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Biomedical subjects

C J Porter

Publications and source records attributed to C J Porter.

At least 55 records · Page 3Linked to original sources
PubMed1998

A novel mutation in KVLQT1 is the molecular basis of inherited long QT syndrome in a near-drowning patient's family.

After identifying a 10-year-old boy with inherited long QT syndrome (LQTS) after a near-drowning that required defibrillation from torsades de pointes, evaluation of first degree relatives revealed a four-generation kindred comprising 26 individuals with four additional symptomatic and eight asymptomatic members harboring an abnormally prolonged QTc (defined as > or =0.46 s1/2). We set out to determine the molecular basis of their LQTS. The inherited LQTS represents a collection of genetically distinct ion channelopathies with over 40 mutations in four fundamental cardiac ion channels identified. Molecular studies, including linkage analysis and identification of the disease-associated mutation, were performed on genomic DNA isolated from peripheral blood samples from 29 available family members. Genetic linkage analysis excluded the regions for LQT2, LQT3, and LQT5. However, the chromosome 11p15.5 region (LQT1) showed evidence of linkage with a maximum lod score of 3.36. Examination of the KVLQT1 gene revealed a novel 3-bp deletion resulting in an in-frame deltaF339 (phenylalanine) deletion in the proband. This deltaF339 mutation was confirmed in nine additional family members who shared both an assigned affected phenotype and the disease-associated linked haplotype. Importantly, three asymptomatic family members, with a tentative clinical diagnosis based on their QTc, did not have this mutation and could be reclassified as unaffected. It is noteworthy that the proband's ECG suggested the sodium channel-based LQT3 genotype. These findings show the potential importance of establishing a molecular diagnosis rather than initiating genotype-specific interventions based upon inspection of a patient's ECG.

Chromosomes, Human, Pair 11↗
PubMed1998

Cardiac transplantation for end-stage congenital heart defects: the Mayo Clinic experience. Mayo Cardiothoracic Transplant Team.

OBJECTIVE: To review the outcome of cardiac transplantation undertaken in patients with congenital heart defects. MATERIAL AND METHODS: Between November 1991 and March 1998 at our institution, cardiac transplantation was performed in 16 patients with congenital heart disease (age range, 3 to 57 years; mean, 26.1). Preoperative diagnoses included univentricular heart (N = 4); complete transposition of the great arteries (N = 3); Ebstein's anomaly (N = 2); tetralogy of Fallot (N = 2); levotransposition (N = 2); dextrocardia, corrected transposition, ventricular and atrial septal defects, and pulmonary stenosis (N = 1); double-outlet right ventricle (N = 1); and hypertrophic obstructive cardiomyopathy (N = 1). All patients had undergone from one to five previous palliative operations. RESULTS: Four patients required permanent pacemaker implantation during the first month postoperatively because of bradycardia; more than 2 years later, another patient required a permanent pacemaker because of sick sinus syndrome. In addition, one patient had an automatic implantable cardioverter-defibrillator. Three patients required reconstruction of cardiovascular structures with use of prosthetic material (Teflon patches or donor tissue) at the time of cardiac transplantation. Actuarial 1-, 2-, and 5-year survival was 86.2 +/- 9.1%. During the first year after transplantation, two deaths occurred--one at 41 days of putative vascular rejection and the second at 60 days of severe cellular rejection. All other patients are alive and functionally rehabilitated; the mean follow-up period has been 26.1 months (range, 2 to 89.6). CONCLUSION: Cardiac transplantation for patients with congenital heart disease can be accomplished with a low perioperative mortality and an excellent medium-term survival despite the challenges presented by the technical difficulties during invasive diagnostic procedures and at operation and the need for adherence to long-term multiple-drug therapy in this patient population.

Actuarial Analysis↗
PubMed1997

Syncope in children and adolescents.

OBJECTIVES: The objectives of this study were to 1) define the incidence of syncope coming to medical attention among children and adolescents, 2) determine the outcome of syncope in these patients, and 3) determine changes over time in the evaluation and charges for evaluating this problem. BACKGROUND: Syncope occurs commonly in children and adolescents. However, the mid- and long-term outcome of children and adolescents who experience syncope is unknown. METHODS: Utilizing the Rochester Epidemiology Project, we determined the incidence, outcome and charges for medical evaluation for patients seeking medical attention for syncope during an early 5-year period (1950 to 1954) and a more recent 5-year period (1987 to 1991). RESULTS: The incidence of syncope coming to medical attention was 71.9 and 125.8/100,000 population for the early and more recent cohort, respectively. The incidence was higher for female than for male patients. The incidence peaked in 15- to 19-year old patients. Acute illness and noxious stimuli were associated with 24% and 23% of the episodes, respectively. Although long-term survival was not different from that of the general population, one child died suddenly, and another had hereditary prolonged QT interval syndrome. These were two of only six patients who had exertional syncope. Total charges for evaluation of syncope were similar in the two time periods. However, charges for testing procedures were greater for the more recent cohort. CONCLUSIONS: In general, syncope in children and adolescents is a benign event. Syncope occurring during exercise may identify patients with a potentially fatal condition. Detailed evaluation should be considered for patients who have syncope during exercise or who have a family history of syncope, sudden death, myocardial disease or arrhythmias. It may be prudent to obtain an electrocardiogram for all patients who seek medical attention for syncope.

