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Biomedical subjects

K Gordon

Publications and source records attributed to K Gordon.

At least 55 records · Page 3Linked to original sources
PubMed1996

Effects of caffeine and dbcAMP on zona pellucida penetration by epididymal spermatozoa of cynomolgus monkeys (Macaca fascicularis).

Spermatozoa mature during epididymal transit, acquiring the abilities to swim progressively, fertilize oocytes, and produce viable offspring. In this study, we investigate the capacity of spermatozoa retrieved from the midcorpus and distal cauda regions of the epididymis of the cynomolgus monkey to penetrate homologous zona pellucida. Successful in vitro fertilization by ejaculated macaque sperm is dependent upon the addition of caffeine and dbcAMP. Therefore, the effect of these cyclic nucleotide mediators was also examined in this study. Results of sperm motion analysis indicate no difference in baseline values (without stimulators) for any motion parameter. With the addition of caffeine and dbcAMP, curvilinear velocity significantly increased only for the distal cauda sperm (P = 0.05). Amplitude of the lateral head displacement was significantly increased for distal cauda sperm (P < 0.01); although elevated above baseline, the increase observed after activation by corpus sperm was significantly lower than that achieved by cauda sperm (P < 0.05). The addition of caffeine and dbcAMP was an absolute requirement for zona penetration by both midcorpus and distal cauda sperm. With activation, zona penetration was significantly decreased for corpus sperm compared to cauda sperm (P < 0.001). These results suggest that cynomolgus monkey sperm reaching the midcorpus region of the epididymis have not completed all of the maturational changes requisite for successful fertilization; this immaturity is evidenced by decreased sperm motion and by impedance at the level of zona penetration.

Animals↗
PubMed1996

Inhibition of ovulation by progestin analogs (agonists vs antagonists): preliminary evidence for different sites and mechanisms of actions.

Continuous administration of the antiprogesterone RU486 inhibits ovulation in women and in monkeys; in this regard RU486 may act as a progestin agonist rather than as an antagonist. We compared the site(s) and mechanism(s) of RU486-induced ovulation inhibition with those of levonorgestrel (LNG). Six regularly menstruating cynomolgus monkeys each received placebo, RU486 (1 mg/kg/d) or LNG (2 g/kg/d) i.m. between days (cd) 2-22 of three separate menstrual cycles. Serum levels of estradiol (E2), progesterone (P4), androstenedione, LH and FSH were analyzed by RIAs in daily blood samples. Basal and GnRH-stimulated (1 and 50 g of GnRH i.v. 2 h apart) secretion of LH and FSH was assessed using serial blood samples collected for 12 h on cd 10. Mean cycle length was prolonged by RU486 and LNG treatments from 32 d to 70 d and 52 d, respectively (p < 0.02). Ovulation was inhibited in five of the six primates during RU486, and in all six during LNG treatment. During RU486 treatment, serum E2 levels were similar to those of the control cycle; despite peaks of E2 secretion, no LH peaks were seen. In contrast, E2 concentrations were profoundly suppressed during LNG treatment (p < 0.005). The reduction in serum E2 was accompanied by lower levels of androstenedione, and suppressed ratio of E2/androstenedione (p < 0.02) suggesting both reduced synthesis and aromatization of androgen precursors during administration of LNG. Consequently, LNG treatment was associated with higher levels of serum FSH and LH (p < 0.001; 1-way ANOVA). Similarly, as during the luteal phase of the menstrual cycle, the amplitude of basal LH-pulses was increased during LNG treatment (p < 0.05), whereas RU486 treatment did not affect basal LH secretion. The GnRH-stimulated release of LH was similar during the placebo, RU486 and LNG cycles; enhanced release of FSH was seen during administration of LNG. Thus, in the present model system, RU486 seems to inhibit ovulation mainly at the level of hypothalamus, possibly by interfering with the steroidal positive feedback signals from the ovary. However, LNG inhibits ovulation differently, most likely via direct progesterone-like effects on folliculogenesis and the hypothalamus. The pituitary does not appear to be the major site of action(s) of RU486 or LNG. Thus, the differential mechanisms of ovulation inhibition by RU486 and LNG seem to result from lesser intraovarian impact of RU486 as well as dissimilar influences on tonic gonadotropin secretory levels. We conclude that when inhibiting ovulation, RU486 does not act as a progestin agonist, but rather, functions through a hypothalamic mechanism(s), which might be unique to RU486 as a progesterone antagonist.

