Biomedical subjects

K Hall

Publications and source records attributed to K Hall.

At least 19 recordsLinked to original sources

PubMed1998

Insulin-like growth factor II inhibits glucose-induced insulin exocytosis.

We have investigated the effect of IGF-II on glucose-induced insulin release in the pancreatic beta-cell. Introduction of IGF-II during perifusion of the cells with 20 mM glucose abolished glucose-induced insulin release. Concomitant addition of IGF-II with 20 mM glucose caused a complete inhibition of insulin release. In addition, IGF-II inhibited Ca(2+)-induced insulin release from electropermeabilized pancreatic beta-cells. IGF-II had no effect on K(+)-or tolbutamide-induced insulin release. However, IGF-II could suppress K(+)-stimulated insulin release when cells were pretreated with the protein phosphatase inhibitor okadaic acid. The inhibitory effect of IGF-II on insulin release was not associated with significant changes in membrane potential, activity of the voltage-gated L-type Ca(2+)-channel or cytoplasmic free Ca2+ concentration. Pretreatment of the cells with pertussis toxin or the phorbol ester TPA abolished the inhibitory action of IGF-II on insulin release. Hence, the molecular mechanism whereby activation of the IGF-II/M6P receptor by IGF-II inhibits glucose-stimulated insulin exocytosis in the pancreatic beta-cell involves pertussis toxin-sensitive G proteins and is dependent on PKC activity.

Animals↗

PubMed1997

Analysis of the tricho-dento-osseous syndrome genotype and phenotype.

The tricho-dento-osseous (TDO) syndrome demonstrates kinky curly hair, thin-pitted enamel, taurodontism, and thickening of cortical bone. The purpose of this investigation was to characterize the phenotypic variation of TDO in 3, previously unreported, kindreds and to examine possible candidates for the genomic TDO locus. Thirty-three affected and 20 unaffected individuals were recruited for prospective analysis. Participants were evaluated clinically and photographed by one examiner. Blood was drawn for genetic linkage analyses and radiographs were taken to assess dental and skeletal characteristics. All TDO individuals with teeth had generalized thin and/or pitted enamel hypoplasia. Taurodontism was present in all affected individuals, but was variably expressed. Unique kinky/curly hair at birth was reported in 85% of affected individuals. The curly hair phenotype was retained in 46% of affected individuals after infancy. Thick cranial bones, lack of visible pneumatization of the mastoid process, and/or obliteration of the calvarial diploë was seen in 97% of affected persons compared with 30% of the unaffected individuals. The findings suggest that curly hair at birth, enamel hypoplasia, and taurodontism are highly penetrant yet clinically variable components of TDO. The ABO, Kell, and Gc loci previously suggested to be linked to TDO were excluded as candidates in this TDO population. This investigation characterizes the marked variability in the expression of skeletal, hair, and dental manifestations. The broad range of TDO phenotypes seen in these families, including a variety of skeletal changes, does not support subdividing TDO into multiple subtypes based on subtle phenotypic differences.

Abnormalities, Multiple↗

PubMed1997

Insulin-like growth factor II signaling through the insulin-like growth factor II/mannose-6-phosphate receptor promotes exocytosis in insulin-secreting cells.

The insulin-like growth factor II (IGF-II)/mannose-6-phosphate (M-6-P) receptor is known to participate in endocytosis as well as sorting of lysosomal enzymes and is involved in membrane trafficking through rapid cycling between cytosolic membrane compartments and the plasma membrane. Here we demonstrate that IGF-II, acting through the IGF-II/M-6-P receptor, promotes exocytosis of insulin in the pancreatic beta cell. The effect of IGF-II was evoked at nonstimulatory concentrations of glucose, was mediated by a pertussis toxin sensitive GTP-binding protein, was dependent on protein kinase C-induced phosphorylation, and was independent of changes in cytoplasmic free Ca2+ concentration. Since the applied concentration of IGF-II is within the range normally found free in circulation in humans, this novel signaling pathway for the IGF-II/M-6-P receptor is likely to be involved in modulation of insulin exocytosis under physiological conditions.

Adenosine Triphosphate↗

PubMed1997

The protein composition of normal and developmentally defective enamel.

