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Biomedical subjects

B McIntyre

Publications and source records attributed to B McIntyre.

At least 19 recordsLinked to original sources
PubMed2001

Identification of eight novel 5'-exons in cerebral capillary malformation gene-1 (CCM1) encoding KRIT1.

Truncating mutations in the CCM1 gene encoding KRIT1 were recently found in patients affected by inherited cerebral capillary malformations, lesions that cause a wide variety of neurologic problems. However, CCM1 mutations have not been identified in all the families linked to CCM1. Here we demonstrate that the CCM1 gene contains eight additional exons which may thus encompass the missing mutations.

Alternative Splicing↗
PubMed2001

Hemodynamic unloading leads to regression of pulmonary vascular disease in rats.

OBJECTIVE: Treatment options for patients with advanced pulmonary vascular disease caused by a congenital heart defect are still mainly limited to heart-lung transplantation or lung transplantation with repair of the cardiac lesion. Because we have previously shown that the structural changes associated with pulmonary hypertension can be reversed by stress unloading in an organ culture model, we now investigate whether hemodynamic unloading will lead to regression of pulmonary vascular disease in the intact animal. METHODS: Right middle and lower lobectomy and monocrotaline injection were performed in Lewis rats (n = 22) to cause pulmonary vascular disease from a combined hemodynamic and toxic injury. Twenty-eight days later the left lungs were examined (n = 10) or exposed to normal pulmonary artery pressure for an additional 14 (n = 5) or 28 (n = 7) days by transplantation into healthy recipients. Pulmonary artery pressure, ventricular weight, and pulmonary artery morphology were evaluated in each group. RESULTS: Pulmonary hypertension (50 vs 16 mm Hg; P <.001) and right ventricular hypertrophy (right ventricular/left ventricular weight 0.69 vs 0.32; P <.001) associated with pulmonary artery medial hypertrophy (28.2% vs 7.2% wall thickness; P <.001) and muscularization of small pulmonary arteries (92.3% vs 19.4%; P <.001) developed by day 28 (compared with untreated controls). However, transplantation into healthy recipients effectively unloaded the lungs (mean pulmonary artery pressure 17 and 24 mm Hg at 14 and 28 days after transplantation) and resulted in progressive normalization of medial hypertrophy (15.6% and 12.1% at 14 and 28 days) and muscularization (65.1% and 42.2% at 14 and 28 days) relative to nontransplanted controls (P <.005 in each case). CONCLUSIONS: Hemodynamic unloading of lungs with pulmonary vascular disease results in progressive normalization of pulmonary artery structure. These results are the first to provide a rationale for attempting to induce regression of pulmonary vascular disease by pressure unloading of the pulmonary circulation. Methods to mechanically unload the pulmonary circulation should be critically evaluated as a strategy for staged surgical repair of congenital heart defects despite presumed irreversible pulmonary hypertension.

Animals↗
PubMed2000

Gene transfer of the serine elastase inhibitor elafin protects against vein graft degeneration.

BACKGROUND: Leukocyte infiltration and serine elastase activity lead to smooth muscle cell proliferation in association with posttransplant coronary arteriopathy and may also be involved in vein graft neointimal formation. A number of therapies have targeted cellular proliferation, but the inhibition of serine elastase-mediated extracellular matrix remodeling has not been investigated as a potential strategy to prevent neointimal formation and subsequent atherosclerotic degeneration in vein grafts. METHODS AND RESULTS: We studied jugular vein grafts 48 hours after interposition into the carotid arteries of rabbits and demonstrated inflammatory cell infiltration and elevated serine elastase activity, a stimulus for matrix remodeling and deposition of elastin. Therefore, elastolytic activity in vein grafts was targeted through transient expression of the selective serine elastase inhibitor elafin with hemagglutinating virus of Japan liposome-mediated gene transfer. Elafin transfection reduced inflammation by 60% at 48 hours and neointimal formation by approximately 50% at 4 weeks after implantation. At 3 months, a 74% decrease in neointimal elastin deposition correlated with protection against cholesterol-induced macrophage infiltration and lipid accumulation, which were both reduced by approximately 50% in elafin-transfected grafts relative to controls. CONCLUSIONS: Gene transfer of the selective serine elastase inhibitor elafin in vein grafts is effective in reducing the early inflammatory response. Although transient expression of elafin delays neointimal formation, it is also sufficient to cause an alteration in elastin content of the extracellular matrix, making it relatively resistant to atherosclerotic degeneration.

Animals↗
PubMed1999

Gene transfer in utero biologically engineers a patent ductus arteriosus in lambs by arresting fibronectin-dependent neointimal formation.

