Pharmacogenetic aspects of the immunodepressive action of cyclophosphamide]

The alkylating and immunodepressive activity of the serum of CBA, BALB/c and DBA/2 mice was studied after the cyclophosphamide administration. The interstrain differences between the indices under study were revealed; no direct correlation was shown between them. DBA/2 mice were found to be the most sensitive to the immunodepressive action of cyclophosphamide, and had the highest blood serum immunodepressive activity.     

Comparative study of several structuro-functional parameters of the liver and adrenal cortex in mice of different genetic strains under physiologically normal conditions]

In adult male mice CBA and C57BL there were revealed differences in the morphometric characteristics of the subcellular organization of hepatocytes, as well as in the indices of functional capacity of the adrenal cortex and the rate of metabolism of steroid hormones in the liver. In animals of the strains under study the levels of steroid hormones production by the adrenal cortex and the rate of gross metabolism of steroid hormones in the liver were characterized by inverse relationship. Structural-functional indices of the adrenal cortex and the liver are supposed to cause different liver responses in these strains of mice to the influence of the alterating factors.     

环磷酰胺诱导小鼠血小板减少症模型的建立(英文）

比较由环磷酰胺两种不同给药方式诱导小鼠血小板减少症模型的效果,并对效果较稳定的一种给药方式进行最佳造模剂量摸索,以期确定一个造模效果较好,毒副作用较低,利于观察治疗药物疗效的血小板减少症模型。模型A组,第1天尾静脉注射环磷酰胺200 mg/kg,然后连续6 d,每天1次以维持剂量30 mg/kg腹腔注射环磷酰胺。模型B组,按150 mg/kg皮下注射环磷酰胺,每天1次,连续3 d。结果显示模型B组造模效果较好,故以模型B组给药方法进行剂量摸索实验。由第7天的血小板计数可知环磷酰胺低（100 mg/kg）、中（120 mg/kg）、高（140 mg/kg）剂量均可引起血小板减少症,而低剂量组与其他组比较有高效低毒的特点,更有利于观察治疗药物的作用,可用于具有升血小板作用药物的药效学研究     

Age-related changes in olfactory sensitivity of laboratory mice

Age-related alterations in the electrical response of olfactory epithelium to odorant-induced stimulation and certain morphometric indices were investigated in male and female laboratory mice of strains C57BL/6 (B6) and AKR (AK). It was found that maximum amplitude of response to odorants characterized young and adolescent animals. Ageing is accompanied by a decline in response level in the olfactory epithelium. Age-related distinctions between morphometric characteristics of the olfactory organ such as overall area and depth of the olfactory epithelium were noted.Applied Mathematics and Cybernetics Research Institute, N. I. Lobachevskii University, Gor'kii. Translated from Neirofiziologiya, Vol. 21, No. 6, pp. 723–729, November–December, 1989.     

Morphometric variation among river sturgeons (Scaphirhynchus spp.) of the Middle and Lower Mississippi River

Pallid sturgeon (Scaphirhynchus albus) captured in the Middle and Lower Mississippi River (i.e. below St. Louis, MO, USA) are morphologically very similar to shovelnose sturgeon (Scaphirhynchus platorynchus). Available empirical data are limited to a few studies based on low sample sizes from disjointed populations. Geneticists are currently searching for markers that will differentiate the two species, but the need for unequivocal species‐specific field characters remains. Continuation of commercial fishing for shovelnose sturgeon in some states necessitates an immediate means for accurate field identifications. Previous studies of lower basin river sturgeon classified individuals with simple morphometric character indices and interpreted intermediacy as interspecific hybridization. In this study, morphometric variation among Scaphirhynchus specimens from the Middle and Lower Mississippi River is examined for evidence of hybridization. Data are compared for large (>250‐mm standard length) hatchery‐reared and wild pallid specimens and wild shovelnose specimens. Specimens are compared using two morphometric character indices, two morphometric/meristic character indices and principal components analysis. Results indicate substantial morphological variation among pallid sturgeon below the mouth of the Missouri River. The amount of variation appears to decrease downstream in the Mississippi River. Sheared principal components analysis of morphometric data shows complete separation of shovelnose and pallid sturgeon specimens, whereas character indices indicate overlap. Both character indices and sheared principal components analysis demonstrate that pallid sturgeon in the Lower Mississippi River are morphologically more similar to shovelnose sturgeon than are pallids from the Upper Missouri River. This similarity, explained in previous studies as hybridization, may be the result of latitudinal morphometric variation and length‐at‐age differences between populations of the upper and lower extremes of the range.     

