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Biomedical subjects

J R Hamilton

Publications and source records attributed to J R Hamilton.

At least 19 recordsLinked to original sources
PubMed2004

Impaired hemostasis and protection against thrombosis in protease-activated receptor 4-deficient mice is due to lack of thrombin signaling in platelets.

Platelets from protease-activated receptor 4 (PAR4)-deficient mice are unresponsive to thrombin, and Par4-/- mice have prolonged bleeding times and are protected against thrombosis. However, in addition to its role in platelets, PAR4 contributes to thrombin signaling in cells in the blood vessel wall that might participate in hemostasis and thrombosis, such as endothelial cells. To determine whether the hemostatic and thrombotic phenotypes of Par4-/- mice were due to loss of PAR4 function in hematopoietic vs. other cell types, tail bleed times and thromboplastin-induced pulmonary embolism were examined in lethally irradiated mice reconstituted with Par4+/+ or Par4-/- bone marrow. In Par4+/+ and Par4-/- mice reconstituted with Par4+/+ marrow, the median tail bleed times were 2.0 and 1.7 min, respectively, vs. > 10 min for both Par4+/+ and Par4-/- mice reconstituted with Par4-/- marrow. In the pulmonary embolism model, Par4+/+ and Par4-/- mice reconstituted with Par4+/+ marrow survived a median of 3.7 and 2.8 min, respectively, after administration of thromboplastin, vs. > 20 min for both Par4+/+ and Par4-/- mice reconstituted with Par4-/- marrow. Further, the phenotype of mice reconstituted with Par4-/- marrow was almost as dramatic as that seen in Nf-e2-/- mice, which lack platelets. These data strongly suggest that increased tail bleed times and protection against thrombosis in Par4-/- mice are accounted for by lack of PAR4 function in platelets, emphasize the importance of thrombin signaling in platelets among the multiple pathways and cell types that govern hemostasis and thrombosis.

Animals↗
PubMed2001

Increased expression of protease-activated receptor-2 (PAR2) and PAR4 in human coronary artery by inflammatory stimuli unveils endothelium-dependent relaxations to PAR2 and PAR4 agonists.

Protease-activated receptor (PAR)1 and PAR2 are expressed on vascular endothelial cells and mediate endothelium-dependent relaxation in several species, and PAR4 agonists cause similar responses in rat aortas. To date, only PAR1 has been reported to mediate relaxation of human arteries despite endothelial cell expression of both PAR1 and PAR2 in these tissues. Because inflammatory stimuli increase PAR2 expression in human endothelial cells in culture, the present study investigated the effect of similar stimuli on PARs in human isolated coronary arteries (HCAs). In HCA ring segments suspended for isometric tension measurements, the selective PAR1-activating peptide, TFLLR (0.01 to 10 micromol/L), caused endothelium-dependent relaxation of precontracted preparations. Little or no change in vascular tension was elicited by either the PAR2- or PAR4-activating peptides, SLIGKV and GYPGQV, respectively (up to 100 micromol/L). Exposure of HCAs to interleukin (IL)-1alpha (1 ng/mL, 12 hours) or tumor necrosis factor-alpha (3 nmol/L, 12 hours) did not affect PAR1 expression but increased PAR2 and PAR4 mRNA levels by approximately 5- and 4-fold, respectively, as determined by quantitative polymerase chain reaction. Similar IL-1alpha treatment did not affect TFLLR-induced relaxations but revealed significant endothelium-dependent relaxations to SLIGKV (100 micromol/L, 61.4+/-6.7%) and GYPGQV (100 micromol/L, 34.8+/-6.4%). These studies are the first to demonstrate functional PAR2 and PAR4 in human arteries in situ. The selective upregulation of PAR2 and PAR4 expression and the increased vascular response in HCAs after exposure to inflammatory stimuli suggest a role for these endothelial receptors during inflammation.

Adult↗
PubMed2001

A policy of elective delayed sternal closure does not improve the outcome after arterial switch.

BACKGROUND: Delayed sternal closure is regularly used in the immediate management of hemodynamic instability after neonatal cardiac procedures. The aim of this study was to assess whether the routine, elective use of delayed sternal closure would reduce morbidity in neonates undergoing arterial switch for transposition of the great arteries. METHODS: A retrospective statistical analysis was performed on 52 neonates operated on from 1991 to 1998. Until 1994, chest closure was routinely attempted in all patients after arterial switch; the policy was then changed to delayed sternal closure in all cases in the latter half of the study period. RESULTS: Delayed sternal closure did not significantly alter the mean duration of ventilation (2.7 +/- 2.37 versus 2.7 +/- 1.3 days) nor intensive care stay (4.1 +/- 2.8 versus 5.7 +/- 10.0 days; p = 0.46). There was no increase in the incidence of wound sepsis (7.7% versus 3.8%; p = 0.55), and mortality was unchanged (7.7% in both groups). There was an increase in the incidence of urgent reexploration (7.7% versus 19.2%; p = 0.22), which did not reach significance. CONCLUSIONS: This study does not support the hypothesis that elective delayed sternal closure reduces the morbidity after arterial switch in neonates but does, however, confirm the safety and efficacy of the procedure.