Analysis of Variance↗
PubMed1996

Ectopic growth of endometrium depends on its structural integrity and proteolytic activity in the cynomolgus monkey (Macaca fascicularis) model of endometriosis.

OBJECTIVE: To identify factors influencing the development of endometrial autografts in a monkey model of endometriosis. DESIGN: Prospective, comparative study. SETTING: Animal research unit. SUBJECTS: Thirty regularly cycling cynomolgus monkeys in three groups of 10 each. INTERVENTIONS: Endometrium was minced and spilled into the cul-de-sac in group 1. In group 2, the tissue additionally was digested enzymatically. In group 3, the tissue was incubated with a protease inhibitor. MAIN OUTCOME MEASURES: Staging laparotomies after 3 weeks and 3 months. RESULTS: In groups 1, 2, and 3, moderate or severe disease was seen in eight, two, and four monkeys, respectively, after 3 weeks and in eight, three, and two monkeys, respectively, at 3 months. CONCLUSIONS: An intact structure leads to ectopic implantation of endometrial fragments in most cases. Conversely, enzymatic digestion of endometrial fragments and treatment with proteinase inhibitor impair ectopic growth. Intrinsic endometrial factors that influence extracellular matrix remodeling may play a role in the pathogenesis of human endometriosis.

Animals↗
PubMed1996

Endometrial effects of RU486 in primates--antiproliferative action despite signs of estrogen action and increased cyclin-B expression.

Continuous antiprogestin administration to hormone replaced, castrate monkeys inhibits estrogen-induced endometrial proliferation through mechanisms which remains unclear. To elucidate the molecular mechanisms of RU486-induced endometrial suppression, we treated six intact female cynomolgus monkeys on cycle days 2-22 sequentially with placebo, RU486 (1 mg/kg/day) and levonorgestrel (LNG) (2 microg/kg/day) intramuscularly (i.m.), with uterine wedge sections and endometrial biopsies collected on day 22 of each cycle. The uterine sections were evaluated for morphology, mitosis and proliferating cell nuclear antigen (PCNA) immunohistochemistry. Changes in the mRNA levels of ER, PR, cyclin-B and tumour suppressor gene p21 were assessed using co-amplification with beta-actin by reverse transcriptase-polymerase chain reaction (RT-PCR). Administration of RU486 uniformly resulted in characteristic suppression of endometrium with few mitosis, dense stroma and simple glands, whereas the effects of LNG were less uniform. Following RU486 administration, the levels of endometrial ER and PR mRNA were comparable to proliferative phase endometrium, and significantly higher than those seen in the secretory endometrium, indicating that some of the biological actions of E2 were not inhibited during RU486 treatment. Despite scarce mitosis, PCNA was readily detectable in all samples. Curiously, in comparison to secretory phase controls, the levels of cyclin-B, but not p21, mRNA were markedly increased following RU486. The effects of LNG on the levels of these mRNA species varied, with mean levels falling between those of the secretory phase controls, and RU486-treated specimens. The increase in cyclin-B mRNA and lack of mitosis suggests that anti-proliferative actions of RU486 in the primate endometrium might be associated with a cell-cycle block at the G2-M interphase. Whether mechanisms similar to these are associated with the beneficial clinical effects of RU486 seen in the treatment of various hormone dependent maladies remains to be determined.

Animals↗
PubMed1996

Role of the complement membrane attack complex (C5b-9) in mediating experimental mesangioproliferative glomerulonephritis.

