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Biomedical subjects

M J Edwards

Publications and source records attributed to M J Edwards.

At least 163 records · Page 9Linked to original sources
PubMed1994

Phenotypic variability in X-linked ocular albinism: relationship to linkage genotypes.

One hundred nineteen individuals from 11 families with X-linked ocular albinism (OA1) were studied with respect to both their clinical phenotypes and their linkage genotypes. In a four-generation Australian family, two affected males and an obligatory carrier lacked cutaneous melanin macroglobules (MMGs); ocular features were identical to those of Nettleship-Falls OA1. Four other families had more unusual phenotypic features in addition to OA1. All OA1 families were genotyped at DXS16, DXS85, DXS143, STS, and DXS452 and for a CA-repeat polymorphism at the Kallmann syndrome locus (KAL). Separate two-point linkage analyses were performed for the following: group A, six families with biopsy-proved MMGs in at least one affected male; group B, four families whose biopsy status was not known; and group C, OA-9 only (16 samples), the family without MMGs. At the set of loci closest to OA1, there is no clear evidence in our data set for locus heterogeneity between groups A and C or among the four other families with complex phenotypes. Combined multipoint analysis (LINKMAP) in the 11 families and analysis of individual recombination events confirms that the major locus for OA1 resides within the DXS85-DXS143 interval. We suggest that more detailed clinical evaluations of OA1 individuals and families should be performed for future correlation with specific mutations in candidate OA1 genes.

Albinism, Ocular↗
PubMed1994

Breast conserving surgery for early cancer: who, when, where, and how?

Breast-conserving surgery combined with postoperative radiation therapy is a therapeutic option for the early stages of breast cancer that has been proven efficacious by multiple studies with long-term follow-up. The validity of this approach has been recently questioned following the discovery of erroneous data submitted by a single investigator to a study of the National Surgical Adjuvant Breast and Bowel Project. When this individual's contributed data was eliminated, and the residual data reexamined and reviewed by National Cancer Institute statisticians, the conclusions of the study were unchanged and supported other clinical investigations in affirming that breast-conserving therapy is an effective and appropriate treatment for early breast cancer. Marked geographical, institutional, and individual physician variation persists today regarding the acceptance of breast-conserving surgery in the treatment of breast carcinoma. Currently, the trend, however, is toward increased acceptance and utilization of this treatment option. A woman's choice of treatment can be remarkably enhanced if she is carefully provided the pros and cons of all treatment options and then allowed to choose.

Breast Neoplasms↗
PubMed1994

Major hepatic resection under total vascular exclusion with extracorporeal venovenous bypass.

Techniques and principles pioneered during the development of hepatic transplantation have now been applied to hepatic resectional surgery. Primary and metastatic hepatic neoplasms that are centrally located or in proximity to the vena cava or major branches have been resected successfully by total hepatic vascular exclusion. Herein, the authors report the use of extracorporeal venovenous bypass from the infrahepatic vena cava to the axillary vein to provide adequate central venous filling during total vascular exclusion. The use of this technology, pioneered in transplantation, has extended the indication for hepatic resection to patients previously considered unresectable.

Axillary Vein↗
PubMed1993

Structure, expression, and hormonal control of genes from the mosquito, Aedes aegypti, which encode proteins similar to the vitelline membrane proteins of Drosophila melanogaster.

Genomic and cDNA clones of a gene expressed after a blood meal in the mosquito, Aedes aegypti, were identified as having significant similarity to the vitelline membrane protein genes of Drosophila melanogaster. The predicted protein had unusually high contents of alanine, histidine, and proline and contained a region of hydrophobic amino acids that was highly conserved in the predicted protein of the D. melanogaster vitelline membrane protein genes. The 15a gene was expressed from 5 to 40 hr after a blood meal. It was expressed only in the follicle cells of the ovary, particularly in the cells surrounding the oocyte. The 15a gene was expressed in ovaries of the blood-fed, decapitated female in response to an injection of 20-hydroxyecdysone, and in ovaries from non-blood-fed females incubated with the hormone, even in the presence of cycloheximide. A second gene, with weaker homology to 15a, is presumably another member of a family of related genes, as is the case with D. melanogaster vitelline membrane protein genes. This second gene contained a coding sequence similar to a decapeptide recently isolated from mosquito ovaries as an "oostatic factor" (Borovsky et al., FASEB J. 4, 3015-3020, 1990).

