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Biomedical subjects

J Kirk

Publications and source records attributed to J Kirk.

At least 19 recordsLinked to original sources
PubMed1992

X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene.

Kallmann syndrome represents the association of hypogonadotropic hypogonadism with anosmia. This syndrome is from a defect in the embryonic migratory pathway of gonadotropin-releasing hormone synthesizing neurons and olfactory axons. A candidate gene for the X chromosome-linked form of the syndrome was recently isolated by using a positional cloning strategy based on deletion mapping in the Xp22.3 region. With the PCR, two exons of this candidate gene were amplified on the genomic DNAs from 18 unrelated patients affected with the X chromosome-linked Kallmann syndrome. Three different base transitions--all leading to a stop codon--and one single-base deletion responsible for a frameshift were identified. We thus conclude that the candidate gene is the actual KAL gene responsible for the X chromosome-linked Kallmann syndrome. Furthermore, unilateral renal aplasia in two unrelated patients carrying a stop mutation indicates that the KAL gene is itself responsible for this Kallmann syndrome-associated anomaly. The gene is, therefore, also involved in kidney organogenesis. Additional neurologic symptoms in Kallmann patients are also discussed.

Base Sequence↗
PubMed1992

High-dose tamoxifen as an enhancer of etoposide cytotoxicity. Clinical effects and in vitro assessment in p-glycoprotein expressing cell lines.

Twenty-six patients with relapsed or drug-resistant cancer were treated with a combination of oral etoposide (300 mg day-1 for 3 days) and high-dose oral tamoxifen as a potential modulator of drug resistance (480 or 720 mg day-1 for 6 days beginning 3 days before etoposide). One patient with relapsed high-grade lymphoma and one with adenocarcinoma of unknown primary site has a partial response. Toxicity consisting of nausea, vomiting and subjective dizziness, unsteadiness of gait and malaise occurred during tamoxifen treatment. Serum levels of tamoxifen averaged 3-3.5 microM on day 4 of all courses of treatment at both 480 and 720 mg day-1. N-desmethyltamoxifen levels were lower than tamoxifen during the first course (2 microM) but increased to equal tamoxifen levels during the second course. Didesmethyltamoxifen levels remained below 1 microM. In vitro, both tamoxifen and the standard modulator of multidrug resistance, verapamil, produced minor enhancement of etoposide cytotoxicity in the MCF-7 wt cell line but produced no enhancement with any other cell line. High, intermittent doses of tamoxifen can be given with acceptable toxicity and produce serum levels that have been shown to modulate drug resistance in vitro. In vitro, however, such levels have no significant effect on etoposide cytotoxicity towards a range of wild-type and MDR cell lines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Physiological and perceptual responses to load-carrying in female subjects using internal and external frame backpacks.

Eleven female subjects (ages 18-33 years) walked on a motor-driven treadmill at 86 m/min for 1 h carrying 33% of their body weight in a backpack. The grade of the treadmill alternated every 15 min between 0 and 3%. Each subject carried an internal frame backpack for one trial and an external frame backpack for another trial on a separate day. The variables measured during the two load-carrying experiments included oxygen consumption (VO2), heart rate (HR), respiratory exchange ratio (R), minute ventilation VE, and the ratings of perceived exertion for the chest (RPE-chest), shoulders (RPE-shoulders), and legs (RPE-legs). When oxygen uptake measured during load-carrying was expressed as a percentage of VO2max, the average values were 40.1% (63.5% HRmax) at 0% grade and 49.0% (69.6% HRmax) at 3% grade for both backpacks. No significant differences were found between the two packs for any of the metabolic, cardiorespiratory, or perceptual variables measured. Changes in treadmill grade had a significant effect on VO2, HR, and VE, regardless of the type of pack carried. Minute ventilation was the only physiological response to load-carrying that increased significantly as exercise duration increased. The values for RPE-chest, RPE-shoulders, and RPE-legs were significantly increased by both exercise time and treadmill slope, regardless of the type of pack frame carried. Thus despite relatively constant metabolic responses over time, increased perception of effort could compromise completion of the load-carrying task. It was concluded that differences in backpack frame design were not great enough to produce significant differences in the energy cost or perception of carrying a moderately heavy load on the back.

