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Biomedical subjects

M Harvey

Publications and source records attributed to M Harvey.

At least 109 records · Page 6Linked to original sources
PubMed1996

Bone marrow gene transfer in three patients with adenosine deaminase deficiency.

Adenosine deaminase (ADA) deficiency results in severe combined immune deficiency disease (SCID), which is fatal without treatment. Allogeneic bone marrow transplantation (BMT) is the treatment of choice if an HLA-identical sibling bone marrow donor is available, resulting in almost 100% cure rate. BMT-related mortality is high in patients lacking such a donor. For these patients, efficient transfer of a recombinant ADA gene into hematopoietic stem cells is a therapeutic option if it results in the outgrowth of a 'genetically repaired' lymphoid system. Based on successful gene transfer studies in monkeys, we performed retrovirus-mediated gene transfer into CD34+ bone marrow cells of three patients with ADA deficiency. Two patients received bovine ADA conjugated to polyethylene glycol (PEG-ADA); in the third patient, PEG-ADA was started 4 months after gene transfer. Gene transfer resulted in a 5-12% transduction frequency of in vitro colony forming cells (CFU-Cs). No toxicity was observed during and after infusion of the graft. Following infusion of the transduced CD34+ cells, transduced granulocytes and mononuclear cells persisted in the circulation for 3 months. In addition, the gene was present in the marrow of one of the patients at 6 months after gene transfer. Expression of the gene was not detected. After this period, the gene could not be detected. In monkey studies we showed that myeloablation, which was not performed in the patients, may enhance engraftment of genetically modified cells. We hypothesize that lack of myeloablation, administration of bovine ADA and low numbers of transduced progenitor cells all may have contributed to the relative low numbers of transduced cells in the patients. Under these conditions, no selective advantage of the genetically corrected progenitor cells was observed.

Adenosine Deaminase↗
PubMed1995

Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin.

To examine whether a cooperative role exists between inherited Rb and p53 deficiency in tumorigenesis, crosses were made between p53- and Rb-deficient mice and were monitored for subsequent tumor incidence and spectrum. Parental mice containing either Rb or p53 mutant alleles showed a predisposition for pituitary adenomas or lymphomas and sarcomas, respectively. Mice heterozygous for both Rb and p53 mutant alleles developed tumors of endocrine origin (medullary thyroid carcinomas, pancreatic islet cell carcinomas, and pituitary adenomas) in addition to lymphomas and sarcomas. Except for pituitary adenomas, these endocrine tumors were rarely seen in the parental p53 or Rb mutant mice. Mice deficient for both Rb and p53 showed a faster rate of tumor development than mice deficient only in Rb or p53. These results indicate that p53 and Rb do cooperate in the acceleration of tumorigenesis and in the development of endocrine tumor types.

Adenocarcinoma↗
PubMed1995

Distortion of size perception in visuospatial neglect.

BACKGROUND: A number of studies have shown that most patients with symptoms of unilateral (left-sided) visuospatial neglect make consistently rightward errors when attempting to bisect a horizontal line at its midpoint. One possible interpretation of this impairment is that such patients misperceive the left half of the line: that is, that they underestimate its extent relative to the right half. RESULTS: We have carried out direct tests for such a perceptual distortion in three neglect patients by asking them to make matching judgements on pairs of horizontal rectangles, vertical rectangles or nonsense shapes, of varying relative size, presented on a computer screen. We report here that all of the patients tested showed a significant and substantial relative underestimation of the horizontal extent or area of stimuli presented on the left side of their egocentric space. There was no such misperception of vertical extent. CONCLUSIONS: It is suggested that size perception may be partially determined by a representational system that is anatomically centred in the parieto-temporal region of the brain. The results are interpreted in terms of damage to this system in neglect patients.

Attention↗
PubMed1995

Effects of genetic background on tumorigenesis in p53-deficient mice.

