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K Rajkumar

Publications and source records attributed to K Rajkumar.

At least 19 recordsLinked to original sources
PubMed2005

Histopathological changes in the human larynx following expanded polytetrafluroethylene (Gore-Tex(R)) implantation.

BACKGROUND: Expanded polytetrafluroethelyne (e PTFE, Gore-Tex(R)) has been advocated as an implant material for medialization of the vocal fold. Animal studies involving rabbits and a porcine model have demonstrated host tolerance of the implant. There have been no reports describing the histological changes in a human laryngectomy specimen with a Gore-Tex implant. CASE PRESENTATION: The histological findings in a laryngectomy specimen of a patient previously implanted with e PTFE for medialization of a paralyzed vocal fold following excision of a vagal neurofibroma were studied.Histopathology revealed a mild foreign-body giant cell granulomatous reaction with some associated fibrosis. The granulomatous response was limited to the periphery of the Gore-Tex and although it closely followed the profile of the material it did not encroach into or significantly break up the material. There was no significant neutrophilic or lymphocytic inflammation. CONCLUSIONS: Our findings are consistent with the animal models confirming that Gore-Tex implantation does not result in a significant granulomatous reaction in the human larynx over a 13-month period. Moreover, there is no evidence of resorption or infection. Further, the lack of lymphocytes in association with the granulomas indicates that there is no significant immunological hypersensitivity. Histologically, the slight permeation by connective tissue is similar to that seen in Gore-Tex vascular and cardiac implants. The degree of the slight giant cell response appears to be dependent on the profile of the material; a sharp edge incited more of a response than a flat surface.

Journal Article↗
PubMed1999

Enhanced gluconeogenesis and hepatic insulin resistance in insulin-like growth factor binding protein-1 transgenic mice.

Fasting hyperglycemia is observed in transgenic mice which overexpress insulin-like growth factor binding protein-1. In an attempt to understand the mechanisms underlying this observation we have examined glycogenolysis and gluconeogenesis in isolated hepatocytes from wild-type and transgenic mice. Glucose production from pyruvate was significantly less responsive to inhibition by insulin in hepatocytes from transgenic mice compared to hepatocytes from wild-type mice. Serum from transgenic mice resulted in more glucose production by hepatocytes than serum from wild-type mice. Serum alanine was increased while serum lactate was significantly reduced in transgenic mice compared to wild-type mice. Serum free fatty acids and beta-hydroxybutyrate were similar in both groups of mice. These data suggest that fasting hyperglycemia is due to enhanced gluconeogenesis, hepatic insulin resistance and increased serum gluconeogenic substrate in transgenic mice.

Animals↗
PubMed1999

Hepatic regeneration in insulin-like growth factor binding protein-1 transgenic mice.

BACKGROUND/AIMS: Partial hepatectomy results in activation of genes in the residual liver tissue which serve to restore glucose homeostasis and regenerate liver mass. Expression of insulin-like growth factor binding protein-1 (IGFBP-1) is up-regulated following partial hepatectomy and IGFBP-1 can modulate both the metabolic and mitogenic effects of insulin-like growth factor-1 (IGF-I). The aim of the study was to compare the effects of partial hepatectomy on blood glucose levels and hepatic regeneration in wild-type and transgenic mice which constitutively overexpress IGFBP-1. METHODS: Hepatic IGFBP-1 mRNA, blood glucose concentrations, liver mass and hepatic DNA synthesis were compared in sham-operated and partially hepatectomized transgenic and wild-type mice. RESULTS: Hepatic IGFBP-1 mRNA was higher in sham-operated transgenic than wild-type mice, but in both groups of mice, partial hepatectomy was associated with a significant rise in IGFBP-1 mRNA. The absolute decline in blood glucose levels following partial hepatectomy was greater in transgenic mice. Basal DNA synthesis and the response to IGF-I in isolated hepatocytes from both groups of mice were similar, and DNA synthesis in the regenerating liver in vivo was not significantly different in transgenic as compared to wild-type mice: 449.3 +/- 63.9 vs. 321.6 +/- 52.3 cpm/microgram DNA. Hepatic regeneration as measured by liver weight after hepatectomy was not different between transgenic and wild-type mice. CONCLUSIONS: Constitutive overexpression of IGFBP-1 does not enhance hepatic regeneration and does not prevent the decline in blood glucose following partial hepatectomy.

