Hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation in mice lacking insulin receptor substrate-1

Insulin resistance is often associated with atherosclerotic diseases in subjects with obesity and impaired glucose tolerance. This study examined the effects of insulin resistance on coronary risk factors in IRS-1 deficient mice, a nonobese animal model of insulin resistance. Blood pressure and plasma triglyceride levels were significantly higher in IRS-1 deficient mice than in normal mice. Impaired endothelium-dependent vascular relaxation was also observed in IRS-1 deficient mice. Furthermore, lipoprotein lipase activity was lower than in normal mice, suggesting impaired lipolysis to be involved in the increase in plasma triglyceride levels under insulin-resistant conditions. Thus, insulin resistance plays an important role in the clustering of coronary risk factors which may accelerate the progression of atherosclerosis in subjects with insulin resistance.     

Polymerase chain reaction-single-strand conformation polymorphism analysis for the VHL gene in chemically induced kidney tumors of rats using intron-derived primers

In patients with insulin-dependent diabetes mellitus (IDDM), albuminuria reflects widespread vascular dysfunction. Albuminuria has been associated to defects of heparan sulfate proteoglycan (HSPG) within the extracellular matrix. Our hypothesis is that loss of HSPG in vascular walls reduces the HSPG-bound lipoprotein-lipase activity (LPLA), thereby causing elevated levels of plasma triglyceride (TG) seen in IDDM patients with albuminuria. The aim of the present study was to evaluate whether LPLA in muscle capillaries could be related to TG in IDDM patients with and without albuminuria. This is a cross-sectional study including ten healthy control subjects (group C), nine patients with IDDM and urinary albumin excretion rate (AER) of 30 mg/24 h or less (group D0) and 20 patients with IDDM and AER greater than 30 mg/24 h (group DA). Muscle LPLA, plasma TG, total cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and very-low-density lipoprotein cholesterol (VLDL) were measured. Between groups no difference in total cholesterol, TG, VLDL, and LDL was found. In patients with albuminuria, LPLA was reduced compared to controls, however, the difference between the groups was not statistically significant [median (range)] 35.9 mU/g (20.4-103) versus 44.6 mU/g (28.2-57.2) and 40.9 mU/g (21.7-53.5) in group DA, C, and D0, respectively, p = 0.76. AER was not correlated to LPLA. An overall negative correlation between TG and LPLA was found; r = -0.33, p = 0.04, supported by an overall significant positive correlation between LPLA and HDL; r = 0.32, p = 0.045. We conclude that, in insulin-dependent diabetes mellitus, skeletal muscle lipoprotein-lipase activity is associated with plasma triglyceride, while an association between lipoprotein-lipase activity and urinary albumin excretion is questionable.     

Hepatic inactivation of renin in the treatment of hyperreninemic hypertension

The concept of the hepatic inactivation of renin secreted by the juxtaglomerular apparatuses of the ischemic kidney was used for reversal of hypertension in dogs. In three dogs, the left renal artery was constricted, and a significant and well established hyperreninemic hypertension was recorded. The performance of an end-to-end splenorenal shunt following renal artery constriction reversed the hyperreninemia and hypertension. Shunting of the renal venous drainage into the portal system prior to constriction of the main renal artery prevented, as demonstrated by the limited data available, the development of hyperreninemic hypertension.     

Developmental quantitative genetics, conditional epigenetic variability and growth in mice

Ontogenetic variation in the causal components of phenotypic variability and covariability is described for body weight and tail length in mice derived from a full 7 x 7 diallel cross. Age-related changes in additive, dominance, sex-linked and maternal variance and covariance between 14 and 70 days of age are described. Age-specific variance components at time t are conditioned on the causal genetic effects at time (t - 1). This procedure demonstrates the generation of significant episodes of new genetic variation arising at specific intervals during ontogeny. These episodes of new genetic variation are placed in the context of epigenetic models in developmental quantitative genetics. These results are also concordant on recent findings on age-specific gene expression in mouse growth as shown by QTL analyses.     