Mice with disrupted germline p53 alleles have been engineered by us and others and have been shown to have enhanced susceptibility to spontaneous tumors of various types. We monitored a large number of p53-deficient mice (p53+/- and p53-/-) and their wild-type littermates (p53+/+) of two different genetic backgrounds (129/Sv and mixed C57BL/6 x 129/Sv) up to 2 yr of age. p53+/- and p53-/- 129/Sv mice show accelerated tumorigenesis rates compared with their p53-deficient counterparts of mixed C57BL/6 x 129/Sv genetic background. The tumor spectra of the two strains of mice are similar except that almost half of 129/Sv p53-/- males develop malignant teratomas, whereas these tumors are rarely observed in C57BL/6 x 129/Sv mice and never in 129/Sv p53+/- males. In the study reported here, we further characterized the lymphomas that arose in the p53-nullizygous mice and found that over three-quarters of the lymphomas were of thymic origin and contained primarily immature (CD4+/CD8+) T-cells, whereas the remainder originated in the spleen and peripheral lymph nodes and were of B-cell type. The high incidence of early-onset lymphomas in the nullizygous mice makes these animals a good lymphoma model, whereas the heterozygous mice may be a useful model for Li-Fraumeni syndrome, a human inherited cancer predisposition.

Alleles↗
PubMed1995

An investigation of hemispatial neglect using the Landmark Task.

The "Landmark Task" is designed to tease apart two major factors in determining line bisection errors in spatial neglect: one whose general nature is perceptual, the other whose nature is motor. On critical test trials, the subject is required to point to whichever end of a mid-transected line is judged as nearer to the transection. Seven out of eight neglect patients pointed consistently to the left end of such lines. Thus their misjudgments were made in the direction opposite to any putative "directional hypokinesia." One patient, however, pointed predominantly rightward on these test trials. Normal controls and unilateral stroke patients were also tested on the Landmark Task. Cueing of one end of a line led to a relative perceptual overestimation of that half of the line in all of these groups.

Aged↗
PubMed1995

Differential effects of line length on bisection judgements in hemispatial neglect.

Recent studies have shown that certain symptoms of spatial neglect are co-determined by two major factors: one whose general nature is perceptual, the other whose nature is directional and/or motor. In the present study, patients whose neglect was classified as predominantly 'perceptual' or 'directional' through use of the Landmark task (Milner, Brechmann and Pagliarini, 1992) were asked to bisect lines ranging in length from 20 to only 2.5 cm. It was found that the one patient with predominantly directional neglect showed large rightward errors at all line lengths. In contrast, those with perceptual neglect made very small (usually leftward) errors on short lines. It is argued that it is essential to separate these different subtypes of neglect patient if we are to understand the causation of their behaviour in tasks such as line bisection.

Aged↗
PubMed1995

Ethics in paediatric intensive care.

Although many nurses may not consciously acknowledge the fact, ethical considerations are a vital part of nursing practice. The concept and definition of ethics, and how these may be applied to Paediatric Intensive Care in particular are considered here. Suggested frameworks for addressing ethical dilemmas are examined, as well as the possible conflict between ethics and the law.

Child↗
PubMed1995

A mutant p53 transgene accelerates tumour development in heterozygous but not nullizygous p53-deficient mice.

To test the behaviour of a mutant form of p53 in the presence and absence of wild-type p53 in vivo, we mated p53-deficient mice containing a p53 null allele to transgenic mice containing multiple copies of a mutant p53 gene (Val 135). Animals hemizygous for the endogenous wild-type p53 gene with the mutant transgene exhibited accelerated tumour development and an altered tumour spectrum compared to their non-transgenic counterparts. In contrast, transgenic and non-transgenic animals nullizygous for endogenous p53 developed tumours at the same rate. Thus, the mutant Val-135 p53 allele may act in vivo in a dominant negative manner in the presence of wild-type p53 but does not display gain of function activity in the absence of wild-type p53.