Adolescent↗
PubMed1997

Physiochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH.

Drugs are absorbed after oral administration as a consequence of a complex array of interactions between the drug, its formulation, and the gastrointestinal (GI) tract. The presence of food within the GI tract impacts significantly on transit profiles, pH, and its solubilization capacity. Consequently, food would be expected to affect the absorption of co-administered drugs when their physicochemical properties are sensitive to these changes. The physicochemical basis by which ingested food/lipids induce changes in the GI tract and influence drug absorption are reviewed. The process of lipid digestion is briefly reviewed and considered in the context of the absorption of poorly water-soluble drugs. The effect of food on GI pH is reviewed in terms of location (stomach, upper and lower small intestine) and the temporal relationship between pH and drug absorption. Case studies are presented in which postprandial changes in bioavailability are rationalized in terms of the sensitivity of the physicochemical properties of the administered drug to the altered GI environment.

Bile↗
PubMed1997

Impaired bacterial killing and hydrogen peroxide production by polymorphonuclear neutrophils in end-stage renal failure.

Polymorphonuclear leukocytes (PMN) isolated from a sub-population of patients with end-stage renal failure (ESRF) who were identified because they demonstrated impaired intracellular bacterial killing, were assayed for hydrogen peroxide activity using two different techniques capable of distinguishing between total and intracellular hydrogen peroxide generation. In an attempt to elucidate the mechanism of impaired intracellular bacterial killing further, hydrogen peroxide activity was compared to PMN isolated from patients receiving continuous ambulatory peritoneal dialysis and a control group of healthy normal volunteers. PMN from conservatively treated ESRF patients demonstrated reduced production of intracellular hydrogen peroxide (mean 37.7 +/- 4.3 fluorescence units), compared to PMN from both ESRF patients treated with continuous ambulatory peritoneal dialysis (mean 57.9 +/- 6.6 fluorescence units) and normal controls (mean 60.4 +/- 3.5 fluorescence units). This suggests that the probable mechanism of impaired bacterial intracellular killing by the PMN of conservatively treated ESRF patients involves the production of intracellular hydrogen peroxide.

Adult↗
PubMed1997

Drug delivery to the lymphatic system.

The specialized structure and function of the lymphatics has stimulated considerable interest in both site-specific drug delivery to the lymph and lymphoid tissue, and delivery to the systemic circulation via lymphatic transport mechanisms. In this review, drug access to the lymphatic system from the vasculature or interstitium after parenteral administration, and from the gastrointestinal tract after enteral administration, is discussed. Macromolecular and lipophilic prodrug approaches to lymphatic delivery and the use of microparticulate systems such as microspheres, liposomes, and colloidal carbon are also examined and discussed.

Animals↗
PubMed1996

Improved early morbidity and mortality after Fontan operation: the Mayo Clinic experience, 1987 to 1992.

OBJECTIVES: This study sought to evaluate changes in early morbidity and mortality as well as predictors of outcome in our most recent 339 patients undergoing modified Fontan operations. BACKGROUND: The Fontan operation is the preferred definitive palliation for patients with functional single ventricles. Previously reported early mortality rates after Fontan operation have been substantial. METHODS: Records of 339 consecutive patients who had a Fontan operation at the Mayo Clinic between 1987 and 1992 (recent cohort) were reviewed. This cohort was compared with the previous 500 patients who had Fontan operations performed between 1973 and 1986 (early cohort). RESULTS: Recently, overall early mortality after Fontan has decreased significantly compared with that for the early cohort (from 16% to 9%, p = 0.002). This decline occurred despite increased anatomic complexity of patients. Short-term posthospital survival has also improved significantly in recent patients. One-year survival improved to 88% from 79%, and 5-year survival to 81% from 73% (p = 0.006). Patients with common atrioventricular valves and those who took daily preoperative diuretic medication or had either postoperative renal failure or elevated postbypass right atrial pressure were at increased risk for early mortality. Young age was not found to be a risk factor for early mortality. Early mortality for patients with heterotaxia decreased dramatically: recent 30-day mortality was 15% compared with 41% in the early heterotaxy cohort. CONCLUSIONS: Many factors may have contributed to decreased early mortality after Fontan. Improved patient selection, younger age at time of operation, refinements in surgical techniques and postoperative management may all have had important roles. Proposed technical modifications of the Fontan operation must be evaluated in light of these improved results.

