Assessing Transition Cow Management in Dairy Cows for Improved Health, Milk Production, Pregnancy and Culling Outcomes.

Understanding of the social environment has the potential to benefit dairy cow welfare and production. Our aim was to evaluate the associations of stocking density, calving density, days spent in a pre-partum group before calving (days spent in close-up, DCU) and the number of days from a pen filling event (addition of new cows to the pre-partum pen) on early-lactation health, production, pregnancy and culling outcomes in dairy cows. Data were gathered from 2780 cows in 2 herds. Herd management and reproductive records were analyzed for cows receiving treatment in the first 30 d of lactation (days in milk, DIM) for clinical mastitis, reproductive tract disease, ketosis, milk fever and displaced abomasum. Principal component analysis was used to account for the relationship between gestation length (GL) and DCU and their association with early lactation disease, milk production, pregnancy and culling outcomes. The effect of stocking density, the number of days from a pen filling event to calving and the calving density experienced by a cow in her week of calving was also evaluated. Causal inference was used to correct for confounding bias due to farm identity. The odds of disease in the first 30 DIM increased with stocking density before calving. A quadratic association was found between the first principal component (PC1), representing the combined effect of GL and DCU, and the odds of disease in multiparous cows only. Early lactation milk production and 305 d milk production in multiparous cows increased with PC1 score. Quadratic relationships were found between stocking density at d 8 to 2 before calving with both early lactation and 305 d milk production in multiparous cows but no associations were found in primiparous cows. Calving density showed a quadratic association with 305 d milk production in primiparous cows. The number of days from the last pen filling event to calving was not associated with changes in milk production. Disease occurrence was negatively associated with both early lactation and 305 d milk yield in multiparous cows but only with early lactation milk production in primiparous cows. The occurrence of disease was associated with a delayed time to pregnancy only in primiparous cows while both disease and being in lactation group ≥ 3 were negatively associated with time to pregnancy in multiparous cows. Week 4 milk (W4MK) was positively associated with reduced time to pregnancy in multiparous cows. For primiparous cows, increasing age at calving was associated with increased culling risk, while being in lactation group ≥ 3 was associated with increased culling risk in multiparous cows. Culling risk decreased with increasing W4MK in all cows. These results suggest that gestation length, time spent in close-up and stocking density are important factors influencing disease incidence in early lactation and subsequent lactation performance but had differing effects on primiparous versus multiparous cows. A better understanding of how pre-partum management factors influence postpartum health and milk production can help farms to plan facilities and organize the day-to-day management of cows and will assist in improving cow welfare and productivity.

Identifying the best surface topography parameters for detecting idiopathic scoliosis curve progression.

There is no consensus on which surface topography (ST) parameters may be used to detect scoliosis progression. The sensitivity to change of common ST parameters has not yet been compared. The goal of this study was to determine which ST parameters are most sensitive to scoliosis progression in patients with adolescent idiopathic scoliosis (AIS) receiving conservative treatment. Fifty-eight subjects with AIS were included whose Cobb angle had progressed by at least 5 degrees during a 1 year interval. All had had ST scans and frontal radiographs at a 12 month interval at our clinic. Commonly used back-only ST parameters and contributing scores were derived by one evaluator. Standardized response mean (SRM) and 95% confidence intervals (CI) were calculated using the absolute value of the changes between baseline and follow-up to reflect change in deformity, independent of direction. Decompensation, cosmetic score, Deformity in the Axial Plane Index (DAPI), trunk rotation, Hump Sum, and lordosis angle were highly sensitive to scoliosis progression (SRM>0.8). Cosmetic score, Posterior Trunk Symmetry Index (POTSI), and kyphosis angle had significantly poorer SRM values than the Cobb angle. All other ST parameters had SRM estimates that did not differ significantly from the Cobb angle, suggesting that they have a similar ability to detect progression The ST measures that were most sensitive to detection of scoliosis progression in the frontal, transverse, and sagittal planes were decompensation, trunk rotation, and lordosis angle, respectively. Absolute changes in surface parameters representing either worsening or improvement externally could reflect worsening of the internal deformity. The majority of ST parameters are potentially sensitive to scoliosis progression.

Influences of dietary sodium on functional taste receptor development: a sensitive period.

