Falsely elevated urinary ethanolamine levels due to vigabatrin.
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Anticonvulsants↗
Biomedical subjects
K Gordon
Publications and source records attributed to K Gordon.
CANDEES. The Canadian Dry Eye Epidemiology Study.
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Adult↗
Fatal cytophagic histiocytic panniculitis after a short response to cyclosporine.
Cytophagic histiocytic panniculitis (CHP) is a disorder characterized by a histiocytic infiltrate in the subcutaneous adipose tissue which often extends to involve systemic organs. Fever, pancytopenia, hepatosplenomegaly, mucosal ulcers and serositis are common systemic symptoms. Although remissions have been reported, the disease tends to follow a chronic course often complicated by terminal hemorrhagic diathesis and death. Several reports in the recent literature have suggested that cyclosporine is the treatment of choice in CHP. We report the first case of cyclosporine treatment failure in CPH. Despite an initial response to treatment and persistent resolution of cutaneous lesions, the internal disease progressed resulting in the patient's death. Therefore the evolution of skin lesions and signs of systemic involvement may not be an accurate assessment of disease activity in patients with CHP being treated with cyclosporine.
Cyclosporine↗
Stimulatory effect of a specific substance P antagonist (RPR 100893) of the human NK1 receptor on the estradiol-induced LH and FSH surges in the ovariectomized cynomolgus monkey.
Utilizing a human NK1 receptor antagonist (RPR 100893), the present in vivo study was designed to test the hypothesis that endogenous substance P (SP) modulates the action of 17beta-estradiol in inducing luteinizing hormone (LH) and follicle stimulating hormone (FSH) surges in ovariectomized cynomolgus monkey. Plasma concentrations of LH and FSH as well as NK1 receptor antagonist and SP were measured during the development of the negative and positive feedback phases which follow a single administration of estradiol benzoate (50 microg/kg) to long-term ovariectomized monkeys. Daily administration by gastric intubation of 1 mg/kg or 10 mg/kg of the NK1 receptor antagonist (RPR 100893) leads to detectable levels of the antagonist in the blood of treated animals for at least 6 hr after its administration. These levels are in agreement with the experimentally determined IC50 value of the antagonist. The most striking finding of this study is that LH and FSH releases are enhanced during the descending arm of the estradiol benzoate-induced LH and FSH surges, which suggests that endogenous SP normally has an inhibitory role during this time. The enhancement of LH release is approximately 50%, regardless of the amount of the NK1 antagonist used. However, the enhanced FSH release is more important. Furthermore, blockade of the NK1 receptor with the smaller dose of the antagonist leads to a small, but significant, increase in plasma levels of SP, indicating that blockade of SP receptors leads to an increased release of SP. Collectively, these results further substantiate the link which exists between the ovarian steroid 17beta-estradiol and SP systems. Also, for the first time, these results demonstrate an inhibitory involvement of the human NK1 receptor in the 17beta-estradiol-induced pseudo-ovulatory gonadotropin surges in the ovariectomized monkey.
Animals↗
Neandertal incisor beveling.
In discussions of the Neandertals, there has been repeated emphasis on the accelerated rate of attrition and the frequent presence of labial beveling of their incisors. Interpretations of this dental attrition have related it to paramasticatory and dietary uses of their anterior teeth as well as to aspects of their facial morphology. In light of this, we examined the rate of beveling (the angle between the labial and incisal surfaces) of central incisors relative to tooth wear in samples of Neandertals, Inuits and Puebloan Amerindians. I1s show little change in the beveling angle with wear and no significant differences between the samples. I1s, however, exhibit a consistent pattern of increased beveling with dental attrition, progressing rapidly until the crown height approximates its labiolinguinal cervical diameter, and then proceeding at a slower rate. All three samples exhibit a similar pattern. However, the Neandertals have significantly greater beveling in more worn teeth than either recent human sample, and the Inuits have nonsignificantly increased beveling relative to the Puebloans in these more worn I1s. In this, it is the degree of development of beveling, not the pattern of beveling, which differentiates the Neandertals. It is hypothesized that the differences between the Neandertals and recent samples could be the product of: (1) contrast in initial incisor procumbency, (2) a labial separation of the maxillary and mandibular incisal occlusal surfaces during edge-to-edge bite, and/or (3) a greater degree of interproximal wear promoting increased "posterior tipping" of the maxillary incisors. The last appears most likely.
Animals↗
If a first antiepileptic drug fails to control a child's epilepsy, what are the chances of success with the next drug?