Previous studies have demonstrated that most pathologic changes in the antithymocyte serum (ATS) model of mesangioproliferative glomerulonephritis are complement-dependent. These include mesangiolysis, glomerular platelet infiltration, mesangial cell proliferation, mesangial cell production of growth factors and phenotypic change to express alpha-actin, glomerular macrophage infiltrate, mesangial matrix expansion, and proteinuria. The mechanism by which complement mediates these effects has not been defined. Because neutrophils do not participate in the ATS model, we hypothesized that the complement effects observed are consequent to glomerular cell insertion of the C5b-9 membrane attack complex of complement. This hypothesis was tested utilizing PVG rats which exhibit an absence of C6 inherited in an autosomal recessive pattern. C6 deficient (C-) PVG rat serum activated by zymosan produced normal amounts of C5a compared to normocomplementemic (C+) PVG rat controls but no C5b-9. When ATS was induced, C- PVG rats had a significant and marked reduction in mesangiolysis, platelet infiltration, mesangial cell proliferation, alpha-actin expression, macrophage infiltration, collagen IV deposition, and proteinuria compared to C+ controls. The reduction in each of these parameters was comparable to that achieved by systemic complement depletion of C+ PVG rats with cobra venom factor. These findings establish the role of C5b-9 in mediating each of the complement-dependent features of the ATS model and indicate that C5b-9 accounts for all of the complement-mediated effects observed. This study provides the first documentation of a functional role for C5b-9 in mediating a non-membranous inflammatory type of glomerular injury in vivo.

Animals↗
PubMed1996

MRI and nonverbal cognitive deficits in children with neurofibromatosis 1.

Magnetic resonance imaging brain scans and neuropsychological assessments of 17 children who met the NIH consensus diagnostic criteria for neurofibromatosis Type 1 were carried out in order to determine if there is a relationship between presence of high intensity signal abnormalities on MRI scans and nonverbal cognitive deficits. Cranial MRI scans in 10 patients (58.8%) demonstrated high intensity signal abnormalities, most frequently in the cerebral peduncles. Fifteen patients had nonverbal cognitive deficits (88.2%), including difficulty judging the orientation of lines, matching complex visual stimulus configurations, recalling pictures of faces, as well as copying and drawing from memory a complex geometric figure. There was not a significant association between nonverbal neuropsychological deficits and presence of high intensity signal abnormalities on MRI scans, possibly because the location of these hyperintense abnormalities was typically below the level of the basal ganglia. These findings suggest that the high intensity signal lesions seen on the MRI scans of children with neurofibromatosis Type 1 do not predict or explain their nonverbal cognitive deficits.

Adolescent↗
PubMed1996

An observational asthma study alters emergency department use: the Hawthorne effect.

The objective of this study was to document that an observational study decreases the use of the emergency department (ED) for asthma. Comparison of rates between an audit and prospective period were used at a regional referral pediatric hospital ED. A total of 526 asthma visits from February 12, 1992, to April 10, 1992, were examined in an initial audit and compared to 725 visits during a prospective study from May 16, 1993, to September 29, 1993. A physician check list for medications and follow-up plans was utilized during the prospective study. The rate of repeat visits and admissions was compared between the audit and the prospective periods. In the audit, 422 asthma patients were seen, and there were 68 repeat visits within one week of the initial visit and 153 admissions. For 29 of the 68 repeat visits there was no documentation that medication had been increased after the initial visit. No follow-up plans were recorded in 275 of the 526 visits. During the prospective period 668 children presented to the ED with asthma, and 346 were enrolled into the study on risks for repeat visits. There were 57 repeat visits and 89 admissions. The repeat visit rate during the prospective period was 9 and 8%, respectively, in the enrolled and nonenrolled subjects. The repeat visit and admission rate decreased during the prospective period as compared to during the audit by 39% (P = 0.004) and 58% (P < 0.0001), respectively. A possible explanation for the difference in admission and repeat visit rates between the audit and prospective study is that physicians' behavior may have been altered by the awareness that their behavior was being closely monitored during the study.

