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Biomedical subjects

J Noonan

Publications and source records attributed to J Noonan.

At least 19 recordsLinked to original sources
PubMed2006

The cardiofaciocutaneous syndrome.

The cardiofaciocutaneous (CFC) syndrome is a condition of sporadic occurrence, with patients showing multiple congenital anomalies and mental retardation. It is characterised by failure to thrive, relative macrocephaly, a distinctive face with prominent forehead, bitemporal constriction, absence of eyebrows, hypertelorism, downward-slanting palpebral fissures often with epicanthic folds, depressed nasal root and a bulbous tip of the nose. The cutaneous involvement consists of dry, hyperkeratotic, scaly skin, sparse and curly hair, and cavernous haemangiomata. Most patients have a congenital heart defect, most commonly pulmonic stenosis and hypertrophic cardiomyopathy. The developmental delay usually is moderate to severe. The syndrome is caused by gain-of-function mutations in four different genes BRAF, KRAS, mitogen-activated protein/extracellular signal-regulated kinase MEK1 and MEK2, all belonging to the same RAS-extracellular signal-regulated kinase (ERK) pathway that regulates cell differentiation, proliferation and apoptosis. The CFC syndrome is a member of a family of syndromes that includes the Noonan and Costello syndromes, presenting with phenotypic similarities. Noonan syndrome is caused by mutations in the protein tyrosine phosphatase SHP-2 gene (PTPN11), with a few people having a mutation in KRAS. Costello syndrome is caused by mutations in HRAS. The protein products of these genes also belong to the RAS-ERK pathway. Thus, the clinical overlap of these three conditions, which often poses a problem of differential diagnosis, is explained by their pathogenetic relatedness.

Abnormalities, Multiple↗
PubMed2000

Nonoperative treatment of rotator cuff tears.

Rotator cuff tears and subacromial impingement are second only to acromioclavicular joint disorders as the most common causes of shoulder pain. Although most orthopedic surgeons are willing to initially treat shoulder impingement syndrome conservatively, they are reluctant to manage rotator cuff tears-especially full-thickness tears-nonoperatively. The purpose of this article is to explain the biomechanical rationale of nonoperative treatment, review the literature pertaining to nonoperative treatment of full-thickness rotator cuff tears, and describe a nonoperative treatment program.

Biomechanical Phenomena↗
PubMed1999

The DNA helicase activity of BLM is necessary for the correction of the genomic instability of bloom syndrome cells.

Bloom syndrome (BS) is a rare autosomal recessive disorder characterized by growth deficiency, immunodeficiency, genomic instability, and the early development of cancers of many types. BLM, the protein encoded by BLM, the gene mutated in BS, is localized in nuclear foci and absent from BS cells. BLM encodes a DNA helicase, and proteins from three missense alleles lack displacement activity. BLM transfected into BS cells reduces the frequency of sister chromatid exchanges and restores BLM in the nucleus. Missense alleles fail to reduce the sister chromatid exchanges in transfected BS cells or restore the normal nuclear pattern. BLM complements a phenotype of a Saccharomyces cerevisiae sgs1 top3 strain, and the missense alleles do not. This work demonstrates the importance of the enzymatic activity of BLM for its function and nuclear localization pattern.

Adenosine Triphosphatases↗
PubMed1998

A cluster of equine granulomatous enteritis cases: the link with aluminium.

A cluster of 6 cases of equine granulomatous enteritis is described. Aluminium was demonstrated in the tissues and lesions of these horses and in the intimal bodies of intestinal vessels. The relationship between granulomatous lesions, aluminium, acidity and invading microorganisms, particularly parasites, is presented and discussed.

Aluminum↗
PubMed1997

Role of aspartic proteases in disseminated Candida albicans infection in mice.