The development of human enamel involves a complex series of events including the secretion and degradation of a unique extracellular matrix. Ameloblasts progress through a succession of cellular phenotypes executing specialized secretory and regulatory functions. When performing optimally, ameloblasts produce a highly structured and mineralized tissue. Given the elaborate developmental events required for normal enamel formation, it is not surprising that a variety of enamel malformations arise from defects in matrix synthesis, secretion and extracellular processing. Normal matrix secretion and post-secretory processing by ameloblasts can be affected by a variety of hereditary and environmental conditions. These disturbances can result in an abnormal amount and/or composition of matrix proteins, and subsequently, an altered enamel structure and/or mineral content. For example, abnormal matrix removal during enamel maturation apparently contributes to hypomineralization associated with dental fluorosis. Incomplete matrix removal can also occur in several different forms of the hereditary condition amelogenesis imperfects. Specific types of this condition can have retention of substantial enamel protein (e.g. 5% by weight) that is, at least in part, composed of amelogenin and/or its breakdown products. Characterization of the enamel proteins in teeth affected by developmental disturbances can provide insight into the pathogenesis and normal formation of this highly specialized tissue.

Adult↗

PubMed1997

Multifunctional cytokine expression by human mast cells: regulation by T cell membrane contact and glucocorticoids.

Human mast cells readily release a variety of mediators, including cytokines, in response to IgE receptor crosslinking, but the mechanisms governing the expression of cytokines are still unclear. Using a human mast cell line, HMC-1, we show expression of cytokine transcripts as early as 2 h after activation with ionomycin and phorbol myristate acetate (PMA). Resting HMC-1 cells expressed transcripts for interleukin-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-5, GM-CSF, and weakly for IL-8, and stimulation with ionomycin and PMA induced additional transcripts for IL-6 and IL-13 and upregulated expression of IL-8 transcripts. HMC-1 cells secreted IL-4, IL-8, and GM-CSF protein after activation and dexamethasone significantly inhibited the production of these cytokines. Of significance is the finding that the addition of membranes purified from activated T cells to mast cell cultures induced transcripts selectively for IL-8 and none for other proinflammatory cytokines. Flow cytometry revealed that resting HMC-1 cells express CD40, a molecule involved in contact-dependent signaling of monocytes and B cells by T cells. However, activation of HMC-1 by anti-CD40 antibody did not induce IL-8 gene expression or protein production. This study demonstrates that human mast cells are capable of expressing multiple cytokines that can be inhibited by glucocorticoids. It also raises the possibility that T cells may activate mast cell cytokine synthesis by novel contact-dependent mechanisms. This phenomenon of T cell regulation of mast cell function requires further study.

Anti-Inflammatory Agents↗

PubMed1997

Genetic linkage of the tricho-dento-osseous syndrome to chromosome 17q21.

Tricho-dento-osseous syndrome (TDO), MIM# 190320, is transmitted as a highly penetrant autosomal dominant trait that is characterized by variable clinical expression. The principal clinical features include kinky/curly hair in infancy, enamel hypoplasia, taurodontism, as well as increased thickness and density of cranial bones. Possible genetic linkage has been reported for TDO with the ABO blood group locus, but the gene defect remains unknown. We have identified four multiplex families (n = 63, 39 affected, 24 unaffected) from North Carolina segregating TDO. We previously have excluded a major locus for TDO in the ABO region for these families. Utilizing a genome-wide search strategy, we obtained conclusive evidence for linkage of the TDO syndrome locus to markers on chromosome 17q21 (D17S791, Z max = 10.54, Theta = 0.00) with no indication of genetic heterogeneity. Multipoint analysis suggests the TDO locus is located in a 7 cM chromosomal segment flanked by D17S932 and D17S941. This finding represents the first step towards isolation and cloning of the TDO gene. Identification of this gene has important implications for understanding normal and abnormal craniofacial development of hair, teeth and bone.

Abnormalities, Multiple↗

PubMed1997

Early stroke recognition: developing an out-of-hospital NIH Stroke Scale.

