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Biomedical subjects

I Shimokawa

Publications and source records attributed to I Shimokawa.

At least 37 records · Page 2Linked to original sources
PubMed1998

Acinar cell carcinoma of the pancreas associated with hypoglycemia: involvement of "big" insulin-like growth factor-II.

Apart from insulinomas, pancreatic tumors are rarely complicated by hypoglycemia and some may produce insulin-like growth factor II (IGF-II). To our knowledge, IGF-II-producing pancreatic tumors associated with hypoglycemia have not been reported previously. We describe what we believe to be the first case of "big" IGF-II-producing pancreatic acinar cell carcinoma. A 68-year-old man presented with a history of recurrent hypoglycemia. Abdominal computed tomography scan and magnetic resonance imaging showed a mass, approximately 5 cm in diameter, in the tail of the pancreas and two low-density areas in the liver. Low serum glucose was associated with low insulin levels and high levels of hormones (i.e., glucagon and IGF-II) that are functionally opposite to insulin. Although serum IGF-II level was within the normal range, most IGF-II was of the high molecular weight form, as determined by Western immunoblot analysis. Based on these findings, a diagnosis of hypoglycemia induced by IGF-II-producing pancreatic tumor was made. Surgery was not possible because of the patient's poor general condition. The patient ultimately died as a result of malignant cachexia. At autopsy, a yellowish-white tumor was found in the tail of the pancreas, and a histopathologic diagnosis of acinar cell carcinoma was made. Immunohistologically, the tumor cells contained IGF-II in an irregular staining pattern, suggesting that the hypoglycemia was caused by a pancreatic tumor producing "big" IGF-II.

Aged↗
PubMed1998

Advanced glycosylation end products in adrenal lipofuscin.

The present study examined the presence of advanced glycosylation end products (AGEs) in lipofuscin present in the brain and adrenal gland of aging rats by immunohistochemistry using antibodies raised against AGEs. Lipofuscin identified as yellow to brown granules emitting bright yellow to orange autofluorescence with ultraviolet light were detected in cortical neurons, cerebellar Purkinje cells, and adrenal cells in the inner part of the zona reticularis. However, none of the antibodies visualized lipofuscin in these areas. The outer part of the zona reticularis contained yellow granules emitting a faint orange autofluorescence. These granules were immunostained by an antibody that reacted with AGEs structures unrelated to the carboxymethyllysine moiety. Newly formed adrenal cortical cells are thought to migrate from the outer layer to the inner layer of the zona reticularis. Therefore, our results suggest that glycosylation-related processes are involved in lipofuscinogenesis, at least in its early stage, in the adrenal zona reticularis.

Adrenal Cortex↗
PubMed1997

Effect of aging and dietary restriction on hepatocyte proliferation and death in male F344 rats.

The proliferation and death of hepatocytes in rats fed ad libitum and rats on dietary restriction were evaluated in 3 to 24-month-old rats by employing immunocytochemistry for proliferating cell nuclear antigen (PCNA) and terminal dUTP nick end labeling (TUNEL). These techniques were also used to examine hepatic tissue infiltrated with leukemic cells in 24-month-old rats fed ad libitum. PCNA-strongly positive hepatocytes, PCNA-positive hepatocytes, and TUNEL-positive hepatocytes were reported previously to be equivalent to hepatocytes in the S phase, hepatocytes in the cell cycle, and dying hepatocytes, respectively. The proportion of PCNA-strongly positive hepatocytes and PCNA-positive hepatocytes declined with age. Dietary restriction diminished PCNA-strongly positive hepatocytes significantly but not PCNA-positive hepatocytes in young rats, but the proportion of PCNA-strongly positive hepatocytes was significantly higher following dietary restriction than that in rats fed ad libitum in advanced age. Growth stimulation by leukemic cell infiltration resulted in a recovery of the age-related decline of PCNA-strongly positive hepatocytes. Aging was associated with a progressive increase in the proportion of TUNEL-positive hepatocytes, with a smaller effect following dietary restriction than in rats fed ad libitum after 6 months of age. Our results indicate that age and dietary restriction induce proliferative inhibition. The inhibition depends on PCNA expression; this suggests that suppression of cell proliferation and cell death are enhanced in hepatocytes of senile rats.

Aging↗
PubMed1997

VEGF and bFGF mRNA are expressed in ethylnitrosourea-induced experimental rat gliomas.

1. Which angiogenic growth factors actually mediate tumor growth in ethylnitrosourea (ENU)-induced gliomas in rats was examined. 2. In situ hybridization histochemistry with digoxigenin-labeled oligonucleotide probes was used to investigate the cellular expression and distribution of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) mRNAs in ENU-induced gliomas. 3. Both VEGF and bFGF mRNAs were not detected in normal gial cells but in ENU-induced glioma cells. 4. Our results suggest that the growth of ENU-induced glioma may be regulated by multiple angiogenic growth factors and that these gliomas may proliferate by synthesizing such growth factors.

