Increased polyploid incidence is associated with abnormal copper accumulation in the liver of LEC mutant rat

Long-Evans Cinnamon (LEC) rats are deleted at the p-type copper transport ATPase gene (Atp7b), so that they exhibit abnormal hepatic copper concentration. In this study, it was confirmed that LEC rat liver possesses a feature of increase in polyploid. Furthermore, a segregation analysis using backcrosses between LEC and F344 normal rats showed that the increased polyploid incidence is strongly associated with excessive copper content in their liver. These results should demonstrate that copper cytotoxicity leads to the impairment of mitotic progression, resulting in the increase of polyploid in the liver of LEC rats.     

Increased incidence of stings in venom-sensitive patients.

We compared the histories of 29 venom-sensitive and 28 control subjects who were selected from our venom referral and general allergy clinics respectively. The variables in the study included insect avoidance knowledge, the number of stings during the previous 2 years, insects involved, and time spent out of doors per week. There was no significant difference between the two groups with respect to age. All venom-sensitive patients were well versed in avoidance techniques while only 3 of 28 controls (11%) claimed such knowledge. Venom-sensitive subjects were stung almost ten times more frequently than control subjects. Wasp stings were the most common, followed by yellow jacket, honey bee, and hornet. The venom-sensitive patients also reported spending a greater amount of time outdoors (x 17.4 hours versus x 11.8, P < .05). An analysis of covariance showed that this difference in outdoor exposure was insufficient to account for the disparity in the number of stings. We conclude that other factors such as intrinsic attractants must be responsible for this phenomenon.     

Morphological analysis of the megakaryocytes in myelodysplastic syndrome

Morphological features of megakaryocytes were studied in 31 patients with myelodysplastic syndrome. Mean nuclear size (N), mean cytoplasmic size (C) and mean N/C ratio were 586 +/- 105 mu 2, 1,391 +/- 327 mu 2 and 0.42 +/- 0.04, respectively. Cell sizes were found to be reduced in 12 patients compared to control subjects. Atypical megakaryocytes were frequently found in patients with RAEB and micromegakaryocytes were also often found in patients with CMML. Mean platelet volume was 0.9 +/- 1.6 fl and the giant platelets were seen in one patient with CMML. In the patients with presence of more than 10% of atypical megakaryocytes, template Ivy bleeding time prolonged and epinephrine- and collagen-induced aggregation decreased. We believe that reduction of megakaryocytes' size and appearance of micromegakryocytes would be helpful in diagnosis of MDS.     

A new type of chondrodystrophic mutant in the mouse.

Stumpy is a new chondrodystrophic mutant in the mouse. The condition is inherited as a fully penetrant Mendelian recessive, and is not allelic with brachymorphic, achondroplasia, or stubby-three similar, previously described mutants. No chromosomal position has yet been assigned to the gene. Phenotypically, stumpy mice are chondrodystrophic dwarfs with all cartilage-formed bones in the skeleton affected. The condition differs from the usual chondrodystrophy described in mice in that proximal elements in the limbs are affected more than distal ones.     

Developmental analysis of GFAP immunoreactivity in the cerebellum of the meander tail mutant mouse

It is thought that Bergmann glial fibers assist in the inward migration of granule cells. Model systems in which there is a perturbation of either the migrating cells or the glial cell population have been useful in understanding the migratory process. In the meander tail mutant mouse, the anterior cerebellar region is agranular, whereas the posterior cerebellum is relatively unaffected by the mutation. This study presents a qualitative analysis of the development of cerebellar radial glia in mea/mea and +/mea mice aged from postnatal day 0 to adult, using an antibody against the glia specific antigen, glial fibrillary acidic protein. The results indicate a slight delay in the onset of immunoreactivity in the mea/mea cerebellum and abnormal glial formation in the anterior and posterior regions by postnatal day 5. At postnatal day 11, the full complement of labeled fibers appears to be present and although they appear abnormal in formation, they eventually reach the surface and terminate in oddly shaped and irregularly spaced endfeet. In adult mea/mea and +/mea mice, as compared to the early postnatal stages, there is a significant reduction in GFAP immunoreactive fibers. Cresyl violet stained adult mea/mea sections revealed the presence of ectopic granule cells in radial columns and small clumps at the surface of and within the molecular layer of the caudal cerebellum. Quantitative analyses revealed a 4- to 5-fold increase in the number of ectopic granule cells in lobule VIII of the mea/mea when compared with the +/mea cerebellum. These results suggest that the radial glia in the mea/mea cerebellum exhibit some uncharacteristic morphologies, but that these abnormalities are most likely the consequence of environmental alterations produced by the mutant gene.     