OBJECTIVE: To develop an abbreviated and practical neurologic scale that could assist emergency medical services or triage personnel in identifying patients with stroke. METHODS: A prospective, observational, cohort study was performed at university-based EDs. Participants were 74 patients treated in a thrombolytic stroke trial and 225 consecutive non-stroke patients evaluated during 4 random 12-hour shifts in the ED. Scores on the NIH Stroke Scale were obtained for all patients by physicians. Items of this scale were modified and recoded to a binomial (normal or abnormal) scale. Serial univariate analyses using chi 2 were performed to rank items. Recursive partitioning was then performed to develop the decision rule for predicting the presence of stroke. RESULTS: Three items identified 100% of patients with stroke: facial palsy, motor arm, and dysarthria. An Abbreviated NIH Stroke Scale based on these items had a sensitivity of 100% and a specificity of 92%. A proposed Out-of-hospital NIH Stroke Scale consisting of facial palsy, motor arm, and a combination of dysarthria and best language items (abnormal speech) had a sensitivity of 100% and a specificity of 88%. CONCLUSION: Using the derivation data set, a proposed Out-of-hospital NIH Stroke Scale had a high sensitivity and specificity for identifying patients with stroke when performed by physicians in this group of 299 ED patients. Prospective studies of other health care professionals using the scale in the out-of-hospital arena are needed.

Adult↗

PubMed1997

Mosaicism for trisomy 3q arising from an unbalanced, de novo t(3;15).

We report on a 2 1/2 year old girl who is dysmorphic, developmentally delayed, and mosaic for an unbalanced, de novo translocation between chromosomes 3 and 15. The karyotype from peripheral blood lymphocytes is 46,XX (50) and the karyotype from skin fibroblasts is 46,XX (28)/46,XX,der(15)t(3;15)(q11;p11) (23). The mechanism for the generation of this unbalanced, de novo translocation is discussed.

Abnormalities, Multiple↗

PubMed1997

Serum insulin-like growth factor I (IGF-I), IGF-binding protein-1 and -3, and the acid-labile subunit as serum markers of body composition during growth hormone (GH) therapy in adults with GH deficiency.

Serum levels of insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), the acid-labile subunit (ALS), insulin, and IGFBP-1 were evaluated as indicators of body composition during GH replacement therapy in 20 GH-deficient patients (9 women and 11 men), aged 22-57 yr, with IGF-I levels below -2 SD. The mean GH dose was 0.128 +/- 0.003 IU/kg.week during the first month and thereafter 0.23 +/- 0.01 IU/kg.week, divided into daily doses (0.7-4.3 IU/day). Serum levels of IGF-I, ALS, and IGFBP-3 above the normal range were reached in seven, five, and three subjects, respectively, after 12 months of GH therapy. IGF-I and ALS levels, but not IGFBP-3 levels, correlated with the total daily GH dose (r = 0.676; P = 0.001 and r = 0.631; P = 0.003). The mean increase in lean body mass (LBM) measured by dual energy x-ray absorptiometry was 3.0 +/- 0.5 kg (P < 0.001). At 12 months, the LBM values were significantly correlated to the IGF-I levels (r = 0.718; P < 0.001), but not to ALS or IGFBP-3 levels. No correlation was found before therapy, and the increase in LBM at 12 months correlated with the IGF-I increase (r = 0.514; P = 0.029) only after exclusion of two nonresponders. Both before and during therapy, LBM was inversely related to IGFBP-1 (r = -0.715; P < 0.004 at 12 months). None of the GH-induced proteins could be used as indicators of body fat changes. In conclusion, both IGF-I and ALS can be used as indicators to avoid GH excess during replacement therapy, but only IGF-I relates to changes in LBM.

Adipose Tissue↗

PubMed1997

Associations between insulin-like growth factor-I (IGF-I), IGF-binding protein-1, insulin and other metabolic measures after controlling for genetic influences: results from middle-aged and elderly monozygotic twins.