Changes of the morphometric indices and fractal dimension of the spinal cord neurons during ontogenesis of the cherry salmon Oncorhynchus masou

For the quantitative characteristics of the morphology of two groups of spinal cord neurons in the cherry salmon at the early stages of ontogenesis, the fractal dimension and some more traditional morphometric indices, such as the total length of neuronal branches, the number of terminal branches and branchpoints, and the cell area, are determined. The values of the morphometric indices and the fractal dimension of the bivariate neuronal pattern are shown to increase in the course of ontogenesis from the first to the second year of fish life. The correlation between the main morphometric value and the fractal dimension is found, and their correspondence to the morphometric modifications of the dendrite tree in the neurons investigated during ontogenesis is detected.     

建立小鼠淋巴瘤模型所需环磷酰胺最佳预处理剂量探索

目的:探讨不同剂量环磷酰胺对小鼠肿瘤成模情况的影响,寻找一种简单、有效的建立肿瘤模型的预处理方法。方法:给予BALB/c裸鼠腹腔注射不同剂量环磷酰胺,72小时后再给予小鼠皮下接种淋巴瘤细胞,观察预处理前后小鼠外周血白细胞数量及体重变化情况,以及肿瘤成模率、急性死亡率等。结果:①组1(NS对照组)、组2(100mg/kg×1d)、组3(125mg/kg×1d)、组4(75mg/kg×2d)预处理后体重较处理前无显著性变化,亦无急性死亡情况发生;而组5(125mg/kg×2d)、组6(200mg/kg×2d)、组7(125mg/kg×3d)、组8(250mg/kg×3d)小鼠体重较预处理前明显减轻,且急性死亡率依次为30%、58.3%、50%、75%;②组1和组2小鼠预处理后72小时外周血白细胞数较处理前无明显差异,同时均未成模;而组3、组4、组5、组6、组7、组8小鼠白细胞较预处理前均显著下降,成模率依次为20%、83.3%、60%、33.3%、50%、25%。结论:使用环磷酰胺75mg/kg连续2天腹腔注射的预处理方案,操作简单,成本低廉,通过观察外周血白细胞数和小鼠体重水平等指标即可初步判断建模情况,同时肿瘤成模率高,毒副作用小,是理想的预处理方案。     

Immunomodulating effect of cyclophosphamide on cytotoxic activity of rat and mouse splenocytes

The goal of this work consisted in study of the immunomodulating action of the cytostatic drug cyclophosphamide (CP) on the natural cytotoxic activity of rat and mice splenocytes. The cytotoxicity of effector cells (EC) with respect to monolayer cell lines of the Zajdela rat hepatoma and the HTC rat hepatoma and of the MH-22a mouse hepatoma was determined with the aid of morphometric analysis. CP at a dose of 100 mg/kg 48 h after administration to animals has been shown to produce an immunomodulating effect on cytotoxicity of splenocytes—a suppressive one with respect to cell-targets (CT) of Zajdela hepatoma and an immunopotentiating one with respect to CT of HTC and MH-22 hepatomas. Possible mechanisms of the CP immunopotentiating action are discussed.     