Animals↗
PubMed1997

In vivo retrovirus-mediated herpes simplex virus thymidine kinase gene therapy approach for adult T cell leukemia in a rat model.

We have previously demonstrated that human T-lymphotropic virus type I (HTLV-I) tax-expressing human T cell lines are selectively eliminated in the presence of aciclovir, using a retroviral vector carrying the herpes simplex virus thymidine kinase (HSV TK) gene under the control of the long terminal repeat (LTR) of HTLV-I. Based on these findings in vitro, we investigated whether this system could also be effective in vivo, using a rat model. Following infection of the HTLV-I-transformed and tax-expressing rat T cell line TARS-1 with this retrovirus (LNLTK virus), high levels of HSV TK expression were observed and resulted in increased susceptibility to ganciclovir (GCV). Tumors were generated by subcutaneous injection of TARS-1 in newborn syngeneic WKA/H rats. While the tumors derived from infected TARS-1 cells with control virus, as well as uninfected cells, continued to grow in all the rats with or without administration of GCV, those derived from LNLTK-infected cells exhibited dramatic regression upon GCV treatment. These results indicate that the HTLV-I LTR-HSV TK system also causes selective elimination of HTLV-I-transformed, tax-expressing T cells in vivo. Therefore, our present study may provide a rationale for clinical gene therapy against adult T cell leukemia.

Animals↗
PubMed1997

Effect of somatostatin-28 on growth hormone response to growth hormone-releasing hormone--impact of aging and lifelong dietary restriction.

The present study was designed to investigate the modulating effect of aging and lifelong dietary restriction (DR), a powerful anti-aging intervention in laboratory rodents, on growth hormone (GH) secretion from pituitary cells in response to GH-releasing hormone (GHRH) in the presence of somatostatin (SS)-28. Dispersed pituitary cells from 6- and 24-month-old rats fed ad libitum (AL-Y, AL-O, respectively) and 24-month-old rats dietary restricted from 6 weeks of age (DR-O) were subjected to a reverse hemolytic plaque assay under variable conditions including GHRH (0, 1, 10 nM) and SS-28 (0, 10 nM). The proportion of GH plaque-forming cells in dispersed pituitary cells increased by GHRH and decreased by SS-28. The proportion of these cells was lowest in AL-O rats; it was lower in DR-O than in AL-Y rats, particularly in the presence of SS-28. The reduction in these cells by SS-28 was greatest in Group AL-O. The mean area of these plaques, reflecting the amount of GH released from individual cells, was not different among the three rat groups in the absence of SS-28. In contrast, SS-28 produced a significantly higher reduction in the plaque area in Group AL-O compared with AL-Y and DR-O rats. Our results indicated that: (1) aging did not alter the responsiveness of GH-secreting cells to GHRH for GH secretion, while increased sensitivity of GH-secreting cells to SS-28 was noted in aged rats; (2) lifelong dietary restriction did not modulate the responsiveness to GHRH but partially inhibited the age-related increase in the sensitivity to SS-28 of GH-secreting cells, and (3) the major impact of the dietary regimen may include modulation of the number of pituitary cells, which leads to a high proportion of GH-secreting cells compared with that in AL rats at the same chronological age.

Aging↗
PubMed1997

Aging accelerates but life-long dietary restriction suppresses apoptosis-related Fas expression on hepatocytes.

Aging enhances apoptosis of hepatocytes under normal physiological conditions and increases the susceptibility of hepatocytes to apoptosis whereas life-long dietary restriction suppresses the age-enhanced susceptibility to apoptosis. We examined the subcellular mechanisms of the age-associated changes and effect of dietary restriction using quantitative reverse transcription polymerase chain reaction and immunohistochemistry for Fas in the livers of 6- and 24-month-old male Fischer 344 rats fed ad libitum or 70% diet restricted. We also analyzed the level of ordinary and variant forms of Fas mRNA. The ordinary form of Fas mRNA, but not the variant form of Fas mRNA, significantly increased with age. Dietary restriction significantly suppressed the ordinary form of Fas mRNA in advanced age. Aging enhanced Fas immunoreactivity in the hyperplastic bile epithelium and hepatocytes whereas dietary restriction suppressed it. Our findings indicate that Fas protein, particularly the ordinary form of Fas, is involved in age-associated apoptosis of hepatocytes. Fas overexpression in advanced age may explain the age-enhanced susceptibility to apoptosis. Our results also suggest that dietary restriction suppresses Fas overexpression, resulting in a reduction of the age-enhanced susceptibility to apoptosis.

