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Biomedical subjects

M J Edwards

Publications and source records attributed to M J Edwards.

At least 181 records · Page 10Linked to original sources
PubMed1992

Passive immunization against tumor necrosis factor inhibits interleukin-2-induced microvascular alterations and reduces toxicity.

BACKGROUND: Antineoplastic therapy with interleukin-2 (IL-2) has been limited by dose-dependent systemic toxicities. Previous studies suggest that the hemodynamic instability and "vascular leak syndrome" that develop immediately after IL-2 administration occur secondary to neutrophil-mediated events in the microcirculation. Because IL-2 has limited direct effects on neutrophils and acutely induces the production of tumor necrosis factor-alpha (TNF), we hypothesized that the acute microvascular alterations and hemodynamic instability induced by IL-2 were mediated by TNF. METHODS: The cremaster muscles of anesthetized rats were prepared for intravital microscopy. All animals were injected with fluorescein isothiocyanate conjugated to bovine serum albumin, and relative interstitial fluorescence was quantitated as an index of macromolecular leakage. Vital signs, leukocyte-endothelial interactions, and interstitial fluorescence were quantitated every 30 minutes for 2 hours after intravenous injections of IL-2, TNF, and IL-2 with polyclonal antibody to TNF. RESULTS: Both IL-2 and TNF acutely induced hypotension, tachycardia, increased macromolecular leakage, and increased leukocyte-endothelial adherence. Polyclonal antibody to TNF effectively inhibited IL-2-induced leukocyte-endothelial adherence, macromolecular leakage, and hypotension. CONCLUSIONS: These data suggest that the acute microvascular alterations and hypotension induced by IL-2 are mediated by TNF.

Animals↗
PubMed1991

Familial translocation 5;14 resulting in an unbalanced offspring.

We report on an infant with multiple congenital anomalies possessing a derivative 14 chromosome in excess of the normal complement, resulting from transmission of a familial t(5;14)(p13;q22). The proposita's phenotypically normal mother, mentally retarded half-brother, and fetal sib are carriers of the apparently balanced translocation. Previous cases of similar familial t(5;14) are reviewed. The proposita's phenotype is characterized by failure to thrive, developmental retardation, cleft palate, congenital heart anomaly, abnormal hands and feet, unusual face with abnormal ears, and recurrent respiratory infections. The proposita died at age 9 months and postmortem examination showed multiple central nervous system, cardiopulmonary, gastrointestinal, and genital malformations. Our proposita's phenotype is attributable to contributions from both chromosomes and is consistent with the consequences of both the dup(5p) and dup(14q).

Abnormalities, Multiple↗
PubMed1991

Interleukin-2 acutely induces protein leakage from the microcirculation.

Interleukin-2 has been shown to mediate the regression of metastatic cancer. However, therapeutic application has been limited by the induction of dose-dependent toxicities in normal tissues secondary to a vascular leak syndrome. To better understand the pathophysiology of this vascular leak syndrome, the earliest microvascular effects of interleukin-2 were directly observed and quantitated by intravital microscopy. The cremaster muscle of anesthetized Sprague-Dawley rats was prepared for in vivo microvascular observation. Animals were injected with fluorescein isothiocyanate-labeled albumin, and the interstitial emission intensity was used to assess macromolecular leakage. Both the intravenous injection and topical application of interleukin-2 to the cremaster muscle acutely induced the leakage of macromolecules from the microcirculation. The topical application of interleukin-2 induced macromolecular leakage without changes in central hemodynamic parameters. Furthermore, topically applied interleukin-2 did not produce changes in arteriolar or venular diameters, or in regional microvascular blood flow, which could have influenced the protein leakage. These data support the hypothesis that the acute increase in macromolecular leakage produced by interleukin-2 occurs secondary to an increase in endothelial porosity and not as a result of changes in hemodynamic or hydrostatic forces.