A murine model of disseminated candidiasis involving intranasal challenge with Candida albicans was developed and used to explore the role of C. albicans aspartic proteases as virulence factors during early dissemination. Pretreatment of neutropenic mice with the aspartic protease inhibitor pepstatin A by intraperitoneal injection afforded strong dose-dependent protection against a subsequent lethal intranasal dose of an aspartic protease-producing strain (ATCC 32354) of C. albicans. Administration of 0.6 mg of pepstatin A kg of body weight(-1) prior to challenge and on days 1 to 4 postchallenge resulted in 100% survival at day 15 postchallenge, whereas 100% of animals receiving saline had died by day 6. This effect was comparable to the dose-dependent protection obtained with amphotericin B, which resulted in 100% survival when administered at 0.1 mg kg(-1). The reduction in mortality afforded by pepstatin A correlated with its dose-dependent blockade of C. albicans numbers in the lungs, liver, and kidneys. By sharp contrast, no protection by pepstatin A was observed in mice challenged intravenously, and protection was markedly attenuated in mice given pepstatin A after intranasal challenge only. These data show the utility of pepstatin A in the prophylaxis of disseminated Candida infections and suggest that Candida aspartic proteases play an essential role early in dissemination.

Administration, Intranasal↗
PubMed1992

Ventilatory failure induced by tracheal banding in the hamster.

Previous animal models of hypercapnic ventilatory failure are limited in that the resistive load has only been applied acutely and often in anesthetized animals. We therefore developed a chronic animal model of hypercapnic ventilatory failure by increasing airway resistance via tracheal banding over several days. To test the efficacy of this model, we compared arterial blood gases, pulmonary function, and internal area of the trachea 6 days after the banding or sham procedure in 20 hamsters. Six days later, banded animals had an increased airway resistance as indicated by a 66% reduction in internal cross-sectional area of the trachea and a 6.5-fold increase in pulmonary resistance compared with control hamsters. The increased airway resistance resulted in a severe respiratory acidosis and hypoxemia in the awake banded hamsters. Banded hamsters were also hyperinflated. This animal model will be useful for investigating the various mechanisms that contribute to hypercapnic ventilatory failure and interventions that may promote recovery.

Acidosis, Respiratory↗
PubMed1987

Free radical-mediated damage during myocardial ischemia and reperfusion and protection by carnitine esters.

Ischemic injury may be exacerbated by readmission of oxygen into the myocardium, probably due to the formation of free radicals and their interaction with membrane lipids. We tested the hypothesis that ischemic myocardial damage is potentiated during reperfusion with excess free fatty acids in the globally ischemic rat heart, and in parallel studies, we investigated the protective effects of carnitine derivatives. Intermittent ischemia, i.e. three 20 min periods of ischemia followed by 10 min reperfusion each, was induced in isolated working rat hearts perfused with either glucose (11 mM) alone or glucose with palmitate (11 mM and 1.2 mM). The ischemic coronary flow was reduced to 1.1 ml/min in a low-flow group and equalled 0 ml/min in a no-flow group. Loss of functional recovery in the low-flow and no-flow group was more pronounced when palmitate was present in the perfusate. This was associated with increased levels of long-chain acyl-CoA esters in the palmitate perfused hearts. Malondialdehyde, an indicator of free radical formation, was elevated in both low-flow and no-flow groups when either substrate was used. We therefore suggest that free radical formation contributes to myocardial injury in intermittent ischemia. The mechanism of free radical formation and their sites of action have not yet been completely elucidated - the peroxidation of membrane lipids is probably involved, particularly in the presence of high palmitate. The protective effect of the carnitine derivatives D-propionylcarnitine, L-propionylcarnitine and propionylcarnitine taurine amide was studied in the no-flow hearts (Table 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Protection of the ischemic myocardium by propionylcarnitine taurine amide. Comparison with other carnitine derivatives.