Asthma↗
PubMed1996

Incidence of epilepsy in childhood and adolescence: a population-based study in Nova Scotia from 1977 to 1985.

Data from a regional EEG laboratory allowed us to identify almost all children in Nova Scotia (population 85,000) with one or more unprovoked, afebrile seizures from 1977 through 1985. We then reviewed hospital and pediatric neurology physician charts to limit cases to those with two or more definite afebrile seizures between the ages of 1 month and 16 years. In all, 693 children developed epilepsy: typical childhood absence seizures (AS) (97), either generalized tonic-clonic (GTCs) or partial seizures either secondarily generalized or not (511), and other generalized seizure types, including infantile spasms (IS) as well as myoclonic, akinetic, tonic, and atypical AS (85). The incidence of epilepsy was 118 in 100,000 for children aged less than 1 year, 48 in 100,000 for those aged 1-5 years, 43 in 100,000 for those aged 6-10 years, and 21 in 100,000 for those aged 11-15 years. The incidence for each year of age between 1 and 10 years was remarkably constant (mean 46 in 100,000 +/- 7 SD). Comparison of the incidence rates showed significant differences for those aged less than one year as compared with all others, and for those aged greater than 10 years as compared with those aged 1-10 years. We conclude that the incidence of epilepsy is highest in the first year of life, plateaus in early childhood, and decreases markedly after age 10 years. The overall incidence of epilepsy in childhood is lower than that reported in previous studies.

Adolescent↗
PubMed1996

Families are content to discontinue antiepileptic drugs at different risks than their physicians.

PURPOSE: To define the risk of seizure recurrence (RSR) that families and physicians would accept before discontinuing antiepileptic drugs (AEDs) for children with controlled epilepsy. METHODS: A questionnaire was completed by families of 76 children with epilepsy > or = 3 months seizure-free and by their attending epilepsy specialist (n = 4). RESULTS: Forty-two percent of families were unwilling to discontinue AEDs with an RSR of 25%. In contrast, 20% were willing to accept a > 75% RSR. Several factors differentiated the risk acceptable to families: previous seizure frequency (risk adverse with intermediate frequency), multiple seizure types (risk taking), grade or grades repeated in school (risk adverse), and the family's strategy of playing lotteries. Although families and physicians were prepared to accept similar median RSR (35 and 40%, respectively), individual answers did not correlate (r2 = -0.07). Physicians were unable to predict the families response (r2 = 0.09). CONCLUSIONS: Our current practice is to discontinue AEDs after 2 years of seizure-free results in seizure recurrence of 30-40%. This risk may seem excessive to more than half of families, whereas other families will risk stopping AEDs at higher risks of recurrence. Physicians are poor judges of the degree of risk that is acceptable to a particular family, which may account in part for the anxiety manifested by families at AED discontinuation.

Adolescent↗
PubMed1996

Valproic acid treatment of learning disorder and severely epileptiform EEG without clinical seizures.

Using a single-patient (n = 1) clinical trial, we studied a 7-year-old boy who presented with unsatisfactory progress in school and whose electroencephalogram had very active independent frontal spike discharges. He had not had clinical seizures. The patient was randomized to receive valproic acid, 125 mg twice daily, (four periods) or matching placebo (four periods) over 8 weeks. Primary endpoints were the Wechsler Intelligence Scale for Children-Revised Coding sub-test and a handwriting sample. Behavior was monitored using teacher's and parent's Conners questionnaires. His score on the Wechsler Intelligence Scale for Children-Revised Coding subtest was significantly improved while he was taking valproic acid (P = .03). His electroencephalogram improved from a pretreatment recording of 28 spike discharges per minute to a normal recording while on valproic acid. We conclude that in this patient, valproic acid had a cognitive enhancing effect, probably by reducing epileptiform discharges.

Anticonvulsants↗
PubMed1996

Lamotrigine-induced rash in children.