Aging↗
PubMed1996

Susceptibility of hepatocytes to cell death induced by single administration of cycloheximide in young and old F344 rats. Effect of dietary restriction.

We evaluated the effect of a single dose of 1.0 mg/100 g body weight of cycloheximide (CHX) on the susceptibility of hepatocytes to cell death in young (6 months old) and old (24 months old) F344 rats fed ad libitum (AL) or on dietary restriction (DR), using terminal dUTP nick end labeling (TUNEL). The proportion of TUNEL-positive hepatocytes (TPH) at baseline (without administration of CHX) was significantly higher in advanced age. However, dietary intake did not influence the proportion of TPH at baseline irrespective of age Hepatocytes cell death, detected by TUNEL, was induced in the animal by a single intravenous injection of CHX. The proportion of TPH increased with time and reached a plateau 2.5 h after the administration of CHX in young AL and DR rats and old DR rats, but continued to significantly increase 4 hours after the administration of CHX in old AL rats. Our results indicate that the death of hepatocytes at baseline and susceptibility to cell death was enhanced by CHX in hepatocytes of senile rats. Our results also suggest that dietary restriction does not suppress the enhancement of cell death at baseline, but prevents age-associated increase in the susceptibility to cell death.

Aging↗
PubMed1996

Influence of dietary components on occurrence of and mortality due to neoplasms in male F344 rats.

The influence of dietary components on the occurrence of, and mortality from spontaneous neoplasms in male F344 rats was investigated. The dietary regimens studied included restriction of specific dietary components (energy, fat, protein and mineral), as well as different sources of dietary protein (casein, soy protein and lactalbumin). A statistical approach based on contributing causes of death was used to obtain the mortality due to all neoplasms, and the relative onset rate of frequently observed neoplasms, e.g., leukemia, pituitary adenoma, testicular interstitial cell tumor, etc. Only the regimen involving energy restriction reduced the mortality due to all neoplasms. Neither reduction of individual components without energy restriction, nor replacement of casein with soy protein or lactalbumin as the protein source affected mortality. Analyses of the relative onset rate of selected neoplasms also indicated that only a reduction of energy intake suppressed the occurrence of most of these neoplasms. Other dietary regimens, at most, suppressed a few types of neoplasm. It is concluded that a reduction in energy intake is a key dietary factor for the prevention of neoplastic diseases in rats.

Age Factors↗
PubMed1996

Effects of lifelong dietary restriction on somatotropes: immunohistochemical and functional aspects.

We investigated the effects of lifelong dietary restriction (DR) on growth hormone (GH)-immunoreactivity and secretory function of somatotropes using a computerized image analysis in tissue sections and a reverse hemolytic plaque assay (RHPA) in dispersed pituitary cells of male F344 rats. DR did not prevent an aging-related reduction in GH immunoreactivity in somatotropes. However, it did augment the mean optical density of GH-immunoreactive area in somatotropes, although it did not alter the immunoreactive area in somatotropes, suggestive of a greater amount of immunoreactive GH in somatotropes of DR rats. DR also increased the percentage of aggregated GH-immunoreactive area in the anterior lobe, indicating a higher cell density of immunoreactive somatotropes. RHPA also confirmed the presence of larger proportions of GH-secreting cells in dispersed cells of DR rats in response to GH-releasing hormone (GHRH) at 24 months, although no change by DR was observed in the estimated amount of GH secreted from individual cells. Our results suggest that lifelong dietary restriction may influence the cytoplasmic GH-content at the steady state, while not modulating the responsiveness of individual somatotropes to GHRH for GH release, and that the major action of DR on somatotropes is an increment in the cell number.

Aging↗
PubMed1996

Spontaneous rupture of non-aneurysmal ascending aorta.

Two autopsy cases with pericardial tamponade and spontaneous rupture of non-aneurysmal ascending aorta are described. In case 1, no apparent predisposing factor was clinically noticed in a 74 year old male patient, but postmortem examination revealed laceration of the ascending aorta associated with aortic valvular deformity and slight dilatation of the ascending aorta. In case 2, a 61 year old man, a mild to moderate grade of aortic regurgitation was noticed clinically 5 months before death. Postmortem examination revealed a slight dilatation of the aortic annulus and post-valvular portion of the ascending aorta. These two cases emphasize the clinical significance of aortic valvular disease with subsequent disordered blood flow, even when asymptomatic, as a potential causative factor for spontaneous rupture of the ascending aorta.

Aged↗
PubMed1995

A long surviving case of amyotrophic lateral sclerosis with atrophy of the frontal lobe: a comparison with the Mitsuyama type.

