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Biomedical subjects

K Gordon

Publications and source records attributed to K Gordon.

At least 109 records · Page 6Linked to original sources
PubMed1993

Biologic factors as predictors of social outcome of epilepsy in intellectually normal children: a population-based study.

We studied social outcome for all the normally intelligent children in our province with onset of epilepsy between 1977 and 1985 (excluding absence and "minor motor" seizures). After follow-up averaging 7 1/2 years, the 337 patients were 7 to 28 years of age. Outcome measures were age dependent. Of those old enough to be at risk, the percentage with each unfavorable outcome was as follows: school failure 34%, use of special educational resources 34%, mental health consultation 22%, psychotropic medication 5%, unemployment 20%, social isolation 27%, inadvertent pregnancy 12%, and criminal conviction 2%. In social isolation 27%, inadvertent pregnancy 12%, and criminal conviction 2%. In a multivariate model correcting for number of potential unfavorable outcomes (based on age at end of follow-up), many variables related to epilepsy, seizure control, and electroencephalographic findings were not associated with social outcome. Only two variables were associated with at least one unfavorable outcome--learning disorder (p < 0.001) and more than 21 seizures before treatment was begun (p < 0.03). The only variable with no unfavorable outcome was simple partial seizures (p < 0.003). Sensitivity and specificity of this model were 54% and 68%, respectively, indicating that social outcome for these children was often not related to biologic factors reflected by the medical details and clinical course of their disorder.

Adolescent↗
PubMed1993

Management of pituitary gonadal function via gonadotrophin releasing hormone (GnRH) antagonists, including ovulation induction by co-administration of either gonadotrophins or pulsatile GnRH.

GnRH agonists are now familiar clinical agents and are often the drugs of choice for suppression of the pituitary gonadal axis as part of various clinical indications. GnRH antagonists, which are likely to become clinically available soon, offer several advantages over the currently available GnRH agonists for many applications including ovulation induction. Here, we review the results from a series of pre-clinical studies designed to evaluate the potential clinical utility of this new class of compounds for ovulation induction protocols.

Female↗
PubMed1993

Mycoplasma pneumoniae infection associated with central nervous system complications.

We describe two children who had central nervous system complications, encephalitis and meningoencephalitis, temporally associated with Mycoplasma pneumoniae. M pneumoniae was identified as the cause of the illnesses on the basis of at least a fourfold increase in complement fixation antibody titers. Despite extensive viral and bacterial investigation, no evidence of any other pathogen was found. Two strategies were used to determine whether M pneumoniae was directly invasive: (1) by examining cerebrospinal fluid using a M pneumoniae-specific DNA probe and (2) by determining whether complement-fixating antibody to M pneumoniae was produced locally through comparison of the cerebrospinal fluid/serum ratio of M pneumoniae antibody to the cerebrospinal fluid/serum ratio of immunoglobulin M. Both assessments were negative. M pneumoniae did not appear to directly invade the central nervous system in these two patients. We conclude that the direct invasion of the cerebrospinal fluid is not necessary in the pathogenesis of M pneumoniae-induced neurologic disease.

Antibodies, Bacterial↗
PubMed1993

Successful treatment of hereditary trembling chin with botulinum toxin.

Hereditary trembling chin is an autosomal dominant condition characterized by recurrent bouts of tremor involving the chin. These episodes are precipitated by emotional upset. There has been considerable debate about the gravity of this condition. This may be a benign movement disorder; however, the rhythmic trembling of mentalis at rest or during times of stress in these patients is often misinterpreted as betraying an incipient emotional upset. For this reason, some patients with this condition may find it socially disabling. We have recently successfully treated one such family with regular botulinum toxin injections to the mentalis muscle.

Adult↗
PubMed1993

Hypothalamo-anterior pituitary gonadotropin-releasing hormone and substance-P systems during the 17 beta-estradiol-induced plasma luteinizing hormone surge in the ovariectomized female monkey.

