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Biomedical subjects

D A Carpenter

Publications and source records attributed to D A Carpenter.

At least 19 recordsLinked to original sources
PubMed1995

Pleiotropy in microdeletion syndromes: neurologic and spermatogenic abnormalities in mice homozygous for the p6H deletion are likely due to dysfunction of a single gene.

Variability and complexity of phenotypes observed in microdeletion syndromes can be due to deletion of a single gene whose product participates in several aspects of development or can be due to the deletion of a number of tightly linked genes, each adding its own effect to the syndrome. The p6H deletion in mouse chromosome 7 presents a good model with which to address this question of multigene vs. single-gene pleiotropy. Mice homozygous for the p6H deletion are diluted in pigmentation, are smaller than their littermates, and manifest a nervous jerky-gait phenotype. Male homozygotes are sterile and exhibit profound abnormalities in spermiogenesis. By using N-ethyl-N-nitrosourea (EtNU) mutagenesis and a breeding protocol designed to recover recessive mutations expressed hemizygously opposite a large p-locus deletion, we have generated three noncomplementing mutations that map to the p6H deletion. Each of these EtNU-induced mutations has adverse effects on the size, nervous behavior, and progression of spermiogenesis that characterize p6H deletion homozygotes. Because EtNU is thought to induce primarily intragenic (point) mutations in mouse stem-cell spermatogonia, we propose that the trio of phenotypes (runtiness, nervous jerky gait, and male sterility) expressed in p6H deletion homozygotes is the result of deletion of a single highly pleiotropic gene. We also predict that a homologous single locus, quite possibly tightly linked and distal to the D15S12 (P) locus in human chromosome 15q11-q13, may be associated with similar developmental abnormalities in humans.

Animals↗
PubMed1995

Genetic and physical mapping of the fitness 1 (fit1) locus within the Fes-Hbb region of mouse chromosome 7.

Mutations at the fit1 locus affect normal pre- and post-natal development by retarding growth and reducing viability. We report mapping of the fit1 locus, by trans-complementation crosses to mice carrying deletions of the albino (c) locus in Chromosome (Chr) 7, to a subregion of the c-deletion complex within the Mod2-sh1 interval. The fit1 locus, which is currently defined by five N-ethyl-N-nitrosourea (ENU)-induced mutations, was found to map in a subregion between the eed and exed loci. A restriction fragment containing a deletion breakpoint that genetically defines the proximal border of fit1 was cloned, providing a DNA probe (RN302) that maps proximal to fit1. Long-range mapping with this probe, and with a DNA probe that maps distal to the fit1 interval, established that the region containing at least part of the fit1 gene is 530 kb or less. Positioning of fit1 between deletion breakpoints, and the isolation and mapping of a DNA probe proximal to it, should facilitate the cloning and molecular characterization of fit1, as well as of the eed locus and the tightly linked l(7)5Rn and l(7)6Rn loci.

Animals↗
PubMed1995

Correction of distortion in US images caused by subcutaneous tissues: results in tissue phantoms and human subjects.

PURPOSE: To correct distortion in ultrasonic images caused by refraction at fat-muscle interfaces in the subcutaneous tissues. MATERIALS AND METHODS: A forward-propagation technique was developed that used a priori information of the acoustic properties of the layers. The thickness and shape of these tissues were measured, and a correction was applied for the different velocities in the tissues. A synthetic-aperture scanning technique was used to allow correction to be applied with data obtained in a single scan. The technique was tested in three tissue phantoms with overlying aberrating layers (six images) and in eight volunteer subjects (37 images). The superior mesenteric artery and the aorta were used as test sites within the body, because it is relatively easy to obtain double images of these vessels owing to refraction of the scanning beam by the rectus muscles. RESULTS: Distortions such as double-image artifacts and texture disruption were corrected with use of this technique. Six of the six phantom images and 22 of the 37 images in humans were corrected with use of this technique. CONCLUSION: The forward-propagation technique compensates for refraction at subcutaneous fat-muscle interfaces.

Abdominal Muscles↗
PubMed1991

Cerebral oxygen metabolism after aneurysmal subarachnoid hemorrhage.

Previous studies of cerebral oxygen metabolism and extraction in patients with subarachnoid hemorrhage (SAH) have yielded conflicting results. We used positron emission tomography (PET) to measure the regional cerebral metabolic rate for oxygen (rCMRO2), oxygen extraction fraction (rOEF), and cerebral blood flow (rCBF) 16 times in 11 patients with aneurysmal SAH. All studies were performed preoperatively; no patient had hydrocephalus or intracerebral hematoma on brain CT. Eight patients with no arteriographic vasospasm who were studied on days 1-4 post-SAH had a significant 25% reduction in global CMRO2 compared to age-matched controls, and no significant change in global OEF, suggesting a primary reduction in CMRO2 caused by SAH. Four patients studied seven times during arteriographic vasospasm had significantly increased rOEF with unchanged CMRO2 in arterial territories affected by arteriographic vasospasm compared to territories without vasospasm, indicative of cerebral ischemia without infarction. No brain regions studied with PET were infarcted on follow-up CT. We conclude that the initial aneurysm rupture produces a primary reduction in CMRO2, and that subsequent vasospasm causes ischemia.

