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M Walsh

Publications and source records attributed to M Walsh.

At least 163 records · Page 9Linked to original sources

Cell dispersion patterns in different cortical regions studied with an X-inactivated transgenic marker.

Inactivation of the X-linked lacZ transgene provides a novel and powerful way of distinguishing between clonally related cellular populations in X inactivation mosaics. This ability to distinguish between clonal populations of cells in the mature cortex permits inferences to be made about cellular dispersion patterns during cortical development. The present study addresses the extent to which radial and tangential dispersion patterns contribute to different regions of the cerebral cortex by quantifying the extent of cellular mixing between clonally distinct cells in separate domains of the medial, dorsolateral and lateral cortices. We show that stripes running perpendicular to the cortical layers are more likely to be seen in the medial and dorsolateral regions, and that the appearance of a stripe is attributed to about two-thirds of the cells being of the same colour. Both neurons and glia appeared to exhibit the same ratio of cell mixing. In the lateral regions of the cortex, stripes were not apparent, and cell mixing was roughly equal. In the barrel-field region of the somatosensory cortex we looked for a correspondence between cytoarchitectural features and clonal borders but found no correlation. These results demonstrate, first, that although there is widespread radial dispersion, no cortical region is composed of radially arrayed stripes of cells in which all members of a stripe are derived from a single progenitor. Second, they demonstrate that, within regions containing a sizeable fraction of cells that do migrate radially, the boundaries of individual stripes do not always coincide with single anatomical units of cortical specialization, such as individual barrels.

Animals↗

Identification of a potentially radiosensitive subgroup among patients with breast cancer.

BACKGROUND: The description of genes and genetic syndromes, such as ataxia-telangiectasia, that predispose some women to breast cancer will provide greater insight into the genetic basis of cancer susceptibility. PURPOSE: Our goal was to establish cell lines from patients with breast and bladder cancers, to screen for enhanced levels of radiation-induced arrest in the G2 phase of the cell cycle such as is observed in ataxia-telangiectasia heterozygotes, and to correlate G2 arrest with other prognostic indicators of these cancers and in vivo radiosensitivity. METHODS: Epstein-Barr virus-transformed lymphoblastoid cells were established from 108 female patients with breast cancer and 24 age-matched female control subjects, and from 45 patients with bladder cancer and 18 age-matched control subjects. Cells were exposed to 3 Gy of gamma radiation, and the percentages of cells in G1 and G2 phases were determined at 18 and 24 hours after irradiation by fluorescence-activated cell sorter analysis. Postirradiation delay in G2 phase was determined by calculating the percentage of cells in G2 and by using the ratio G2/G1. RESULTS: When we determined the percentage of cells in G2 phase at 18 hours after irradiation in 108 lymphoblastoid cells from breast cancer patients, we observed an increase of between 3% and 38% in the number of cells in G2 phase in comparison with cells that were not irradiated. Comparison with previous G2-phase arrest data for ataxia-telangiectasia heterozygotes using a cutoff point at 29% delay demonstrated that 20% and 8% of the breast cancer cell lines of the case patients and control subjects, respectively, fell into that category (P < .001). At the same time after irradiation, it was not possible to distinguish between bladder cancer cell lines (7%) and those of the corresponding control group (6%). Assessment of radiation effects by G2/G1 ratio showed that 18% of the breast cancer patients and 8% of the control subjects were in the high range. When G2 arrest was correlated with other prognostic factors, we found that case patients with a greater G2 block were more likely to have had a family history of breast cancer (P < .006) and more aggressive tumors when assessed by number of involved lymph nodes (P < .002) and tumor size (P < .05). Furthermore, an adverse response to radiotherapy was observed in a group of patients with high G2 arrest. IMPLICATIONS: While the postirradiation increase in G2-phase arrest in cells from breast cancer patients observed in this study may indicate genetic heterozygosity for ataxia-telangiectasia, it might also reflect other genetic abnormalities important to breast cancer.

