability of lindane associated tumor development was estimated as 2.2times10-10. Because this cancer risk is five orders of magnitude below the acceptable health risk, this evaluation concludes that environmental exposure to lindane does not pose a threat to human health.
Advances in the Design and Reporting of Conventional Carcinogenicity Tests
Authors: Hess Robert , Bretz Rolf , Gfeller Walter
Published: September 2009

It is generally acknowledged that animal experiments provide the most important and best reliable service of information for assessing the possible carcinogenic activity of chemicals. In the past, experimental procedure has mainly concentrated on the choice of species, improved animal husbandry, the modes of exposure, test conditions and pathological examination. Although experience gained thereby indicated the necessity for further scientific exploitation of bioassay models, the rather rigid stereotyped procedures—proposed for convenience—were generally accepted and adopted.

Nevertheless, continuous improvements have been made in the design of carcinogenicity tests in rodents.

Current developments in test design tend to be primarily concerned with the predictive significance of carcinogenicity studies. Modern protocols call for optimum facility operation as much as for computerized support of study monitoring and data evaluation. Of particular significance are the automated handling of autopsy and histopathological data and their proper statistical evaluation. By the economical use of modern technology, cost-saving protocols can be designed for the production of the data which are essential for the reliable assessment of risk.
Current Genetic Assays in Long Term Protocols
Authors: Schreiner Ceinwen A.
Published: September 2009

Incorporation of mutagenicity tests in long term bioassays contributes relevant data for characterizing the oncogenic potential of a test compound. Additionally, genetic insult occurring in the germ cells may result in reproductive failure or the damage may be fixed as an inherited mutation with consequences in future generations. Tissues from animals necropsied at intervals throughout a study can be evaluated for chromosome damage and DNA perturbation. Comparatively non-invasive methods of collecting body fluids for developing a clinical chemistry profile also provide samples of blood for chromosome analysis, sister chromatid exchange or unscheduled DNA synthesis, or urine and feces to identify mutagenic excretory products in the Ames test. Such monitoring techniques can be employed in continuously treated animals and in animals set aside for recovery. Identification of genotoxic or non-genotoxic steps in carcinogenic activity in a variety of target organs provides insight into the mechanism of action of a test compound and may have implications for human risk assessment and regulation.
Incidence of Hepatic Metastases for Various Neoplasms in Several Strains of Mice
Authors: Frith Charles H.
Published: September 2009

The incidence of hepatic metastases for a variety of spontaneous and carcinogen-induced malignant neoplasms was studied in several strains of mice. Forty percent of osteogenic sarcomas metastasized to the liver in C57BL/6 female mice. Fourteen percent of mesotheliomas metastasized to the liver in C3H mice and 11.5% of alveolar/bronchiolar carcinomas metastasized to the liver in BALB/c male mice. All other malignant neoplasms metastasized to the liver at a rate of less than 10% and most at less than 5%.
Comparison of Fresh and Fixed Organ Weights of Rats
Authors: Kanerva Robert L. , Lefever Frank R. , Alden Carl L.
Published: September 2009

Male and female rats (20 of each sex) were killed, and a broad sample of organs were excised, weighed, and immersed in 10% neutral buffered formalin. Following 72 hours fixation the organs were reweighed. Comparison of fresh and fixed organ weights revealed statistically significant organ weight changes due to fixation. Although the fixation-induced organ weight changes varied in both direction and magnitude among organs and between sexes, the changes were consistent throughout samplings of each specific organ. The results of this study therefore suggest that fixed organ weights may be a valid alternative to fresh organ weights. A significantly larger data base must be generated, however, to determine the influence of fixation prior to weighing in the presence of the various pathologic tissue alterations observed in safety evaluation studies.
Basis of Cellular Autonomy in the Subsceptibility to Carcinogenesis
Authors: Russo Jose
Published: September 2009