The present study examined the effects of 17 beta-estradiol benzoate (E2B) on the hypothalamic (HT) and anterior pituitary (AP) content of GnRH precursor (pro-GnRH-GAP), GnRH, GnRH-associated peptide (GAP), and substance-P (SP) during the various phases of the E2B-induced LH surge in cynomolgus monkeys. Changes in GnRH and GnRH-associated peptide (GAP) at both hypothalamic and AP levels were closely related at all times after E2B treatment. However, the pattern of change in the AP was very different from that in the HT. In the HT, pro-GnRH-GAP levels did not change significantly throughout the experimental period. In the AP, the pro-GnRH-GAP increased 48 h post-E2B treatment, the time of initiation of the LH surge. An 8-fold increase in AP GnRH occurred 30 h post-E2B treatment. There were no significant changes in the HT content of SP at any time after E2B treatment. However, there was a depletion of AP content by 48 h post-E2B, the time of the LH surge. These results demonstrate that E2 activates and deactivates in a coordinated manner the GnRH and SP systems of the HT-AP complex during initiation of the E2-induced LH surge. The observation that more significant changes occur in the AP than in the HT suggests that an important component of the E2 effect in inducing the LH surge may be directly at the AP level. This action involves changes in the contents of GnRH and SP in the AP.

Animals↗
PubMed1993

Visceral glomerular epithelial cells can proliferate in vivo and synthesize platelet-derived growth factor B-chain.

In glomerular diseases associated with antibody- and complement-mediated injury to endothelial and mesangial cells, cell proliferation is an important early response that precedes matrix accumulation and glomerulosclerosis. In contrast, in diseases in which the visceral glomerular epithelial cell (vGEC) is the principal target of injury, cell proliferation is not a recognized consequence, although vGECs respond in vitro to a variety of growth factors and inflammatory mediators. To explore the possibility that low levels of vGEC proliferation may occur and participate in such diseases, serial studies were done in the passive Heymann nephritis model of membranous nephropathy, in which the vGEC is the primary target of antibody- and C5b-9-mediated injury. The results showed mitotic figures and positive staining for the proliferating cell nuclear antigen in cells whose location defined them as vGECs. The proliferating cell nuclear antigen-positive cells at the edge of the capillary wall were confirmed to be vGECs by double-immunostaining with antibodies to SPARC/osteonectin, which preferentially label vGECs in passive Heymann nephritis. Proliferation of vGECs in vivo was preceded by increased glomerular expression of platelet-derived growth factor (PDGF) B-chain protein and messenger RNA, both of which localized to vGECs. PDGF B-chain protein and messenger RNA were also detected in cultured vGECs. PDGF receptor beta-subunit protein or messenger RNA could not be demonstrated in vGECs in vivo or in vitro, and no growth response of cultured vGECs to PDGF was noted. These results suggest that proliferation of vGECs does occur in a model of glomerular injury induced by antibody and C5b-9 on vGECs. VGEC proliferation and production of PDGF may be involved in the restoration of the capillary wall but could also contribute to local capillary wall injury and proliferation of other cells in Bowman's capsule, interstitium, and tubules.

Animals↗
PubMed1992

Cloning of the goat beta-casein-encoding gene and expression in transgenic mice.

The goat beta-casein-encoding gene (CSN2), which encodes the most abundant protein of goat milk, has been cloned and sequenced. The intron/exon organization of the 9.0-kb goat CSN2 gene is similar to that of other CSN2 genes. Expression of the goat gene was principally restricted to the mammary gland of lactating transgenic animals. A low level of expression was also observed in skeletal muscle and skin. In contrast to a rat CSN2 transgene [Lee et al., Nucleic Acids Res. 16 (1988) 1027-1041], the goat gene was expressed to a high degree in the lactating mammary gland. Differences in the content or context of regulatory elements may account for the enhanced performance of the goat relative to the rat CSN2 gene in transgenic mice.

Amino Acid Sequence↗
PubMed1992

Antide bioavailability: single dose administration for suppression of testosterone and inhibin in male monkeys.

The pharmacokinetics and pharmacodynamics of a single sc injection of Antide on testosterone (T) and inhibin secretion in intact male cynomolgus monkeys were examined. Fifteen primates were randomized to three groups receiving: propylene glycol and water vehicle, 3 mg/kg Antide, and 10 mg/kg of Antide. Antide at the 10 mg/kg dose caused long-term suppression of T ranging from 24-56 days. At the 3 mg/kg dose, suppression of T was of shorter duration. Serum Antide levels were significantly greater in the 10 mg/kg group than the 3 mg/kg group (p less than 0.02), both initially and through 35 days post-treatment. The duration of testosterone inhibition and sustained Antide levels were significantly correlated (p less than 0.01). Inhibin concentrations followed the same general pattern as testosterone reaching a nadir on day 21 post-treatment before subsequent recovery. The prolonged suppressive effect of Antide on T without detectable side effects makes this compound an excellent candidate for clinical evaluation.