Adult↗

Lithium response and genetics of affective disorders.

The authors have carried out an investigation of psychiatric morbidity in families of patients who responded and failed to respond to long-term lithium treatment. The study included 121 probands with RDC primary affective disorders and 903 first-degree relatives and spouses. Seventy-one probands were responders and 50 were nonresponders to long-term lithium treatment. Extended to 20 years, the follow-up of patients and their families provided substantial information relevant for the diagnosis and reliable assessment of lithium response. The diagnoses were based on all available information, SADS-L interviews and RDC criteria. The principal statistical methods were survival analysis and Cox regression analysis. The results revealed a significantly higher frequency of bipolar disorder in the relatives of lithium responders (3.8% vs. 0%). Schizophrenia was more common in the families of nonresponders (2.4% vs. 0.3%). There were no significant differences in the rates of other psychiatric disorders. Both family history and the proband's diagnosis contribute independently to predicting response to long-term lithium.

Adult↗

The value of a baseline liver biopsy prior to methotrexate treatment.

Two patients with severe disabling psoriasis were treated with methotrexate (MTX). As a short course of treatment was envisaged, a pretreatment liver biopsy was not performed. Although both patients developed similarly abnormal levels of hepatic enzymes after low cumulative doses of MTX (440 and 450 mg), subsequent liver biopsies revealed contrasting findings. In one patient the histological features were normal. However, in the second, there was hepatic fibrosis, and the absence of a pretreatment biopsy led to problems with interpretation of these histological findings. As a liver biopsy is by far the most reliable method of detecting liver disease, we suggest that it is still of value to include a baseline liver biopsy in the pretreatment assessment of patients even when only a short course of MTX is planned.

Adult↗

Mode of inheritance in families of patients with lithium-responsive affective disorders.

A better understanding of the role of genetic factors in affective disorders is likely to result from investigating more homogeneous populations. To achieve this goal, we have systematically studied patients who are excellent responders to long-term lithium treatment and their relatives. In the families of 71 such probands, we have analyzed the mode of inheritance by comparing the observed morbidity risks with the risks expected under different genetic models. The results demonstrate major-gene effects in the transmission of primary affective disorders; the polygenic model with sex-specific thresholds could be rejected. Discrimination between the autosomal and X-chromosome models was not possible, but the autosomal recessive model predicts more realistic, gender-specific frequencies of affective disorders in the general population. These results suggest that autosomal recessive inheritance deserves serious consideration in molecular genetic investigations.

Adult↗

Lipoprotein(a) in restenosis after percutaneous transluminal coronary angioplasty and coronary artery disease.

BACKGROUND: The purpose of the study was to investigate the relation of lipoprotein(a) and serum lipid parameters to restenosis after percutaneous transluminal coronary angioplasty (PTCA) and to assess the association of these same biochemical markers to coronary artery disease (CAD) in individuals with angiographically defined normal and diseased coronary arteries. METHODS AND RESULTS: Sixty-two patients with successful PTCA had follow-up angiography at 35 +/- 10 weeks. Restenosis occurred in 21 male patients (46%) and 6 female patients (38%). Elevated apolipoprotein B (P < .01) and decreased high-density lipoprotein-2 cholesterol (P < .02) were found to be independently associated with restenosis after angioplasty, whereas lipoprotein(a) was not. Eighty-five patients undergoing PTCA were compared with 46 subjects who had no evidence of CAD on angiography. Elevated lipoprotein(a) (P < .001) and reduced apolipoprotein A1 to B ratio (P < .001) were found to be strong independent risk factors for the presence of CAD when adjustment was made for age (P < .005), male sex (P < .01), smoking (P < .005), and hypertension (P = .06). CONCLUSIONS: Serum lipoprotein(a) levels are not associated with restenosis after PTCA, but elevated levels are strongly associated with CAD. Low-serum, high-density lipoprotein-2 cholesterol concentration and elevated apolipoprotein B concentration were found to be associated with restenosis after PTCA.