Restriction of maternal dietary sodium on or before embryonic day 8 reduced taste responses of the chorda tympani nerve to sodium chloride in the offspring. The response attenuation was substantial; responses to sodium chloride in the offspring of deprived rats were approximately 40 percent of those in control animals. Instituting the low sodium diet at embryonic day 10 or later did not produce functional changes. Thus, a sensitive period for the gustatory system exists, and the abrupt transition from maximal environmental susceptibility to no susceptibility occurs during a 2-day prenatal period. Moreover, events important in determining the developmental fate of taste membrane components occur before the initial formation of taste buds.

Nonpneumonic, short-incubation-period Legionellosis (Pontiac fever) in men who cleaned a steam turbine condenser.

Pontiac fever affected ten men who had cleaned a steam turbine condenser with compressed air. Previous epidemics of Pontiac fever and Legionnaires' disease--both caused by Legionella Pneumophila (proposed sp. nov.)--involved "airborne spread" from air-conditioning cooling towers or evaporative condensers. Aerosols of contaminated water in heat-rejection systems appear to be important sources of epidemic legionellosis.

Ribosomal protein S7 as a novel modulator of p53-MDM2 interaction: binding to MDM2, stabilization of p53 protein, and activation of p53 function.

As a major negative regulator of p53, the MDM2 oncogene plays an important role in carcinogenesis and tumor progression. MDM2 promotes p53 proteasomal degradation and negatively regulates p53 function. The mechanisms by which the MDM2-p53 interaction is regulated are not fully understood, although several MDM2-interacting molecules have recently been identified. To search for novel MDM2-binding partners, we screened a human prostate cDNA library by the yeast two-hybrid assay using full-length MDM2 protein as the bait. Among the candidate proteins, ribosomal protein S7 was identified and confirmed as a novel MDM2-interacting protein. Herein, we demonstrate that S7 binds to MDM2, in vitro and in vivo, and that the interaction between MDM2 and S7 leads to modulation of MDM2-p53 binding by forming a ternary complex among MDM2, p53 and S7. This results in the stabilization of p53 protein through abrogation of MDM2-mediated p53 ubiquitination. Consequently, S7 overexpression increases p53 transactivational activities, induces apoptosis, and inhibits cell proliferation. The identification of S7 as a novel MDM2-interacting partner contributes to elucidation of the complex regulation of the MDM2-p53 interaction and has implications in cancer prevention and therapy.

The effects of dietary protein restriction on chorda tympani nerve taste responses and terminal field organization.

Prenatal dietary sodium restriction produces profound developmental effects on rat functional taste responses and formation of neural circuits in the brainstem. Converging evidence indicates that the underlying mechanisms for these effects are related to a compromised nutritional state and not to direct stimulus-receptor interactions. We explored whether early malnourishment produces similar functional and structural effects to those seen following dietary sodium restriction by using a protein deficient, sodium replete diet. To determine if early dietary protein-restriction affects the development of the peripheral gustatory system, multi-fiber neurophysiological recordings were made from the chorda tympani nerve and anterograde track tracing of the chorda tympani nerve into the nucleus of the solitary tract (NTS) was accomplished in rats fed a protein-restricted or a control diet (6% and 20%, respectively). The dietary regimens began on embryonic day 7 and continued until rats were used for neurophysiological recordings (postnatal days (P) 35-50) or for chorda tympani terminal field labeling (P40-50). Responses to a concentration series of NaCl, sodium acetate, KCl, and to 0.50 M sucrose, 0.03 M quinine-HCl, and 0.01 N HCl revealed attenuated responses (30-60%) to sodium-specific stimuli in rats fed the 6% protein diet compared with those fed the 20% protein diet. Responses to all other stimuli were similar between groups. Terminal field volumes were nearly twofold larger in protein-restricted rats compared with controls, with the differences located primarily in the dorsal-caudal zone of the terminal field. These results are similar to the results seen previously in rats fed a sodium-restricted diet throughout pre- and postnatal development, suggesting that dietary sodium- and protein-restriction share similar mechanisms in altering gustatory development.

Myelination of the developing lateral olfactory tract and anterior commissure.