Adult↗
PubMed1991

Reverse genetics in the mouse and its application to the study of deafness.

Genetic variants of the laboratory mouse can serve as useful models for hereditary deafness syndromes in humans. Recessive mutations at the shaker-1 (sh-1) and whirler (wi) loci, in chromosomes 7 and 4, respectively, both result in circling behavior and a deafness syndrome. In sh-1 homozygotes this deafness is associated with neurophysiological abnormalities that may be accompanied by structural abnormalities of the inner ear. Radiation-induced deletion mutations are being used in a strategy of reverse genetics to identify the genes defined by these mutations. Genetic analyses have refined the position of sh-1 to a chromosomal interval between break points of deletions involving the closely linked albino (c) locus. A cDNA encoding olfactory marker protein (OMP) and the anonymous locus D7OR1 have also been mapped to this interval. These clones contribute to the physical map of the sh-1 region and could be important for accessing the sh-1 gene itself. Similarly, we have identified a radiation-induced deletion of the brown (b) locus that covers the wi locus and two that do not. Thus, the wi locus has been located within a chromosome 4 interval defined by structural rearrangements, which should likewise aid in identifying closely linked molecular clones.

Animals↗
PubMed1990

A strategy for fine-structure functional analysis of a 6- to 11-centimorgan region of mouse chromosome 7 by high-efficiency mutagenesis.

A refined functional map of a 6- to 11-centimorgan region surrounding the albino (c) locus in mouse chromosome 7 is being generated by N-ethyl-N-nitrosourea (EtNU) "saturation" mutagenesis of stem-cell spermatogonia. In the first phase of an experiment that will eventually test at least 3000 gametes, we screened 972 mutagenized gametes for the induction of both lethal and visible mutations with a two-cross breeding protocol. Thirteen mutations mapping within the limits of a segment corresponding to the cytologically visible Df(c Mod-2 sh-1)26DVT deletion were recovered. They represented three phenotypic groups: prenatal lethality (six mutations); a fitness/runting syndrome (three mutations, provisionally designated as fit variants); and a neurological/balance-defect abnormality (four mutations). Complementation analysis provided evidence for a true repeat mutation at the sh-1 (shaker-1) locus (for the neurological mutations) and another at the here defined fit-1 (fitness-1) locus. In addition, four complementation groups were defined by induced lethal mutations; the two other lethal mutations were each part of a cluster. The recovery of the repeat mutations suggests that the EtNU-induced mutation rate, estimated from specific-locus tests, should make it possible to achieve saturation mutagenesis of a chromosomal region. This experiment is providing basic logistical and statistical information on which to base strategies for expanding the functional map of larger segments of the mouse genome by experimental mutagenesis. It is also yielding additional mutations useful in dissecting the functional and molecular complexity of this segment of chromosome 7.

Albinism↗
PubMed1990

Borderzone hemodynamics in cerebrovascular disease.

To investigate the possible existence of chronic selective hemodynamic impairment in the arterial borderzone regions of the brain, we used positron emission tomography (PET) to measure regional mean vascular transit time (rt, equal to the ratio of regional cerebral blood volume to cerebral blood flow) and regional oxygen extraction fraction (rOEF) in 32 patients with either severe internal carotid artery stenosis or occlusion and 11 normal controls. Twenty-four of the patients had had TIAs or amaurosis fugax from 1 to 60 days before PET; all had normal brain CT. We used a stereotactic localization method to locate the anterior and posterior borderzone regions of the middle cerebral artery (MCA) territory. We then calculated ratios of each borderzone to the ipsilateral MCA territory for both rt and rOEF. There was no significant difference from control ratios in any patient subgroup including those with greater than or equal to 75% stenosis or occlusion, those with or without contralateral greater than or equal to 50% stenosis, or those with abnormal hemodynamics in the MCA territory. We therefore found no evidence for selective borderzone hemodynamic impairment in this group of patients with severe carotid artery disease.

Adult↗
PubMed1989

A sonographic technique to reduce beam distortion by curved interfaces.

Ultrasonic beams are distorted during propagation between two media with different velocities if the traversed interface is curved within the ultrasonic beamwidth. The distorting effects of various interfaces on a beam generated by a multi-element transducer are analyzed and a technique to reduce these by controlling the time delays to the individual elements is presented.

Equipment Design↗
PubMed1988

Effect of X-ray and ethylnitrosourea exposures separated by 24 h on specific-locus mutation frequency in mouse stem-cell spermatogonia.