Adult↗
PubMed1991

Pulmonary-to-aorta diameter ratio in the normal and abnormal fetal heart.

In an attempt to establish the normal ratio of pulmonary artery to aorta diameters at varying gestational ages, the pulmonary artery and aorta diameters of 316 normally grown fetuses between 14 and 39 weeks' gestational age were measured. The ratios for each fetus were derived, and regression analysis was used to evaluate the relationship between gestational age and each diameter. We conclude that the diameters of the pulmonary artery and aorta are closely related to fetal age but that the ratio is independent of age (mean, 1.09; SD, 0.17). The diameters of the pulmonary artery and aorta in 21 fetuses with proved congenital heart disease were then compared with those of this normal population. The pulmonary artery/aorta ratio was abnormal in 13 of 21 fetuses with congenital heart disease. Actual measurements of the great vessels can be difficult and may be misleading, but a quick comparison of relative size by inspection is feasible.

Aorta↗
PubMed1991

Cerebral endothelial cell infection by measles virus in subacute sclerosing panencephalitis: ultrastructural and in situ hybridization evidence.

Infection of vascular endothelium plays a central role in the pathogenesis of acute measles virus infection outside the central nervous system (CNS) but has not been described in the human CNS. An ultrastructural survey was made of blood vessels in five cases of subacute sclerosing panencephalitis (SSPE) to determine whether or not infection of cerebral vascular endothelium occurred in this persistent fatal CNS disease caused by measles virus. Morbillivirus nucleocapsids were found in a few endothelial cells in three necropsy cases but not in the limited tissue available from two biopsies. In a severe parenchymal lesion in one necropsied case, endothelial cells hybridized in situ with a biotinylated probe specific for the N genomic RNA of measles virus. It is concluded that human cerebral endothelium is susceptible to measles virus infection.

Cerebrovascular Circulation↗
PubMed1990

Chief complaint of fatigue: a prospective study.

The Dartmouth COOP Project, a primary care research network, conducted a prospective study of patients presenting to 28 primary care practices with a chief complaint of fatigue. Data were gathered on fatigue status, associated systems, health status, and origin of fatigue. Fatigue patients were demographically similar to nonfatigue patients but had significantly worse physical and mental health at study intake. Sixty-three percent of physicians and 52% of patients rated fatigue origin as primarily physical (gamma = 0.48, P less than .05), but in 41% of cases, physicians indicated there was substantial interaction between physical and psychological factors. Only two factors--depression and anxiety--separated fatigue of physical origin from fatigue of psychological origin. Clinicians must thoughtfully evaluate fatigue's often multiple causes and communicate their understanding of those causes to the patient to gain support for a reasonable treatment regimen.

Adult↗
PubMed1989

Normal or early development of puberty despite gonadal damage in children treated for acute lymphoblastic leukemia.

To determine the timing of pubertal development and the frequency of gonadal dysfunction in children who survive acute lymphoblastic leukemia, we assessed pubertal status and the plasma levels of sex steroids, gonadotropin, and inhibin in 45 children (20 girls and 25 boys) who had received combination chemotherapy along with 24 Gy of irradiation to the cranium (modified LSA2L2 protocol). We also reexamined testicular biopsy specimens, obtained at the time of the cessation of chemotherapy, for the presence of germ cells. Germ-cell damage, indicated by marked elevations in the plasma level of follicle-stimulating hormone (P less than 0.001 for the comparison with normal children), was evident in both sexes and was confirmed in the boys by the absence of germ cells in the testicular biopsy specimens and by the small size of the testes for pubic-hair stage. Only 44 percent of the pubertal girls had measurable plasma inhibin levels, as compared with more than 93 percent of normal pubertal girls. Although plasma sex-steroid levels were normal, the secretion of luteinizing hormone in response to stimulation with gonadotropin-releasing hormone was elevated in the pubertal children (P less than 0.01 for the comparison with normal controls)--a finding that suggests compensation for decreased gonadal function. Despite clear evidence of gonadal damage, girls had early menarche at a mean age (+/- SD) of 11.95 +/- 0.91 years, as compared with the Australian standard of 12.98 +/- 1.11 years (P less than 0.01). Thus, in girls, puberty was early despite primary gonadal damage. Thirteen of 23 boys reached puberty at a mean age of 12.36 +/- 0.73 years. We conclude that treatment for acute lymphoblastic leukemia may lead to primary gonadal damage in both sexes, regardless of the age at treatment, but that the secondary characteristics of puberty develop at a normal age or, in girls, relatively early.

