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Biomedical subjects

T McCarthy

Publications and source records attributed to T McCarthy.

At least 19 recordsLinked to original sources
PubMed2000

Genetics and pathogenesis of malignant hyperthermia.

Malignant hyperthermia (MH) is a potentially life-threatening event in response to anesthetic triggering agents, with symptoms of sustained uncontrolled skeletal muscle calcium homeostasis resulting in organ and systemic failure. Susceptibility to MH, an autosomal dominant trait, may be associated with congenital myopathies, but in the majority of the cases, no clinical signs of disease are visible outside of anesthesia. For diagnosis, a functional test on skeletal muscle biopsy, the in vitro contracture test (IVCT), is performed. Over 50% of the families show linkage of the IVCT phenotype to the gene encoding the skeletal muscle ryanodine receptor and over 20 mutations therein have been described. At least five other loci have been defined implicating greater genetic heterogeneity than previously assumed, but so far only one further gene encoding the main subunit of the voltage-gated dihydropyridine receptor has a confirmed role in MH. As a result of extensive research on the mechanisms of excitation-contraction coupling and recent functional characterization of several disease-causing mutations in heterologous expression systems, much is known today about the molecular etiology of MH.

Animals↗
PubMed2000

Mechanical performance of standard and cannulated 4.0-mm cancellous bone screws.

The mechanical performance of bone screws is determined by their pull-out strength (holding power), compressive force, stripping torque, yield bending moment, ultimate bending moment, and fatigue strength. These parameters are related to the parameters of the screw design, including major thread diameter, minor thread diameter, thread length, pitch, shaft diameter, cannulation diameter, and material properties. The goal of the study was to theoretically predict the static performance of five 4.0-mm, 45-46-mm-long, cancellous, partially threaded standard and cannulated bone screws and compare the predictions with experimental measurements. A secondary goal was to determine if cannulation of the bone screw diminished its mechanical performance. The predicted values for pull-out force, compressive force, and stripping torque were determined by the thread length, major thread diameter, and thread shape factor. The screws with the largest major thread diameter and longest thread length had the greatest pull-out force, compressive strength, and stripping torque. However, when correcting for the thread length, a higher thread shape factor compensated for a smaller major diameter. The coefficient of determination (r2) for the correlation between the predicted and measured pull-out force improved from 0.75 to 0.90 when the theoretical model included the thread shape factor. The yield and ultimate bending moments are a function of the section modulus and material properties of the screw. The Ace solid screw had the greatest section modulus and yield and ultimate bending moments. The experimental data support the theoretical models for predicting the mechanical performance of bone screws. The design of the bone screws can be optimized on the basis of theoretical modeling. The strong correlation between the predicted and measured parameters allows comparison between bone screws without repeated experimental tests. Theoretical and experimental results show that cannulation of the bone screw did not inherently diminish its mechanical performance.

Biomechanical Phenomena↗
PubMed2000

Genetic analysis of insulin-like growth factor II and HLA-G in pre-eclampsia.

Pre-eclampsia (PE) is uniquely a disease of pregnancy and is the major cause of foetal and maternal morbidity and mortality. Epidemiological studies show that PE is highly heritable, with a high incidence in all populations. The underlying pathology indicates that absent or shallow invasion of foetal trophoblasts into maternal arteries is a feature of true PE. The objective of this study was to determine the genetic factors influencing PE. A large number of mother-father-baby trios were collected in which the first pregnancy was complicated by severe PE. After careful examination of the epidemiology and pathology of the disease, two plausible candidate genes, namely insulin-like growth factor II (IGF-II) and HLA-G, were analysed for association with PE. No association was found between a commonly occurring polymorphism in IGF-II and PE. Three polymorphisms in HLA-G were analysed in the sample cohorts. No association was found between three polymorphisms in HLA-G and PE. However, the frequency of the HLA-G insertion/deletion polymorphism in exon 8 deviated significantly from Hardy-Weinberg expectations in PE off-spring, reflecting an excess of heterozygotes for these polymorphisms in PE offspring. The significance of this deviation is not clear and further genetic analysis will be necessary to confirm this finding and to explore further the candidacy of HLA-G in PE.

Adult↗
PubMed1997

The yeast nucleoporin rip1p contributes to multiple export pathways with no essential role for its FG-repeat region.

The FG-repeat domain of the yeast Rip1 protein (Rip1p) was identified initially as a possible target for the nuclear export signal (NES) of the HIV-1 Rev protein in a yeast two-hybrid assay. Rip1p is inessential, associated with nuclear pore complexes, and structurally related to the FG-nucleoporin family of pore proteins. It contributes to HIV-1 Rev-mediated RNA export and is also important for the export of heat shock RNAs at 42 degrees C. We show here that Rip1p is essential for the export of heat shock RNAs, and this function is fulfilled by the unique carboxyl terminus of Rip1p with no substantial contribution from the FG-repeat region. Genetic interactions between Rip1p and the RNA export mediator Gle1p are described, which support a role of the carboxyl terminus of Rip1p in poly(A)+ RNA export. Finally, this domain of Rip1p also contributes to Rev-mediated RNA export. The data suggest that Rip1p promotes the nuclear export of different classes of substrates by contributing to optimal pore function.