Of 68 children treated with lamotrigine, a new antiepileptic medication, five developed a rash. One child developed Stevens-Johnson syndrome on lamotrigine monotherapy. Of the five patients with the rash, three were admitted to the hospital (two to the intensive care unit). All recovered completely, but one child had a recurrence of the rash within 30 minutes of reexposure to lamotrigine after 6 months.

Adult↗
PubMed1996

Does the number of seizures before treatment influence ease of control or remission of childhood epilepsy? Not if the number is 10 or less.

Using a population-based regional cohort of 479 children with epilepsy, we studied the effect of the number of pretreatment afebrile seizures on seizure control and remission. The number of pretreatment seizures varied from 1 to 20. For the first 10 pretreatment seizures, there was no significant difference or trend in (1) the proportion of children who were seizure free long enough to attempt stopping medication (mean, 70%), (2) the number of breakthrough seizures before control was achieved, or (3) the proportion of children who were seizure free after stopping medication for the first time (mean, 70%). More patients with more than 10 pretreatment seizures had complex partial seizures (59%) than those with 10 or fewer seizures (16%) (p < 0.00001). We conclude that there does not appear to be any penalty for seizure control or early remission of epilepsy if medication is delayed for up to 10 pretreatment seizures.

Adolescent↗
PubMed1996

Discontinuation of anticonvulsant therapy in children free of seizures for 1 year: a prospective study.

We studied 97 children who were weaned from antiepileptic drug therapy 1 year after their last seizure. Medication was withdrawn over 4 to 8 weeks, and patients were followed for 12 to 57 months (32.4 +/- 13.1; mean +/- SD) or until seizure recurrence. The overall probability of remaining seizure free was 78% at 3 months, 71% at 6 months, 66% at 12 months, and 61% at 24 months (95% CI, 51, 71), similar to studies that have required longer treatment periods. Factors retained in multivariate analysis were female sex, age at seizure onset over 120 months of age, seizure type, and clinical evidence of neurologic abnormalities. Using these risk factors, a simple method of predicting the 24-month recurrence risk was possible.

Anticonvulsants↗
PubMed1996

The effect of coculture on the postfertilization development of in vitro-matured monkey oocytes.

OBJECTIVE: To determine if the developmental potential of embryos resulting from in vivo- and in vitro-matured monkey oocytes could be increased through the use of a coculture system. DESIGN: Randomized prospective comparison of embryos resulting from either in vitro- or in vivo-matured oocytes cocultured with Vero cells or cultured in medium alone (control). SETTING: Basic research laboratory. MAIN OUTCOME MEASURES: In vitro embryo development to the blastocyst stage and blastocyst hatching. RESULTS: No significant difference in development was noted between coculture and control groups with embryos resulting from in vivo-matured oocytes. However, coculture was found to improve significantly the development of monkey embryos resulting from in vitro-matured oocytes. CONCLUSIONS: These results demonstrate that primate embryos resulting from in vitro-matured and in vitro-fertilized oocytes differ in their culture requirement when compared with embryos resulting from in vivo-matured oocytes.

Animals↗
PubMed1996

The molecular composition of neuronal microfilaments is spatially and temporally regulated.

The actin-based microfilament system is thought to play a critical role in neuronal development. We have determined specific changes in the composition of microfilaments accompanying neuronal morphogenesis. By using specific antibodies against the isoforms for tropomyosin (Tm) (Tm-5 and TmBr-1/-3) and actin (beta- and gamma-actin), we found that during early morphogenesis in vivo immature growing axons contain beta- and gamma-actin and Tm-5. In particular, Tm-5 is exclusively located in the immature axonal processes relative to the neuronal cell body. In contrast, beta-actin and Tm-5 are absent in mature, quiescent axons. This developmental loss from axons is associated with an approximately twofold downregulation of beta-actin and Tm-5 levels in the brain; gamma-actin levels do not change, and this molecule is widely distributed throughout neurons during development. The loss of beta-actin and Tm-5 from axons is accompanied by a progressive appearance of TmBr-1/-3. This apparent replacement of Tm-5 with TmBr-1/-3 occurs over a 2 d time period during rat embryonic hindbrain development and is conserved in evolution between birds and mammals. The loss of Tm-5 from axons involves a redistribution of this molecule to the cell soma and dendrites. These findings suggest that specialized microfilament domains are associated with the development and maintenance of neuronal polarity. We conclude that these Tm isoforms and beta-actin are subject to specific patterns of segregation associated with axonal development and neuronal differentiation. This provides a potential molecular basis for the temporal and spatial specificity of microfilament function during neuronal differentiation.