Peripheral neuropathy in the diabetic mutant mouse. An ultrastructural study.

Structural changes in peripheral nerves were studied sequentially in mutant diabetic mice. Axonal changes were found in both myelinated and unmyelinated fibers, the outstanding early change being the development of honeycombed Schwann cell-axon networks followed by axonal atrophy in both myelinated and unmyelinated fibers. In the late stages of the diabetic syndrome, this axonopathy was accompanied by secondary corrugated myelin breakdown. The changes, indicative of a primary axonal degeneration, are comparable to findings in human diabetic neuropathy for which this seems a suitable experimental model.     

Increased incidence of fungemia caused by Candida krusei.

Candida krusei colonized 12.4% of 868 patients undergoing episodes of therapy-induced granulocytopenia over a 9-year period. The gastrointestinal tract was most frequently colonized, followed by the respiratory tract and urinary tract. Ten patients developed systemic infections with C. krusei; all 10 had two or more positive blood cultures. Nine of the 10 patients were colonized with C. krusei, and 6 were receiving systemic antifungal agents at the time of development of the infection. Seven patients died within 1 month of C. krusei sepsis; systemic candidiasis was seen in the autopsies of the four patients on whom autopsies were performed. Therefore, C. krusei should be recognized as an emerging pathogen in select patient populations.     

Increased incidence of monoclonal B-cell infiltrate in chronic myeloproliferative disorders.

A total of 106 trephine biopsy specimens with clinical, laboratory and pathology findings corresponding to chronic myeloproliferative disorders (CMPD) were analyzed to reveal the nature of the lymphoid infiltrate in the bone marrow. Histological investigation in 31 chronic myeloid leukemia (CML), 29 CMPDs not otherwise specified (CMPD-NOS), 28 essential thrombocytosis (ET), 15 polycythemia vera (PV) and three chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES) exhibited in 32% various amounts of lymphocytic infiltrate of sparsely to moderately diffuse or nodular types in the bone marrow, but the reactive or coinciding lymphomatous nature could not be revealed by histology alone in the majority of cases. PCR analysis of the immunoglobulin heavy chain (IgH) gene rearrangement was successfully performed in 81 out of the 106 DNA specimens extracted from formol-paraffin blocks. Out of the 81 samples with good-quality DNA, 18 gave a single or double discrete amplification band(s), which was reproducible only in four specimens. Sequencing finally proved monoclonal B-cell population of both pre- and postfollicular origin in all four samples (5%), one CML and three CMPD-NOS. Detailed clinical and pathological investigations indicated overt B-cell malignant lymphoma with clonal relationship to the CMPD in two out of these four patients. We conclude that detailed molecular analysis of IgH gene rearrangement in bone marrow samples of CMPD patients is needed to identify the true monoclonal B-cell infiltration, which-even without overt malignant lymphoma-may occur in this group of disorders.Modern Pathology (2004) 17, 1521-1530, advance online publication, 16 July 2004; doi:10.1038/modpathol.3800225.     