Amino Acid Sequence↗
PubMed1997

Contraceptives for lactating women: a comparative trial of a progesterone-releasing vaginal ring and the copper T 380A IUD.

From approximately one week before normal ovulation resumes, lactating women require protection against pregnancy by a contraceptive that is safe for both infant and mother in a multicenter one-year study, the natural hormone, progesterone, delivered vaginally by a sequence of four contraceptive rings designed for continuous use, was evaluated as a contraceptive for nursing mothers in comparison with the Copper T 380A IUD. Individual rings release in effective average dose of 10 mg day for a 3 month period. Evaluation included measures of lactational performance as well as of contraceptive efficacy and safety to mother and child. Nine participating clinics enrolled 802 ring users and 734 IUD acceptors between postpartum days 29 and 63. Life table analyses were performed with parallel decrements for ring and IUD subjects. Continuation in the study and analysis required that subjects not stop breastfeeding. The ring, with a one-year pregnancy rate of 1.5 per 100, did not differ significantly from the IUD with respect to contraceptive effectiveness (p > 0.05). More than half of the ring subjects were continuing at 6 months post admission and a quarter (23.5 per hundred) were still using the ring and breastfeeding one year after admission. Women with the IUD, however, had higher continuation rates (p < 0.001) at both time points. The largest single decrement for each method was that for weaning. Ring users had more complaints of vaginal problems but had fewer vaginal disorders on examination. At 12 months postpartum, 46 per 100 continuing ring users remained in amenorrhea. Lactation performance and the health and weight gain of the infants were similar among users of either regimen.

Administration, Intravaginal↗
PubMed1997

Coexistent Hirschsprung's disease and esophageal achalasia in male siblings.

Achalasia of the esophagus developed in two male siblings soon after birth, and they were successfully treated by surgery. Persistent signs resulted in the later diagnosis of Hirschsprung's disease. One required subtotal colectomy and ileoanal anastomosis, and the other is managing well on conservative treatment. Genetic analysis of the genes encoding the RET protooncogene, endothelin-3, and the endothelin-3 receptor did not show any defect. Familial achalasia of the esophagus in combination with Hirschsprung's disease has never been reported.

Colectomy↗
PubMed1997

Identification of heterozygous and homozygous individuals with the novel RYR1 mutation Cys35Arg in a large kindred.

BACKGROUND: Malignant hyperthermia (MH) is a potentially fatal, often autosomal dominant, disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalational anesthetics. In this article, the authors describe a malignant hyperthermia susceptible (MHS) kindred in which both parents of the proband are MHS and are first-degree cousins. Haplotype analysis in this kindred with chromosome 19 linked markers revealed that the proband and another sibling were homozygous for the affected RYR1 allele. METHODS: Eighteen members of this large pedigree were investigated, with a clinical examination for signs of a myopathy, a caffeine halothane contracture test, a histo-enzymologic study on the muscle biopsies, and linkage analysis on genomic DNA isolated from family blood samples. RYR1 cDNA was amplified by polymerase chain reaction and was cloned and sequenced, facilitating mutation detection. RESULTS: Linkage analysis demonstrated linkage between RYR1-linked markers and MH susceptibility in this family. DNA sequencing identified a T to C transition at nucleotide position 103, resulting in the substitution of an arginine for cysteine 35, representing the most N-terminal mutation reported to date in the RYR1 gene. This mutation segregates fully with the MHS trait, generating a lod score of 4.65 in favor of linkage to MHS at a recombination frequency of 0.0. CONCLUSIONS: The proband in this kindred is the first reported homozygote to have presented with an MH episode. The homozygotes in this pedigree do not have an overt myopathy. The sensitivity of muscle samples to caffeine clearly distinguished the two homozygotes from other heterozygous-susceptible individuals. No clear differentiation was observed with the halothane contracture results.

Adolescent↗
PubMed1995

Randomized cross-over study of a 21-day versus a 28-day hormone replacement therapy (HRT).