Closure of the ductus arteriosus requires prenatal formation of intimal cushions, which occlude the vessel lumen at birth. Survival of newborns with severe congenital heart defects, however, depends on ductal patency. We used a gene transfer approach to create a patent ductus arteriosus by targeting the fibronectin-dependent smooth muscle cell migration required for intimal cushion formation. Fetal lamb ductus arteriosus was transfected in utero with hemagglutinating virus of Japan liposomes containing plasmid encoding 'decoy' RNA to sequester the fibronectin mRNA binding protein. Fibronectin translation was inhibited and intimal cushion formation was prevented. We thus established the essential role of fibronectin-dependent smooth muscle cell migration in intimal cushion formation in the intact animal and the feasibility of incorporating biological engineering in the management of congenital heart disease.

Animals↗
PubMed1999

Significance of commonly used prognostic factors differs for children with T cell acute lymphocytic leukemia (ALL), as compared to those with B-precursor ALL. A Pediatric Oncology Group (POG) study.

T cell acute lymphocytic leukemia (T-ALL) and B-precursor ALL differ significantly in the clinical characteristics of the patients at presentation and in laboratory-defined characteristics of the leukemic cells. We assessed for pediatric patients with T-ALL the relative importance of prognostic factors previously demonstrated to predict outcome in B-precursor ALL. Presenting clinical and laboratory features were correlated with outcome for 441 children 12 months to 21 years of age with previously untreated T-ALL, registered on the Pediatric Oncology Group (POG) T3 protocol between 1986 and 1992. These T-ALL prognostic factor analyses were then compared to similar analyses for 1993 patients with B-precursor ALL enrolled during the same time period on the POG ALinC 14 protocol. Quantitative interaction between phenotype and each prognostic factor was studied to determine the relative importance of the prognostic factor for each of the two major immunophenotypes. We also analyzed the importance of maturational stage as a T-ALL prognostic factor, using a modified Ludwig definition of maturational stage. We conclude that several of the clinical and laboratory prognostic factors, which are used reliably for B-precursor ALL, are much less predictive in T-ALL (ie age, WBC, consensus risk group, hyperdiploidy, presence of trans- locations and CALLA expression). There was no significant difference between the phenotypes in the prognostic importance of race or gender. Our data demonstrate a significant difference in outcome among the three maturational stages of T-cell ALL, with the intermediate group faring best. Using traditional risk group criteria to stratify patients with T-ALL for therapy may not be appropriate.

Adolescent↗
PubMed1999

Traumatic wound rupture after penetrating keratoplasty in Africa.

AIM: To investigate risk factors, visual outcome, and graft survival for traumatic wound rupture after penetrating keratoplasty. METHODS: A retrospective analysis of 336 patients who underwent penetrating keratoplasty from 1988 to 1995. RESULTS: 19 patients (5.7%) suffered traumatic postoperative wound rupture requiring surgical repair. They were younger (mean age 16.6 years, 95% CI 13.2-20.6) and more frequently keratoconic (p = 0.01) than other patients (mean age 28.9 years, 95% CI 26.-31.0). Mean postoperative follow up was 37.7 (SD 22.9) months and 24.5 (18.9) months for the rupture and non-rupture patients. Mean interval between keratoplasty and rupture was 18 (21) weeks. The lens was damaged and removed in 37% of ruptured eyes. For keratoconics, the probability of graft survival at 5 years was lower (p = 0.03) in the ruptured eyes (75%) than in the non-ruptured eyes (90%). Endothelial failure was a more common (p <0.05) cause of graft opacification in ruptured grafts than in intact grafts. Of the ruptured eyes, 53% achieved a final corrected acuity of at least 6/18 and 63% achieved at least 6/60 compared with 48% and 71% of the intact eyes respectively (both p >0.1). The proportion of keratoconic eyes which achieved at least 6/60 was lower (p = 0.02) in the ruptured eyes (67%) than the non-ruptured eyes (87%). Eyes with wound ruptures of 5 clock hours or greater were less likely (p <0.05) to achieve an acuity of 6/18 and were more likely (p <0.05) to have an associated lens injury. CONCLUSIONS: Graft rupture is relatively common in African practice, particularly in young keratoconics. Visual outcome and graft survival are not significantly worse than for other grafted eyes, but are significantly worse than for other grafted keratoconic eyes.

Adolescent↗
PubMed1998

Decline in rates of seropositivity for measles, mumps, and rubella antibodies among previously immunized children treated for acute leukemia.

We prospectively determined the measles-mumps-rubella (MMR) antibody status of 39 previously vaccinated children before and after administering protocol-directed chemotherapy for acute leukemia. At diagnosis the seropositivity rates for measles and mumps-specific immunoglobulin G were > or = 90%, while the seropositivity rate for rubella was 85%. After treatment, rates of seropositivity for measles antibody declined by 13% (90% of patients to 77%; P = .13); for mumps antibody, by 18% (97%-79%; P = .02); and for rubella antibody, by 21% (85%-64%; P = .03). These findings suggest that some survivors of acute leukemia during childhood have an increased susceptibility to MMR viruses and would benefit from posttreatment evaluation of their immune statuses and from possible revaccination.