Increased incidence of prostate cancer in Nigerians

An increased incidence of prostate cancer among African-American men (now the second most common cause of cancer death) has been attributed mainly to the introduction of screening techniques, which have enabled earlier diagnosis of patients. This study reviewed male cancer patients recorded in a Nigerian cancer registry to assess the current trends in prostate cancer in Nigeria. For comparison, data were broken into two groups: 1980-1988 and 1989-1996. Only the top 10 cancers occurring in both periods were considered initially in this report. For emphasis, an analysis of adult male cancers was done per decade since 1960. Results show that prostate cancer has become the number one cancer in Nigerian men and constitutes 11% of all male cancers. The median age of patients was 67.5 years (variance 5.6), and the mean age was 71.4 years (variance 14.3). These results indicate that despite the absence of screening programs in Nigeria, the number of prostate cancer cases has increased. The known risk factors probably contribute to a varying degree among Nigerians, who are generally of average build or in the low-normal range for body mass index. Moreover, the role of genetics cannot be underplayed. Given its biological characteristics, more cases of prostate cancer probably would be recorded among this population if screening were undertaken.     

Gait analysis in the mouse.

The gait of the adult Swiss (Mike Flack--MF1 subtype) mouse during spontaneous walk/trot locomotion at velocities ranging from 14-43 cm s(-1) has been analysed using simultaneous video and reaction force analysis. No differences were observed between males and females. Velocity adjustments within this range are accounted for to a greater extent (>70%) by stride time decreases and to a lesser degree (<30%) by stride length increases. Equivalent stride times for fore and hindlimbs were, in the former, composed of a shorter stance and a longer swing time. Peak vertical reaction force increases with decreasing stance time, with that for the forelimb being about 5% greater than that for the hindlimb across the whole stance time range studied. The areas under the vertical reaction force curves for fore and hindlimbs are, however, not significantly different. The results are discussed in the light of in vitro work cycle studies on the properties of some of the major hindlimb locomotor mouse muscles, and with previously established data in the rat. It is concluded that the mouse shows a consistent and quantifiable gait that would allow incorporation of locomotor assessment into the evaluation of a number of pathophysiological states.     

A possible human homologue for the mouse mutant disorganisation.

The mouse mutant disorganisation (Ds) is a semidominant gene with variable penetrance in heterozygotes and lethality in homozygotes; 67% of heterozygotes have multiple defects and the rest have single defects. Fifty-three percent have cranioschisis and execephaly, 40% have hamartomas represented by papillae of variable size and shape protruding from the body, sometimes containing cartilage, and 33% have limb abnormalities. A child is presented with defects similar to those seen in mice heterozygous for Ds. He had shortening of the upper and lower segments of the right leg with a popliteal web and nine toes on the same side. A finger-like structure arose from the abdomen and one kidney was absent. The homology between this infant and Ds mice is discussed and published reports of human cases with similar abnormalities are reviewed.     

A new transgenic mouse model for the study of cell cycle control in megakaryocytes

During the development of the megakaryocytic lineage, the megakaryoblasts give rise to megakaryocytes which undergo repeated S phases in the absence of cytokinesis (endomitosis). The cellular oncogene myc plays a central role in the proliferation and differentiation of several cell types. In a previous study, we generated transgenic mice carrying c-myc fused to the estrogen receptor under the control of the platelet factor four (PF4) megakaryocyte-specific promoter. The bone marrow of female transgenic mice, but not of male mice, displayed increased megakaryopoiesis. Here we report that beta-estradiol-induced activation of c-myc in cultured bone marrow cells derived from male or female transgenic mice resulted in prolonged survival of the cells in vitro. Addition of a cocktail of hemopoietic growth factors to beta-estradiol-treated cells, including interleukin 6 (IL-6), IL-3 and stem cell factor further improved the survival time in culture and increased the percentage of large mature cells, but did not result in immortalization. The majority of these PF4-expressing cells, however, did not reach the differentiation stage at which acetylcholinesterase is expressed and did not appear as large megakaryocytes. We conclude that cultured megakaryocytes overexpressing myc are induced to proliferate, but have a limited potential to fully differentiate. Under these conditions, cyclin D3 was downregulated while the level of cyclin A was slightly upregulated.     