Animals↗
PubMed1999

Thyroid gland function and growth in IGF binding protein-1 transgenic mice.

OBJECTIVE: IGF-I, IGF-I receptor and IGF-binding proteins (IGFBPs) are expressed in thyroid tissue and are associated with the function and growth of the thyroid. This study investigated the in vivo and in vitro effects of increased IGFBP-1 levels on the function and growth of the thyroid gland. DESIGN: Transgenic mice which constitutively overexpress IGFBP-1 were used. These mice have a phenotype consistent with partial inhibition of IGF-I action. METHODS: Thyroid growth, morphology and hormonogenesis were determined in transgenic mice treated with goitrogens, sodium perchlorate and methimazole. In vitro cell proliferation in thyroid follicles was assessed in response to IGF-I and TSH. RESULTS: Thyroid weight was increased in transgenic mice, relative to their body mass, whereas serum tri-iodothyronine (T(3)), thyroxine and T(3)-binding capacity were reduced, compared with wild-type. While an inverse relationship between T(3) and TSH was observed in both groups of goitrogen-treated mice, the slope of the line of best fit was less steep in transgenic mice compared with wild-type mice. Thyroid growth was less marked in transgenic than wild-type mice in response to goitrogens, although TSH levels were higher in goitrogen-treated transgenics. In vitro proliferative response of isolated thyroid follicles to IGF-I, but not to TSH, was reduced in transgenic, compared with wild-type mice. CONCLUSIONS: The results of this study suggest that, while overexpression of IGFBP-1 attenuates IGF-I action in vitro, it enhances thyroid growth in vivo, presumably as a result of perturbations in thyroid function at multiple levels.

Aging↗
PubMed1999

Impaired adipogenesis in insulin-like growth factor binding protein-1 transgenic mice.

Differentiation of precursor cells into mature fat cells is accompanied by enhanced expression of insulin-like growth factor (IGF)-I and is stimulated by multiple hormones including growth hormone, glucocorticoids, IGF-I and insulin. We used transgenic mice that overexpress insulin-like growth factor binding protein-1 to investigate the role of IGF-I in the accumulation of fat tissue. In response to a sucrose-enriched diet, transgenic mice gained significantly less body weight and the epididymal fat mass was significantly reduced compared with wild-type mice. The increase in adipocyte size was also significantly reduced in transgenic mice compared with wild-type mice. Fewer colonies were generated from adipose tissue from transgenic mice and the mitogenic response of these cells to IGF-I was significantly reduced compared with those from wild-type mice. Induction of glycerol-3-phosphate dehydrogenase, a measure of adipocyte differentiation, by IGF-I but not insulin, was reduced in preadipocytes from transgenic mice. These data indicate that IGF-I has a critical role in the proliferation of adipocyte precursors, the differentiation of preadipocytes and the development of obesity in response to calorie excess.

Adipocytes↗
PubMed1997

Impaired brain development and reduced astrocyte response to injury in transgenic mice expressing IGF binding protein-1.

Numerous reports indicate that insulin-like growth factor-I (IGF-I) has a critical role in brain development, that it contributes to neuronal survival and that its activity is regulated by a family of IGF binding proteins (IGFBPs). In the present study, brain development was investigated in transgenic (Tg) mice that overexpress rat IGFBP-1 under the control of phosphoglycerate kinase promoter. Adult Tg mice had significantly decreased brain weight (299 +/- 17 vs. 499 +/- 11 mg), brain DNA content (684 +/- 8 vs. 810 +/- 31 microg) and brain protein (37 +/- 1 vs. 48 +/- 2 mg) compared with wild-type (Wt) mice and these deficits were already evident at birth. In Tg mice, myelin staining was generally reduced and there was a diminished thickness of the corpus callosum. The total area of hippocampus and dentate gyrus were significantly reduced by 55% and 72%, respectively. Bromodeoxyuridine labeling of proliferating cells in 3-day-old mice was markedly reduced by 41% in the dentate gyrus and by 19% in ventricular zones of Tg mice. Reactive astrogliosis reflected by morphology and glial fibrillary acidic protein expression of astrocytes in response to a mechanical lesion was substantially less in Tg compared with Wt mice. Mixed glial cell cultures from Tg animals were significantly less responsive to stimulation of proliferation by IGF-I than cultures from Wt mice. We conclude that overexpression of IGFBP-1 impairs brain development and reduces glial cell proliferation in response to injury.