Female↗
PubMed2001

Assessment of mortality rates for congenital heart defects and surgeons' performance.

BACKGROUND: In the absence of reliable national data, we have collected results of all operations for congenital heart defects from five departments to assess mortality rates and compare them among surgeons and departments. METHODS: Data relating to all operations (2,718) carried out at the five centers during a period from April 1, 1997 through March 31, 1999. Clearly defined criteria were agreed for the classification of patients into various subgroups. RESULTS: The overall hospital mortality was 4.4% (95% confidence intervals 3.7%-5.3%). Mortality for open-operations was 12.6% in neonates, 5.1% in infants, and 3.5% in children. Mortality rates were 1.1% for coarctation, 0.4% ventricular septal defect, 4.1% atrioventricular septal defect, 2.9% Fallot, 0.9% switch, and 15.6% truncus arteriosus. Although individual surgeons' mortality rates ranged from 1.8% to 7.5%, none of the 12 surgeons' data were above 95% confidence intervals. For individual surgeons, the change in mortality rates between the 2 years ranged between -3.3% and +3.8%. CONCLUSIONS: With 2 years' data available, estimates of mortality rates are more precise as reflected by tighter confidence intervals. There were relatively small data sets for individual hospitals and surgeons, which made statistical evaluation difficult. For setting standards, data from more departments for a longer period will be required. Statistical methods alone cannot be used as a sole arbiter of what is considered acceptable performance.

Cause of Death↗
PubMed2001

Anomalous left coronary artery from the pulmonary artery: creating an autogenous arterial conduit for aortic implantation.

Anomalous origin of the left coronary artery from the pulmonary artery requires surgical correction. A surgical technique is presented. Two infants underwent re-implantation of their anomalous left coronary arteries by creating a tunnel using autogenous aortic and pulmonary arterial walls. The advantage of this technique is that the new left coronary artery lies in the horizontal plane and in an anatomically correct axis running in the groove behind the pulmonary artery. It also provides a tension free endothelialized autogenous arterial walls with normal growth anticipated.

Aorta, Thoracic↗
PubMed2001

The use of left heart bypass in adult and recurrent coarctation repair.

OBJECTIVES: Paraplegia following coarctation repair occurs in 0.4% of infants. However, for older children, adults and re-operations, the incidence can be as high as 2.6%. Yet there is no consensus on the need for spinal cord protection or the optimal method. This paper reports our experience with left heart bypass (LHB) in adult and re-do coarctation. METHODS: Between 1997 and 2000, nine patients underwent elective resection of coarctation (three re-dos, two balloons) with a mean age of 17.9 years (range, 8-44) and weight of 52 kg (range, 17.3-109). The mean trans-coarctation gradient was 29.6 mmHg (range, 20-45). Patients were placed on LHB using a centrifugal pump with full heparinization through a fourth-space thoracotomy. Patients were cooled to 31-34 degrees C for additional spinal cord protection. Repair was carried out with an inter-positional graft (5/9), a Gore-Tex patch (2/9) or end-to-end anastomosis (2/9). The mean cross-clamp and bypass times were 36.4 (range, 19-65) and 40.3 min (range, 22-70), respectively. RESULTS: No patient developed transient or permanent paraplegia. The mean peak creatinine was 80 micromol/l (range, 51-123). CONCLUSIONS: LHB is simple, easy and safe to implement, and is the only technique capable of maintaining independent upper and lower body perfusion pressure. Potentially, it provides the best spinal cord protection, and extends the margin of safety and time to execute an accurate repair.

Adolescent↗
PubMed2001

Exfoliation syndrome: clinical and genetic features.

We have ascertained a large number of individuals and families with exfoliation syndrome in order to clarify the disorder's mode of inheritance. Patients with exfoliation syndrome and their relatives were recruited from the practices of a group of ophthalmologists in Maritime Canada. The degree to which the subjects were affected was graded according to a standardized 1-4-point clinical scheme. Pedigrees were constructed from information supplied by family members and from genealogical sources. A total of 782 patients and relatives participated, of whom 467 were definitely affected. The mean age of affected males and females did not differ significantly, but females appeared to be more severely affected at ascertainment than males. More than half of the affected subjects had definite exfoliation in only one eye. Approximately 30 multiplex families were discovered, including one containing 23 affected members among a total of 137 examined individuals that constitutes the largest exfoliative pedigree thus far described. We observed well-documented paternal transmission of the trait, a finding that has not to our knowledge been previously reported. Clustering of cases in the families provides evidence for the involvement of genetic factors. The possibility of homozygosity is suggested in a few patients by the earlier or more frequent presentation of the disorder in the offspring of two affected parents or consanguineous pairings. Although a multifactorial mode of inheritance cannot be excluded, exfoliation syndrome appears to be inherited as an autosomal dominant trait whose late onset and incomplete penetrance poses a significant but not insuperable obstacle to pedigree construction.