OBJECTIVE: To compare the occurrence of climacteric symptoms at two points in the cycle, identified as minE (phase of minimum estrogen effect) and MaxP (phase of maximum progesterone effect). METHODS: Prospective randomized cross-over study in postmenopausal women currently on HRT comparing two opposed, sequential formulations: a regimen of 21 tablets containing estradiol valerate (EV) opposed with cyproterone acetate (CPA) in the last 10 tablets, versus a regimen of 28 tablets of conjugated equine estrogens (CEE), the last 12 tablets of which were taken together with norgestrel (NG). OUTCOME MEASURES: Incidence of 24 climacteric complaints assessed at the specified days of the cycle corresponding to minE (day 6 or 7) and MaxP (day 27 or 28) RESULTS: Contrary to the hypothesis that estrogen-dependent symptoms will recur at minE of the 21-day regimen, no significant differences were noted with the regimen containing 28 days of CEE, which served as the control. There were more complaints with the CEE+NG formulation at both minE and MaxP. Of the 38 patients, 63% preferred the EV+CPA regimen, 18.4% the CEE+NG regimen and 18.4% rated both preparations as equal. CONCLUSIONS: The 7-day pause in the 21-day formulation containing EV+CPA did not affect efficacy; it was as effective in relieving climacteric symptoms as the regimen containing 28 days of estrogen. Based on the frequency of complaints both at minE and MaxP, the EV+CPA formulation induced a more acceptable symptom and mood profile.

Adult↗
PubMed1995

RNA structural patterns and splicing: molecular basis for an RNA-based enhancer.

Efficient splicing of the 325-nt yeast (Saccharomyces cerevisiae) rp51b intron requires the presence of two short interacting sequences located 200 nt apart. We used the powerful technique of randomization-selection to probe the overall structure of the intron and to investigate its role in pre-mRNA splicing. We identified a number of alternative RNA-RNA interactions in the intron that promote efficient splicing, and we showed that similar base pairings can also improve splicing efficiency in artificially designed introns. Only a very limited amount of structural information is necessary to create or maintain such a mechanism. Our results suggest that the base pairing contributes transiently to the spliceosome assembly process, most likely by complementing interactions between splicing factors. We propose that splicing enhancement by structure represents a general mechanism operating in large yeast introns that evolutionarily preceded the protein-based splicing enhancers of higher eukaryotes.

Base Sequence↗
PubMed1995

Role of reactive intermediates in tumor promotion and progression.

Many tumor promoters, including the phorbol esters, do not require biotransformation to stimulate cell growth. By contrast, some promoters, notably organic peroxides and hydroperoxides, must be metabolized to reactive intermediates to trigger signal transduction pathways for mitogenesis. These intermediates can be both free radicals and electrophiles. For example, skin tumor promoters such as tert-butyl hydroperoxide, cumene hydroperoxide, dicumyl peroxide and benzoyl peroxide undergo metal-dependent activation in keratinocytes to form alkoxyl, alkyl and aryl radicals as determined by spin trapping and electron paramagnetic resonance spectroscopy. These radicals can participate in substitution, addition or hydrogen-abstraction reactions leading to protein oxidation or alkylation, lipid peroxidation and/or DNA damage. Scavenger studies indicate that these macromolecular interactions mediate the cytotoxic and mitogenic effects of these peroxides. In some instances radicals can undergo further oxidation to electrophiles. The promoting activity of butylated hydroxytoluene hydroperoxide is mediated by a quinone methide, an electrophile formed through a phenoxyl radical intermediate. In this instance, covalent interaction of the quinone methide with sulfhydryl groups or other nucleophiles in the target cell appears to transmit the molecular signal for cell division and replication. Like the phorbol esters, peroxides and hydroperoxides lead to a genetic reprogramming manifest by the induction of immediate early response genes such as c-jun and late response genes such as ornithine decarboxylase, suggesting convergence in the molecular signalling processes among different classes of promoters.

Animals↗
PubMed1994

The prevalence of symptoms in menopausal women in the Far East: Singapore segment.

Questionnaires (4000) on experience of menopausal symptoms in Singaporean women aged 40-55 were distributed by students. In total, 524 envelopes were returned (13.1%) and of these 420 were analyzed. Of these, 366 were classified as either pre-, peri- or postmenopausal on the basis of their menstrual patterns. Menopausal symptoms in this sample of Singaporean women were, in general, similar to those experienced in the West though the prevalence was low compared to European studies. No significant differences in individual symptoms were found between the 3 groups but, taken together, symptoms were significantly highest in the perimenopausal and lowest in the other menopausal groups. In the postmenopausal group 50% had been menopausal for at least 1 year at 50.5 years.

Adult↗
PubMed1994

Acetaminophen ingestion in childhood--cost and relative risk of alternative referral strategies.