Spontaneous tumors in long-term--vasectomized mice. Increased incidence and association with antisperm immunity

In two independent studies the authors have observed a significantly higher incidence of spontaneous tumors in vasectomized BDF1 mice over the long term than in age-matched sham-vasectomized control mice. In the first study, necropsies were performed on the animals at 30 months of age (27 months after surgery), and 15 of 24 vasectomized versus 2 of 14 sham-vasectomized mice (P less than or equal to 0.025) had detectable tumors in various tissues. In a second study, necropsies were performed on the animals at a younger age (18 months, 15 months after surgery), and liver tumors predominated: 82 of 171 vasectomized versus 33 of 97 controls (48% versus 34%, P less than or equal to 0.037) had at least one hepatic tumor, and a significantly higher percentage of vasectomized animals had large (greater than or equal to 31 sq mm) hepatic tumor burdens (80% versus 49%; P less than or equal to 0.002) and multiple hepatic tumors (19% versus 5%; P less than or equal to 0.002). In combined data from both studies, the vasectomy group had a higher incidence of (1) at least one tumor (P less than or equal to 0.025), (2) multiple tumors (P less than or equal to 0.005), and (3) more than one type of tumor (P less than or equal to 0.05. Furthermore, in both studies tumor number and size were significantly associated with antisperm immunity detected by antibody or aspermatogenesis evaluation. It is speculated that sperm degradation products and/or the autoimmune response to sperm that commonly accompanies vasectomy may affect tumor induction or growth directly or indirectly by interfering with immunosurveillance mechanisms.     

Heterotransplantation of human malignant melanomas to the mouse mutant nude.

In 32 experiments involving transplantation of human malignant melanomas to the mouse mutant nude, tumourtake was observed in 14 instances. The tumour tissue which took and grew after inoculation was derived from malignant melanoma metastases of the skin (10 takes from 13 transplantations), and from primary malignant melanomas of the eye (4 takes from 6 transplantations). Not one of 13 attempts to transplant primary tumours of the skin was successful. In 7 instances serial transfers of transplanted tumour were successful, the degree of success ranging from 3 to 41 passages. Some passages were wilfully interrupted but two are continuing. The transplanted tumours grow locally. Neither lymph node metastases nor organ metastases have been observed. Histological appearances of the transplanted tumours, also after serial passages, were identical with those of the original human donor material. The human tumour/nude mouse system is contrasted and compared with other heterotransplantation models.     

Developmental analysis of GFAP immunoreactivity in the cerebellum of the meander tail mutant mouse

It is thought that Bergmann glial fibers assist in the inward migration of granule cells. Model systems in which there is a perturbation of either the migrating cells or the glial cell population have been useful in understanding the migratory process. In the meander tail mutant mouse, the anterior cerebellar region is agranular, whereas the posterior cerebellum is relatively unaffected by the mutation. This study presents a qualitative analysis of the development of cerebellar radial glia in mea/mea and +/mea mice aged from postnatal day 0 to adult, using an antibody against the glia specific antigen, glial fibrillary acidic protein. The results indicate a slight delay in the onset of immunoreactivity in the mea/mea cerebellum and abnormal glial formation in the anterior and posterior regions by postnatal day 5. At postnatal day 11, the full complement of labeled fibers appears to be present and although they appear abnormal in formation, they eventually reach the surface and terminate in oddly shaped and irregularly spaced endfeet. In adult mea/mea and +/mea mice, as compared to the early postnatal stages, there is a significant reduction in GFAP immunoreactive fibers. Cresyl violet stained adult mea/mea sections revealed the presence of ectopic granule cells in radial columns and small clumps at the surface of and within the molecular layer of the caudal cerebellum. Quantitative analyses revealed a 4- to 5-fold increase in the number of ectopic granule cells in lobule VIII of the mea/mea when compared with the +/mea cerebellum. These results suggest that the radial glia in the mea/mea cerebellum exhibit some uncharacteristic morphologies, but that these abnormalities are most likely the consequence of environmental alterations produced by the mutant gene.     