Aged↗
PubMed2001

Protease-activated receptor (PAR) 1 but not PAR2 or PAR4 mediates endothelium-dependent relaxation to thrombin and trypsin in human pulmonary arteries.

Endothelial protease-activated receptors (PARs) may be important sensors of vascular inflammation and injury. Activation of endothelial PAR1 and PAR2 causes nitric oxide-mediated arterial smooth muscle relaxation in a number of species and PAR4 activation causes similar responses in isolated rat aorta. However, it is unclear whether these receptors mediate such responses in human arteries because the most potent activators of PAR1, PAR2, and PAR4, thrombin and trypsin, cause endothelium-dependent relaxation of human coronary arteries through a common PAR1-like receptor. This study aimed to determine whether this unique pharmacology of PARs in human coronary arteries extends to human pulmonary arteries. PAR1 and PAR2 mRNA and protein were detected in human pulmonary arteries via reverse transcription polymerase chain reaction and immunohistochemistry, respectively. PAR4 mRNA was also detected in human pulmonary arteries. Contracted human pulmonary artery ring segments suspended for isometric tension measurement relaxed in a concentration- and endothelium-dependent manner to thrombin (0.001-0.1 U/ml), trypsin (0.01-1 U/ml), and the PAR1-activating peptide, SFLLRN (0.1-10 microM). By contrast, the PAR2- and PAR4-activating peptides, SLIGKV and GYPGQV, respectively, caused neither contraction nor relaxation of precontracted human pulmonary arteries. Relaxations to thrombin and trypsin cross-desensitized, while tachyphylaxis to SFLLRN abolished subsequent relaxations to both thrombin and trypsin. We conclude that human pulmonary arteries express PAR1, PAR2, and PAR4, but that only PAR1, or a PAR1-like receptor, is coupled to endothelium-dependent relaxation.

Dose-Response Relationship, Drug↗
PubMed2000

Donor organ transmission of varicella zoster due to cardiac transplantation.

BACKGROUND: We report a case of donor-transmitted varicella zoster viral (VZV) infection in a cardiac transplant recipient. A 15-month-old girl developed primary VZV infection 12 days after cardiac transplantation. The donor suffered from varicella 2 weeks before death from pneumococcal meningitis. METHODS: Despite treatment of the seronegative recipient with intravenous acyclovir from the time of surgery, she developed symptoms of fever, a nonspecific macular rash, and small palatal vesicles. RESULTS: After rapid diagnostic confirmation by direct immunofluorescence on vesicular fluid, high-dose intravenous acyclovir was commenced. In addition, the cyclosporine dose was reduced by 25%. The child made a quick and uncomplicated recovery. CONCLUSIONS: Donor organ transmission of VZV has not, to our knowledge, been previously reported. It occurred despite treatment with acyclovir and resulted in an atypical cutaneous eruption. It responded to an increased dose of acyclovir and a reduced level of immunosuppression.

Acyclovir↗
PubMed2000

Mortality rates after surgery for congenital heart defects in children and surgeons' performance.

BACKGROUND: A public inquiry into surgery for paediatric congenital heart defects in Bristol, UK, underscored the need for reliable data on overall mortality rates, which would allow assessment of individual surgeons' performance. We aimed to gather and report such data for 1 year to provide information for clinicians, researchers, policy makers, and the general public. METHODS: We collected data on all operations (1378) for congenital heart defects done by 11 surgeons in five departments in the UK between April 1, 1997, and March 31, 1998. These operations represented about 36% of all operations done in the UK during that time. Clearly defined criteria were agreed to classify operations into subgroups. FINDINGS: The overall mortality rate for all operations was 4.0% (95% CI 3.0-5.2). No deaths occurred for 67 arterial-switch operations. Mortality rates for coarctation, ventricular septal defect, atrioventricular septal defect, Fallot, and truncus arteriosus operations were 1.1%, 0.6%, 3.6%, 2.3%, and 28.6%, respectively. Although overall mortality rates between surgeons varied (1.6-6.9%), no surgeon's were higher than the 95% CI. The numbers of operations done by individual surgeons were small, which led to wide confidence intervals and made the detection of differences in performance difficult. INTERPRETATION: The participating departments seemed to reach high standards of care for children with congenital heart defects, although more data would be needed to assess performance of individual surgeons. The development of quality standards will be difficult because of the complexity of defects, the different types of operations, and few patients in each subgroup. Collection of larger sets of data for more patients and centres are needed.