Aedes↗
PubMed1993

Tumor necrosis factor mediates disseminated intravascular inflammation (DII) in the genesis of multiple organ edema.

Multiple system organ failure (MSOF), resulting from a diffuse overwhelming inflammatory response, is frequently the cause of death in patients suffering either severe injury or infection. Previous studies have demonstrated increased circulating levels of tumor necrosis factor with both severe injury and infection. In addition, the intravenous administration of tumor necrosis factor (TNF) has been shown to induce systemic responses similar to those seen in patients with MSOF. The data from in vitro studies suggest that TNF-mediated events at the level of the microcirculation may be primary in the genesis of multiple system organ edema and dysfunction. We hypothesized that the intravenous administration of TNF would acutely induce alterations in the microcirculation that were associated with the development of multiple organ edema and cardiorespiratory impairment. The cremaster microcirculation model was used to quantitate changes in microvascular indices. We directly observed increased numbers of firmly adherent leukocytes to the microvascular endothelium and quantitated decreased leukocyte rolling along the surface of the endothelium as leukocytes became firmly adherent following TNF injection. This TNF-mediated leukocyte-endothelial adherence was also associated with the development of microvascular protein leakage. TNF also acutely induced arteriolar vasodilation and increased microvascular blood flow. These changes in microvascular parameters were associated with the synchronous development of TNF-mediated multiple organ edema and cardiorespiratory impairment. These data support the hypothesis that TNF acutely mediates disseminated intravascular inflammation resulting in multiple organ edema and subsequent hemodynamic instability.

Animals↗
PubMed1993

The involvement of Kupffer cells in carbon tetrachloride toxicity.

Carbon tetrachloride (CCl4) is a classical pericentral hepatotoxicant; however, precise details of its mechanism of action remain unknown. One possibility is that Kupffer cells participant in this mechanism since CCl4 elevates calcium, and the release of toxic eicosanoids and cytokines by Kupffer cells is calcium-dependent. Therefore, these studies were designed to evaluate the role of Kupffer cells in CCl4 toxicity in the rat in vivo. Kupffer cells were destroyed selectively with gadolinium chloride treatment (10 mg/kg GdCl3 iv) 1 day prior to administration of CCl4 (4 g/kg ig). Twenty-four hours after CCl4 treatment, rats were anesthetized, blood samples were drawn for aspartate aminotransferase (AST) determination, which is indicative of parenchymal cell damage, and trypan blue was infused into the liver to stain the nuclei of dead hepatocytes. AST levels were in the normal range and trypan blue staining was negligible in livers from vehicle- or GdCl3-treated rats. As expected, CCl4 treatment alone elevated AST levels to values over 4000 U/liter and caused massive cell death (60-90 trypan blue-positive cells/pericentral field). In dramatic contrast, the elevation in AST and cell death due to CCl4 were almost completely prevented by GdCl3 treatment. In attempts to understand this phenomenon, metabolic and detoxification pathways were assessed. CCl4 is metabolized via cytochrome P450 II.E.1; however, GdCl3 treatment did not alter this pathway as assessed from p-nitrocatechol formation from the selective substrate, p-nitrophenol. GdCl3 treatment also had no effect on hepatic glutathione levels. On the other hand, GdCl3 treatment significantly reduced infiltration of neutrophils resulting from exposure to CCl4. These data clearly support the hypothesis that Kupffer cells participate in the mechanism of toxicity of CCl4 in vivo, possibly by release of chemoattractants for neutrophils.

Animals↗
PubMed1993

Heating of guinea-pig fetal brain during exposure to pulsed ultrasound.

Ultrasound-induced temperature elevations in fresh and formalin-fixed fetal guinea-pig brains were measured during in vitro insonation, with a stationary beam in a tank containing water at 38 degrees C. The pulsing regimen used 6.25 microseconds pulses, repeated at a frequency of 4 kHz emitted from a focussed transducer operating with a centre frequency of 3.2 MHz. The greatest temperature rise in brain tissue occurred close to bone and correlated with both gestational age and progression in bone development. After a 2 min insonation with a spatial peak temporal average intensity (ISPTA) of 2.9 W/cm2, a mean temperature elevation of 5.2 degrees C was recorded in fetuses of 60 days gestation (dg). The same exposure produced an increase of 2.6 degrees C in the centre of whole brains of 60 dg fetuses when the bony cranium was removed. As most of the heating occurs within 40 s, these findings have implications for the safety of pulsed Doppler examinations where dwell-time may be an important factor.