Administration, Topical↗
PubMed1991

Interference with neural crest migration by maternal hyperthermia as a cause of embryonic death due to heart failure.

Maternal hyperthermia has been demonstrated to be a teratogen in every animal species studied, and a minimum core temperature rise of 2.5 degrees C can produce a number of developmental defects. However, numerous embryos fail to survive to term. In the guinea-pig, heating the embryos prior to neural tube closure induces significant neural tube defects, but all embryos die within 20 days of heating. A number have aberrant cardiac development and many show spectacular pericardial effusions and congestion in the peripheral circulation. We suggest that maternal hyperthermia has interfered with neural crest migration which is a major component in the induction of these changes.

Animals↗
PubMed1991

Mastectomy following preoperative chemotherapy. Strict operative criteria control operative morbidity.

The surgical morbidity associated with aggressive preoperative chemotherapy in 106 patients with advanced primary breast cancer who had chemotherapy followed by mastectomy was examined. These patients were compared with a group of 91 consecutive patients who had mastectomy without preoperative chemotherapy. Strict operative criteria were used to determine the timing of mastectomy following chemotherapy. Wound infection rates were no different in the preoperative chemotherapy group compared to the mastectomy-alone groups (7% versus 4%; p = 0.62). The incidence of wound necrosis was similar (11% versus 6%; p = 0.29). Seroma formation was decreased significantly in the preoperative chemotherapy group compared to the mastectomy-alone group (15% versus 28%; p = 0.04). Intensive preoperative chemotherapy did not delay the reinstitution of postoperative treatment (30% versus 20%; p = 0.27). However, when delay in instituting postoperative chemotherapy was more than 30 days, there was a significant decrease in overall survival rate (p = 0.04). This study provides evidence that intensive preoperative chemotherapy and mastectomy can be performed without increased morbidity. Furthermore it is important to institute systemic chemotherapy within 30 days of mastectomy to achieve maximum survival.

Adult↗
PubMed1991

Heat shock proteins in cultured human keratinocytes and fibroblasts.

Heat shock induces in cells the synthesis of specific proteins called heat-shock proteins. We have compared the induction of these proteins in human keratinocytes, skin fibroblasts, and a human epithelial tumor cell line following exposure to weak and strong inducing agents (heat, cadmium sulphate, and sodium arsenite). The induction of heat shock proteins was measured in cells by one-dimensional gel electrophoresis of [35S] methionine-labeled proteins and by immunofluorescence using a specific HSP72 monoclonal antibody. Both HSP90 and HSP116 were constitutively expressed in these cell types. Exposure of these cells to weak inducing agents such as heat or cadmium sulphate resulted in the synthesis of HSP72 and HSP90, whereas HSP28 and HSP116 synthesis was detected in keratinocytes and fibroblasts following exposure to the strong inducing agent sodium arsenite. In addition, sodium arsenite induced the synthesis of HSP46 in human keratinocytes. Immunofluorescence demonstrated a rapid and reversible accumulation of the 72-kD heat shock protein within the nucleolus of heat-stressed human keratinocytes and fibroblasts.

Arsenic↗
PubMed1991

Pentoxifylline inhibits interleukin-2-induced leukocyte-endothelial adherence and reduces systemic toxicity.

Interleukin-2 (IL-2) mediates the regression of metastatic cancer, but clinical application has been limited by the induction of dose-dependent toxicities in normal tissues. The most clinically significant toxicities occur secondary to a vascular leak syndrome and include acute respiratory failure and hemodynamic instability. Because previous studies suggested a role for pentoxifylline in attenuating the toxic effects of IL-2, we hypothesized that pentoxifylline would inhibit alterations in the microvasculature induced by IL-2 and would ultimately reduce IL-2-induced toxicity. To determine the validity of this hypothesis, we prepared four groups of rats for in vivo microvascular observation. In the first group, a bolus intravenous injection of IL-2 (1 x 10(6) units/kg) acutely induced hypotension, tachypnea, hypoxia, increased lung water, decreased microvascular blood flow, and increased leukocyte-endothelial adherence. No significant changes occurred in animals treated by pentoxifylline alone or the control IL-2 vehicle-alone group. However, pentoxifylline inhibited many of the IL-2-induced systemic and microvascular effects, such as hypotension, tachypnea, increased lung water, hypoxia, and increased leukocyte-endothelial adherence, but not tachycardia or increased microvascular protein leakage. These data support our hypothesis that systemic toxicities induced by IL-2 are associated with alterations in the microcirculation, which may be ameliorated by pentoxifylline.