Actin Cytoskeleton↗
PubMed1995

Activation of the hypothalamo-anterior pituitary corticotropin-releasing hormone, adrenocorticotropin hormone and beta-endorphin systems during the estradiol 17 beta-induced plasma LH surge in the ovariectomized monkey.

The present work describes time-dependent changes in the content of corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH), and beta-endorphin (beta-EP) in the hypothalamus (HT) and anterior pituitary (AP) and in the concentration of ACTH and beta-EP in the plasma during the 17 beta estradiol (E2) benzoate (E2B)-induced luteinizing hormone (LH) surge in ovariectomized cynomolgus monkeys. Monkeys were euthanized at 0, 30, 48, 72, and 96 hr post-E2B. HT and AP were rapidly dissected, extracted in 2 N acetic acid containing 1 mM phenylmethane sulfonyl fluoride at 4 degrees C, and centrifuged at 18,000g for 30 min. Peptide concentrations were measured in the supernatant by specific radioimmunoassays (RIAs). In the HT, there were significant (P < 0.05) decreases in ACTH and beta-EP content by 30 hr post-E2B and a significant (P < 0.05) decrease in HT CRH content 48 hr post-E2B. Thereafter, CRH, ACTH, and beta-EP content increased up to 72 hr post-E2B. In the AP, there was an almost linear decrease in the CRH content through 48 hr post-E2B followed by a marked 20-fold (P < 0.01) increase in the AP CRH content at 72 hr post-E2B, which corresponds to the time of the descending arm of the LH surge. The patterns of ACTH and beta-EP content were very similar in the AP, while that of CRH differed markedly. In contrast, in the HT CRH, ACTH, and beta-EP profiles were very similar. Significant (P < 0.05) increases in circulating levels of ACTH, beta-EP, and cortisol were evident at 30 hr (all 3 hormones), 48 hr (beta-EP and cortisol), and 72 hr (cortisol) post-E2B, which corresponds with the time of decreased hypothalamic content of CRH, ACTH, and beta-EP. These results suggest that there maybe a marked activation of the hypothalamo-anterior pituitary-adrenal axis during the negative and positive feedback phases of the E2B-induced LH surge in the ovariectomized monkey.

Adrenocorticotropic Hormone↗
PubMed1995

Use of a spherical multiparameter transducer for flow cytometry.

Fused silicon dioxide, multiparameter flow transducers with 50 microns internal square cross section and approximately 60 microns length can simultaneously measure DC and RF impedance as well as fluorescence and multiple-angle light scattering. A spherical version of such a transducer was mounted in an EPICS CVA flow-cell housing and was installed on a research prototype equipped with an argon-ion laser. The signal that was produced by the spherical transducer with EPICS DNA-Check beads was 1.73 times greater than that produced with the standard cylindrical flow cell. Similarly, with EPICS Immuno-Brite beads, the average ratio was 1.96. The Coulter impedance and light-scattering measurements were similar to those produced with the conventional cylindrical outside flow cell, although the internal cross section of the sphere was square and that of the cylinder was circular. The theoretical arguments of Leif and Wells have been demonstrated to be correct. At present, monolithic, spherical fused-silica transducers are the optimal design for combined electrooptical, multiparameter flow cytometry analyzers.

Blood Cells↗