A female patient with amyotrophic lateral sclerosis (ALS) showing psychiatric symptoms during her last 2 years of life is reported. Although pseudobulbar signs were seen at the onset of ALS and no respirator was used, the period from onset to death was rather long (9 years). The spinal lesions showed features common to ordinary ALS, while the marked atrophy with destructive changes throughout the frontal lobe seemed to be considerably more severe than that seen with either ordinary ALS or the Mitsuyama type of ALS. Since the clinical manifestations and histological characteristics are apparently different from those of the Mitsuyama type, our case may be a new nosological variant of ALS with psychiatric manifestations.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Ret-oncogene expression correlates with neuronal differentiation of neuroblastic tumors.

An antibody to the ret proto-oncogene product (RET) was raised and applied to formalin-fixed, paraffin-embedded neuroblastic tumors (NBTs) to investigate its usefulness in diagnosis and evaluation of cell differentiation. In normal neural crest-derived tissues, most ganglion cells were moderately stained while large ganglion cells were weakly stained. In NBTs, the intensity of the staining in moderately differentiated neuroblasts and small ganglion cells was more prominent than in undifferentiated neuroblasts, while the cytoplasm of large ganglionic cells was weakly stained as in normal ganglion cells. The RET immunoreactivity was compared with that of nine neural and neuroendocrine markers. The results revealed a parallelism with the protein gene product 9.5 (PGP9.5), neuron specific enolase (NSE) and NF-150 kD (NF = M). These findings indicated that the RET immunoreactivity was correlated with ganglionic differentiation and maturation. Thus, RET was considered to be a new marker that would be implemented in diagnosis and estimation of neuronal differentiation of NBTs.

Adrenal Gland Neoplasms↗
PubMed1995

Temporal pattern of food intake not a factor in the retardation of aging processes by dietary restriction.

Long-term dietary restriction programs which retard aging processes in rodents usually involve meal eating rather than the nibbling pattern of food intake of ad libitum fed rodents. Thus, the possibility arises that the antiaging action may at least in part result from an altered temporal pattern of food intake. This possibility was investigated using male F344 rats maintained on the following dietary regimens: Group A rats fed ad libitum; Group B rats fed 60% the ad libitum intake in a single meal at 1500 h; Group B-2 rats fed 60% of the ad libitum intake in two meals (0700 h and 1500 h). The diurnal pattern of plasma corticosterone concentration differed among the groups as did that of the plasma glucose concentration. The median length of life and age of tenth percentile survivors were similar for Group B and B-2 rats and much greater than those for Group A rats. Both modes of dietary restriction influenced age-associated disease processes in a similar fashion. Thus, although the temporal pattern of food intake influenced circadian rhythms of food-restricted rats, it did not significantly affect the antiaging action.

Aging↗
PubMed1995

Anti-tumor action of dietary restriction is lesion-dependent in male Fischer 344 rats.

The effects of dietary restriction (DR) on spontaneous oncogenesis in male Fischer 344 rats were analyzed. Previously reported analyses of studies carried out in our laboratory demonstrated that DR reduces the incidence and delays the onset, but not the progression, of leukemia in male F344 rats. In this report, the influence of DR on pituitary tumors, adrenal pheochromocytoma, pancreatic islet cell tumors, and interstitial cell tumors of the testis was analyzed. DR reduced the relative incidence (relative onset rates) and delayed the onset of the four tumors. DR also retarded the progression (duration from onset to death) of pituitary tumors and pheochromocytoma. DR has delayed the onset of all tumors of the male F344 rat so far analyzed, but its effect on tumor progression appears to be lesion-dependent.

Adenoma, Islet Cell↗
PubMed1995

Minigemistocytic astrocytoma with frequent apoptoses: analysis of tumor growth.

A rare glial tumor known as 'minigemistocytic astrocytoma (gliofibrillary oligodendroglioma)' is reported in a 73 year old Japanese male. A low-density area found by computed tomography and thought to be an operative scare remaining after hematoma in the right frontal lobe of the cerebrum had been followed for 10 years. This area, however, had been accompanied by a cyst for 2 years and had developed gradually for 1 year prior to dissection. The tumor was poorly demarcated from the surrounding normal tissue macroscopically at operation. Microscopically, the tumor consisted of small gemistocytic cells in uniform sheets intersected by a small vascular stroma with frequent eosinophilic granular bodies, mitoses and apoptotic bodies. Immunohistochemical examination for glial fibrillary acidic protein (GFAP) revealed remarkable positive reactivity in the perinuclear cytoplasm, but no immunoreactivity for vimentin or Leu 7 was found. Electron microscopically, rich filaments arranged in parallel bundles were found in the neoplastic cells. These histological findings are closely consistent with those of previously reported minigemistocytic astrocytoma cases. The GFAP-rich minigemistocytic astrocytoma with granular bodies and frequent mitoses in the present case is considered to indicate a higher degree of astrocytic differentiation and malignant potential than previous cases. The frequent apoptoses, however, might inhibit tumor growth in this case.

Aged↗