Animals↗
PubMed1992

Interleukin 2 acutely induces platelet and neutrophil-endothelial adherence and macromolecular leakage.

The acute effects of interleukin 2 (IL-2) were determined in the rat cremaster microcirculation model by intravital, light, and electron microscopy to better understand the pathophysiology of the IL-2-induced vascular leak syndrome. Four groups of rats were studied over a 2-h monitoring period. One group received 1 x 10(6) units of IL-2/kg i.v. (n = 10), while the remaining groups received IL-2 topically applied to the cremaster muscle in dosages of either 1 x 10(5) (n = 9), 1 x 10(6) (n = 5), or 3 x 10(6) (n = 5) units. Each group was compared with controls (n = 9). IL-2 administered i.v. acutely induced platelet and polymorphonuclear leukocyte-endothelial adherence and microvascular macromolecular leakage that occurred synchronous with the development of tachycardia, hypotension, tachypnea, and hypoxemia. Topically applied IL-2 induced similar microvascular alterations but without changes in hemodynamic and respiratory parameters, which suggests that microvascular alterations were not caused by IL-2-induced changes in hemodynamic parameters. Electron microscopy of cremaster muscle sections demonstrated platelet and neutrophil adherence to the endothelium and endothelial injury. We conclude that IL-2 (or a locally generated mediator) acutely induces platelet and neutrophil-endothelial adherence in the rat skeletal muscle microcirculation that is associated with the development of macromolecular leakage from the microcirculation.

Administration, Topical↗
PubMed1992

Recurrence of lethal osteogenesis imperfecta due to parental mosaicism for a mutation in the COL1A2 gene of type I collagen. The mosaic parent exhibits phenotypic features of a mild form of the disease.

We have determined that a man, ascertained because he fathered a child with lethal osteogenesis imperfecta (OI) with each of two partners, is mosaic in both his germline and somatic tissues for a mutation in the COL1A2 gene which encodes the pro alpha 2(I) chain of type I procollagen. His dermal fibroblasts were previously shown to synthesize a population of cysteine-containing alpha 2(I) chains that were posttranslationally overmodified. DNA sequence analysis of COL1A2 cDNAs demonstrated that the cysteine-containing chain resulted from a point mutation (G to T) in the first position of the codon for the glycine at residue 472 of the triple helical domain. Genomic DNA from the one available affected infant contained the mutant and normal COL1A2 alleles in equal proportion. Examination of DNA from several tissues of the father showed that the mutant allele was present in approximately 40% of his sperm, 80% of his lymphocytes, and nearly 100% of his dermal fibroblasts. Despite the high level of mosaicism detected in somatic tissues, the only phenotypic manifestation of OI in the proband was that he was shorter than his unaffected male relatives and had mild dentinogenesis imperfecta. Thermal stability of type I collagen molecules containing the substitution was decreased, but to a lesser extent than for a nonlethal cysteine for glycine substitution at residue 259 of alpha 2(I), indicating that this measure of molecular stability may be of limited use in explaining the pathogenesis of osteogenesis imperfecta.

Adult↗
PubMed1992

Mast cell degranulation inhibits IL-2-induced microvascular protein leakage.

The therapeutic efficacy of interleukin-2 (IL-2) in the treatment of cancer has been limited by a "vascular leak syndrome" and related toxicities. To better understand the pathophysiology of the "vascular leak syndrome," we tested a hypothesis that mast cell degranulation mediated the acute increase in microvascular protein leakage seen immediately following IL-2 administration. After the cremaster muscle was prepared for intravital microscopy, anesthetized Sprague-Dawley rats were injected with fluorescein isothiocyanate-labeled albumin for fluorescent microscopy. Animals were treated by the intravenous injection of IL-2 (1 x 10(6) U/kg) (n = 6), the control IL-2-vehicle (n = 5), or IL-2 (1 x 10(6) U/kg) after mast cell degranulation with compound 48/80 (n = 6). Relative interstitial fluorescent intensity was quantitated by a computerized image analysis system as an index of microvascular protein leakage. IL-2 acutely induced protein leakage from the microcirculation. Mast cell degranulation with 48/80 prior to IL-2 treatment prevented protein leakage, but did not alter IL-2-induced leukocyte-endothelial adherence. These data suggest that mast cell-mediated events may be responsible for the acute increase in microvascular permeability seen with IL-2 administration and that leukocyte-endothelial adherence alone is not solely responsible.