This paper summarizes our contributions in the basic understanding of the different susceptibility of the mammary gland to carcinogenesis according to age and parity history. Mammary carcinomas induced by the administration of 7,12-dimethylbenz-(DMBA) to young virgin rats arise from undifferentiated terminal ductal structures called terminal end buds (TEBs). TEBs, that normally differentiate into alveolar buds (ABs) and lobules, under the influence of DMBA develop intraductal proliferations which progress to carcinoma. The high susceptibility of the young virgin rat TEBs to neoplastic transformation is due to its large proliferative compartment, with cells cycling every 10 hours, and to a higher 3H-DMBA uptake. Progressive differentiation of TEBs into ABs and lobules or their regression to terminal ducts (TDs) is seen with aging. Complete differentiation of the gland is attained through pregnancy and lactation or through exogenous administration of chorionic gonadotrophin. The greater differentiation of the gland is manifested as permanent structural changes, consisting in the disappearance of TEBs and in a diminution of the number of TDs due to their differentiation into ABs and lobules. This greater differentiation results in a diminished or total refractoriness of the gland to the carcinogen because ABs and lobules have a lower proliferative compartment, and a longer cell cycle than TEBs and TDs. Cells of parous rats have both in vivo and in vitro lower DMBA-DNA binding capacity, lower DNA synthesis and greater ability to repair DMBA-damaged DNA than cells of young virgin rats. The more efficient DNA repair capacity of the parous rat mammary gland is demonstrated by the induction of unscheduled DNA synthesis and a removal of DMBA-DNA adducts.
Interface Between Pathology and Epidemiology in Carcinogenesis
Authors: Campbell James S. , Tryphonas Leander
Published: September 2009

The bottom line here is how or whether our toxicological studies relate to ourselves, to human neoplasia—but the latter is, in important ways, imperfectly defined by the best that can so far be arranged using morphological and epidemiologic methods. There are at least three basic questons: 1) with what precision can the histopathologist define and diagnose cancer in humans—hence emphasis here upon human cancer models, 2) to what extents can difficulties be resolved using animal models, where some similar difficulties are met, and 3) to what extents can epidemiology resolve these difficulties. Not all these problems can be resolved, and the investigator is left with a residue of questions for which no answers are presently available. Some of these are exemplified or precipitated by inconclusive or mistaken diagnoses.

In the future awaits practical help from specific biochemical markers and morphometry, but in the present, vigilance and consultation should limit error to a small fraction of observations. In the meantime, existing methods and data are perfectly adequate for study and action in various clinical problems, eg. transmission of familial polyposis of colon, definition and control of various adverse drug reactions.
Morphologic Features and Incidence of Spontaneous Hyperplastic and Neoplastic Mammary Gland Lesions in Wistar Rats
Authors: Barsoum Nabila J. , Gough Alexander W. , Sturgess Jennifer M. , de la Iglesia Felix A.
Published: September 2009

A morphologic study of spontaneous proliferative lesions of the mammary gland was based on histologic examination of mammary glands from 1020 male and 1145 female albino Wistar rats aged 6 to 110 weeks. Three hundred and seventy-five mammary tumors representing an overall incidence of 33% were identified in the female groups, while the males had a total of five tumors which represented an incidence of 0.5%. Histologically, the most common types of tumors in females were: fibroadenoma (236), carcinoma (85), adenoma (40) and fibroma (8). Duct papilloma (1), lobular carcinoma (1), fibrosarcoma (1) and phyllodes tumor (1), were rare and constituted less than 2% of mammary neoplastic lesions. Mammary tumors were rare before one year of age, but increased with age thereafter. Nine percent of female rats studied also had proliferative non-neoplastic lesions that showed a mixture of benign ductular and/or lobular hyperplasia. One hundred and six of these lesions were identified, representing 22% of all grossly palpable nodules, thus stressing the importance of histologic examination of all gross mammary nodules for tumor evaluation.
Variations in Aryl Hydrocarbon Hydroxylase Activities in Mitogen-Activated Human and Nonhuman Primate Lymphocytes
Authors: Kouri Richard E. , McKinney Cindy E. , Levine Arthur S. , Edwards Brenda K. , Vesell Elliot S. , Nebert Daniel W. , McLemore Theodore L.
Published: September 2009