Both the lateral olfactory tract (LOT) and anterior limb of the anterior commissure (AC) carry olfactory information. The LOT forms the projection from the olfactory bulb to the ipsilateral olfactory cortices, while the AC carries odor information across the midline to the contralateral olfactory cortex and bulb. The LOT and AC differ on a number of dimensions, including early development and functional onset. The present work, examining their myelination in mice, reveals additional important differences. For example, the LOT initiates myelination 3-4 days earlier than the AC, evidenced by both an earlier increase in myelin basic protein staining seen with immunohistochemistry and an earlier appearance of myelinated fibers using electron microscopy. While both exhibit a period of rapid myelination, it occurs 4-5 days earlier in the LOT than the AC. The tracts also respond differently to early sensory restriction. Unilateral naris occlusion from the day after birth to postnatal day 30 had no consistent effects on the AC but resulted in significantly thinner myelin sheaths relative to axon caliber in the LOT. Finally, the two tracts differ structurally (the LOT contains larger, more densely packed axons with significantly thicker myelin sheaths resulting in a conduction velocity that is more than twice as fast as the AC). The findings indicate that these two large, accessible tracts provide an important means for studying brain maturation due to basic differences in both the timing of their maturation and general organization.

Isolation, structural determination, and evaluation of the biological activity of 20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol [20(S)-25-OCH3-PPD], a novel natural product from Panax notoginseng.

Ginseng has been used extensively for medicinal purposes, with suggested utility for indications as diverse as diabetes, cardiovascular disease and cancer. Herein we report the discovery and characterization of 20(S)-25-OCH3-PPD, a ginsenoside that inhibits growth and survival of cancer cells. The novel dammarane triterpene sapogenin (C31H56O4; molecular weight 492) was isolated from the total hydrolyzed saponins extracted from the leaves of Panax notoginseng using conventional and reverse-phase silica gel chromatography. Based on physicochemical characteristics and NMR data, the compound was identified as 20(S)-25-OCH3-PPD. The biological activities of 20(S)-25-OCH3-PPD and its known analogs, 20(S)-PPD and Rg3, were evaluated in 12 human cancer cell lines. In all cell lines, the order of cytotoxicity of the test compounds was 20(S)-25-OCH3-PPD >> 20(S)-PPD >> Rg3. 20(S)-25-OCH3-PPD also induced apoptosis and cell cycle arrest in the G1 phase, and inhibited proliferation in breast cancer cell lines, demonstrating its potent biological effects. In regard to cytotoxicity, the IC50 values of 20(S)-25-OCH3-PPD for most cell lines were in the lower microM range, a 5-15-fold greater cytotoxicity relative to 20(S)-PPD and a 10-100-fold increase over Rg3. These findings suggest a structure-activity relationship among dammarane-type sapogenins. The data presented here may provide a basis for the future development of 20(S)-25-OCH3-PPD as a novel anti-cancer agent.

Developmental neurobiology of salt taste sensation.

A principal process in the homeostatic control of sodium levels is salt intake, and the sense of taste has a primary role in regulating ingestion. Because ingestion of sodium chloride (NaCl) is essential for life, the taste system for salt sensation might be expected to exhibit mature functional characteristics from very early development. However, major changes in gustatory nerve responses to NaCl take place during development. In sheep and rat, the peripheral nerve responses to NaCl are of low magnitude during early development. Progressively, the taste system acquires an increasing proportion of fibers that respond maximally to NaCl. The sodium responsiveness emerges in the context of shifting peripheral innervation patterns and the apparent addition of functional receptor membrane channels sensitive to the sodium transport blocker, amiloride. These developmental processes can be altered by early manipulation of sodium in the diet.

Age-related decrease of the chorda tympani nerve terminal field in the nucleus of the solitary tract is prevented by dietary sodium restriction during development.

Institution of a low-NaCl diet beginning at embryonic day 3 and continued throughout pre- and postnatal development has widespread effects on the neuroanatomical organization of the first gustatory relay in the nucleus of the solitary tract. To determine when these effects are expressed postnatally, the terminal field of the chorda tympani nerve was compared between sodium-restricted and sodium-replete rats at postnatal days 15-17, postnatal days 25-27, postnatal days 35-37, and adults. Total terminal fields were significantly larger in postnatal days 35-37 and adult sodium-restricted rats compared with aged-matched controls. The group-related differences appear related more to a remodeling of the terminal field in the dorsal zone of the terminal field in controls. Specifically, the terminal field volume in the dorsal zone in controls decreased dramatically from postnatal days 25-27 to postnatal days 35-37 and then again from postnatal days 35-37 to adulthood. In contrast, the fields did not change during development in sodium-restricted rats. These findings suggest that remodeling of the chorda tympani field occurs in controls at about the developmental period of taste response maturation. The lack of remodeling in sodium-restricted rats may be explained by a corresponding lack of functional response development to sodium salts. These results also illustrate the specificity and extent of how early dietary manipulations shape the developing brainstem.