OBJECTIVE: This study was carried out to determine how often a child's epilepsy is controlled and remits if a first antiepileptic drug (AED) fails to control seizures. STUDY DESIGN: We used the Nova Scotia population-based epilepsy study, which identified children between 1977 and 1985 who had two or more unprovoked seizures without progressive cause and followed them up for at least 4 years. Seizure types were partial, primary, and secondarily generalized (excluding absence seizures). The study documented success or failure of the initial AED in the first year of treatment, as well as long-term seizure control and remission. RESULTS: The number of eligible children was 417, with an average follow-up period of 8 years. The initial prescribed AEDs were phenobarbital (48%), carbamazepine (38%), and phenytoin (11%). Overall, 345 (83%) children received only one AED in the first year of treatment; 61% became free of seizures and no longer required AED treatment at the end of follow-up (remission). Only 4% of those treated with a single AED during the first year later experienced intractable epilepsy. In contrast, 72 of 417 (17%) had inadequate seizure control with their first AED and received a second AED, with only 42% having complete remission of their epilepsy. The 72 children in whom seizures were not controlled with the first AED were more likely to have neurologic deficits (p = 0.01) and complex partial seizures (p = 0.01), and 29% had intractable epilepsy (p < 0.0001). CONCLUSIONS: If the first AED is not efficacious, the outcome is less favorable, although many children will have remission of their epilepsy. Invasive or complex treatments for epilepsy with partial and generalized tonic-clonic seizures should not be used until at least two AEDs have failed to control seizures.
Age of Onset↗
Vomiting after mild head injury is related to migraine.
OBJECTIVE: To determine whether vomiting after mild head injury in children is related to migraine and to identify predictors of vomiting after head injury. METHODS: A series of consecutive children admitted to the observation unit of an emergency department after mild head injury was identified by chart review. A telephone interview with the parents or child or both was then conducted by using a structured questionnaire. RESULTS: Of 47 eligible children with acute head injury, 44 (94%) were contacted. The mean age at head injury was 7.4 years. Twenty-nine children (66%) vomited after the head injury. The likelihood of vomiting was increased if the child had a history of recurrent headache (p = 0.05). If the headaches were migrainous, the likelihood of vomiting increased further (p <0.002). All 15 children with a history of motion sickness vomited after the head injury. Family history of migraine, particularly maternal (n = 21), also predicted recurrent vomiting (p <0.001). If more than one of these predictive variables was present, the likelihood of vomiting was 100%. CONCLUSIONS: History of motion sickness, migraine headaches, and family history of migraine are highly predictive of vomiting after a mild head injury.
Acute Disease↗
Pediatric pseudotumor cerebri: descriptive epidemiology.
OBJECTIVE: To determine the epidemiological profile for pediatric pseudotumor cerebri. METHODS: A retrospective case series was identified from a geographically limited region of 205,765 children aged 2-15 years at the only tertiary care pediatric hospital with all pediatric neurologists and ophthalmologists. Health records identified 35 children with ICD9 code 348.2 (benign intracranial hypertension) presenting between April 1, 1979 and March 31, 1994. After chart review, 29 cases were identified which satisfied modified Dandy's diagnostic criteria for pseudotumor cerebri. RESULTS: The 29 cases ranged in age from 3-15 years. The annual incidence of symptomatic disease was 0.9 per 100,000 children (95% CI 0.6, 1.4). Cases were 2.7 times more likely to be female (21/29, X2 p = .01) and twice as likely to be adolescent (age 12-15 years), (X2 p = .04). Based upon these distinctions, the following estimates of age and sex specific disease incidence were derived (based upon 100,000 child years of exposure): male age 2-11 years: 0.4; male age 12-15 years: 0.8; female age 2-11 years: 1.1; female age 12-16 years: 2.2. CONCLUSIONS: These data appear to be unique for its the estimation of age and sex specific incidence rates for pediatric pseudotumor cerebri.
Adolescent↗
A patient questionnaire approach to estimating the prevalence of dry eye symptoms in patients presenting to optometric practices across Canada.
OBJECTIVE: To collect questionnaire data from patients in a large clinical population that would allow for an estimate of the prevalence of self-reported symptoms of dry eyes. METHODS: A 13-point questionnaire (The Canada Dry Eye Epidemiology Study, CANDEES) was mailed to all optometric practices in Canada in October 1994, with the request that it be completed by 30 successive nonselected patients. RESULTS: Four hundred fifty sets of questionnaires (total, 13,517) were analyzed (a 15.7% return rate) from patients aged from < 10 years to > 80 years; 55% were in the 21- to 50-year age group; 60.7% were female; and 24.3% were contact lens wearers. A total of 28.7% reported dry eye symptoms, of whom 24.2% reported concurrent dry mouth, 24.5% had worse symptoms in the morning, 30.3% reported concurrent lid problems, and 35.7% reported a history of allergies. Of the 3716 patients reporting symptoms, 62 (1.6%) were in the "severe" category and 290 (7.8%) were in the "constant but moderate" category. Contact lens wear, concurrent allergies, dry mouth, lid problems, or use of medications increased the chance of a patient reporting dry eye symptoms. CONCLUSIONS: The prevalence of patients reporting any level of symptoms of dry eyes was approximately 1 in 4; severe symptoms were reported by 1 in 225 patients.
Adolescent↗
Metachromatic leucodystrophy in three families from Nova Scotia, Canada: a recurring mutation in the arylsulphatase A gene.