Animals↗
PubMed1997

Reduced fecundity in insulin-like growth factor-binding protein-1 transgenic mice.

Transgenic mice that overexpress insulin-like growth factor-binding protein-1 (IGFBP-1) demonstrate a reduced litter size compared to nontransgenic, wild-type mice derived from the same genetic background. To determine the mechanism underlying this phenomenon, we examined the number of ovulatory follicles per cycle in naturally mated transgenic and wild-type mice by counting the corpora lutea and the blastocysts harvested by uterine flushing. In addition, we investigated the effects of insulin-like growth factor-I (IGF-I) on blastocyst DNA synthesis and examined the effects of a transgenic maternal environment on fetal outcome by cross transfer of blastocysts. Significantly fewer corpora lutea were observed in ovaries from transgenic vs. wild-type mice (7.6 +/- 1.8 vs. 11.8 +/- 1.5), and fewer blastocysts were harvested from transgenic mice compared to wild-type mice (7.6 +/- 2.3 vs. 10.1 +/- 2.0). DNA content and basal DNA synthesis were similar in blastocysts from nontransgenic and transgenic mice. However, unlike wild-type blastocysts, transgenic blastocysts did not respond to IGF-I with an increase in DNA synthesis. To determine the effects of maternal environment on fetal outcome, a mixture of equal numbers of transgenic and nontransgenic blastocysts was transferred into foster mothers. The ratio of transgenic to nontransgenic pups was not significantly different from the theoretically predicted value of 1. However, the litter size was significantly reduced in wild-type compared to transgenic foster mothers. These data suggest that the reduced fecundity is due to reduced ovulation and blastocyst number. Furthermore, expression of the transgene in neither the blastocyst nor the maternal tissues had any significant negative effect on implantation or fetal wastage.

Animals↗
PubMed1997

Expression of insulin-like growth factor binding proteins (IGFBPs) in IGFBP-1 transgenic mice.

The hepatic and renal expressions of the insulin-like growth factor binding proteins (IGFBPs) were examined in transgenic (Tg) mice which overexpress a rat IGFBP-1 transgene driven by the phosphoglycerate kinase-1 promoter. There were no significant difference in the abundance of serum IGFBPs in Tg and wild-type (Wt) mice. Although total hepatic IGFBP-1 mRNA mouse and transgene-derived) levels were similar in Tg mice to the levels of mouse IGFBP-1 mRNA in Wt mice on day 1 of life, in Tg mice only approximately 30% of the IGFBP-1 mRNA was derived from transcription of the mouse gene. An age-related decline in hepatic IGFBP-1 mRNA levels was apparent in both Tg and Wt mice. Food deprivation resulted in increased levels of mouse IGFBP-1 mRNA but the total IGFBP-1 mRNA levels were not significantly different in Tg and Wt mice. In the kidney, unlike the liver, IGFBP-1 mRNA levels in Tg mice were markedly elevated compared with Wt mice and no significant decline was seen with age. Northern blots of hepatic and renal RNA demonstrated similar levels of IGFBP-3, -4, -5 and -6 mRNAs in Tg and Wt mice. From these data we can conclude that in the liver expression of the transgene leads to a coordinated reduction in mouse IGFBP-1 mRNA levels.

Aging↗
PubMed1997

Islet cell proliferation and apoptosis in insulin-like growth factor binding protein-1 in transgenic mice.