A sensitivity analysis of the volumetric spatial decomposition algorithm

Recently, we proposed a new computational approach for the volumetric spatial decomposition of a three-dimensional bone structure into its basic rod and plate elements. This method was based on an image skeletonization approach, where two model parameters were used to identify an ideal skeleton. The goal of this study was to estimate the sensitivity of local morphometric indices to these two model parameters. Our results showed that the rod derived indices behaved more smoothly than plate derived indices, which suggests that rod derived indices are more trustworthy. The results also demonstrated that it was reasonable to reduce the model to only one parameter by setting the noise parameter n to twice the value of the slenderness parameter s. In conclusion, we found that local morphometric indices are reliable measures showing large differences between samples and thus may shed new light on structural differences of trabecular bone in a local fashion by adequately choosing one single optimization parameter.     

Enhancing tumor implantation and growth rate of Ramos B-cell lymphoma in nude mice

The ability of a human B-cell lymphoma cell line to grow subcutaneously as tumors in nude mice was investigated. The effect of pretreating mice with cyclophosphamide or whole-body irradiation (WBI) was compared with no pretreatment of the mice. Both methods of pretreatment resulted in a higher tumor implantation rate, compared with that for non-pretreated controls. In mice that underwent WBI-pretreatment, a tumor implantation rate of 100% was observed, whereas mice pretreated with cyclophosphamide had a tumor implantation rate of 80%. In non-pretreated control mice, an implantation rate of only 50% was observed. Three weeks after injection, tumor size was significantly larger in mice of the pretreated groups, compared with that in mice of the group that did not receive pretreatment. Furthermore, particularly in the group pretreated with WBI, the tumors grew more synchronously, compared with tumors in the control group. Results of this study indicate that pretreatment with cyclophosphamide or WBI improves the tumor implantation rate of Ramos cells in nude mice, providing a workable animal model for studying human B-cell lymphoma.     

Experimental lethal infection of Leptospira interrogans in mice treated with cyclophosphamide

After preadministration of cyclophosphamide (300 mg/kg), BALB/c mice were lethally infected with Leptospira interrogans serovar lai and a virulent strain of Leptospira interrogans serovar copenhageni, and leptospiral cells were detected in both kidneys of infected mice by indirect immunofluorescent assay. Nonpathogenic leptospirae, Leptospira biflexa serovar patoc, Leptonema illini, and an avirulent strain of L. interrogans serovar copenhageni, were not parasitic to the mice treated with cyclophosphamide. The cyclophosphamide-treated mice were protected from the homologous leptospiral infection by passive immunization with anti-leptospiral monoclonal antibody or with rabbit antiserum and by active immunization with lyophilized organisms or with protective antigen. The results of active immunization in mice treated with cyclophosphamide agreed well with those in nontreated hamsters, which were sensitive to the organisms. Furthermore, these experiments were reproducible with any lot of cyclophosphamide used. These results indicated that cyclophosphamide-treated mice can be used in the experimental infection of Leptospira in place of hamsters or guinea pigs.     

A comparative MRI-based morphometric study of the corpus callosum in term and preterm infants

A comparative morphometric study was performed with MRI brain scans of term- and preterm-born infants. The structural characteristics of the brain were analyzed using conventional morphometric indices, and a novel quantitative parameter, the corpus callosum coefficient (kCC), was introduced based on patterns of the prenatal cortex ontogeny. All these quantitative indices reflected anatomical features of the preterm brain. It was found that reduced kCC values in preterm infants were associated with an altered proportion between the rostral and caudal segments of the corpus callosum. The threshold kCC value was established that allowed significant discrimination between the brains of full-term and preterm infants.     

Distinction between Mulloidichthys flavolineatus juveniles from Reunion Island and Mauritius Island (south-west Indian Ocean) based on otolith morphometrics

Sagittal otoliths of the yellowstripe goatfish Mulloidichthys flavolineatus were analysed in order to compare Reunion Island fish stocks with those of Mauritius (south-west Indian Ocean). Conventional otolith morphometric variables (area, perimeter, length and width), shape indices (form factor, roundness, circularity, rectangularity, ellipticity and eccentricity) and Fourier shape analysis were compared between three sites; two in Reunion Island and one in Mauritius. Regional and site-specific differences were found for all the conventional otolith morphometric features. Regarding the shape indices, the differences between sites were best described by form factor, roundness, circularity and rectangularity. A classification by canonical discriminant analysis indicated significant differences between the three sampling sites. The combined use of morphometric variables (size and shape) and external outlines (shape analysis through Fourier series) showed the importance of otolith shape for intraspecific discrimination.     