Animals↗
PubMed1990

Isolated limb perfusion for localized melanoma of the extremity. A matched comparison of wide local excision with isolated limb perfusion and wide local excision alone.

The therapeutic efficacy of isolated limb perfusion in patients with localized melanoma of the extremity remains controversial. We compared patients treated at the University of Texas M.D. Anderson Cancer Center, Houston, with wide local excision and isolated limb perfusion using either melphalan or imidazole carboxamide with a group matched for prognostic factors from the University of Alabama at Birmingham and the University of Sydney (Australia) who were treated with wide local excision alone. No significant difference in disease-free or overall survival rates was found between patients treated with wide local excision with adjuvant isolated limb perfusion or wide local excision alone. However, a subset of patients with thicker lesions (greater than 2.0 mm) treated with wide local excision and isolated limb perfusion using melphalan had a significant improvement in both disease-free and overall survival rates. These data suggest that isolated limb perfusion using melphalan may improve survival rates in selected patients with localized melanoma of the extremity who are at increased risk for local and regional micrometastases, and justifies the continued study of this treatment approach in prospective clinical trials.

Aminoimidazole Carboxamide↗
PubMed1990

Effects of pulsed ultrasound and temperature on the development of rat embryos in culture.

Rat embryos in culture were exposed to pulsed ultrasound at SPTA intensity of 1.2 W/cm2 for 5, 15, and 30 min on day 9.5 of development. The whole embryo culture system allowed precise temperature control for directly examining the effects of ultrasound on the developing neural plate. After exposure, embryos were maintained in culture for a further 48 hr. No major morphological abnormalities were observed but a reduction in somite number occurred in the group insonated for 30 min, which was equivalent to a 2 hr delay in embryonic development. Similar delay in growth and "blistering" in the prosencephalon region of some embryos were observed after insonation for 15 min at 40.0 degrees C, an elevation of 1.5 degrees C over the temperature used for controls. Exposure to ultrasound for 15 min at 40 degrees C caused significant reduction in the growth of the head compared with that of control embryos. Heat shock genes for hsps 71/73 and 88 kD were induced after insonation for 30 min at 38.5 degrees C. Insonation did not cause any temperature changes in the culture medium. However, when the temperature of the culture medium was increased during insonation, defective development occurred. The results of these in vitro experiments suggest that ultrasound if resulting in significant hyperthermia could affect the development during early organogenesis of the neural plate and in particular they suggest that the embryo is at greater risk of damage during hyperthermic conditions. These results should provoke discussion of the concept that ultrasound in the febrile patient may present an increased embryonic risk which should be considered when deliberating on the use of diagnostic ultrasound procedures in the pregnant patient.

Animals↗
PubMed1990

Outpatient percutaneous central venous access in cancer patients.