Animals↗
PubMed1995

Assessment of pacing maneuvers used to validate anterograde accessory pathway potentials.

Four pacing maneuvers have been proposed to validate an anterograde accessory pathway potential (APP): (1) atrial pacing to induce complete block between the atrial electrogram and the APP; (2) ventricular pacing to advance the APP without altering the timing of the atrial electrogram; (3) atrial pacing to induce complete block between the APP and the ventricular electrogram; and (4) ventricular pacing to advance the ventricular electrogram without altering the timing of the APP. The purpose of this study was to assess these validation techniques by applying them to electrograms that simulated APPs but which were known to be atrial in origin. In 32 patients undergoing an electrophysiology procedure, a split atrial electrogram containing two components separated by at least 30 msec (mean 54 +/- 15 msec) was recorded. Using an atrial extrastimulus technique, complete block between the two components of the atrial electrogram (criterion 1) could never be induced, but complete block between the second component of the atrial electrogram and the ventricular electrogram (criterion 3) consistently was induced. Using a ventricular extrastimulus technique, the second component of the atrial electrogram consistently could be advanced by 10 to 40 msec without altering the timing of the first component (criterion 2). In addition, with ventricular pacing, the ventricular electrogram consistently was advanced without altering the timing of the two components of the atrial electrogram (criterion 4). In conclusion, among the four pacing maneuvers used to validate an anterograde APP, the only one that may be specific for an APP is the ability to induce complete block between the atrial electrogram and the APP.

Adult↗
PubMed1994

Spatial bias in visually-guided reaching and bisection following right cerebral stroke.

Groups of patients with left or right unilateral cerebral stroke were tested for their ability to reach either toward a single visual target or midway between 2 targets. The tasks were performed both in free vision and in conditions preventing visual feedback from the hand. It was found that only the right CVA patients were inaccurate in reaching, and only when visual feedback was absent. This effect of right hemisphere lesions took the form of a rightward bias, present throughout the trajectory of the hand during the reach. It was present regardless of the hand used in reaching and whichever of the two tasks was performed, and was of a similar magnitude irrespective of target location. It is suggested that this rightward bias might reflect the 'premotor' effects that have been proposed to contribute to line-bisection errors in certain patients with visuospatial neglect.

Aged↗
PubMed1993

Dbp45A encodes a Drosophila DEAD box protein with similarity to a putative yeast helicase involved in ribosome assembly.

Proteins of the DEAD family of putative ATP-dependent RNA helicases have been implicated in translation initiation, ribosome assembly, and RNA processing in a variety of organisms from Escherichia coli to man. Among these proteins are eIF-4A, an essential component of the cap-binding complex, numerous yeast proteins required for pre-mRNA splicing, and proteins from yeast and E. coli necessary for ribosome assembly. We report the isolation of a new DEAD gene from Drosophila, Dbp45A, which is most abundantly expressed in 6-12 h embryos and adults. The predicted amino acid sequence of the Dbp45A product contains all eight highly conserved DEAD family motifs, and most closely resembles the Saccharomyces cerevisiae DRS1p among known DEAD box proteins. DRS1p has been implicated in ribosomal RNA processing.

Amino Acid Sequence↗
PubMed1993

Expression of IGF ligand and receptor genes during preimplantation mammalian development.