Acute Disease↗
PubMed1995

Antidotal efficacy of alpha-ketoglutaric acid and sodium thiosulfate in cyanide poisoning.

Alpha-ketoglutaric acid and sodium thiosulfate antagonize the toxic effects of cyanide. The present study was performed to test whether a synergistic effect may occur. The alpha-ketoglutaric acid/sodium thiosulfate solutions were injected intraperitoneally into mice prior to exposure to hydrogen cyanide (HCN) in a dynamic inhalation chamber or preceding an intraperitoneal injection of sodium cyanide (NaCN). All lethal concentration (LCT) and lethal dose (LD) values were determined after a period of 24 h. Alpha-ketoglutaric acid alone provided no protection at 250 mg/kg when challenged with HCN. Sodium thiosulfate 500 mg/kg provided a 5% protection. However, when these doses of alpha-ketoglutaric acid and sodium thiosulfate were combined, protection was increased by 18%. Alpha-ketoglutaric acid (250 mg/kg) and sodium thiosulfate (1000 mg/kg) provided an additional 48% protection against a LCT88 of HCN. A single dose of alpha-ketoglutaric acid (500 mg/kg) and sodium thiosulfate (1000 mg/kg) solutions afforded a 70% increase in survivability of the exposed animals. When mice were injected ip with 100 mg/kg of alpha-ketoglutaric acid 15 min prior to the injection of 5.5 mg/kg (LD50) of NaCN, the lethality was reduced to an LD30. Two hundred mg/kg alpha-ketoglutaric acid, challenged with the same dose of NaCN, reduced the lethality to 23%. When mice were challenged with 6.0 mg/kg of NaCN (LD70) pretreated with 100 mg/kg of alpha-ketoglutaric acid or 200 mg/kg of sodium thiosulfate, the LD was not altered in the former but reduced to an LD15 in the latter. At higher doses of sodium thiosulfate (500 mg/kg), an LD60 occurred at 13.6 mg/kg NaCN (2.5 x LD50).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

[Undetermined colitis].

Indeterminate colitis combines features of chronic ulcerative colitis and Crohn's colitis and contemplates a dilemma for the patient and surgeon contemplating ileal pouch anal anastomosis. Some series have reported a high incidence of failure of pouch procedures in patients with indeterminate colitis. A series reported by the authors in 1989 reported a failure rate on approximately 9% with indeterminate colitis. In updating this series with additional patients operated on since that time, the incidence in our series approaches 20%. We feel that an 80% success rate, however, justifies performing the ileal pouch anal procedure in carefully selected patients with indeterminate colitis, knowing that the failure rate may be somewhat higher than in patients with type ordainer chronic ulcerative colitis.

Colitis↗
PubMed1991

Reduced left ventricular afterload and increased contractility in children with insulin-dependent diabetes mellitus: an M-mode and Doppler-echocardiographic evaluation of left ventricular diastolic and systolic function.

Twenty-three children with diabetes mellitus, their ages ranging from 0.2-9.8 years, but with no sign of diabetic microvascular disease were investigated by M-mode and Doppler echocardiography, along with a comparable group of control subjects. In the diabetics, the fractional shortening and the mean velocity of fractional shortening were 14 and 18% higher, respectively, whereas the left ventricular end-systolic wall stress, an indicator of left ventricular afterload, was markedly reduced (22%). Assuming an unchanged preload in the two groups, this indicates a reduced afterload in these children. Systolic and diastolic time intervals, heart rate, and blood pressure were similar in diabetics and controls. Doppler-derived transmitral left ventricular filling indices were also similar. Thus, in these diabetic children no signs of left ventricular diastolic abnormality were detected. The state of hypercontractility of the left ventricle is considered to be due to a reduced afterload in early insulin-dependent diabetes.

Child↗
PubMed1990

Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma.

Interferon-gamma (IFN-gamma) is produced during the response to infection and participates in immunostimulatory events. We have previously reported the induction of diabetes in transgenic mice (ins-IFN-gamma) in which the expression of the lymphokine IFN-gamma is directed by the insulin promoter. This diabetes is a result of the progressive destruction of pancreatic islets that occurs with the influx of inflammatory cells. Here we demonstrate that this islet cell loss is mediated by lymphocytes, that engrafted histocompatible islets are destroyed, and that lymphocytes from the transgenic mice are cytotoxic to normal islets in vitro. These results indicate that the pancreatic expression of IFN-gamma can result in a loss of tolerance to normal islets, consistent with its role as an inducer of costimulatory activity, which is essential for lymphocyte activation during an immune response.