It has previously been shown that the serum levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-1 (IGFBP-1), and insulin are influenced by genetic effects to various degrees. From a clinical and preventive point of view, however, it is important to identify potentially modifiable non-genetic factors influencing the levels of these measures. Because monozygotic twin pairs share the same genetic background, differences in phenotypic levels within monozygotic twin paris are believed to be due to non-genetic influences. Accordingly, the associations between intrapair differences in one phenotype and intrapair differences in another phenotype are also due to non-genetic influences. The present sample of 97 pairs of monozygotic twins from the population-based Swedish Adoption/Twin Study of Aging (SATSA) provided the opportunity to assess non-genetic influences on the levels of IGF-I, IGFBP-1, and insulin. Several metabolic measures were found to account for the variation of IGF-I, IGFBP-1, and insulin after controlling for the genetic influences. IGFBP-1 and glucose were significant predictors for the levels of IGF-I. IGFBP-1 and glucose together explained about one quarter of the non-genetic variation of IGF-I. However, when IGFBP-1 was dropped from the regression model, insulin was the only independent predictor of IGF-I, and explained about 19% of the non-genetic variation for IGF-I. For IGFBP-1, insulin and IGF-I, were the significant non-genetic predictors. Insulin and IGF-I explained about 28 and 8% respectively of the non-genetic variation for IGFBP-1, while for insulin, IGF-I, triglycerides, body height, glucose, and body mass index (BMI) explained approximately 20, 12, 6, 5 and 5% respectively of the non-genetic variation.

Aged↗

PubMed1997

Determinants of growth in diabetic pubertal subjects.

OBJECTIVE: To analyze the relationship among metabolic control, IGF-I, and growth in pubertal diabetic subjects. RESEARCH DESIGN AND METHODS: In 72 diabetic children, we have studied the pattern of change of IGF-I, IGF-I SD score, IGF binding protein (BP)-1, and growth rate in different pubertal stages and have analyzed their relation to age sex, weight/length index, HbA1c, insulin concentration, insulin dose, and dehydroepiandrosteronesulfate (DHEAS). RESULTS: The serum IGF-I values increased up to Tanner stage 4 and thereafter decreased, whereas IGFBP-1 showed the inverse pattern. When transforming the IGF-I values into SD scores, correcting for age, sex, and pubertal stage, it was shown that the deviation from normal values increased with increasing pubertal stage in boys, but was equal in stages 3-5 in girls. Using multiple regression analysis, HbA1c, insulin dose, and DHEAS were significantly correlated to IGF-I SD score (R2 = 0.253, P = 0.001). IGFBP-I levels in the afternoon were within normal range. LogIGFBP-1 showed an inverse correlation, to insulin concentration in single correlation (r = -0.26, P = 0.02). In single correlation, growth rate correlated significantly to insulin dose (r = 0.25, P = 0.03). In a multiple regression analysis, only DHEAS and IGF-I SD score were found to be significantly correlated to growth rate (R2 = 0.370, P < 0.001). The 18 adolescents who had reached their final height did not deviate from their target final height, according to their recorded growth since birth. CONCLUSIONS: In a group of fairly well-controlled diabetic children, the normal increase in IGF-I during puberty is blunted. Despite decreased IGF-I levels, target final height was attained, probably because of adequate insulin compensation leading to normal IGFBP-l, thus adequate bioavailability of IGF-I. Our results point out the importance of sufficient exogenous insulin in the period of rapid linear growth.

Adolescent↗

PubMed1996

Monoclonal antibodies to HPV-6 L1 virus-like particles identify conformational and linear neutralizing epitopes on HPV-11 in addition to type-specific epitopes on HPV-6.

A set of 13 monoclonal antibodies (MAbs) was generated against HPV-6 L1 virus-like particles (VLPs), screened for reactivity to HPV-6 and HPV-11 L1 VLPs by ELISA, and tested for neutralization of HPV-11 infection. Both cross-reactive and type-specific epitopes were detected such that 4 of 13 MAbs reacted to surface conformational sites on HPV-6 L1 VLPs and the remaining 9 MAbs were cross-reactive to both HPV-6 and HPV-11 L1 VLPs. four of the 9 cross-reactive MAbs were able to neutralize HPV-11 infectivity, and 3 of 4 of these neutralizing MAbs (N-MAbs) identified shared surface conformational sites. One N-MAb therefore recognized a surface linear epitope as judged by positive binding to L1 in a Western blot assay. The neutralization status of these cross-reactive MAbs with regard to HPV-6 could not be assayed. These results demonstrated that the closely related HPV types 6 and 11 contain both type-specific and shared neutralizing epitopes.