Transgenic mice which overexpress insulin-like growth factor binding protein-1 (IGFPB-1) demonstrate fasting hyperglycemia, hyperinsulinemia and glucose intolerance in adult life. Here we have examined the ontogeny of pancreatic endocrine dysfunction and investigated islet cell proliferation and apoptosis in this mouse model. In addition we have examined pancreatic insulin content in transgenic mice derived from blastocyst transfer into non-transgenic mice. Transgenic mice were normoglycemic at birth but had markedly elevated plasma insulin levels, 56.2 +/- 4.5 versus 25.4 +/- 1.5 pmol/l, p < 0.001, and pancreatic insulin concentration, 60.5 +/- 2.5 versus 49.0 +/- 2.6 ng/mg of tissue, P < 0.01, compared with wild-type mice. Transgenic mice derived from blastocyst transfer to wild-type foster mothers had an elevated pancreatic insulin content similar to that seen in pups from transgenic mice. There was an age-related decline in pancreatic insulin content and plasma insulin levels and an increase in fasting blood glucose concentrations, such that adult transgenic mice had significantly less pancreatic insulin than wild-type mice. Pancreatic islet number and the size of mature islets were increased in transgenic animals at birth compared with wild-type mice. Both islet cell proliferation, measured by 5-bromo-2'-deoxyuridine labeling, and apoptosis, assessed by the in situ terminal deoxynucleotidyl transferase and nick translation assay, were increased in islets of newborn transgenic mice compared with wild-type mice. In adult mice both islet cell proliferation and apoptosis were low and similar in transgenic and wild-type mice. Islets remained significantly larger and more numerous in adult transgenic mice despite a reduction in pancreatic insulin content. These data suggest that overexpression of IGFBP-1, either directly or indirectly via local or systemic mechanisms, has a positive trophic effect on islet development.

Animals↗
PubMed1996

Impaired glucose homeostasis in insulin-like growth factor binding protein-1 transgenic mice.

Transgenic mice that overexpressed IGFBP-1 are hyperinsulinemic in the first week of life and gradually develop fasting hyperglycemia. In adult transgenic mice, the hypoglycemic response to IGF-I but not insulin or des (1-3) IGF-I was attenuated (P < 0.05) compared with wild-type mice. Furthermore, in isolated adipocytes from transgenic mice, the stimulatory effect of IGF-I but not insulin on 2-deoxy-[3H]-glucose uptake was reduced (P < 0.02). In contrast, in isolated soleus muscle, the effects of both IGF-I and insulin on 2-deoxy-3H-glucose uptake and on [3H]-glucose incorporation into glycogen were significantly reduced compared to wild-type mice. The decline in specific activity of the 2-deoxy-3H-glucose, a measure of glucose appearance in the circulation, was more marked in transgenic animals (P < 0.05). In addition, tissue uptake of glucose was significantly higher in diaphragm, heart, intestine, liver, soleus muscle, and adipose tissue from fasting transgenic mice. Plasma concentrations of alanine, lysine, and methionine were also elevated in transgenic mice. These data suggest that overexpression of IGFBP-1 attenuates the hypoglycemic effect of endogenous IGF-I, which is initially compensated for by enhanced pancreatic insulin production. However, in adult mice pancreatic insulin content is reduced, insulin resistance is demonstrable in skeletal muscle and fasting hyperglycemia develops.

Animals↗
PubMed1996

Effects of insulin-like growth factors (IGF) on pancreatic islet function in IGF binding protein-1 transgenic mice.