Animals↗
PubMed1992

The induction of neural tube defects by maternal hyperthermia: a comparison of the guinea-pig and human.

In our recent studies on the effects of maternal hyperthermia on the embryonic guinea-pig, we have demonstrated two 'teratogenic windows' at embryonic days 13 and 21 (E13 and E21). E13 encompasses the period of the closure of the neural groove and anterior neuropore, and E21 the commencement of the cortical plate. The approximate equivalent developmental times in the human are E23-E25 and E49-E56 respectively. In the guinea-pig, maternal hyperthermia at E13 results in a high incidence of neural tube defects (NTD), many open, and associated with other defects such as microphthalmia, and scoliosis or kyphosis. The NTD were most common in the developing hindbrain and all demonstrated considerable infoldings of neural tissue, rosettes of neuroepithelial cells, outpocketings of neural tissue and large cystic cavities beneath the defect. In human examples from the Kyoto Human Embryo Collection, 16 had verified hyperthermic insults at E23-E25 and all had NTD which showed similar deformities to the guinea-pig. Most embryos with such gross defects are aborted in the early fetal period in both species.

Animals↗
PubMed1992

Pentoxifylline inhibits interleukin-2-induced toxicity in C57BL/6 mice but preserves antitumor efficacy.

Interleukin 2 (IL-2) mediates the regression of metastatic cancer but clinical use has been limited due to associated toxicities. Tumor necrosis factor (TNF) is an important mediator of IL-2 toxicity and may have a limited role in IL-2 antitumor efficacy. Because pentoxifylline (PTXF) inhibits TNF production, we hypothesized that PTXF would ameliorate IL-2 toxicity without compromising antitumor efficacy. Four groups of female C57BL/6 mice with pulmonary metastases from a 3-methylcholanthrene-induced fibrosarcoma (MCA-105) and four groups of nontumored mice were treated every 6 h for 4 d by intraperitoneal injections of either IL-2 alone, IL-2 and PTXF, PTXF alone, or equal volumes of saline. Upon completion of therapy, we found that PTXF suppressed many of the IL-2-induced effects including TNF production, lymphocytic infiltration of multiple organs, multiple organ edema, hepatic dysfunction, leukopenia, and thrombocytopenia. Tumor response was determined 21 d after cessation of therapy by quantitating the number and surface area of pulmonary metastases. PTXF preserved antitumor efficacy while reducing the morbidity and mortality caused by IL-2 treatment. These data strongly support the use of PTXF in extending the therapeutic index of IL-2 in the treatment of cancer.

Animals↗
PubMed1992

Deletion in blood mitochondrial DNA in Kearns-Sayre syndrome.

Mitochondrial DNA deletions have been described in the Kearns-Sayre syndrome (KSS) and the Pearson's marrow-pancreas syndrome. In some cases, the same 4,977-bp deletion has been identified in these two very different diseases. Therefore, it is not currently possible to predict the clinical phenotype from the size or location of the deletion. Instead, differential tissue distribution of the deletion has been implicated as one possible determinant of phenotype. In particular, in KSS the deletions have not been detected by Southern blotting in the blood, whereas in Pearson's syndrome they are easily detectable. We describe here an 11-y-old boy with clinically characteristic KSS and a 7.4-kb mitochondrial DNA deletion between nucleotides 7,194 and 14,595. Southern blotting reveals that 75% of the mitochondrial DNA molecules from his peripheral blood have this deletion. This case blurs further the molecular distinction between the KSS and Pearson's marrow-pancreas syndrome, questioning whether tissue distribution is a sufficient explanation for the very different phenotypes of these disorders.

Anemia, Sideroblastic↗