Cardiac function estimation from MRI using a heart model and data assimilation: advances and difficulties.

In this paper, we present a framework to estimate local ventricular myocardium contractility using clinical MRI, a heart model and data assimilation. First, we build a generic anatomical model of the ventricles including muscle fibre orientations and anatomical subdivisions. Then, this model is deformed to fit a clinical MRI, using a semi-automatic fuzzy segmentation, an affine registration method and a local deformable biomechanical model. An electromechanical model of the heart is then presented and simulated. Finally, a data assimilation procedure is described, and applied to this model. Data assimilation makes it possible to estimate local contractility from given displacements. Presented results on fitting to patient-specific anatomy and assimilation with simulated data are very promising. Current work on model calibration and estimation of patient parameters opens up possibilities to apply this framework in a clinical environment.

Immunoelectron microscopic localization of a tumor-associated antigen (TAA) in the canine transmissible venereal sarcoma by anti-TAA-antiferritin hybrid antibodies.

Immunoferritin and immunoperoxidase reagents were used to localize a tumor-associated antigen (TAA) of the canine transmissible venereal sarcoma (CTVS). Round tumor cells from the CTVS at different stages of growth, i.e., progressive, steady state, and regressing, had TAA diffusely distributed throughout the cytoplasm. In general, TAA was not found on the plasma membrane, within the nucleus, between inner and outer membranes, in cytoplasmic vacuoles, or specifically with any part of the cytocavitary system. Transitional tumor cells, which are intermediate cell types between round cells and spindle-shaped cells and which appear in the tumors at steady state and regressing stages, contained less TAA in their cytoplasm than did the round cell type. The microvilli of tumor cells also contained TAA, suggesting that, in addition to whole cell lysis, shedding of all or parts of these processes may be a mechanism of TAA release as evidenced by the presence of antigenic activity in the extracellular material.

Chemoprevention of N-nitroso-N-methylurea-induced mammary cancers by pretreatment with 17 beta-estradiol and progesterone.

Because hormones of pregnancy are thought to alter the mammary gland such that the epithelial cells are less susceptible to future carcinogenic insults, the present study was conducted to determine the ability of short-term treatment with 17 beta-estradiol and/or progesterone, administered immediately after puberty, to prevent mammary cancers in rats subsequently exposed to N-nitroso-N-methylurea [(NMU) CAS:684-93-5]. Beginning at 40 days of age, female outbred Sprague-Dawley rats received 20 micrograms 17 beta-estradiol and/or 4 mg progesterone for 5 weeks. NMU (50 mg/kg body wt) was administered at 96 and 103 days of age (3 and 4 wk, respectively, after the last hormone injection). Pretreatment of rats with 17 beta-estradiol plus progesterone was highly effective in preventing mammary cancer induction (88% fewer cancers compared to the cancer incidence in rats pretreated with the hormone vehicle). Wholemounts of the mammary glands of rats treated with 17 beta-estradiol plus progesterone revealed that the gland was stimulated to a highly differentiated state (similar to that observed in late pregnancy). At the time of NMU treatment, the gland had involuted but was quite different from controls; i.e. an absence of terminal end buds and terminal ducts was noted. The short-term treatment with hormones did not induce tumors and did not interfere with subsequent reproductive and lactational performance. It is apparent that stimulation of the mammary gland to a highly differentiated state early in life can provide protection against future carcinogen exposure.

N-nitroso-N-methylurea-induced mammary carcinogenesis: effect of pregnancy on preneoplastic cells.