We have previously reported fasting hyperglycaemia, hyperinsulinaemia, and glucose intolerance in transgenic (Tg) mice which overexpress rat insulin-like growth factor binding protein-1 (IGFBP-1). An increase in pancreatic islet size and number was also observed in this model. Islets from Tg mice had relatively more beta cells and less alpha cells than islets from wild-type (Wt) mice. These observations prompted us to investigate the effects of glucose and insulin-like growth factor-I (IGF-I) on insulin and glucagon release by isolated islets from Tg and Wt mice. Under basal glucose conditions, islets from Tg mice released significantly more insulin and less glucagon than islets from Wt mice. This difference was significant even when corrected for the increased size and cellularity of islets from Tg mice. A dose-dependent increase in insulin release was observed with increased glucose concentrations in both Wt and Tg mice. At all but the highest glucose concentration, islets from Tg mice released significantly greater amounts of insulin than islets from Wt mice. Addition of IGF-I to islet incubations resulted in a dose-dependent increase in insulin release. However, the effect of IGF-I on islets from Tg mice was reduced compared to islets from Wt mice. From these data we conclude that IGF-I stimulates rather than inhibits insulin secretion in isolated murine islets. Furthermore, an intrinsic defect in pancreatic islet insulin release is not responsible for the glucose intolerance in Tg mice. Rather, the data suggest that the hyperglycaemia or local effects of IGFBP-1 over-expression results in a state of enhanced insulin secretion which persists under short-term in vitro culture conditions.

Animals↗
PubMed1996

Hyperglycemia and impaired glucose tolerance in IGF binding protein-1 transgenic mice.

The insulin-like growth factors (IGFs) are present in the serum in association with high-affinity binding proteins (IGFBPs), which limit the hypoglycemic insulin-like actions of these growth factors. By utilizing the mouse phosphoglycerate kinase promoter to drive a rat genomic fragment, we developed three transgenic mouse strains that overexpressed IGFBP-1. Homozygous offspring demonstrated fasting hyperglycemia. The blood glucose values were 4.97 +/- 0.37, 4.57 +/- 0.33, and 5.58 +/- 0.50 mM for transgenic mice compared with 3.33 +/- 0.19 mM (mean +/- SE, P < 0.05) for the wild-type mice. The transgenic mice had more marked hyperglycemia after an intraperitoneal glucose challenge. The fasting serum insulin levels were significantly elevated in the transgenic mice; however, the insulin-to-glucose ratio was only modestly elevated in the fasting state and fell after a glucose challenge. Islet size and number were significantly increased; however, pancreatic insulin content was reduced (P < 0.05) compared with that of wild-type mice. The glucose response to subcutaneous insulin was similar in transgenic and wild-type mice. These data demonstrate that constitutive overexpression of IGFBP-1 results in impaired glucose tolerance with normal insulin sensitivity.

Animals↗
PubMed1996

Impaired estrogen action in the uterus of insulin-like growth factor binding protein-1 transgenic mice.

Insulin-like growth factor-I (IGF-I) has been implicated as autocrine/paracrine mediator of estrogen action in the rodent uterus. Here, we examined the effects of 17-beta estradiol (E2), epidermal growth factor (EGF), and IGF-I on DNA synthesis in the uterus of ovariectomized (ovex) transgenic mice (Tg), which overexpress rat insulin-like growth factor binding protein-1 (IGFBP-1). Litter size was significantly reduced in Tg mice compared with wild-type mice. Immunohistochemical studies localized the expression of the transgene to the luminal and glandular epithelium. In addition, rat IGFBP-1 immunoreactivity was present in luminal secretions. E2-induced uterine DNA synthesis as measured by methyl-3H thymidine incorporation, was significantly reduced in ovex Tg mice; 4.77 +/- 0.59 and 4.97 +/- 0.53 for Tg strains 57C and 277A, respectively, compared with 8.65 +/- 0.73 fmol/microgram of DNA for Wt mice. Similarly, uterine weight after three daily injections of E2 was reduced in Tg mice compared with Wt mice; 2.85 +/- 0.39 vs. 4.23 +/- 0.26 mg/g BW, P < 0.01. Semiquantitative RT-PCR assays were used to demonstrate changes in uterine IGF-I messenger RNA (mRNA) and EGF mRNA abundance after administration of E2. An approximately 3-fold increase in IGF-I mRNA abundance was seen 6 h after E2 in both Tg and Wt mice. Over the same time course, little change was seen in EGF mRNA levels, which were similar in Tg and Wt mice. After 3 days of E2 treatment, an increase in EGF mRNA was apparent in Wt mice but not in Tg mice. The uterine DNA response to both IGF-I and EGF was significantly attenuated in Tg mice compared with Wt mice. The data reported here together with previous reports of E2 regulation of IGF-I and IGFBP-1 expression in uterus support the hypothesis that the IGF-I is a mediator of estrogen action in the uterus. In addition attenuation of the EGF response in the uterine tissue of Tg mice suggests that this response is also mediated, in part, by IGF-I.