A fluorometric assay for the cytochrome P-450-dependent enzyme system, aryl hydrocarbon hydroxylase (AHH), was performed in mitogen-activated human lymphocytes from over 300 different humans and from 64 baboons. Results reveal: a) an average interindividual variation in AHH activity of −0.25 (coefficient of variation); range of activities among humans and baboon subjects of −40-fold; c) both genetic and environmental determinants of interindividual variation, and d) high AHH activity in humans associated with primary lung cancer. Confirmation of these results awaits the development of improved methods for phenotyping humans and for prospective cancer patient studies. DNA probes might be employed in future studies to determine specific mRNA content, and to search for DNA polymorphisms in and near the human cytochrome P-450 gene.
Metabolic Basis for the Pulmonary Clara Cell as a Target for Pulmonary Carcinogenesis
Authors: Boyd Michael R. , Reznik-Schüller Hildegard M.
Published: September 2009

The furan compound, 4-ipomeanol, is activated in lung tissue by cytochrome P-450 dependent oxidation to a highly reactive, electrophilic product that binds covalently to tissue marcomolecules. Although the reactive metabolite(s) of 4-ipomeanol have not yet been definitively identified, recent studies with 3-methylfuran have indicated that a highly reactive, unsaturated dialdehyde is formed from microsomal oxidation and ring-opening of the furan nucleus. Metabolic experiments with 4-ipomeanol in intact lungs, lung slices, lung cells, lung microsomes and purified lung cytochromes P-450, supported the conclusion that the Clara cell is an important locus of cytochrome P-450 monooxygenase activity in lung. In vivo, 4-ipomeanol was bound covalently and caused necrosis preferentially in the pulmonary Clara cells of laboratory animals. Similarly, N-nitrosamines require metabolic activation mediated by the cytochrome P-450 monooxygenase system in the host organism. A number of nitrosamines which are lung carcinogens in rats and hamsters have been shown to bind preferentially to bronchial and bronchiolar Clara cells in these species. Early pathological changes occurred specifically in Clara cells and lung tumors that developed under continuous nitrosamine treatment originated from such altered Clara cells. The well-differentiated counterparts of these tumors clearly retained their ability to bind the nitrosamine that had induced their formation. Thus, the studies on these two different classes of compounds together supported the view that metabolism may be a factor critical to the progenitor role of the Clara cell in chemically-induced bronchogenic lung cancer.
Liver Hyperplasia and Regression after Lead Nitrate Administration
Authors: Columbano Amedeo , Ledda-Columbano Giovanna M. , Coni Piero P. , Vargiu Massimo , Faa Gavino , Pani Paolo
Published: September 2009

The effect of a single intravenous injection of lead nitrate on liver, was investigated in male Wistar rats. Lead nitrate at 5 and 10 μmoles/100 g of body weight stimulated a 19-fold increase in the incorporation of 3H-thymidine into liver DNA and resulted in temporal changes in DNA synthesis, as determined by assays of specific activity. Thirty-six hours after lead nitrate administration, the incorporation of 3H-thyrnidine reached its maximum and returned to normal levels within 3 days. A significant increase in the number of cells entering mitosis at 36 hours indicated the capacity of lead to stimulate liver cell proliferation. Enlargement of the liver after lead treatment was also observed in both female Wistar rats as well in male Fischer rats. This stimulatory effect of lead on liver growth was reversible; during the involution of the liver, cell death morphologically similar to the one described as apoptosis was observed in histological sections of liver from animals sacrificed 4-7 days after lead treatment.
Olefinic Hydrocarbons: A First Risk Estimate for Ethene
Authors: Bolt Hermann M. , Filser Johannes G.
Published: September 2009