Animals↗
PubMed1992

GnRH antagonists suppress prolactin release in non-human primates.

GnRH antagonists, such as Antide, are being evaluated for potential contraceptive applications. Although their contraceptive efficacy clearly results from their rapid inhibitory effects on gonadotropin release, there remains the possibility of other incidental effects. Under certain physiological conditions, the release of prolactin (Prl) appears to be temporally related to the secretion of luteinizing hormone (LH) and hence by inference to the secretion of GnRH. Here, we examined the effects of the GnRH antagonist Antide on the release of LH and Prl. Under agonadal conditions, a remarkable concordance was seen between LH and Prl pulses with up to 100% of pulses being coincident. Administration of Antide resulted in a rapid parallel decline in both LH and Prl with LH levels falling by 50% within 2 h and Prl levels falling by 30-40%. At this dose of Antide (1.0 mg/kg, sc), pulsatile release of LH and Prl continued albeit at a much reduced amplitude. The administration of a bolus of exogenous GnRH in the face of GnRHant-induced suppression resulted in prompt release of LH and Prl in all 3 monkeys. Since Antide inhibits the release of LH and Prl in a parallel fashion, and GnRH re-stimulates the release of both hormones in a parallel fashion, we conclude that the synchronous pulsatile release of LH and Prl observed in the agonadal monkey is due to a direct action of GnRH. What this action is for Prl release, and how it relates to the control of dopamine or other neuroendocrine mechanisms normally controlling the release of Prl remains unclear. It also remains to be seen whether this GnRH antagonist-induced suppression of Prl will have physiologic significance.

Animals↗
PubMed1992

Interval required for gonadotropin-releasing hormone-agonist-induced down regulation of the pituitary in cynomolgus monkeys and duration of the refractory state.

OBJECTIVES: To determine the minimal interval of gonadotropin-releasing hormone agonist (GnRH-a) administration required to induce pituitary refractoriness to the positive feedback effects of estradiol (E2) and to determine the duration of the induced refractory state in a nonhuman primate model. SETTING: Research laboratories of The Jones Institute for Reproductive Medicine. SUBJECTS: Cynomolgus monkeys with documented regular menstrual cycles. INTERVENTIONS: Part 1. Groups of four monkeys treated with leuprolide acetate (LA) for increasing intervals (0, 2, 4, 6, and 8 days), then challenged with E2 benzoate to induce a gonadotropin surge. Part 2. Groups of four monkeys treated with LA for the minimal time required to induce pituitary refractoriness (6 days), then challenged with E2 benzoate 2, 4, or 7 days after cessation of LA treatment. MAIN OUTCOME MEASURE(S): Pituitary luteinizing hormone and follicle-stimulating hormone and E2 levels were monitored. RESULTS: A minimum of 5 days of treatment is required for LA to induce pituitary refractoriness to the positive feedback effects of E2 benzoate. Once the down regulated condition is achieved, the refractory state lasts for at least 4 but not more than 6 days. CONCLUSION: The minimal treatment interval required for a GnRH-a to induce pituitary refractoriness to the positive feedback effects of estrogen and the duration of the induced refractory state are determined to be 5 days for these primates.

Animals↗
PubMed1992

Altered glomerular extracellular matrix synthesis in experimental membranous nephropathy.