Age Factors↗
PubMed1996

Lymphatic transport of halofantrine in the triple-cannulated anesthetized rat model: effect of lipid vehicle dispersion.

Halofantrine hydrochloride is an important, highly lipophilic anti-malarial agent. A triple-cannulated anesthetized rat model was used to investigate the potential lymphatic transport of halofantrine (Hf). The effect of formulating Hf in vehicles representative of different physical (digestion) states of triglyceride lipid was also evaluated. The lipid vehicles were either a lipid solution, emulsion, or micellar system comprised of 50 microL of a 2:1 molar ratio of oleic acid:glycerol monooleate containing 2 mg of Hf free base. Lymph was collected from the mesenteric lymph duct, and blood was sampled from the jugular vein following intraduodenal infusion of the different formulations. Lymphatic transport was a major contributor to bioavailability as demonstrated by the recovery of up to approximately 20% of the administered dose in the intestinal lymph. The rank order effect of the vehicles for the promotion of lymphatic transport was micellar > emulsion > lipid solution. Lymphatic drug transport was predominantly associated with chylomicron-based transport. The extent of Hf absorption via the portal blood, estimated from the systemic plasma profiles in the lymph-cannulated rats, was largely independent of the administered formulations. These data indicate that lymphatic transport of the free base of Hf is a major contributor to oral bioavailability when formulated in appropriate lipid vehicles. The data suggest that formulation as increasingly disperse systems facilitates transport in this animal model.

Anesthesia↗
PubMed1996

Lymphatic transport of halofantrine in the conscious rat when administered as either the free base or the hydrochloride salt: effect of lipid class and lipid vehicle dispersion.

The intestinal lymphatic transport of halofantrine, an important, highly lipophilic antimalarial drug, has been studied in a conscious rat model after oral administration. In these studies, the lymphatic transport of Hf free base when coadministered with lipid was approximately 20% of the administered dose compared with 5% transport after administration of the HCl salt with or without lipid. These differences in transport can be attributed to the increased lipophilicity of the free base (relative to the HCl salt) thereby facilitating greater association of Hf base with the products of luminal lipid digestion and the subsequent interaction with the intestinally derived chylomicrons responsible for lymphatic drug transport. In contrast to previous results in an anesthetized rat model where lymphatic transport was dependent on the characteristics of the intraduodenally administered lipid formulations, the lymphatic transport of Hf base in the conscious rat was independent of both the class of administered lipid (triglyceride or fatty acid) and the extent of formulation dispersion (micellar lipid or lipid solution). Considering the different lymphatic transport profiles of Hf base in the anesthetized and conscious rat models, it is proposed that the lipid vehicle effects observed in the intraduodenally dosed anesthetized model most likely reflects the lack of gastric processing by preduodenal lipase and the shear action of the stomach otherwise present in the conscious rat model.

Administration, Oral↗
PubMed1996

A physicochemical basis for the effect of food on the absolute oral bioavailability of halofantrine.

Halofantrine hydrochloride (Hf.HCl) is a highly lipophilic phenanthrenemethanol antimalarial. The poor and erratic absorption of Hf after oral administration has been implicated in some treatment failures. Food increases the oral bioavailability of Hf in humans approximately 3-5-fold, although neither the absolute bioavailability nor the basis for the food effect has been fully defined. In this study, the mean (+/-SD, n = 3) absolute oral bioavailability of 250 mg Hf.HCl tablets in beagles was 8.6 +/- 5.3% in the fasted state, which increased approximately 12-fold when administered postprandially. These data indicate that Hf.HCl is efficiently absorbed from the postprandial intestinal environment. The solubility and intrinsic dissolution rate of Hf.HCl were investigated as a function of bile salt concentration (sodium taurocholate, NaTC, 0-30 mM) and micellar composition (4:1 NaTC:lecithin). At premicellar (fasted) concentrations of NaTC (< 5 mM), the solubility and intrinsic dissolution rate were very low (< 15 micrograms/mL; < 0.01 microgram s-1 cm-2). At NaTC concentrations typical of the postprandial state, the solubility and dissolution rate improved dramatically. For example, solubility in 30 mM NaTC increased approximately 1000-fold relative to buffer control, with even greater enhancement (3000-fold) associated with mixed micellar systems. These data suggest that the improved absorption of Hf.HCl in the fed state is most likely due to the increased solubilization and dissolution of the drug in the presence of bile salt mixed micelles.