A 1-year experience of percutaneous subclavian catheterization in outpatients with cancer was reviewed to document reliability, safety, and cost. There were 763 catheter insertions attempted with prospective documentation of complications in 664 consecutive patients. Catheter insertion was successful in 722 attempts (95%). There were only 13 pneumothoraces (2%). Thirty catheters required repositioning (4%). The average catheter duration was 191 days (range: 0 to 892 days). Fifty-six catheters (8%) were removed because of suspected infection. Documented catheter sepsis occurred in 21 patients (3%); catheter site infection occurred in 8 patients (1%). Thus, only 0.22 infections per catheter year occurred during this 382 catheter-year experience. The estimated cost of catheter insertion was $562, which is one-third the estimated cost for tunneled catheters ($1,403) and for reservoir devices ($1,738). In our experience, percutaneous subclavian catheterization is a reliable, cost-effective method compared with tunneled or reservoir devices, with an equivalent incidence of catheter-related infections. The cornerstone of our success with this program is a staff dedicated to catheter care and intensive patient education. In centers where a large number of patients require central venous access, percutaneous catheterization should be the technique of choice.

Ambulatory Care↗
PubMed1990

Studies of type I collagen in osteogenesis imperfecta.

We used the results of skin fibroblast type I collagen analysis to improve the accuracy of diagnosis and genetic counseling for six patients with osteogenesis imperfecta. The fibroblasts of two patients with osteogenesis imperfecta type I synthesized a reduced quantity of qualitatively normal type I procollagen. Another patient with osteogenesis imperfecta type I had two populations of type I collagen molecules, one apparently normal and the other with a substitution of cysteine for glycine in the triple helical domain. Three sporadic cases with osteogenesis imperfecta types II, III, and IV were studied; in each proband a normal and an abnormal overmodified population of type I collagen molecules were demonstrated, and parental collagens were normal in the two available patients. These results indicated that the probands were heterozygous for new dominant mutations and assisted our genetic counseling, especially in osteogenesis imperfecta types II and III, which were formerly believed to be inherited in an autosomal recessive fashion. The results could not exclude parental germ line mosaicism for a new dominant mutation, which has resulted in recurrence in siblings of some patients with osteogenesis imperfecta, so prenatal diagnosis was therefore offered for future pregnancies. Analysis of chorionic villus cell collagen may facilitate antenatal diagnosis in selected cases, and the study of a larger number of patients may allow correlation of the biochemical defects with the natural history and prognosis.

Adult↗
PubMed1990

Posterior nuchal cystic hygroma.

When cystic hygroma is detected antenatally, the prognosis is usually poor, and intrauterine or neonatal death are common. This seems especially true for Turner syndrome (the largest etiologic group associated with cystic hygroma) and the lethal multiple pterygium syndromes. However, some fetuses with Turner syndrome, and also with certain other diagnoses, had a good outcome, and further study of these conditions is required before more definite prognostic indicators and risk figures will be available. Increasing numbers of syndromes are being reported in association with fetal cystic hygroma, and lymphedema may be a common element in their pathogenesis. Mild, short-lived, or otherwise uncomplicated jugular lymphatic obstruction may be a cause of the neck webbing seen in the Noonan, familial pterygium colli, and distichiasis-lymphedema syndromes. With earlier and more widespread fetal ultrasonography, and more sensitive techniques, a greater number of resolving fetal cases may be reported. This may clarify the natural history and provide prospective criteria for the conditions that have better prognoses. The associated conditions include autosomal dominant and recessive genetic traits. Careful ultrasound study for other malformations, polyhydramnios and fetal growth parameters, a fetal karyotype, and, if appropriate, pathologic examination are required to determine the etiology and recurrence risk. The parents should be asked about exposure to alcohol or other agents and should be examined for signs of pterygium colli or Noonan syndrome. If the decision is made to continue the pregnancy, and there is doubt about the natural history and prognosis, multi-disciplinary supervision should include social services, neonatology, pediatric surgery, cardiology, and genetics specialties when indicated.

Female↗
PubMed1990

Current management of soft tissue sarcomas.

Sarcomas are rare. They comprise a heterogenous group of malignancies. Prognosis is determined by presence of distant metastasis, the size of the primary malignancy, and the grade and histogenic classification of the tumor. Careful consideration of the extirpative surgical resection is necessary for appropriate placement of the biopsy incision for diagnosis. Effective therapy includes adequate surgical resection in the form of radical compartmental resection, wide local excision with either pre- or postoperative radiotherapy, or amputation. Progress over the last two decades has resulted in limb salvage and maintenance of limb function for the vast majority of patients.