Animals↗
PubMed1990

Hyperkalaemia during rapid blood transfusion and hypovolaemic cardiac arrest in children.

A morbidity and mortality review documented a high occurrence of hyperkalaemia in cardiac arrests associated with rapid blood transfusion, which resulted in further study. In order to stimulate events during rapid blood transfusion and cardiac arrest, the central circulation was modeled as a linear one compartment, and used to stimulate a child who suffered a hypovolaemic cardiac arrest and was resuscitated with rapid blood transfusion (RBT). The simulation suggested that the combination of RBT and a low cardiac output state could be associated with hyperkalaemia, if the potassium concentration in the plasma fraction of the transfused blood was greater than or equal to 10 mmol.L-1. In an associated clinical study the plasma potassium concentration during cardiac arrest was documented from a retrospective review of 138 cardiac arrests in a paediatric population. Patients were divided into two groups. The RBT-group received a rapid blood transfusion during resuscitation. The non-RBT group did not receive blood during resuscitation. During cardiac arrest the plasma [K] in the non-RBT group was 5.63 +/- 2.39 mmol.L-1 compared with 8.23 +/- 1.99 mmol.L-1 in the RBT-group (P less than 0.05). The hyperkalaemia during cardiac arrest in the RBT-group could be explained as a consequence of RBT to a hypovolaemic child with a low cardiac output.

Adolescent↗
PubMed1986

Function and cell distribution of KC-1, a novel natural killer cell-associated antigen.

Natural killer (NK) cell have been implicated in immune responses to tumor and viral antigens. We describe here a monoclonal antibody, anti-KC-1, that blocks lysis of NK targets by fresh but not activated NK cells. Anti-KC-1 has no effect on cytotoxic T lymphocyte activity or on antibody-dependent cellular cytotoxicity. This antibody may be useful in the analysis of NK cell activation and the mechanism of lysis.

Animals↗
PubMed1986

Reoperation for prosthetic valve degeneration after Konno aortoventriculoplasty.

Since the introduction of the aortoventriculoplasty procedure by Konno in 1975, 16 patients have undergone aortic root augmentation by this method at the Woodruff Medical Center of Emory University. In four patients bioprosthetic valve degeneration 2 to 5 years after the Konno procedure has necessitated repeat operation and replacement of the prosthetic aortic valve. Modification of the septal patch or repeat right ventriculotomy has not been required. One patient required an additional lateral anulus-enlargement procedure (Manouguian) whereas the other three have demonstrated stability or growth of the aortic anulus. We have not observed recurrent subvalvular stenosis or problems with the right ventricular outflow tract. Repeat operation after aortoventriculoplasty has been relatively simple and has usually involved only the supra-annular aorta.

Adult↗
PubMed1985

Gastric emptying of combined liquid-solid meals in healed duodenal ulcer.

The gastric emptying rates of combined liquid and solid radioisotopically labeled meals in 47 healed duodenal ulcer subjects and 17 healthy control subjects are compared. No significant differences were found between the groups in emptying slopes and the emptying half-times or in the percent retention values at any of the counting intervals for either the liquid or solid meals. These results are compatible with the observation that the rapid gastric emptying in many patients with duodenal ulcer is associated with the disease and that healing results in a return to normal gastric emptying rates. However, since gastric emptying rates during active ulceration were not determined in our patients, a more definitive interpretation awaits a study comparing emptying rates obtained during and after healing of active ulceration in the same patient.

Adult↗
PubMed1985

Combined treatment approach in surgical management of carcinoma of the esophagus: a preliminary report.

Surgical management of squamous cell carcinoma of the esophagus continues to be a controversial area in thoracic surgery. In a series of 20 patients, 15 received preoperative chemotherapy with cis-platinum (cisplatin), 2 received cisplatin plus 5-fluorouracil, and 3 received cisplatin plus vinblastine sulfate. Eighteen patients underwent en bloc esophagogastrectomy and postoperative radiation therapy. All patients were staged preoperatively by thoracoabdominal computed axial tomographic scan, bone scan, bronchoscopy, esophagoscopy, and barium swallow. Patients with liver or bone metastasis were excluded. The majority of patients received preoperative enteral hyperalimentation. Eighteen of the 20 patients completed the study with a follow-up of 12 to 24 months. There was 1 operative death, and 3 patients were in the hospital for more than three weeks after operation before they were discharged. Fourteen of the 18 patients survived for a year, and 11 survived for 12 to 24 months. Substantial reduction in mucosal disease and tumor burden based on preoperative barium swallow and endoscopy was evident in 11 of 18 patients, but in no patient was the tumor completely eradicated by preoperative chemotherapy. Although follow-up is short, this treatment regimen involving a combined treatment offers hope in the palliation of this disease.

Adult↗