Chronic progressive membranous nephropathy (MN) in humans is characterized by thickening of the glomerular basement membrane (GBM) with formation of spikes which contain laminin and other extracellular matrix (ECM) proteins. We have utilized two models of MN in the rat (active and passive Heymann nephritis, AICN, PHN) to define the sequential changes in composition of GBM as they relate to changes in glomerular gene expression for ECM components, altered permeability and morphological changes. Renal biopsies obtained during the course of AICN and PHN were immunostained for various ECM proteins and total glomerular RNA was hybridized with cDNA probes specific for laminin B2-chain, s-laminin, and types I and IV collagen. In addition, the ability of anti-glomerular epithelial cell (GEC) antibody and complement on rat GEC in culture to induce laminin release or laminin and s-laminin mRNA expression was determined. The results demonstrate that at weeks 12, 16, and 20 of AICN, immunostaining for laminin, s-laminin, fibronectin, entactin, and heparan sulfate proteoglycan increased in the GBM in a spike-like pattern. Concomitantly, glomerular mRNA levels of laminin B2-chain and of s-laminin increased. Type IV collagen protein and gene expression remained unchanged or decreased. No glomerular immunostaining for type I collagen occurred during AICN despite increased expression of mRNA for this collagen type. In contrast to AICN, in PHN no pronounced changes of the glomerular ECM occurred, except for transient expression of type I collagen mRNA in whole glomerular RNA and type I collagen protein the GEC cytoplasm. Stimulation of GEC in culture with anti-GEC antibody and complement also failed to induce transcription of laminin or s-laminin mRNA or the release of laminin protein. These findings suggest that the polyantigenic expansion of GBM which occurs in chronic experimental MN may be stimulated by factors different from the C5b-9 mediated processes that cause the initial proteinuria.

Animals↗
PubMed1992

Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model.

Increasing evidence supports a role of glomerular cell proliferation in the development of focal or diffuse glomerulosclerosis. This study investigates the chronology and sequence of cellular events that precede glomerulosclerosis in 5/6 nephrectomized rats. Within three days of renal ablation, a phenotypic switch occurred in which some mesangial cells expressed alpha-smooth muscle actin. This was followed by proliferation of mesangial cells, and to a lesser degree endothelial cells from day 5 to week 4 as detected by immunostaining for the proliferating cell nuclear antigen (PCNA). Glomerular cell proliferation was accompanied by increased immunohistochemical expression of PDGF B-chain. In situ hybridization showed no glomerular PDGF B-chain mRNA expression at the induction of proliferation (day 5), and a marked increase between week 1 and 4 in operated rats. In parallel, increased expression of PDGF receptor beta-subunit protein and mRNA was demonstrated by immunohistochemistry and Northern analysis of total glomerular RNA. The onset of glomerular cell proliferation was also associated with mild glomerular platelet accumulation (as defined by 111In-labelled platelet studies) as well as with fibrinogen deposition. Proteinuria, glomerular sclerotic changes, and leukocyte infiltration all followed cell proliferation. The glomerular leukocyte infiltrate consisted of monocytes/macrophages and increased markedly at week 10 in rats with renal ablation. Thus, our results suggest that in the remnant kidney model: 1) proliferation of intrinsic glomerular cells precedes glomerulosclerosis; 2) proliferation may be initiated by degranulating platelets and sustained by PDGF released from intrinsic glomerular cells; and 3) glomerular monocyte/macrophage infiltration occurs after the proliferation, and may possibly contribute to the development of glomerular sclerotic changes.

Actins↗
PubMed1992

Chronic hyperestrogenemia: lack of positive feedback action on gonadotropin-releasing hormone-induced luteinizing hormone release and dual site of negative feedback action.