Increased numbers of pulmonary megakaryocytes in patients with arterial pulmonary tumour embolism and with lung metastases seen at necropsy.

AIMS: To compare the number of pulmonary megakaryocytes in patients with local malignant disease without metastases with the numbers in patients with pulmonary tumour emboli without lung metastases and with those with pulmonary metastases. METHODS: The prevalence of pulmonary megakaryocytes was studied in 40 necropsies divided into four groups of 10 cases each: normal lungs (I); localised malignancies (II); pulmonary tumour embolism without lung metastases (III); pulmonary tumour embolism and lung metastases (IV). Five fragments (one of each pulmonary lobe) of tissue lung were collected, embedded in paraffin wax, sectioned, and stained by an immunohistochemical method to detect factor VIII related antigen. The number of megakaryocytes was evaluated in 500 high power fields/case. RESULTS: No differences were observed between groups I and II or between groups III and IV, but there was a 3.5-fold increase in the number of megakaryocytes in the groups with pulmonary tumour embolism or lung metastases compared with those with local neoplasms or normal lungs. CONCLUSIONS: An increased number of pulmonary megakaryocytes correlated with the presence of tumour cells in the microcirculation of the lungs or parenchymal metastases, but not with local malignancies without lung disease. The permanent siting of tumour emboli may stimulate megakaryocytes to migrate to the lungs, and may increase the release of platelets into the pulmonary circulation.     

Persistent truncus arteriosus in the Splotch mutant mouse

Summary The Splotch mutant mouse shows defects in neural crest-derived cell populations. The septation of the truneus arteriosus and the development of the aortic arch-derived blood vessels was studied in homozygotes of the Splotch mutant allele Sp^1H. It is shown that in homozygous mutant embryos, the septation of the truncus arteriosus does not proceed normally, resulting in persistent truncus arteriosus. The ostium of the persistent truncus arteriosus opens to the right ventricle. Frequently, variations of the aortic arch-derived blood vessels are observed. The development of the thymus, the parathyroid and the ultimobranchial bodies are also variably affected in mutants.These results provide indirect evidence, that cells contributing to the aortic arches and the septum of the truncus arteriosus in mice are derived from the neural crest. The Splotch mutant mouse is proposed to be an animal model for persistent truncus arteriosus. The implications of the vascular malformations for the midgestational death of this mutant are discussed.     

Locomotor deficits in the mutant mouse,Lurcher

Summary The effect of total Purkinje cell degeneration on treadmill locomotion was studied in the cerebellar mutant mouse Lurcher. Other movements such as swimming and scratchting were also studied in order to evaluate the cerebellar control of rhythmic actions. Cinematographic and electromyographic recordings were taken from normal and Lurcher mice that were subsequently perfused to obtain a Purkinje cell count. Walking deteriorated progressively and was clearly abnormal in 30 day old Lurchers with 90% Purkinje cell degeneration. In adult Lurcher mice in which Purkinje cells were totally absent, walking was characterized by short steps with exaggerated hindlimb flexion in the swing phase. Also, both the interlimb step ratio, defined as the step length of the reference limb divided by the step length of the opposite limb, and the interlimb coupling, defined as the temporal relation of one footfall with respect to the footfall of another limb, varied more than in normal mice. Furthermore, the locomotion of Lurcher mice displayed increased vertical displacement of the hip and an inability to produce continuous step cycles without stumbling. Both the EMG onset relative to foot contact and the EMG burst duration were highly variable, and a greater overlap in the activities of antagonist muscles at the transition from ankle extension to flexion was evident. Although both walking and swimming involve cyclical limb movements, the disorganization of the cycle and the irregular EMG pattern seen in the Lurcher during walking were not observed during swimming. Furthermore, scratching was well executed in the Lurcher mice. However, a consistently higher tonic extensor activity at the ankle appeared during walking, swimming and scratching. These results suggest that, in contrast to swimming and scratching, the requirements of walking depend to a greater degree on a functional cerebellar cortex for successful performance.