Adolescent↗
PubMed1989

Use of CA 125 to monitor patients with ovarian epithelial carcinomas.

The CA 125 radioimmunoassay has been increasingly used to monitor the course of patients with ovarian epithelial carcinomas. The purpose of this report is to describe our experience in the use of this assay and to better define its clinical utility. Fifty-one patients had serum CA 125 follow-up during primary chemotherapy. All 51 patients demonstrated either a normal CA 125 level at the completion of chemotherapy or a substantial fall in CA 125 values with treatment. In 48 of 51 patients, the drop in CA 125 levels was temporally related to the clinical regression or remission of tumor. Forty of these patients underwent second-look laparotomy; 23 patients (58%) had residual disease. A total of 45 patients had serum CA 125 determinations at the time of second-look laparotomy. Eight patients with microscopic disease and 11 of 18 patients with gross residual disease had a "negative" (less than 35 U/ml) CA 125 level. The predictive value of an elevated CA 125 level was 1.00. However, the predictive value of a negative value was only 0.50. Hence, a negative CA 125 level cannot be a substitute for a second-look laparotomy. Only 7 of 18 patients (39%) with gross residual disease at second-look surgery had an elevated CA 125 level. Patients with an elevated CA 125 and gross residual tumor at the second-look laparotomy uniformly demonstrated large, bulky disease. Furthermore, the survival of patients with gross residual disease at second-look laparotomy correlated with the preoperative CA 125 value. Serum CA 125 determinations also show promise in the follow-up of patients with a negative second-look laparotomy. The serum CA 125 level from patients with a "negative" second-look laparotomy can become elevated months before recurrent disease is appreciated.

Actuarial Analysis↗
PubMed1989

Unusual immunophenotypes in acute leukaemias: incidence and clinical correlations.

The incidence and clinical implications of unusual patterns of expression of leucocyte differentiation antigens in acute leukaemia were assessed on 568 newly diagnosed paediatric and adult cases undergoing immunophenotyping with a panel of monoclonal antibodies at a single centre. Among patients with the precursor B (common) form of acute lymphoblastic leukaemia (ALL), the major variant seen was the group of 15 cases with expression of myeloid surface antigens. 4.5% of ALL cases tested with antibody to CD-11b were positive, 5.1% were CD-13+, and 10.8% CD-33+. All 15 patients achieved a complete remission with chemotherapy, with six of eight children and four of seven adults remaining disease free. A smaller proportion (1.5%) of precursor B ALL patients showed expression of the T lineage marker, CD-7. The only significant variant seen in the precursor T-ALL group was expression of HLA-DR antigen, which was found in five of 35 cases; although all responded to treatment, only one remains a disease-free survivor. Among patients with acute myeloid leukaemia (AML), expression of the lymphoid markers terminal transferase (TdT) and CD-7 were commonly seen (22.2% and 28.4% respectively of cases tested). Other lymphoid markers detected on AML cases were CD2 (11.1%), CD-10 (1%) and CD-19 (4.4%). These results confirm that examples of lineage infidelity are regularly seen in large series of patients with acute leukaemia. Prospective studies using uniform treatment protocols are required to establish whether these patients have significantly different disease outcomes.

Acute Disease↗
PubMed1987

Assessment of function in routine clinical practice: description of the COOP Chart method and preliminary findings.

The COOP Project, a primary care research network, has begun development of a Chart method to screen function quickly. The COOP Charts, analogous to Snellen Charts, were pretested in two practices on adult patients (N = 117) to test feasibility, clinical utility, and validity. Patients completed questionnaires containing validated health status scales and sociodemographic variables. Practice staff filled out forms indicating COOP Chart scores and clinical data. We held debriefing interviews with staff who administered the Charts. The results indicate the Charts take 1-2 minutes to administer, are easy to use, and produce important clinical data. The patterns of correlations between the Charts and validity indicator variables provide evidence for both convergent and discriminant validity. We conclude that new measures are needed to assess function in a busy office practice and that the COOP Chart system represents one promising strategy.

Activities of Daily Living↗