Animals↗

PubMed1996

Influence of treatment with tamoxifen and change in tumor burden on the IGF-system in breast cancer patients.

Plasma levels of IGF-I, IGFBP-I and IGFBP-3 were measured before and during treatment with tamoxifen up to 19+ months in 34 post-menopausal patients with advanced breast cancer. In 28 patients, pro-IGF-IIE (IGF-IIE) levels were determined and IGFBP-3 was evaluated by immunoblot in 27 patients. Tamoxifen suppressed plasma levels of IGF-I by a mean value of 25.5%-37.7% at different times. This effect was fully developed after 1-2 months of treatment. IGF-IIE was decreased by a mean value of 7.7-23.2% at different time intervals during treatment with tamoxifen, but this effect was significant after long-term treatment (19 months +) only. Plasma IGFBP-I increased by a mean value varying between 48.6% and 190.1%. Tamoxifen had no significant effect on total IGFBP-3 levels. However, patients responding to treatment had a 28% reduction in fragmentation of IGFBP-3, while patients with progressive disease had a 36% increase in fragmentation. The difference between responders and non-responders was highly significant. These findings confirm and extend previous observations regarding the effects of treatment with tamoxifen on IGF-I and IGFBP-I. The finding that patients responding to tamoxifen achieve a reduction in the ratio of fragmented to intact IGFBP-3, while patients progressing on therapy experience an increase in the IGFBP-3 fragmentation ratio, suggest that the tumor burden influences IGFBP-3 protease activity in breast- cancer patients.

Aged↗

PubMed1996

Partial purification of an IGF-II receptor/binding protein from the erythroleukemia cell line K562.

We previously reported that insulin-like growth factor II (IGF-II) stimulated clonal growth of an erythroleukemia cell line, K562, in semi-solid agar, an effect not mimicked by insulin-like growth factor I (IGF-I), as IGF-I receptors are generally not expressed in this cell line. Affinity crosslinking of intact K562 cells with 125I-IGF-II revealed that the labeled hormone predominantly bound to a protein with a molecular weight of approximately 75 K. We report here the partial purification of the 75 K IGF-II binding protein from K562 cells. Triton X-100-solubilized K562 cells were subjected to Sephacryl-400, followed by Sephacryl-200 chromatography. Fractions of interest were collected and applied to a Sepharose-IGF-II column or an immuno-affinity column. The immuno-affinity column was prepared using an antiserum against placental membrane-derived material eluted from the Sephacryl-400 column in the elution volume, corresponding to the IGF-II binding protein from K562 cells. An affi-gel 10 affinity column, prepared with a protein A purified IgG fraction of this antiserum (antibody-29), retarded proteins showing binding specificity for IGF-II, with apparent molecular weights of 76 K, 87 K, and 70 K under reducing conditions. These protein bands were similar to the proteins retarded in the IGF-II affinity column, when evaluated by affinity crosslinking and SDS-PAGE. Fractionation of the purified material from the antibody-29 affinity column on Superose 12 revealed 6 protein peaks. Affinity crosslinking of the peak fractions from FPLC resulted in single bands with a molecular weight of 75 K under reducing conditions with variable specificity for IGF-II.

Animals↗

PubMed1996

Craniocervical bone pneumatisation.

We report a case of extensive craniocervical bone pneumatisation presenting after minor trauma. The patient had neurological signs and initial radiographs showed multiple lucencies in the skull base and the atlas vertebra. CT established the true nature of this rare condition.

Athletic Injuries↗

PubMed1996

Influence of droloxifene on plasma levels of insulin-like growth factor (IGF)-I, Pro-IGF-IIE, insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-3 in breast cancer patients.