The effect of pregnancy and lactation on mammary cancers induced with N-nitroso-N-methylurea (NMU) was determined in female outbred Sprague-Dawley rats. The animals received 5 mg NMU/100 g body weight at 50 days of age and were divided into the following groups: virgin, pregnancy (beginning 10 days after NMU administration), pregnancy and lactation (beginning 10 days after NMU), and pregnancy and lactation (beginning 82 days after NMU). The time of appearance of the first palpable cancers was shorter in rats undergoing an early pregnancy. Few cancers, however, were detected from rats after pregnancy or pregnancy and lactation was completed, and a decrease in cancer incidence from virgin rats was observed in these animals at termination of the study. Since NMU is a direct-acting carcinogen with a short half-life, no effect of pregnancy on carcinogen metabolism or binding could have occurred. Preneoplastic cells present before pregnancy appeared to have been either altered (such that their latent period was increased) or destroyed by the hormones associated with pregnancy.

Microsomal metabolism of triazenylimidazoles.

The antitumor agents 5-(3,3-dimethyl-1-triazenyl)imidazole-4-carboxamide (DIC) and 5-[3,3-bis(2-chloroethyl)-1-triazenyl]imidazole-4-carboxamide (BIC) are substrates for NADPH-requiring microsomal enzymes of mouse liver. The products of DIC oxidation are 5-aminoimidazole-4-carboxamide (AIC) and formaldehyde. Those for BIC are AIC and, presumably, 2-chloroacetaldehyde. For DIC, the reaction has a pH optimum of 9.0; and the Michaelis constant (Km) is 0.25 mM. At lower pH values, the Km is not greatly increased; but there is a sharp rise in the Km values above pH 9.0. For the enzyme-catalyzed production of AIC from BIC, the pH optimum is 7.5; the Km value for BIC is 0.47 mM. Of a variety of tissues tested for enzymatic activity, only liver accomplishes the conversion of DIC and BIC to AIC. Most of the activity in the liver is located in the microsomal fraction, although detectable activity is present in washed mitochondria. For liver microsomes, the rate of reaction for BIC is greater than that for DIC, but apparently neither rate is fast enough to allow extensive metabolism of large doses of these agents.

A retinoic acid-binding protein from chick embryo skin.

Previous studies by others have indicated that retinoic acid reverses metaplastic changes caused by chemical caricinogens in vivo and in organ culture. The present study deals with the detection of a specific retinoic acid-binding protein from chick embryo metatarsal skin that may be mediating these biological effects. The protein has an S20 value of 2 and an isoelectric pH of 4.6. Competition experiments with labeled retinoic acid and 200-fold molar excesses of unlabeled retinoic acid, retinol, retinal, methyl retinoate, diethylretinamide, synthetic analogs of retinoic acid, and gamma-linolenic acid reveal that only retinoic acid and its analogs with a free carboxyl group bind to this protein. Among the analogs of retinoic acid, a cyclopentenyl analog, a trimethylmethoxyphenyl analog, 13-cis-retinoic acid, and alpha-retinoic acid compete for the binding site on the protein, with the cyclopentenyl analog having greater affinity than retinoic acid does. Phenyl and pyridyl analogs of retinoic acid are poor binders. In general, the ability of the various analgos to bind to this protein correlates with their biological activity in the reversal of keratinization and in the production of mucous metaplasia by chick embryo metatarsal skin as reported by others.

Inhibition of benzo(alpha)pyrene metabolism catalyzed by mouse and hamster lung microsomes.

Induced and constitutive microsomal enzymes of mouse and hamster lungs catalyze both the hydroxylation of benzo(alpha)pyrene and reactions that lead to its irreversible binding to macromolecules. For mouse and hamster, the induced lung hydroxylases have Km values of 1.10 and 0.52 muM, respectively. The induced hydroxylases are strongly inhibited by 7,8-benzoflavone and are stimulated by cyclohexene oxide, an inhibitor of epoxide hydrase. Formation of the macromolecular product by the induced "binding" enzyme follows. Michaelis-Menten kinetics, except for substrate inhibition, and has Km values of 0.52 and 0.25 muM for lung microsomes from mouse and hamster, respectively. These reactions are also inhibited by 7,8-benzoflavone. The reaction catalyzed by the constitutive hydroxylase of mouse lungs is characterized by a brief lag period but proceeds in a linear fashion after the lag. The enzyme requires 60 muM benzo(alpha)pyrene to achieve maximum reaction velocity. Above this concentration, strong substrate inhibition is observed; accurate values for Vmax and Km cannot be derived. The constitutive hydroxylases are moderately inhibited by butylated hydroxytoluene, retinol, cyclohexene oxide, and 7,8-benzoflavone. The product of the constitutive "binding" enzyme is formed in a reaction that follows Michaelis-Menten kinetics. The Km value for enzymes from mouse and hamster lungs are 11.8 and 4.9 muM, respectively. Formation of this product is strongly inhibited by butylated hydroxytoluene and by retinol but not strongly by 7,8-benzoflavone or cyclohexene oxide. Since other evidence indicates that a constitutive enzyme may be involved in carcinogenesis by benzo(alpha)pyrene and since this reaction is inhibited by two known anticarcinogens, we suggest that it may be involved in this process.