Metachromatic leucodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulphatase A. We have identified a child with infantile onset MLD who is homozygous for an A212V mutation, a mutation previously reported but not further characterised. We have introduced this mutation into an arylsulphatase A expression vector by site directed mutagenesis. Transient expression of this mutant plasmid in COS cells yields very low levels of arylsulphatase A activity consistent with the patient's phenotype. The arylsulphatase A pseudodeficiency also segregates in this family causing difficulty in interpreting enzyme levels in the absence of DNA data. Two other patients from the same province, also carrying the A212V allele, have juvenile and adult onset MLD and are heterozygous for P426L ("A" allele) and I179S alleles respectively, known late onset alleles.
Adult↗
Neutrophil fate in experimental glomerular capillary injury in the rat. Emigration exceeds in situ clearance by apoptosis.
Neutrophils (PMNs) and their toxic contents can injure glomeruli, but to date their fate in glomerulonephritis has been unknown. We studied glomerulonephritis induced in rats by formation of concanavalin A (Con A)/anti-Con A immune complexes on glomerular endothelial cells. PMN infiltration, which was almost exclusively confined to the lumen of glomerular capillaries, was transient, peaking at 4 hours, with only 9.0 +/- 4.1% (mean +/- SEM) of the maximum remaining at 24 hours. There was clear evidence of PMN apoptosis leading to phagocytosis in situ by intraluminal macrophages. However, the kinetics of leukocyte infiltration and PMN apoptosis, the preferential location at 24 hours of apoptotic PMNs within occluded capillary loops, and tracking of radiolabeled PMNs all indicated that in situ phagocytic clearance after apoptosis was the fate of a minority of PMNs, amounting to no more than one-fifth of the peak infiltrating load. Instead, the majority of infiltrating PMNs (72.9 +/- 3.1%) had emigrated from inflamed glomeruli by 24 hours, apparently returning to the circulation. We conclude that PMN emigration from inflamed glomeruli is a hitherto unrecognized mechanism for regulation of PMN-mediated glomerular injury.
Animals↗
The Paediatric Cochlear Implant Program at the Hospital for Sick Children, Toronto.
Ontario has a province-wide program for provision of cochlear implants. Toronto's Hospital for Sick Children is one of three designated centres that service the paediatric population. This cochlear implant program was established in 1989. Since that time, 37 children (as of May 1996) have been provided with cochlear implants. The program also services Ontario residents who were implanted elsewhere. In the following, we provide a detailed description of the program, including the processes through which children are selected as candidates, the follow-up studies that we carry out, and the roles of various health care professionals involved. We present a demographic survey of our patient population to date, and discuss some of the important issues relating to candidacy.
Child, Preschool↗
The cytoskeletal linking proteins, moesin and radixin, are upregulated by platelet-derived growth factor, but not basic fibroblast growth factor in experimental mesangial proliferative glomerulonephritis.
The expression of the two cytoskeletal linking proteins, moesin and radixin, was examined in experimental mesangial proliferative nephritis in rats (anti-Thy1 model). Moesin and radixin mRNA and protein are constitutively expressed in all cell types of normal rat glomeruli, except podocytes. In the anti-Thy1 model the expression of moesin and radixin was increased in infiltrating macrophages and in activated, alpha-smooth muscle actin-positive mesangial cells and was concentrated in the cellular extensions of mesangial cells in areas of glomerular remodelling. Studies using neutralizing antibodies demonstrated that the increase in moesin and radixin expression by mesangial cells is mediated by PDGF, but not bFGF. The increase in these cytoskeletal proteins appears to be regulated primarily (radixin) or partially (moesin) posttranscriptionally. The data suggest that PDGF mediated upregulation of the cytoskeletal proteins, moesin and radixin, is important for cell migration and other changes that accompany the coordinated restoration of glomerular architecture after injury.
Actins↗
Multiple transcription start sites for the GnRH gene in rhesus and cynomolgus monkeys: a non-human primate model for studying GnRH gene regulation.
In humans, transcription of the gonadotropin-releasing hormone (GnRH) gene can be initiated at two transcription start sites to produce different GnRH mRNAs. The upstream transcription start site is used only in reproductive tissues and tumors. To determine if a similar pattern of GnRH gene expression exists in non-human primates, we cloned GnRH cDNA from rhesus monkey hypothalamic RNA using reverse transcriptase-polymerase chain reaction (RT-PCR) and the 5' flanking region of the monkey GnRH gene by PCR. A 96% similarity between monkey and human GnRH cDNA was found with 94% similarity in the upstream promoter region. An upstream transcriptional start site, was identified in cynomolgus monkey testicular mRNA, 504 base pairs upstream from the hypothalamic site, which was different from that identified in the human GnRH gene. Various cynomolgus monkey reproductive tissues were found to utilize this upstream transcriptional start site. In contrast, no evidence was found for the use of upstream transcriptional start sites in rat testis or placenta, suggesting that the reproductive tissue specificity of the upstream transcription start site may be a primate specific feature.
Amino Acid Sequence↗
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↗
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↗
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↗