Acetaminophen is the pharmaceutical most frequently ingested by small children. Although past research has allowed the safe management of 90% of these ingestions at home, several thousand are still referred to emergency departments annually. With the goal of further reducing the number of unnecessary referrals, the risk/benefit considerations of alternate referral strategies were analyzed. In a retrospective poison center chart review study from 11 centers, the records of children between the ages 1 and 6 years who acutely ingested acetaminophen and were referred to a hospital for determination of serum acetaminophen concentration in 1986 and 1987 were identified using the database of the American Association of Poison Control Centers. Risk of hepatic injury was assigned on the basis of the Rumack-Matthew acetaminophen toxicity nomogram. The cohort was stratified in terms of the amount ingested and whether a pediatric or adult preparation was ingested. The direct cost of an evaluation was estimated from four centers. Sensitivity, specificity and direct cost of each risk identification strategy were calculated. Eight hundred sixty six of 2091 patients had a timed serum acetaminophen concentration recorded. Of these, three patients had results in the "probable risk" area of the nomogram. A referral reduction strategy which would refer only children who ingest 200 mg/kg or more of an adult preparation could eliminate 82% of referrals without missing any of these "probable risk" patients. Six other children were determined to have serum acetaminophen concentrations in an area of the nomogram labeled "possible risk". No referral reduction strategy explored identified all of these patients. The average charge for an emergency department evaluation in 1992 was $272.00. These data suggest that children less than six years of age who ingest pediatric acetaminophen products other than those from packages containing greater than 30 tablets or who ingest less than 200 mg/kg of an adult preparation may be safely managed at home without referral to a hospital. This strategy would result in significant cost savings and prevent unnecessary inconvenience to many patients and families.

Acetaminophen↗
PubMed1993

Influence of time until emesis on the efficacy of decontamination using acetaminophen as a marker in a pediatric population.

STUDY OBJECTIVE: To determine the extent of drug removal by emesis at different times after the ingestion of a toxic substance. DESIGN: Multicenter retrospective chart review. METHODS: Using the American Association of Poison Control Centers' aggregate data base, children who had ingested acetaminophen and who were referred to a health care facility by one of 11 poison centers during a two-year period were identified. Charts of these patients were reviewed to determine the quantity ingested per kilogram of body weight, method of decontamination used, the timing of decontamination, and the serum acetaminophen concentration obtained four hours after ingestion. RESULT: Charts of 455 patients met all requirements for inclusion. When emesis occurred within one-half hour after ingestion, mean serum acetaminophen concentration drawn four hours after ingestion was approximately half that in a control group that received no decontamination. Emesis had less impact when it was delayed further and had no demonstrable impact when it occurred more than 90 minutes after ingestion. CONCLUSION: Many factors must be considered when deciding if and by what method a given patient should receive decontamination. When delayed gastric emptying is not expected, emesis can at best decrease a toxic burden by half if it occurs early. Medical care givers must continue to scrutinize management practice to ensure that syrup of ipecac is given only in situations in which it is likely to make a difference in outcome and in which it is the most effective agent to achieve this goal.

Acetaminophen↗
PubMed1992

Use of two types of estradiol-releasing skin patches for menopausal patients in a tropical climate.

As part of a program to evaluate nonoral routes for delivery of estrogen replacement therapy at the National University Hospital, Singapore, we assessed two different 50 micrograms estradiol patches. The first study (patch A) was terminated because of a high rate of skin reactions. Tests of the components of this patch identified the alcohol carrier as the cause of these reactions when combined with an occlusive membrane in the tropical Singapore climate. A subsequent clinical trial with 21 female subjects was undertaken with a different 50 micrograms estradiol patch (patch B). Twenty patients completed the 6-month study. Patch B was as effective as patch A, caused fewer skin reactions, and adhered better.

Administration, Cutaneous↗
PubMed1992

Rates and outcomes of planned pregnancy after use of Norplant capsules, Norplant II rods, or levonorgestrel-releasing or copper TCu 380Ag intrauterine contraceptive devices.

OBJECTIVES: The objectives were to measure rates of planned pregnancy and factors affecting these rates after use of very-long-acting contraceptive methods (Norplant or Norplant II implants, a levonorgestrel-releasing intrauterine contraceptive device, or the copper T (model TCu 380Ag) intrauterine contraceptive device. STUDY DESIGN: The design was a concurrent, multicenter prospective study of 372 women who stopped contraception for planned pregnancy. Analysis was by life-table, log-rank, and standard chi 2 methods. RESULTS: Pregnancy rates 12 and 24 months after cessation of contraceptive use were 82 and 89 per 100, respectively. Age at removal and family planning intentions at initiation of contraception were both significantly correlated with pregnancy rates (p less than 0.05), but former contraceptive regimen and duration of contraceptive use were not. Pregnancy outcomes did not deviate from normal limits and did not differ by contraceptive formerly used. CONCLUSION: Contraceptive implants releasing 30 micrograms/day of levonorgestrel or intrauterine contraceptive devices releasing 20 micrograms/day of levonorgestrel or having copper surface areas of 380 mm2 are associated with normal fertility after use for women seeking pregnancy at termination. Durations of use do not affect pregnancy rates.

Adult↗