Effects of retinoids on metabolizing enzymes and on binding of benzo(a)pyrene to rat tissue DNA.

Retinyl acetate, 13-cis-retinoic acid (13cisRA), and N-(4-hydroxyphenyl)-retinamide (4HPR) were assayed for their in vivo effects on hepatic levels of cytochrome P450, cytosolic glutathione-S-transferase, and quinone reductase. When given p.o. to Sprague-Dawley rats, all of the retinoids caused significant suppression in the levels of arylhydrocarbon hydroxylase, yet 13cisRA and 4HPR caused elevations in cytosolic levels of quinone reductase and glutathione-S-transferase, respectively. Scans of sodium dodecyl sulfate-polyacrylamide gels of microsomal proteins from the livers of retinoid-dosed animals showed changes in both the intensities and the number of stained bands. For microsomes from 13cisRA-dosed animals, there were additional changes in the absorption maximum of the carbon monoxide and octylamine difference spectra. There was, compared to controls, a 62% reduction in the NADPH-dependent binding of (+)-7S-trans-7,8-dihydro[7-14C]benzo(a)pyrene-7,8-diol to microsomal proteins from 13cisRA-dosed animals. Fluorography of the sodium dodecyl sulfate-polyacrylamide gels showed that the major reduction in metabolite binding occurred in the Mr 50,000 region of the gel. The reduction in the NADPH-dependent binding of (+)-7S-trans-7,8-dihydro[7-14C]benzo(a)pyrene-7,8-diol to microsomal proteins in vitro and the reduction in hepatic arylhydrocarbon hydroxylase levels correlated with a reduction in the in vivo binding of benzo(a)pyrene to rat liver DNA. Animals dosed for 7 days with 13cisRA, retinyl acetate, or 4HPR showed a 38, 27, and 40% reduction in binding of benzo(a)pyrene to liver DNA and a 29, 32, and 21% reduction in binding to stomach DNA, respectively, when the carcinogen was administered on the eighth day, and the tissues were harvested 24 h later. Binding to lung DNA was reduced by 23 and 11%, respectively, in the 13cisRA- and 4HPR-dosed rats. No differences were observed in binding to kidney. Thus, retinoids, by altering the metabolism of carcinogens, could influence the initiation stage of carcinogenesis.

Microsomal metabolism of nitrosoureas.

N, N-Bis (2-chloroethyl)-N-nitrosourea (BCNU) is a substrate for a microsomal enzyme of mouse liver. The reaction requires NADPH, and the product is 1, 3-bis (2-chloroethyl) urea. This activity is also found in mouse lungs but not in several other tissues. With reaction conditions under which BCNU is not chemically degraded, the Km for BCNU with liver microsomes is 1.7 mM; nicotine is a competitive inhibitor with a Ki of 0.6 mM. N-Methyl-N-nitrosourea is denitrosated in a similar reaction. N- (2-Chloroetyhy)- N-cyclohexyl-N-nitrosourea and N-(2-chloroethyl)-N-(trans-4-methylcyclohexyl)-N-nitrosourea are also substrates for microsomal enzymes, but the products of these reactions are ring-hydroxylated derivatives. The Km value for N-(2-CHLOROETHYL)-N-cyclohexyl-N-nitrosourea is 3.0 mM and that for N-(2-chloroethyl)-N-(trans-4-methylcyclohexyl)-N-nitrosourea is 1.0 mM. The hydroxylase activity is also present in lungs, but not in the other mouse tissues. The rates of microsomal metabolism of BCNU, N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea, and N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea, and N-(2-chloroethyl-N-(trans-4-methylcyclohexyl)-N-nitrosourea are fast enough to allow metabolism of large portions of administered doses before chemical decomposition of the drugs occurs.