Administration, Oral↗
PubMed1996

Hydrogen peroxide generation by polymorphonuclear leukocytes exposed to peritoneal dialysis effluent.

In the presence of peritoneal dialysis effluent (PDE), human polymorphonuclear leukocytes (PMN) showed reduced production of hydrogen peroxide and hypochlorous acid (H2O2 and HOCl, respectively) when at rest and when stimulated with both soluble (formylmethionyl-leucyl-phenylalanine and phorbol myristate acetate) and particulate (Staphylococcus epidermidis) agonists. This effect occurred in a concentration-dependent manner between 0 and 70%. (vol/vol) dialysis effluent. The inhibition of H2O2 and HOCl observed in resting, formy-methionylleucyphenyalanine-stimulated, and S. epidermidis-stimulated PMN was confined to a low-molecular-mass (< 10,000-Da) fraction of PDE, whereas the inhibition of the PMA response was equally dispersed throughout both low (< 10,000-Da)- and high-molecular-mass (> 10,000-Da) fractions. Human serum albumin, a major component of PDE, also inhibited H2O2 and HOCl production by PMN; however, results from cell-free systems suggested that human serum albumin was not wholly responsible for the inhibition of PMN function seen with PDE. The solute(s) responsible did not affect myloperoxidase but very rapidly scavenged H2O2 and HOCl. These data suggest that the factors capable of affecting H2O2 and HOCl production by PMN accumulate in uremia and are removed from the circulation into dialysis effluent.

Ascitic Fluid↗
PubMed1995

A simplified liquid chromatography assay for the quantitation of halofantrine and desbutylhalofantrine in plasma and identification of a degradation product of desbutylhalofantrine formed under alkaline conditions.

The development of a new and simplified, validated LC assay for the quantitation of halofantrine and desbutylhalofantrine in plasma is described. The methodology employs an inexpensive, rapid and simple liquid-liquid extraction procedure in combination with previously reported chromatographic conditions. The method has been employed to study aspects of the pharmacokinetics of orally administered halofantrine in beagle dogs and some preliminary data are presented. During development of the extraction procedure, degradation of desbutylhalofantrine was observed under non-acidic conditions in the extraction solvent (tert-butyl methyl ether) and we also report the structural elucidation of the breakdown product and the conditions required to avoid this degradation.

Animals↗
PubMed1995

Impaired polymorphonuclear neutrophil function in end-stage renal failure and its correction by continuous ambulatory peritoneal dialysis.

The polymorphonuclear neutrophil (PMN) function of 22 patients with end-stage renal failure (ESRF) was studied immediately before and 3 months after starting continuous ambulatory peritoneal dialysis (CAPD) and compared with a control group of healthy normal volunteers. The PMN functions studied were phagocytosis and killing of Staphylococcus epidermidis and respiratory burst activity. The results show that in the presence of normal pooled human serum PMN from patients with ESRF before CAPD treatment phagocytose bacteria normally, but have impaired killing. Before treatment, the PMN from patients with ESRF also showed an increase in both unstimulated and stimulated superoxide anion production. Abnormal PMN function was corrected by CAPD treatment, suggesting the involvement of a dialyzable toxin.

Acridines↗
PubMed1995

Accelerated idioventricular rhythm: a benign arrhythmia in childhood.

OBJECTIVE: To determine whether accelerated idioventricular rhythm (AIVR) is benign in pediatric patients. METHODS: The records were reviewed of all patients younger than age 15 years who had been diagnosed with a ventricular arrhythmia between 1976 and 1991. RESULTS: AIVR was diagnosed in 12 patients, ages 1 day to 15 years (mean, 8.9 years). In 3 patients the arrhythmia was discovered on ambulatory electrocardiographic monitoring after presentation with syncope or presyncopal symptoms. One patient had palpitations. The remaining diagnoses were made during routine examinations or at postoperative follow-ups for congenital heart disease. The AIVR rate ranged from 90 to 150 beats per minute. The rate was within 10 beats per minute of the preceding sinus rate in 11 patients. Echocardiograms were normal in 8 patients. Two patients had double-outlet right ventricles; 1 had repair of the tetralogy of Fallot; and 1 had abnormal ventricular septal motion. Seven patients were taking antiarrhythmia medication without control of the AIVR at presentation. Patients were followed for a mean of 68.4 months (range, 31 to 191 months). All patients were alive and asymptomatic, with normal activity at the last follow-ups. CONCLUSIONS: Complete resolution of AIVR may not occur. However, AIVR seems to be a benign arrhythmia. Treatment was not effective in controlling the arrhythmia and is likely unnecessary.

Accelerated Idioventricular Rhythm↗