The cardioprotective effect of the two synthetic carnitine derivatives, propionylcarnitine taurine amide (PCTA) and butyrylcarnitine taurine amide (BCTA), were studied in isolated perfused rat hearts. The protective effects of PCTA and BCTA were compared with those of chemically similar compounds, which have already been investigated in part and reported on; i.e. propionylcarnitine, carnitine, taurine and the combination of propionylcarnitine and taurine. The addition of either PCTA or BCTA significantly improved the recovery of cardiac function of ischemic reperfused hearts. PCTA (0.5 mM) treated hearts regained 75%, 91% and 89% of their preischemic values for cardiac output, left ventricular pressure and dp/dt after 90 min ischemia and 15 min reperfusion. These parameters of cardiac function remained impaired in control hearts which recovered only 38% of the initial preischemic cardiac output, 73% of initial intraventricular developed pressure and 64% of initial positive dp/dt. The cardioprotective effects of PCTA, BCTA and propionylcarnitine were in the same range. However, PCTA and BCTA acted in 20-fold lower molar concentrations compared to propionylcarnitine. Carnitine (11 mM), taurine (11 mM) as well as the combination of propionylcarnitine and taurine at low concentrations had no cardioprotective effect in these experiments. Myocardial adenosine triphosphate (ATP) and creatine phosphate (CP) concentrations were significantly higher in the PCTA or BCTA treated hearts than in controls, and lactate levels were reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Protection of the ischaemic myocardium by L-propionylcarnitine: effects on the recovery of cardiac output after ischaemia and reperfusion, carnitine transport, and fatty acid oxidation.

The effects of L-propionylcarnitine on the recovery of cardiac contractile performance after global ischaemia and reperfusion were studied in isolated perfused rat hearts. The addition of either 5.5 or 11 mmol X litre-1 L-propionylcarnitine significantly improved the recovery of cardiac output, left ventricular pressure, and dP/dt after 90 min of ischaemia and 15 min of reperfusion. Myocardial adenosine triphosphate and creatine phosphate concentrations were significantly higher in the L-propionylcarnitine treated hearts than in controls, but the concentrations of long chain acyl carnitine and coenzyme A were unaffected. The protecting effects of L-propionylcarnitine were compared with those of L-carnitine and L-acetylcarnitine. A 11 mmol X litre-1 dose of L-propionylcarnitine and L-acetylcarnitine significantly improved the recovery of cardiac output after 90 min of ischaemia and 15 min of reperfusion, but L-carnitine did not. L-Propionylcarnitine was the most protective agent. The effects of these derivatives on L-3H-carnitine transport and 14C-palmitate oxidation were also measured. All of these derivatives competitively inhibited L-3H-carnitine transport in isolated cardiac myocytes, but L-propionylcarnitine was the most potent. Carnitine and L-propionylcarnitine stimulated palmitate oxidation in the homogenate, whereas L-acetylcarnitine inhibited it. In myocytes only L-propionylcarnitine affected palmitate oxidation. These data show that L-propionylcarnitine protects the ischaemic myocardium. Its protection is greater than that for L-carnitine or L-acetylcarnitine, and the difference in effectiveness may relate to the rate of transport into the cells and the effects on fatty acid utilisation.

Acetylcarnitine↗
PubMed1981

Cardiopulmonary bypass in the presence of uncorrected coarctation.

We performed correction of intracardiac lesions in 10 patients with coarctation. All cardiovascular lesions were corrected except coarctation. Six patients had a large left-to-right shunt though a ventricular septal defect (VSD), two patients had left ventricular outflow obstruction, two patients had mitral insufficiency, and one patient had mitral stenosis. Arterial perfusion was through the ascending aorta. Urine output was 6.0 +/- 1.5 cc/kg/hr during cardiopulmonary bypass. There was no morbidity related to cardiopulmonary bypass or inadequate perfusion of the lower body, and left ventricular failure did not occur. One patient with Taussig-Bing abnormality and pulmonary vascular disease died postoperatively of right ventricular failure. Intracardiac repair with aortic perfusion in the presence of coarctation is a safe alternative to coarctation repair or combined procedures.

Aortic Coarctation↗