To test whether sustained midfollicular estrogen concentrations sensitize the pituitary response to GnRH in the continued presence of a GnRH stimulus, six female monkeys with regular menstrual cycles were administered hourly pulses of GnRH in the presence or absence of an sc estrone implant. Three were studied in a sequence of 2- to 8-week blocks of 1) control, 2) hourly pulses of exogenous GnRH (6 micrograms/1 min), 3) hourly GnRH pulses plus an estrone (E1) implant, and 4) the E1 alone. In the other three animals the sequence was 1) control, 2) E1, 3) E1 implant plus hourly GnRH pulses, and 4) GnRH pulses only. E1 increased mean estradiol concentrations from 55 pg/ml to 100 pg/ml and the corresponding E1 concentrations from 95 pg/ml to 160 pg/ml. LH concentrations, excluding midcycle surges, were 10.9 +/- 2.2 (SEM) ng/ml, 12.6 +/- 1.5 ng/ml, 11.7 +/- 1.5 ng/ml, and undetectable (less than 6 ng/ml) for the control, GnRH, GnRH plus E1, and E1-treatment periods, respectively. Of note was the suppression of LH concentrations to undetectable levels by midfollicular concentrations of estrogen during the E1-alone treatment period, and the return of LH concentrations to normal follicular phase levels by the application of exogenous GnRH support. This observation suggested that an estrogen negative feedback signal can suppress endogenous GnRH. To further examine this hypothesis we applied the same protocol to two hypogonadal female monkeys. E1 capsule placement increased the mean estradiol concentration from 22 to 61 pg/ml and suppressed LH and FSH to undetectable levels. When hourly pulses of GnRH (6 micrograms/1 min) were supplied, mean LH and FSH increased to 29.8 and 14.9 ng/ml, respectively. These studies demonstrate that elevation of estrogen concentrations to midfollicular levels does not sensitize the pituitary to GnRH stimulation, and pituitary sensitization is therefore unlikely to be important as a cause of elevated LH secretion in anovulatory states, such as the polycystic ovaries syndrome. In the hypogonadal monkeys, a 5-fold decrease in gonadotropin concentrations occurred in spite of full exogenons GnRH support, consistent with a hypophyseal site of estrogen negative feedback action. However, the GnRH clamp did prevent the complete suppression of LH and FSH noted when only estrogen was applied, consistent with an additional negative feedback effect on the hypothalamus. Although this same phenomenon is observed in the eugonadal monkeys, it appears unlikely that a hypothalamic site of estrogen inhibition plays a significant role during the menstrual cycle, otherwise the progressive rise in follicular phase estrogen concentrations would, by arresting GnRH secretion, abort folliculogenesis.

Animals↗
PubMed1992

Postpartum lactational anovulation in a nonhuman primate (Macaca fascicularis): endogenous opiate mediation of suckling-induced hyperprolactinemia.

The physiological amenorrhea occurring in suckled females has been associated with both hypopulsatile gonadotropin secretion and hyperprolactinemia. To test whether these phenomena are opiate mediated and whether these effects are dependent on the presence of ovaries, we studied six suckled, lactating cynomolgus monkeys, three with intact ovaries and three that were ovariectomized 14 days postpartum. Frequent blood sampling (every 15 min) was performed at approximately monthly intervals using chronic venous catheters accessed remotely via a jacket and tether system. Each monkey was administered saline or naloxone (2 mg bolus then 2 mg/h) by constant infusion, in alternating 6-h blocks. During saline infusions, PRL concentrations varied markedly in a diurnal pattern with concentrations varying from 30-70 micrograms/L during the day and from 100-200 micrograms/L during the night. In both gonadal intact and ovariectomized groups of monkeys naloxone dramatically suppressed and maintained PRL concentrations at less than 20 micrograms/L irrespective of the time of day or the order of administration. The effects of naloxone on gonadotropin concentrations were much less dramatic. In gonadal-intact monkeys, no effect of naloxone was seen on pulse frequency of either FSH or LH, or on mean LH concentration, and only a slight increase was noted in mean FSH concentrations. In ovariectomized monkeys, naloxone was also without effect on pulsatile LH secretion, although mean LH concentrations were slightly higher during naloxone infusions than during saline infusions (P less than 0.05). From these results, we conclude that opiate peptides are released in response to the suckling stimulus in the cynomolgus monkey and that they mediate the effects of suckling on PRL secretion in both gonadal-intact and agonadal cynomolgus monkeys. The lack of effect of opiate blockade on gonadotropin concentrations suggests that multiple pathways may be involved with the inhibition of the GnRH pulse generator during lactational anovulation.

Amenorrhea↗
PubMed1992

Aspartame exacerbates EEG spike-wave discharge in children with generalized absence epilepsy: a double-blind controlled study.

There are anecdotal reports of increased seizures in humans after ingestion of aspartame. We studied 10 children with newly diagnosed but untreated generalized absence seizures. Ambulatory cassette recording of EEG allowed quantification of numbers and length of spike-wave discharges in a double-blind study on two consecutive days. On one day the children received 40 mg/kg aspartame and on the other day, a sucrose-sweetened drink. Baseline EEG was the same before aspartame and sucrose. Following aspartame compared with sucrose, the number of spike-wave discharges per hour and mean length of spike-wave discharges increased but not to a statistically significant degree. However, the total duration of spike-wave discharge per hour was significantly increased after aspartame (p = 0.028), with a 40% +/- 17% (SEM) increase in the number of seconds per hour of EEG recording that the children spent in spike-wave discharge. Aspartame appears to exacerbate the amount of EEG spike wave in children with absence seizures. Further studies are needed to establish if this effect occurs at lower doses and in other seizure types.