Reactivity of antibody YU-311 in formalin-fixed, paraffin-embedded specimens of normal organs, non-hematopoietic tumors, and mast cell tumors

YU-311 is a monoclonal antibody that reacts with a human leukemia cell line resistant for cytosine arabinoside and that identifies a 92 kDa membrane protein. The reactivity of YU-311 in normal organs, various non-hematopoietic tumors and in mast cell tumors in formalin-fixed, paraffin-embedded specimens was examined using immunohistochemical methods. In normal organs, YU-311 reacted with fundic glands of the stomach, the intercalated duct of the pancreas, the distal portion and the loop of Henle of renal tubules and tissue mast cells. Benign neoplasms of various organs showed no immunoreaction with YU-311, except for mast cell tumors. Some types of malignant neoplasms were occasionally positive against YU-311, suggesting neoplasms arising from or differentiating along normal YU-311-positive counterparts. Some other types of malignancies were rarely positive for YU-311, although their normal counterparts showed no immunoreactivity with YU-311. None of the non-epithelial tumors reacted with YU-311, except for one case of malignant melanoma. In contrast, normal tissue mast cells and their related tumors, such as urticaria pigmentosa or solitary mastocytoma, were constantly positive for YU-311. None of the non-hematopoietic human tumor cell lines examined in the present study was reactive with YU-311. These findings indicate that YU-311 is a good marker of some types of tumors and mast cell tumors and that an aberrant expression of YU-311 rarely occurs.     

Polyamines and regulation of spermatogenesis: selective stimulation of late spermatogonia in transgenic mice overexpressing the human ornithine decarboxylase gene

Polyamines are believed to participate in the induction of cell growth, differentiation, and proliferation, but their role in spermatogenesis has remained obscure. Two transgenic mouse lines (K2 and K15) that overexpress the human ornithine decarboxylase (ODC) gene coding for a rate-controlling enzyme in polyamine biosynthesis and, hence, contain high levels of tissue putrescine have been used to study the stage-specific role of ODC in spermatogenesis. In K2 mice with 30-fold testicular ODC overexpression, [3H]thymidine incorporation at stages I-VI of the cycle of the seminiferous epithelium was significantly above the control level. This may reflect a specific stimulation of DNA synthesis in type A4, intermediate, and type B spermatogonia. The K15 mice that have about 70-fold ODC overexpression showed an elevation of DNA synthesis only at stage V of the cycle, suggesting a specific dependence of type B spermatogonia on putrescine. In K15 mice, [3H]thymidine incorporation of stage VIII tubule segments was decreased, suggesting that excess amounts of putrescine selectively inhibit meiotic DNA synthesis. We propose that putrescine has strictly selective local stimulatory and inhibitory actions during spermatogenic DNA synthesis, and that its excess amounts ultimately may lead to decreased fertility.     

Spermiogenesis is impaired in mice bearing a targeted mutation in the protein phosphatase 1cgamma gene

Type 1 protein phosphatases (PP1) are involved in diverse cellular activities, ranging from glycogen metabolism to chromatin structure modification, mitosis, and meiosis. The holoenzymes are composed of two or more subunits, including a catalytic subunit (PP1c) and one or more regulatory subunits. Many eukaryotes possess several catalytic subunit genes which encode highly conserved isoforms. In rodents, one of these isoforms, PP1cgamma2, appears to be expressed predominantly in testes. Whether PP1cgamma2 performs a testis-specific function is unclear. To address this and other questions, the PP1cgamma gene was disrupted by targeted insertion in murine embryonic stem cells. Mice derived from these cells were viable, and homozygous females were fertile. However, males homozygous for the targeted insertion were infertile. Histological examination revealed severe impairment of spermiogenesis beginning at the round spermatid stage. In addition, defects in meiosis were inferred from the presence of polyploid spermatids. Immunohistochemistry revealed the presence of PP1calpha protein on condensing spermatids in both wild-type and mutant testes, suggesting that this closely related isoform is unable to compensate for the loss of PP1cgamma. These defects are discussed in the light of known functions of protein phosphatase 1.     

Carcinoid tumors, vascular elastosis, and ischemic disease of the small intestine

Ischemic enteritis or infarction occurred in four of 15 patients who had carcinoid tumors of the small intestine. All four, in addition, had elastic vascular sclerosis of the mesenteric vessels. Both arteries and veins were involved, and the change occurred in the region of tumor deposit. In none of the cases was the tumor occluding the lumen of the vessels, nor was there any evidence of thrombosis. Similar elastosis is seen in cancers of the colon, stomach, and breast, and occurs also with thermal injury and irradiation. The findings of the present study would suggest a direct rather than a humoral effect. It would appear that cancer cells exert an inductive effect on the fibroblast or smooth-muscle cell in vascular walls, with excess production of elastic tissue.     

Embolization of traumatic vascular injuries, arteriovenous malformations and tumors

The article contains a brief survey of the current status of transcatheter embolization of traumatic and iatrogenic vascular lesions, arterio-venous malformations and tumours. Guidelines are suggested for embolization of different lesions is given, with emphasis on indications and contraindications for performing such procedures. Complications following embolization are described. Our own experience of embolization is briefly mentioned. Personally, we have most experience in embolization of liver metastases from neuroendocrine tumours, and some experience of treatment of traumatic vascular lesions and arterio-venous malformations.     

Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-beta1 transgenic mice

Transgenic mice overexpressing a constitutively active human TGF-beta1 under control of the rat phosphoenolpyruvate carboxykinase regulatory sequences developed fibrosis of the liver, kidney, and adipose tissue, and exhibited a severe reduction in body fat. Expression of the transgene in hepatocytes resulted in increased collagen deposition, altered lobular organization, increased hepatocyte turnover, and in extreme cases, hemorrhage and thrombosis. Renal expression of the transgene was localized to the proximal tubule epithelium, and was associated with tubulointerstitial fibrosis, characterized by excessive collagen deposition and increased fibronectin and plasminogen activator inhibitor-1 immunoreactivity. Pronounced glomerulosclerosis was evident, and hydronephrosis developed with low penetrance. Expression of TGF-beta1 in white and brown adipose tissue resulted in a lipodystrophy-like syndrome. All white fat depots and brown fat pads were severely reduced in size, and exhibited prominent fibroplasia. This reduction in WAT was due to impaired adipose accretion. Introduction of the transgene into the ob/ob background suppressed the obesity characteristic of this mutation; however, transgenic mutant mice developed severe hepato- and splenomegaly. These studies strengthen the link between TGF-beta1 expression and fibrotic disease, and demonstrate the potency of TGF-beta1 in modulating mesenchymal cell differentiation in vivo.     

Complete deficiency of glycophorin A in red blood cells from mice with targeted inactivation of the band 3 (AE1) gene

Glycophorin A is the major transmembrane sialoglycoprotein of red blood cells. It has been shown to contribute to the expression of the MN and Wright blood group antigens, to act as a receptor for the malaria parasite Plasmodium falciparum and Sendai virus, and along with the anion transporter, band 3, may contribute to the mechanical properties of the red blood cell membrane. Several lines of evidence suggest a close interaction between glycophorin A and band 3 during their biosynthesis. Recently, we have generated mice where the band 3 expression was completely eliminated by selective inactivation of the AE1 anion exchanger gene, thus allowing us to study the effect of band 3 on the expression of red blood cell membrane proteins. In this report, we show that the band 3 -/- red blood cells contain protein 4.1, adducin, dematin, p55, and glycophorin C. In contrast, the band 3 -/- red blood cells are completely devoid of glycophorin A (GPA), as assessed by Western blot and immunocytochemistry techniques, whereas the polymerase chain reaction (PCR) confirmed the presence of GPA mRNA. Pulse-label and pulse-chase experiments show that GPA is not incorporated in the membrane and is rapidly degraded in the cytoplasm. Based on these findings and other published evidence, we propose that band 3 plays a chaperone-like role, which is necessary for the recruitment of GPA to the red blood cell plasma membrane.     

Hepatic function after acute of subchronic nicotine administration in untreated mice and mice treated with hepatotoxic chemicals

Male mice treated with nicotine hydrochloride either acutely (5 mg/kg i.p.) or subchronically (5 mg/kg i.p. daily for 3 weeks; 25 mg/liter in drinking water for 2-3 months) showed no evidence of hepatic dysfunction, as measured by serum glutamic-pyruvic transaminase or serum alkaline phosphatase activities. Neither acute nor subchronic administration modified the hepatotoxic response to a potent hepatotoxin (carbon tetrachloride), nor that of less potent hepatotoxins chloroform or 1, 1, 1-trichloroethane, nor was the cholestatic effect of alpha-naphthylisothiocyanate modified.     

Radiologic evaluation of the jugular foramen. Anatomy, vascular variants, anomalies, and tumors

The jugular foramen varies considerably in size and shape, along with the jugular vein. The foramen is traversed by several vessels and nerves. CT, in various section planes, demonstrates the bone anatomy optimally, whereas MR (including MR angiography) reveals the vascular and soft tissue structures to best advantage. A diverse group of vascular anomalies originate in the foramen and adjacent carotid canal that must be differentiated from tumors. The most common tumor within the jugular foramen is the hypervascular glomus jugulare tumor followed by neurogenic tumors, predominantly the schwannoma. Less common lesions comprise meningioma, hemangiopericytoma, chondrosarcoma, and plasmacytoma. Metastases and malignant tumors arising in adjacent anatomic structures (nasopharynx, parotid, and temporal bone), in advanced stages, may spread to the jugular foramen. Endolymphatic sac tumors arise at the posterior medial aspect of the petrous bone and frequently extend to the jugular foramen. Irregular lytic bone destruction, with enlargement and hypervascularity, demonstrated by CT and MR imaging, are characteristic for glomus jugulare tumors. Benign tumors, most commonly the jugular foramen schwannoma, display an enlarged jugular foramen with well-defined bone margins.