Animals↗
PubMed1995

Phenotypic manifestations of insulin-like growth factor binding protein-1 (IGFBP-1) and IGFBP-3 overexpression in transgenic mice.

To provide further insight into the function of the IGFBPs, transgenic (Tg) mice which overexpressed IGFBP-1 and IGFBP-3 were generated. In this report we have compared the phenotypic manifestations observed in these Tg mice. The IGFBP-1 Tg mice were significantly smaller at birth, birth weight and gained less weight in the postnatal period. Organ weight was proportionately reduced relative to body weight in most organs. However the brain was markedly smaller in IGFBP-1 Tg mice. Mean plasma levels of Tg-derived IGFBP-1 ranged from 8 to 80 ng ml-1 in the different groups of IGFBP-1 Tg mice. In addition homozygous mice also demonstrated fasting hyperglycemia, impaired glucose tolerance and reduced fecundity. Two of the seven IGFBP-3 founders had measurable levels of hlGFBP-3 in the circulation and were bred to homozygosity. Maximal plasma levels of transgene-derived IGFBP-3 were 72-198 ng ml-1. Transgene expression was detected in the kidney, small intestine and colon by Northern blot analysis. The birth weight, litter size and body weight of IGFBP-3 Tg mice were not significantly different from wild-type mice. However, the spleen, liver and heart of IGFBP-3 Tg mice derived from both founders were significantly heavier compared with organs from wild-type mice. The relative weight of other organs such as the brain, kidney and lungs were similar to wild-type mice. From these data, we conclude that over expression of IGFBP-1 results in inhibition of IGF action and in profound impairment of brain development, modest inhibition of fetal and postnatal growth and inhibition of the metabolic effects of the IGFs. In contrast, modest over-expression of hlGFBP-3 has little effect other than some selective organomegaly.

Animals↗
PubMed1995

Anti-pneumococcal antibody levels three to seven years after first booster immunization in children with sickle cell disease, and after a second booster.

We measured pneumococcal antibody levels in 55 patients (ages 7 to 20 years) with sickle cell disease 3 to 7 years after the first booster immunization. Only 6 of the children had protective levels of antibodies (> 300 ng/ml) against all 12 serotypes tested. Thirty-two children (58%) had suboptimal levels against 1 to 3 serotypes; 17 had suboptimal levels against 4 to 10 serotypes. Ten patients from the latter group (ages 13 to 17 years) received a second booster 6 to 8 years after the first booster immunization, and had a marked increase in antibody levels against all serotypes with the exception of serotypes 3 and 4 in two patients and serotype 6A in one patient.

Adolescent↗
PubMed1995

Growth retardation and hyperglycemia in insulin-like growth factor binding protein-1 transgenic mice.

Transgenic mice that constitutively overexpressed rat insulin-like growth factor binding protein-1 (IGFBP-1) were generated to determine the effects of overexpression of IGFBP-1 on growth and development. In offspring of three of the founders that showed high levels of expression, birth weight was significantly reduced to approximately 83-92% of the weight of their nontransgenic littermates. The transgenic mice gained less weight and were approximately 3.5-8 g lighter than nontransgenic littermates at 40 days of age. The difference in body weight between transgenic and wild-type mice was most apparent around the time of weaning when transgenic mice showed a more marked growth deceleration than wild-type mice. No significant catch-up growth was apparent over the first 3 months of life. In addition, offspring of all three high-expressing founders demonstrated fasting hyperglycemia. The transgene was highly expressed in the brain, uterus, lung, kidney, and heart, but little expression was detected in the liver. The weight of the brain relative to body weight was significantly reduced in transgenic mice compared with wild-type mice, whereas the relative weight of most other organs was similar to wild-type mice. These data demonstrate that IGFBP-1 may function to inhibit IGF action in vivo and that this inhibition selectively impairs development of organs such as the brain.

Animals↗