Humans↗
PubMed1989

Squamous cell carcinoma arising in previously burned or irradiated skin.

Squamous cell carcinoma (SCC) arising in previously burned or irradiated skin was reviewed in 66 patients treated between 1944 and 1986. Healing of the initial injury was complicated in 70% of patients. Mean interval from initial injury to diagnosis of SCC was 37 years. The overwhelming majority of patients presented with a chronic intractable ulcer in previously injured skin. The regional relapse rate after surgical excision was very high, 58% of all patients. Predominant patterns of recurrence were in local skin and regional lymph nodes (93% of recurrences). Survival rates at 5, 10, and 20 years were 52%, 34%, and 23%, respectively. Five-year survival rates in previously burned and irradiated patients were not significantly different (53% and 50%, respectively). This review, one of the largest reported series, better defines SCC arising in previously burned or irradiated skin as a locally aggressive disease that is distinct from SCC arising in sunlight-damaged skin. An increased awareness of the significance of chronic ulceration in scar tissue may allow earlier diagnosis. Regional disease control and survival depend on surgical resection of all known disease and may require radical lymph node dissection or amputation.

Adolescent↗
PubMed1989

Quantitative study of the effects of maternal hyperthermia on cell death and proliferation in the guinea pig brain on day 21 of pregnancy.

On embryonic day 21, pregnant guinea pigs were exposed to a 44 degrees C environment for 1 hour. As a result, all brain ventricular zone cells in M phase of the mitotic cycle when heat-shock occurred became immediately pyknotic and all cell division was stopped for 4-8 hr. The pyknotic cells were removed at a definable rate until mitosis resumed, after which removal occurred in an apparently random manner. Long delays in the return to mitosis were related to increased destruction of S-phase cells deep within the ventricular zone and largely confined to the alar lamina. Upon recovery, a rostrocaudal delay in mitosis was apparent, and the number of mitotic figures was increased compared with control numbers for 1 hr, after which they returned to control numbers. It was evident that up to 40% of the cells within the ventricular zone were destroyed following brief maternal heat stress.

Animals↗
PubMed1989

Regulation of the inducible heat shock 71 genes in early neural development of cultured rat embryos.

Activation of the inducible heat shock 71 genes and their role in the heat shock response was studied in vitro in 9.5 day-old rat embryos at neural tube closure. The transcriptional response of a 71 kilodalton (kD) heat shock gene induced after various regimes of heat shock and acquired thermotolerance was investigated. Expression and accumulation of the heat shock (hs) 71 mRNA in the neuroectoderm was studied by Northern and dot blot analysis. Specific expression in various cell types and regions of the neuroectoderm were examined by in situ hybridization. Exposure of embryos to a heat shock at 43 degrees C for 7.5 min caused high levels of hs mRNA 71 accumulation in the neuroectoderm, pronounced protein synthesis inhibition, and regulated recovery. Specific neuroectoderm cell death followed, resulting in major developmental defects of the eye and forebrain region. A mild heat shock of 42 degrees C for 10 min induced the heat shock response, hsp synthesis, and cell recovery, but produced no cell death or deformities. Preheating the embryo at 42 degrees C resulted in acquired thermotolerance to an otherwise teratogenic 43 degrees C heat shock. Thermotolerance was associated with a rapid recovery of protein synthesis associated with hs 71 mRNA expression. Dot blot analysis showed that after a 42 degrees C heat shock, 71 mRNA was rapidly transcribed and transported into the cytoplasm where it was degraded within 2 hr of the initial response. The results suggest that the heat shock protein (hsp) 71 gene may have a protective rather than a rescuing function.

Animals↗