Angioplasty, Balloon, Coronary↗

A pilot clinical trial of two murine monoclonal antibodies fixing human complement in patients with chronic lymphatic leukaemia.

The use of monoclonal antibodies (MABs) for the therapy of malignant diseases offers the potential advantage of greater target cell specificity, and therefore less toxicity. A major limitation of this therapeutic approach has been the inability of most MABs to kill the cell once bound to the target antigen. We have previously reported the development of two murine IgM MABs, WM63 (CD48) and WM66 (unclustered), that react with panleucocyte antigens widely expressed on cells from lymphoproliferative disorders, and are lytic with human complement. These antibodies have subsequently been administered intravenously to patients with chronic lymphocytic leukaemia (CLL) in a Phase One trial. Seven patients with progressive CLL received increasing daily doses of WM66 (Patients 1-3) or WM63 (Patients 4-7), with one patient also receiving a continuous infusion of WM63 over 20 hours. All patients demonstrated a significant but transient reduction in the number of circulating leucocytes, and no overall effect on disease progression was observed. Antibody coating of circulating lymphocytes was seen in patients receiving WM-63. Patients receiving large doses of WM63 (cases 5-7) demonstrated a decline in complement levels during treatment. There were no major adverse reactions to WM66, but two patients developed dose limiting side effects to WM63. No human anti-mouse antibody (HAMA) responses were documented. These findings indicate that in vitro cytotoxicity mediated by Mabs fixing human complement correlates poorly with clinical responses, and support earlier observations which indicate that cell-mediated cytotoxicity is necessary for effective antibody therapy.

Aged↗

Family physicians' involvement with dying patients and their families. Attitudes, difficulties, and strategies.

OBJECTIVE: To determine family physicians' perceptions of the difficulty in caring for dying patients and how prepared they are to provide such care relative to strategies used with difficulties encountered, personal need for support and development, and cooperation with other caregivers. DESIGN: Exploratory. SETTING: Physicians' offices. SUBJECTS: Thirty-five randomly selected family physicians (doctors of medicine and doctors of osteopathy) representative of family physicians practicing in Franklin County, Ohio. INTERVENTIONS: None. MAJOR OUTCOME MEASURES: A semistructured interview guide corresponding to a three-dimensional theoretical model developed prior to the study was used to determine family physicians' perceptions regarding care of dying patients and their families. The three dimensions include family physicians' involvement with dying patients and their families, their personal needs and development, and their cooperation with other caregivers. RESULTS: Participants agreed that the care of dying patients and their families is an important and special component of practicing family medicine. Generally seeing themselves as adequately prepared, they still found such care difficult and desired more education and training to increase comfort of their patients and of themselves. Their perceptions regarding the care of dying patients and their families could be categorized in terms of communication as part of the care process, family issues, legal and ethical issues, coordination of care, physicians' feelings, and physicians' influence and support. CONCLUSIONS: Family physicians require formal training in death issues and need to find a way to maximize learning through personal experiences. Discussion of cases in a support group may be beneficial.

Attitude to Death↗

Control and regulation of metabolic fluxes in microbes by substrates and enzymes.

The control of enzymes and substrates on the flux through microbial metabolic pathways can be quantified in terms of flux control coefficients. In pathways involving group transfer, the summation theorem for flux control by the enzymes has to be modified: the sum of control by all enzymes is between 1 and 2. The phosphoenolpyruvate:glucose phosphotransferase system is such a pathway. Experimental determination of the control by the enzymes in this pathway is under way. The control of the enzymes on the glycolytic flux in yeast is low, with the possible exception of the uptake step. In Klebsiella pneumoniae potassium and ammonium ions can simultaneously be 'limiting', (i.e. have significant control on growth) at pH6, but not at pH8. This may be due to the fact that at pH8 the high-affinity potassium uptake system is absent.

Ammonia↗

Regional anaesthetic technique and the incidence of tourniquet pain.