Chemoprotective effects of carnosine against genotoxicity induced by cyclophosphamide in mice bone marrow cells

The protective effects of carnosine as a natural dipeptide were investigated in mouse bone marrow cells against genotoxicity induced by cyclophosphamide. Mice were injected with solutions of carnosine at three different doses (10, 50 and 100?mg kg(-1) bw) for five consecutive days. On the fifth day of treatment, mice were injected cyclophosphamide and killed after 24?h. The frequency of micronuclei in polychromatic erythrocytes and the ratio of polychromatic erythrocyte/polychromatic erythrocyte?+?normochromatic erythrocyte [PCE/(PCE?+?NCE)] were evaluated by May-Grunwald/Giemsa staining. Histopathology of bone marrow was examined in mice treated with cyclophosphamide and carnosine. Carnosine significantly reduced micronucleated polychromatic erythrocytes (MnPCEs) induced by cyclophosphamide at all three doses. Carnosine at dose of 100?mg kg(-1) bw reduced MnPCEs 3.76-fold and completely normalized the PCE/(PCE?+?NCE) ratio. Administration of carnosine inhibited bone marrow toxicity induced by cyclophosphamide. It appeared that carnosine with protective activity reduced the oxidative stress and genotoxicity induced by cyclophosphamide in bone marrow cells of mice. Copyright ? 2012 John Wiley & Sons, Ltd.     

Morphometric and functional abnormalities of kidneys in the progeny of mice fed chocolate during pregnancy and lactation

Even most commonly consumed beverages like tea, coffee, chocolate and cocoa contain methylxanthines, biogenic amines and polyphenols, among them catechins, that exhibit significant biological activity and might profoundly affect the organism homeostasis. We have previously shown that 400 mg of bitter chocolate or 6 mg of theobromine added to the daily diet of pregnant and afterwards lactating mice affected embryonic angiogenesis and caused bone mineralization disturbances as well as limb shortening in 4-weeks old offspring. The aim of the present study was the morphometric and functional evaluation of kidneys in the 4-weeks old progeny mice fed according to the protocol mentioned above. Progeny from the mice fed chocolate presented considerable morphometric abnormalities in the kidney structure, with the lower number of glomeruli per mm2 and their increased diameter. Moreover, higher serum creatinine concentration was observed in that group of offspring. No morphometric or functional irregularities were found in the progeny of mice fed theobromine. Abnormalities demonstrated in the offspring of mice fed chocolate are not related to its theobromine content. Consequently, identification of active compound(s) responsible for the observed effects is of vital importance.     

Use of a geometric morphometric method to determine the developmental stability of <Emphasis Type="Italic">Betula pendula</Emphasis> Roth

A geometric morphometric method has been proposed to test the fluctuating asymmetry and the developmental stability of Betula pendula Roth populations. The main factors affecting the developmental stability were the industrial emission level, the relief altitude, and the interaction of both these factors. A strong correlation between the fluctuating asymmetry indices obtained by the normalizing difference method and geometric morphometric method has been revealed. The fluctuating asymmetry determined by the geometric morphometric method is sensitive to the presence of directional asymmetry, which makes it possible to use this method for precise bioindication mapping of the developmental stability.     

Biochemical parameters of the metabolism of the intercellular substance of connective tissue, correlating with morphometric signs of long bone lesions in an open aseptic fracture]

The aim of the research was experimental study of dynamics and correlative dependences between biochemical connective tissue matrix metabolism indices (blood serum collagenase, cathepsin B, elastase, antielastase activity, hydroxyproline fractions and glycosaminoglycans concentration) and tissue damage morphometric indices after long bone aseptic osteotomy of rat in terms 3 h-60 days. The most strong and significant correlation was found between cathepsin B, elastase activity indices and dimensions of bone marrow ischemic damage focuses and summarised periosteal regenerates volume in bone fragments.     