Aortic Coarctation↗
PubMed2000

Heterogeneous mechanisms of endothelium-dependent relaxation for thrombin and peptide activators of protease-activated receptor-1 in porcine isolated coronary artery.

1. Mechanisms of protease-activated receptor-1 (PAR1)- and PAR2-induced relaxation were investigated in pre-contracted porcine coronary artery ring preparations. 2. Thrombin (0.01 - 0.3 u ml(-1)) and the PAR1-activating peptide SFLLRN (0.1 - 10 microM) caused concentration- and endothelium-dependent relaxation. pEC(50)s (-log u ml(-1) for enzymes, -log M for peptides) and maximum relaxations (R(max), %) for thrombin were 1.8+/-0.1 and 93.5+/-2.8% respectively, and for SFLLRN 6.8+/-0.1 and 90.8+/-1.3%. Similar concentration- and endothelium-dependent relaxations occurred with trypsin (pEC(50) 2.3+/-0.2; R(max) 94.1+/-1.9%) and the PAR2-activating peptide SLIGRL (pEC(50) 6.5+/-0.2; R(max) 92.4+/-1.6%). 3. Relaxations to thrombin, SFLLRN, trypsin and SLIGRL were significantly inhibited (P<0.05) to similar extents by the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine (L-NOARG; 100 microM) and the NO scavenger oxyhaemoglobin (20 microM), both separately and in combination. 4. In the presence of the L-type voltage-operated calcium channel (L-VOCC) inhibitor nifedipine (0.3 microM), K(+) (67 mM) abolished the L-NOARG-resistant relaxations to thrombin, SFLLRN, trypsin and SLIGRL. However, nifedipine alone significantly (P<0.05) reduced the pEC(50) (1.5+/-0.1) and R(max) (77.5+/-7.0%) for thrombin but had no effect on relaxations to SFLLRN, trypsin or SLIGRL. Furthermore, L-NOARG-resistant relaxations to thrombin were abolished by nifedipine, whereas relaxations to SFLLRN, trypsin or SLIGRL were not further inhibited by combined treatment with nifedipine and L-NOARG, than they were with L-NOARG treatment alone. 5. Similar selective inhibition of the L-NOARG-resistant relaxation to thrombin, but not SFLLRN, occurred with verapamil (1 microM) and diltiazem (3 microM). 6. Our results suggest heterogeneous mechanisms in the NO-independent relaxation to thrombin and peptide activators of PAR1 in the porcine coronary artery.

Animals↗
PubMed1999

Increases in intracellular pH and Ca(2+) are essential for K(+) channel activation after modest 'physiological' swelling in villus epithelial cells.

We studied the relationship between changes in intracellular pH (pH(i)), intracellular Ca(2+)([Ca(2+)](i)) and charybdotoxin sensitive (CTX) maxi-K(+) channels occurring after modest 'physiological' swelling in guinea pig jejunal villus enterocytes. Villus cell volume was assessed by electronic cell sizing, and pH(i) and [Ca(2+)](i) by fluorescence spectroscopy with 2,7, biscarboxyethyl-5-6-carboxyfluorescein and Indo-1, respectively. In a slightly (0.93 x isotonic) hypotonic medium, villus cells swelled to the same size they would reach during d-glucose or l-alanine absorption; the subsequent Regulatory Volume Decrease (RVD) was prevented by CTX. After the large volume increase in a more hypotonic (0.80 x isotonic) medium, RVD was unaffected by CTX. After modest swelling associated with 0.93 x isotonic dilution, the pH(i) alkalinized but N-5-methyl-isobutyl amiloride (MIA) prevented this DeltapH(i) and the subsequent RVD. Even in the presence of MIA, alkalinization with added NH(4)Cl permitted complete RVD which could be inhibited by CTX. The rate of (86)Rb efflux which also increased after this 0.93 x isotonic dilution was inhibited an equivalent amount by CTX, MIA or Na(+)-free medium. Modest swelling transiently increased [Ca(2+)](i) and Ca(2+)-free medium or blocking alkalinization by MIA or Na(+)-free medium diminished this transient increase an equivalent amount. RVD after modest swelling was prevented in Ca(2+)-free medium but alkalinization still occurred. After large volume increases, alkalinization of cells increased [Ca(2+)](i) and volume changes became sensitive to CTX. We conclude that both alkalinization of pH(i) and increased [Ca(2+)](i) observed with 'physiological' volume increase are essential for the activation of CTX-sensitive maxi-K(+) channels required for RVD.

Amiloride↗