The influence of regional anaesthetic technique on the incidence of lower extremity tourniquet pain was evaluated. We studied 60 patients undergoing orthopaedic procedures of the lower extremity with the use of a pneumatic tourniquet and anticipated inflation of 60 min or longer. Three different anaesthetic techniques were selected by random and draw; spinal anaesthesia (SAB) with plain 0.5% bupivacaine (15 mg) and 0.2 mg epinephrine added, lumbar epidural anaesthesia (EA) with 2% mepivacaine and 1:200,000 epinephrine added, and epidural anaesthesia (AEA) with the same solution alkalinized with bicarbonate. Onset and level of sensory blockade were determined by loss of painful sensation to pinprick. The incidence of tourniquet pain was determined at 15-min intervals or by patient complaint, by an observer unaware of group. Time to onset of pain, amount of treatment (i.v. fentanyl), and sensory level at the time of pain were determined. The SAB was compared with EA and AEA, and EA was compared with AEA. The SAB group was older. The sensory level achieved and duration of tourniquet inflation did not differ among groups. The incidence of tourniquet pain was lower with SAB than with EA and lower with AEA than with EA. There was no difference between SAB and AEA. This study demonstrated a lower incidence of tourniquet pain with spinal anaesthesia than with epidural anaesthesia to the same sensory level. However, this advantage is eliminated if the epidural anaesthetic was performed with an alkalinized local anaesthetic.

Anesthesia, Epidural↗

pH adjustment of mepivacaine decreases the incidence of tourniquet pain during axillary brachial plexus anaesthesia.

The effect of pH adjustment of mepivacaine on the incidence of tourniquet pain during axillary brachial plexus anaesthesia was studied. Thirty-nine patients scheduled for hand surgery, during which use of pneumatic tourniquet for longer than 60 min was planned, were randomized into two groups. Both received axillary brachial plexus block with 40 ml, 1.4% mepivacaine, 1:200,000 epinephrine. The study group had 4 ml sodium bicarbonate (1 mEq.ml-1) added (final pH 7.31), and the control group had 4 ml saline added (final pH 5.6). The incidence of tourniquet pain was determined from cases for which tourniquet inflation lasted longer than 60 min. Tourniquet; pain was defined as poorly localized and distinct from an inadequate axillary block by a blinded observer. More tourniquet pain occurred in the control group. The authors conclude that alkalinization of mepivacaine for axillary brachial plexus anaesthesia may be indicated in cases where use of pneumatic tourniquet for long periods is planned.

Adult↗

Role of magnetic resonance imaging in the assessment of spinal injuries.

Magnetic Resonance Imaging (MRI) examination was carried out on 44 patients who had spinal injuries with neurological involvement. The technique provided valuable information about the nature of the injuries and, in particular, about the state of the spinal cord. The appearances of the cord on MRI ranged from normal, to oedema, to more severe damage such as cord haemorrhage or transection or, in later cases, myelomalacia. The appearance of the cord on MRI correlated strongly with both the severity of the neurological deficit and also the degree of subsequent recovery. In the assessment of the acute spinal injury, MRI has been shown to be a good prognostic indicator; it may also help to identify which patients are likely to benefit from early decompression.

Acute Disease↗

Laryngo-onycho-cutaneous syndrome associated with familial benign hypercalcemia.

A Pakistani boy had chronic ulceration of the cheeks, generalized nail dystrophy, ulceration and hypergranulation of the nail beds, conjunctiva, and vocal cords, and dental enamel hypoplasia. These features are consistent with laryngo-onycho-cutaneous (LOCS) syndrome or Laryngeal and Ocular Granulation tissue in children from the Indian subContinent (LOGIC) syndrome. Both he and his elder brother had elevated levels of serum calcium consistent with familial benign hypercalcemia. Laryngo-onycho-cutaneous syndrome is a newly recognized condition and its association with familial benign hypercalcemia has not been previously reported.

Child, Preschool↗