The temporal patterns of expression of genes encoding insulin-like growth factor (IGF) ligands and receptors during very early development have been investigated in several laboratories in several different mammalian species. Both reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemical techniques have been used to identify the time of appearance of gene transcripts or end-products. In preimplantation mouse embryos, IGF-II ligand and receptor gene activity is detectable as early as at the two-cell stage, the time when transcription from the embryonic genome is activated, but receptors for insulin and IGF-I are not detectable until the compacted eight-cell stage. Transcripts for insulin or IGF-I are not detectable in preimplantation mouse embryos, although the ligands are present in the reproductive tract. The pattern of IGF gene expression is not, however, identical in all mammalian species. In cow embryos, for example, transcripts for IGF-I and IGF-II ligands and receptors and insulin receptors have been detected at all stages of preimplantation development from mature oocyte to blastocyst (Watson et al., 1992). Attempts to quantitate transcript abundance in these early embryos are in progress in our laboratory. In the preimplantation mouse embryo, transcripts for several different IGF-binding proteins (IGFBP-2, -3, -4, and -6) have been detected by RT-PCR procedures. In addition, transcripts for IGFBPs have been identified in RNA derived from cumulus cells, the ovary, the oviduct, the uterus, and the decidua. These findings suggest that the interactions of IGF ligands and receptors in preimplantation development might, indeed, be modulated by IGFPs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Prevention of transmission of HIV by organ and tissue transplantation. HIV testing protocol and a proposal for recommendations concerning donor selection.

Human immunodeficiency virus (HIV) can be transmitted by solid organ and some forms of tissue transplantation. Although routine screening of organ and tissue donors for anti-HIV antibodies was implemented in most Western European countries and North America in 1985, several recent case reports indicate that a definite, albeit very small, risk of HIV transmission still remains. The screening tests that are currently used cannot rule out a false-negative test result occurring during the window period. Moreover, massive transfusion of the donor during the donor procedure may result in an undetectable anti-HIV antibody titer (by dilution of donor blood) that consequently leads to a false-negative test result. These risks of HIV transmission via transplantation and important issues in HIV testing are discussed in detail. Furthermore, several recommendations for the prevention of transmission and a protocol for HIV testing for both organ and tissue donation are presented. These may serve as intermediary guidelines until official ones, such as already exist for blood donation, are defined by the transplantation communities. The exclusion of donors whose behavior may place potential recipients at risk for HIV infection is essential. A thorough heteroanamnesis of the donor's next of kin during the donor procedure should provide sufficient information about donor history to enable a decision to be made in this respect. Special attention is given to the question of whether the existing donor selection criteria for blood donation should be applied in a similar way to organ donation since the strict application of selection criteria may limit the number of available donor organs.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS Serodiagnosis↗
PubMed1993

Line bisection errors in visual neglect: misguided action or size distortion?

The rightward line bisection errors made by patients with visuospatial neglect can be explained as due to a spatially misdirected response, which would be predicted on either of two accounts. An alternative view, however, is that such patients actually misperceive the left half of a horizontal line as being shorter than the right half. We have tested this possibility directly in three neglect patients, by giving them prebisected lines: they were found to judge a central transection mark as lying nearer to the left end of the lines. We were also able to test one of the patients on a series of size comparisons using computer-generated patterns. She was found to judge horizontal lines as shorter in the left half of visual space than in the right. This was also true for comparisons of the areas of nonsense figures. However she did not make such constant errors when comparing the lengths of vertical lines. It is suggested that an attentional deficit in left hemispace may result in the underestimation of horizontal extent. This would act in combination with misdirected reaching to determine the magnitude of line bisection errors.

Aged↗
PubMed1993

Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice.

Using gene targeting techniques, mice that have been generated with two germ-line p53 null alleles (homozygotes) develop normally but are highly susceptible to early onset spontaneous tumours. Here, we show that mice with a single null p53 allele (heterozygotes) produced in the same way are also susceptible to spontaneous tumours, but with a delayed onset compared to homozygotes. The most frequent tumour type in homozygotes was malignant lymphoma; in heterozygotes, osteosarcomas and soft tissue sarcomas predominated. Heterozygous mice treated with a liver carcinogen, dimethylnitrosamine, showed a decreased survival time in comparison to treated wild type mice, suggesting that the p53-deficient mice may be useful for some in vivo carcinogenesis assays.

Animals↗
PubMed1993

Laparoscopic varicocele repair.

Varicocele is a common condition for which currently accepted methods of treatment are less than satisfactory. Reported herein is a successful laparoscopic technique of repair.

Adult↗