The exhalation of ethene oxide by rats exposed to ethene now allows a first estimate of the genotoxic risk of ethene on a pharmacokinetic basis. The distribution (Keq, Kst) of ethene oxide under conditions of inhalation of ethene oxide, or high levels of ethene and consideration of the saturation behaviour of metabolism of ethene lead to the conclusion that inhalation exposure of rats to 1000 ppm ethene or more would theoretically correspond to about 7.5 ppm ethene oxide exposure. Available carcinogenicity data for inhaled ethene oxide were utilized into a comparison of the genotoxic risks of low levels of ethene oxide and ethene. It has been shown that consideration of ethene as a “simple asphyxiant” is inappropriate. The new intended TLV of 1 ppm for ethene oxide would be consistent with a TLV of 100 ppm for ethene.
Potency of Carcinogens Derived from Covalent DNA Binding and Stimulation of DNA Synthesis in Rat Liver
Authors: Lutz Werner K. , Büsser Marie-Therese , Sagelsdorff Peter
Published: September 2009

In order to investigate the role of the stimulation of cell division for the initiation (and possibly promotion) of liver tumors by chemical carcinogens, the incorporation of radiolabelled thymidine into liver DNA was determined in male rats. Single doses of various levels of aflatoxin Bt, benzidine and carbon tetrachloride (all known to be genotoxic via DNA binding) did not affect cell division, whereas several hepatocarcinogens known not to bind to DNA (alpha-HCH, clofibrate, and 2,3,7,8-tetrachlorodibenzo-p-dioxin) gave rise to a dose-dependent stimulation of liver DNA synthesis within 24 h. An equation combining the influences of mitotic stimulation, expressed as dose required to double the control level of DNA synthesis, and DNA binding potency, expressed as the Covalent Binding Index, correlated well with the carcinogenic potency for both classes of hepatocarcinogens.
Control of DNA Replication and Cell Proliferation in Eukaryotes by Aphidicolin
Authors: Spadari Silvio , Pedrali-Noy Guido , Ciomei Marina , Falaschi Arturo , Ciarrocchi Giovanni
Published: September 2009

The mycotoxin aphidicolin specifically inhibits nuclear DNA synthesis in eukaryotic cells by intereacting with the replicative DNA polymerase a. The drug does not bind directly to DNA nor does it interfere with RNA, protein and nucleic acid precursor synthesis. Aphidicolin offers a new tool for analyzing the mechanism of DNA replication and repair in eukaryotes and for studying the role of eukaryotic DNA polymerases. The drug might also be valuable therapeutically for controlling excessive cell proliferation without adverse effects upon non-multiplying cells. We describe here how to synchronize DNA synthesis in human cells by a double block with aphidicolin and the properties of two human cell lines resistant to the drug.
Control of Protein Degradation and Growth Phase in Normal and Neoplastic Cells
Authors: Baccino Francesco M. , Tessitore Luciana , Bonelli Gabriello
Published: September 2009

Cells have to double their protein mass in order to divide. Whether this is achieved through increased synthesis (PS), decreased degradation (PD), or a combination of both is still debated. Likewise open are other basic questions: whether, beyond differences relating to growth phase (GP) or rate, reduced PD rates are a general characteristic of neoplastic versus normal cells, conferring to them a definite growth advantage; which mechanisms are operating the PD regulation, if any, during GP transitions, and which ones may be defective in neoplastic cells. Growing liver under conditions of regeneration or development is known to achieve a net protein accumulation thanks to increased PS, and particularly, to decreased PD rates, as compared with the adult, steady-state tissue; the level of lysosomal proteinase (LP) activities is reduced; in the regenerating liver this reduction has been located in cycling hepatocytes. AH-130 Yoshida ascites hepatoma cells effect the transition from log to stationary GP by concurrently reducing PS and accelerating PD (slow turnover protein pool); while PD is virtually not affected by lysosomal inhibitors (LI) in growing cells, the extra PD in resting cells is all inhibitable; there is no regulation of LP levels over this GP transition, which is due to depletion of oxygen and nutrients. GP transitions in normal 3T3 cells are also coupled with regulations of both PS and PD, the extra PD in quiescent cells being all suppressible by LI. Quiescence of 3T3 cells, due to depletion of growth factors, is associated with a marked elevation of some LP activities. Transformed 3T3 cells neither cease growth nor elevate PD even at very crowded densities, when PS rates decline; they also fail to regulate LP activities. These findings are discussed in relation to the general problems outlined above.