Adolescent↗
PubMed1992

Glomerular epithelial cells secrete a glomerular basement membrane-degrading metalloproteinase.

Cultured rat glomerular epithelial cells (GEC) were examined for their ability to release extracellular matrix-degrading proteinases with [3H]gelatin as substrate. GEC-conditioned media, under serum-free conditions, contained modest amounts of gelatinase activity (1 to 10 U/mg of protein); the activity was maximal at neutral pH, was inhibited by zinc chelators, was not inhibited by tissue inhibitor of metalloproteinase-2, and could not be further activated by trypsin or organomercurials. Gelatin substrate sodium dodecyl sulfate-polyacrylamide gels of GEC-conditioned medium revealed several zones of lysis, with molecular sizes of 150 kd (major band), and 220, 86 to 93, and 52 to 54 kd (minor bands). Northern blot analysis demonstrated that the GEC metalloproteinase(s) were distinct from the 68- to 72-kd type IV collagenase/gelatinase present in mesangial cells or the 92-kd type IV collagenase present in neutrophils. The GEC gelatinolytic activity also degraded insoluble type IV collagen in glomerular basement membrane in a dose-dependent manner. The major metalloproteinase activity responsible for the type IV collagen degradation has a molecular size of 150 kd with a type IV collagen substrate gel. Thus, GEC produce several neutral metalloproteinases, which, by virtue of their substrate specificity, may play an important role in glomerular basement membrane remodeling and in glomerular diseases characterized by alterations in basement membrane permeability.

Animals↗
PubMed1992

Markers of complement-dependent and complement-independent glomerular visceral epithelial cell injury in vivo. Expression of antiadhesive proteins and cytoskeletal changes.

BACKGROUND: Visceral glomerular epithelial cells (GEC) are an important component of the glomerular filtration barrier to proteins. While ultrastructural GEC changes have frequently been observed in proteinuric states, no suitable light microscopic markers of GEC injury have yet been identified. EXPERIMENTAL DESIGN: We have analyzed in vivo the GEC expression of proteins known to be involved in cell shape changes. SPARC (osteonectin, BM-40) and tenascin (cytotactin, J1, hexabrachion) belong to a group of anti-adhesive glycoproteins, that modulate cell-matrix interactions. We also studied cytoskeletal intermediate filament proteins, including desmin and vimentin. The GEC expression of SPARC, tenascin, desmin, and vimentin was analyzed in various types of GEC injury in the rat, including complement-mediated injury (passive Heymann nephritis, autologous immune complex nephritis, conA anti-conA nephritis), complement-independent injury (nephrotoxic nephritis), toxic injury (aminonucleoside nephrosis) and hypertensive injury (5/6 nephrectomy, angiotensin-II infusion). A complement-mediated model of mesangial cell injury (anti-Thy 1.1 mesangial proliferative nephritis) served as a control. RESULTS: SPARC mRNA and protein were constitutively expressed in normal rat glomeruli. Immunostaining and immunoelectron microscopy primarily localized SPARC to the cytoplasm of GEC. Markedly increased glomerular SPARC synthesis and GEC immunostaining was observed in all instances of complement-mediated GEC injury but in none of the other conditions. In contrast, glomerular immunostaining for tenascin, that also stained in a GEC pattern, either remained unchanged or increased to a minor degree (complement-mediated models). GEC immunostaining for desmin in normal rats was low and variable, and increased significantly in any form of GEC injury but not in anti-Thy 1.1 nephritis. No concomitant increase of GEC immunostaining for vimentin was detectable, which could have been due to the constitutively high expression of vimentin in GEC. CONCLUSIONS: SPARC and desmin, but not tenascin or vimentin, are suitable light microscopic markers of GEC injury. The combined staining for these proteins may be useful in differentiating the mechanisms of GEC injury.

Animals↗