Specific-locus mutation frequencies in mouse stem-cell spermatogonia were determined in 3 experiments in which mature male mice were exposed to 100,m 300, or 500 R of X-rays followed, 24 h later, by intraperitoneal injection of 100 mg/kg of ethylnitrosourea (ENU). The purpose was to find out if the mutation frequencies would be augmented over those expected on the basis of additivity of the effects of the separate treatments. Such augmentation had been observed in earlier work in which exposure to 100 or 500 R of X-rays was followed 24 h later by a second exposure of 500 R. No augmentation was observed for X-rays followed by ENU. The mutation frequencies in all 3 experiments actually fell below those expected on the basis of additivity, although the reductions were not statistically significant.

Animals↗
PubMed1985

Dose-repetition increases the mutagenic effectiveness of N-ethyl-N-nitrosourea in mouse spermatogonia.

In order to maximize the mutagenic effectiveness of N-ethyl-N-nitrosourea in mouse stem-cell spermatogonia, advantage was taken of the fact that these cells can accumulate mutations from repeated doses given over relatively long time periods. Repeated doses (100 mg/kg) of ethylnitrosourea injected intraperitoneally into male mice at weekly intervals were found to allow adequate survival and fertility with total dosages of 300 and 400 mg/kg. The specific-locus mutation frequencies at these dosages were, respectively, 1.8 and 2.2 times that obtained with the maximal practicable single dose of 250 mg/kg. The mutation frequency induced by a 400 mg/kg dosage of ethylnitrosourea is 12 times the maximal mutation frequency achievable with a single exposure to x-rays and 36 times that reported for procarbazine, the most effective chemical mutagen previously known for mouse stem-cell spermatogonia. Ethylnitrosourea is already the mutagen of choice in deliberate attempts to create mouse models for human disease and in any experiments in which a maximal mutation rate is desired. Repeated-dose regimens similar to the ones reported here should increase the efficiency of such studies.

Abnormalities, Drug-Induced↗
PubMed1982

Effect of dose fractionation on the ethylnitrosourea induction of specific-locus mutations in mouse spermatogonia.

As measured by specific-locus mutations in mouse spermatogonia, fractionating a dose of 100 mg of ethylnitrosourea per kg of body weight into doses of 10 mg/kg injected intraperitoneally at weekly intervals greatly reduces the mutation frequency compared with that from a single dose of 100 mg/kg. Because there is independent evidence that the doses of 10 and 100 mg/kg reach the germ cells in amounts directly proportional to the injected dose, the lower mutational response with the fractionated dose is attributed to repair. The induced mutation rate expected from a single 10-mg/kg dose (on the assumption that this would be 1/10th the rate observed after 10 such doses) would be only 75% of the spontaneous mutation rate. Mouse spermatogonia apparently have an efficient repair system that is effective even against a potent mutagen.

Alleles↗
PubMed1978

Unscheduled DNA synthesis induced in mouse spermatids after combined treatment with methyl methanesulfonate and X-rays.

Unscheduled DNA synthesis (UDS), which is considered to be DNA repair, has been studied in early- to mid-spermatid stages of the mouse after combined treatments with X-rays and methyl methanesulfonate (MMS). UDS in spermatids was detected by giving testicular injections of [methyl-3H]thymidine ([3H]dThd) and making use of the fact that no scheduled DNA synthesis occurs in the germ cells after the last S period in primary spermatocytes. X-rays and MMS are each able to induce UDS in mouse spermatids. However, there was a statistically significant reduction in the amount of UDS observed when X-ray exposures of from 200 to 600 R were given 4 h before an i.p. injection of 75 mg/kg of MMS and concurrent testicular injections of [3H]dThd. This reduction in UDS is more than can be explained by the completion of repair of X-ray-induced DNA lesions. We suggest that the reduction in UDS is the result of an X-ray-produced impairment of a least a part of the repair mechanism involved in correcting MMS-induced DNA lesions. When the time interval between a 600-R X-ray exposure and MMS treatment was between 3 and 20 h (latest time interval s;udied) there was a statistically significant reduction of UDS in the spermatids. No significant decrease in UDS response occurred when the time interval between radiation exposure and MMS treatment was less than approximately 3 h.

Animals↗
PubMed1976

Gray scale ultrasound imaging. The anatomy and pathology of the liver.

Gray scale ultrasound imaging circumvents some of the limitations of other diagnostic tools. The authors have extended this technique to the investigation of hepatobiliary disease. The details of their equipment are described and their results in relation to various parameters of the disease are discussed. A major feature of the gray scale technique is the enhanced signal-noise ratio, which allows low-level echoes to be displayed.

Cysts↗
PubMed1976

Gray scale ultrasonic investigation of focal defects on 99Tc sulphur colloid liver scanning.

Radionuclide liver scanning, though a well established technique for the detection of normal liver tissue replacement, has yet to deliver a satisfactory isotope method for distinguishing the benign or malignant nature of a disclosed nonfunctioning area. The solid or cystic nature of focal areas of replacement can be shown by ultrasonic echography, so the malignancy of the area can be inferred. The complementary use of both techniques is recommended.

Adenocarcinoma↗