The influence of the novel anti-estrogen droloxifene on the insulin-like growth factor (IGF) system in plasma was studied in two groups of breast cancer patients receiving droloxifene 40 mg o.d. (group 1, n = 6) or 100 mg o.d. (group 2, n = 7). Fasting blood samples were obtained from all patients before treatment and after 3 months (group 1) or 6 months (group 2) on droloxifene treatment, except for two patients in group 2 from whom the second sample was obtained following 2 months on treatment when the drug was to be terminated due to progressive disease. Insulin-like growth factor (IGF)-I, insulin-like growth factor binding protein (IGFBP)-1, IGFBP-3 and pro-IGF-IIE (IGF-IIE) were measured by radioimmunoassay. In patients in group 1, plasma lGF-I levels decreased by a mean value of 20% (P < 0.05) on treatment with droloxifene, while IGFBP-1 increased by a mean value of 45% (P > 0.1). In group 2 we observed a 42% decrease in IGF-I during treatment (P < 0.025), while the level of IGFBP-1 increased by a mean value of 70% (P < 0.025). No significant effect on IGF-IIE or IGFBP-3 was noted in any of the groups. The change in plasma lGF-I and IGFBP-1 observed during treatment with droloxifene resembles what is found in patients treated with tamoxifen. As IGF-I is a potent mitogen for breast cancer cells in vitro, a decrease in the plasma level of this growth factor with an increase in the concentration of IGFBP-1 may contribute to the anti-tumour effects of droloxifene.

Aged↗

PubMed1996

Kinesin force generation measured using a centrifuge microscope sperm-gliding motility assay.

To measure force generation and characterize the relationship between force and velocity in kinesin-driven motility we have developed a centrifuge microscope sperm-gliding motility assay. The average (extrapolated) value of maximum isometric force at low kinesin density was 0.90 +/- 0.14 pN. Furthermore, in the experiments at low kinesin density, sperm pulled off before stall at forces between 0.40 and 0.75 pN. To further characterize our kinesin-demembranated sperm assay we estimated maximum isometric force using a laser trap-based assay. At low kinesin density, 4.34 +/- 1.5 pN was the maximum force. Using values of axoneme stiffness available from other studies, we concluded that, in our centrifuge microscope-based assay, a sperm axoneme functions as a lever arm, magnifying the centrifugal force and leading to pull-off before stall. In addition, drag of the distal portion of the axoneme is increased by the centrifugal force (because the axoneme is rotated into closer proximity to the glass surface) and represents an additional force that the kinesin motor must overcome.

Animals↗

PubMed1996

Serum levels of insulin-like growth factor I and insulin-like growth factor-binding protein 1 correlate with serum free testosterone and sex hormone binding globulin levels in healthy young and middle-aged men.

OBJECTIVE: Administration of testosterone has been reported to increase serum levels of IGF-I in men with isolated hypogonadotrophic hypogonadism. An inverse relation between serum IGF-I and sex hormone binding globulin (SHBG) is seen in GH deficient children. The biological action of IGF-I is thought to be influenced by binding proteins, one of which is insulin-like growth factor-binding protein-1 (IGFBP-1), which is not only a carrier protein but also actively regulates the cellular actions of IGF-I. These observations suggest associations between IGF-I, IGFBP-1, testosterone and SHBG in serum. The aim of the present study was to investigate these associations in normal healthy men. DESIGN AND PATIENTS: The associations between the serum levels of IGF-I and IGFBP-1 on one hand, and testosterone and SHBG on the other were investigated in 38 normal healthy young and middle-aged men. RESULTS: Serum levels of IGF-I decreased both with increasing age (r = -0.66, P < 0.001) and increasing SHBG levels (r = -0.46, P = 0.002), but increased with increasing free testosterone (f-testosterone) (r = 0.42, P = 0.005). These associations remained after mutual simultaneous adjustments in a multiple regression analysis. IGFBP-1 did not display any significant univariate correlation with age (r = -0.25, P = 0.06) or SHBG (r = 0.18, P = 0.14), but showed a significant positive correlation with both f-testosterone (r = 0.42, P = 0.004), and total testosterone (t-testosterone) (r = 0.39, P = 0.008). In a multiple regression analysis IGFBP-1 was positively correlated with both SHBG and f-testosterone, but not with t-testosterone. CONCLUSION: The present study suggests that among healthy young and middle-aged men, there is an association between serum levels of free-testosterone and SHBG on the one hand, and serum IGF-I and IGFBP-1 on the other.

Adult↗