Enhancement of artificial lung metastases in mice caused by cyclophosphamide

Summary The capacity of IV injected fibrosarcoma cells to form metastatic nodules in the lungs of corresponding syngeneic CBA mice was enhanced by pretreatment of tumor cell recipients with cyclophosphamide. The effet depended upon the dose but not upon the injection route of cyclophosphamide. The enhancement of lung-colony formation lasted for about 10 days after injection of the drug, with its maximum at day 1. Cyclophosphamide was also effective in whole body-irradiated and TIR mice. Its effect, however, was abolished to a great extent by reconstituting mice with nonseparated or nonadherent spleen and bone marrow cells from either normal or TIR mice. Lymphoid cells from CY-treated mice, however, had no such reconstitutive capacity. These observations imply that the cyclophosphamide-induced enhancement of tumor metastasis formation was partly due to nonimmunologic factors and partly due to suppression of non-T lymphocytes.     

Induction of specific-locus and dominant-lethal mutations by cyclophosphamide and combined cyclophosphamide-radiation treatment in male mice

Cyclophosphamide is the most widely used antineoplastic agent. It is also used to condition patients for bone-marrow transplantations. Because of the general interest of this compound we initiated a systematic study of the induction of dominant-lethal and specific-locus mutations in male mice. In addition, we investigated the induction of specific-locus mutations by the combined treatment of cyclophosphamide and ionizing radiation.A dose of 40 mg/kg bw of cyclophosphamide caused dominant-lethal mutations in male mice only in the 1st and 2nd week after treatment. A dose of 120 mg/kg induced dominant-lethal mutations in the mating intervals 1–21 days posttreatment. No dominant lethal mutations were observed after the 3rd week. The same differential spermatogenic response was observed for the induction of specific-locus mutations. Cyclophosphamide induced recessive mutations exclusively in spermatozoa and spermatids. No mutations were recovered from treated spermatocytes and spermatogonia. In contrast to cyclophosphamide, radiation induces specific-locus mutations in all germ-cell stages.The pretreatment with cyclophosphamide 24 h before radiation enhanced the frequency of specific-locus mutations in spermatogonia. The distribution of the observed mutations among the 7 loci and their viability supports the hypothesis that these mutations were induced by radiation rather than by cyclophosphamide. The compound causes an immediate inhibition of DNA and RNA synthesis in spermatogonia. The inhibition very likely interferes with the repair process. The disturbance of the repair process is probably the cause of the synergistic effect for the induction of specific-locus mutations in spermatogonia of mice after pretreatment with cyclophosphamide 24 h before irradiation.     

The diabetes-prone NZO/Hl strain. Proliferation capacity of beta cells in hyperinsulinemia and hyperglycemia

New Zealand Obese (NZO) male mice develop a polygenic juvenile-onset obesity and maturity onset hyperinsulinemia. Approximately 50% transit to chronic hyperglycemia. Here we report on the proliferation of beta cells in relation to both the individual's metabolic status and structural parameters of the endocrine pancreas. Proliferating beta cells were quantified in pancreas sections by immunoenzymatic double staining of Ki-67 protein, as a marker for proliferating cells, and endocrine non-beta cells in order to distinguish them from beta cells. In normoglycemic NZO/Hl males Ki-67 labelling indices (IKi-67) of beta cells varied between 0.14 and 1.5%, and correlated significantly with both serum insulin levels and beta cell size. There was no correlation with the glycemic status. In diabetic males, beta cell size was increased. IKi-67 varied between 1 and 3%. The data suggest that the secretory activity of beta cells triggered by glucose, entailed changes in both beta cell hypertrophy and proliferation. As shown by morphometric measurements, beta cell expansion in diabetic mice was limited, in spite of high IKi-67 values. This suggested increased death rates of beta cells.