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Biomedical subjects

J Rhodes

Publications and source records attributed to J Rhodes.

At least 73 records · Page 4Linked to original sources
PubMed1997

Excessive anaerobic metabolism during exercise after repair of aortic coarctation.

OBJECTIVES: To determine whether survivors of surgery for coarctation of the aorta (CoA) have an excessive reliance on anaerobic metabolism during exercise. BACKGROUND: Patients with peripheral vascular disease cannot increase blood flow to their muscles normally during exercise. Consequently they acquire an early, excessive reliance on anaerobic metabolism and have depression of the ventilatory anaerobic threshold (VAT) and of the slope of the oxygen consumption-work rate relationship (delta VO2/delta WR). We speculated that the capacity to augment blood flow to the lower extremities during exercise may be impaired after CoA surgery and would result in similar metabolic disturbances. STUDY DESIGN: Progressive exercise tests were performed on 15 patients (ages 19 +/- 7 years; range, 10 to 32) after successful repair of CoA (residual resting gradient, 7.7 +/- 7.1 mm Hg; range, 0 to 18), 15 age- and sex-matched healthy control subjects, and 10 patients (ages 13 +/- 3 years; range, 10 to 20) who had undergone ligation of a patent ductus arteriosus. RESULTS: The CoA patients' VAT averaged 14.8 +/- 3.8 ml O2/kg per minute versus 19.3 +/- 3.1 ml O2/kg per minute for the control subjects (p < 0.01), and their delta VO2/delta WR averaged 8.2 +/- 1.8 ml/watt compared with 10.1 +/- 1.4 ml/watt for control subjects (p < 0.01). Furthermore, 10 of 15 CoA patients had a VAT of less than 40% of predicted maximal oxygen consumption, and 9 of 16 had a delta VO2/delta WR of less than 8.7 ml O2/watt (generally accepted abnormal values). Patients with patent ductus arteriosus resembled the healthy control subjects with regard to anaerobic metabolism during exercise. CONCLUSIONS: Patients who have had CoA repairs commonly manifest an excessive reliance on anaerobic metabolism during exercise. This phenomenon may result from persistent blood flow abnormalities across the aortic arch during exercise, which may be present even after apparently successful surgery.

Adolescent↗
PubMed1997

Nicotine enemas for active ulcerative colitis--a pilot study.

BACKGROUND: Since transdermal nicotine is of value in the treatment of active ulcerative colitis but is often associated with side-effects, an alternative in the form of topical therapy with nicotine enemas has been developed. METHODS: In an open study, 22 patients with active colitis, all non-smokers, were asked to take a 100 mL enema containing 6 mg of nicotine every night for 4 weeks. Pre-trial treatment using mesalazine (n = 16), oral prednisolone (8), cyclosporin (1) and azathioprine (1) was kept constant for the month prior to assessment and during the study period. Symptoms, with stool frequency, were recorded on a diary card and an endoscopy was performed with rectal biopsy at the beginning of the study and after 4 weeks. RESULTS: Seventeen of the 22 patients completed 1 month of treatment. Mean duration of relapse was 29 weeks, range 3-94. Sixteen of 17 improved their St Mark's score. Urgency and stool frequency improved in 12 patients, sigmoidoscopic and histological scores in 10. Three patients had a full remission of symptoms with normal sigmoidoscopy. Six of 10 with a partial response continued with the enemas for a second month and five showed further improvement with full remission in two. The enema appeared effective when added to conventional treatment and produced few side-effects. CONCLUSION: Topical nicotine therapy for ulcerative colitis may have a place in future management, but controlled studies are needed.

Adult↗
PubMed1997

Effect of nicotine on large bowel mucus thickness, eicosanoids and faecal proteinase in ferrets.

BACKGROUND: Following observations on the effect of subcutaneous nicotine on rectal mucosal eicosanoids and mucus in the rabbit we have repeated the work in ferrets which may be a more suitable animal model. AIMS AND METHODS: The effect of nicotine on mucosal eicosanoids, the adherent mucus layer, and faecal proteinases in the large bowel of ferrets was examined in forty animals randomly allocated to five groups, a control and four treatment groups. They were given subcutaneous saline or nicotine via an Alzet pump in doses of 0.3, 0.6, 1.2 and 2.0 mg/kg/day for 10 days and then sacrificed; measurements were made of serum nicotine and cotinine levels, rectal mucosal eicosanoids, adherent rectal and colonic mucus thickness, and faecal proteinases. RESULTS: No significant differences were observed for any measurements, except for serum nicotine and cotinine levels, which were raised consistent with the dose given. CONCLUSION: Nicotine had no effect on measurements, which may possibly be important in the relationship between smoking and ulcerative colitis.

Animals↗
PubMed1997

Electrocardiographic markers of late sudden death risk in postoperative tetralogy of Fallot children.

Following surgery for tetralogy of Fallot (TOF), children may develop late onset ventricular arrhythmias. Many patients have both depolarization and repolarization abnormalities, including right bundle branch block (RBBB) and QT prolongation. The goal of this study was to improve prospective risk-assessment screening for late onset sudden death. Resting ECG markers including QRS duration, QTc, JTc, and interlead QT and JT dispersion were statistically analyzed to identify those patients at risk for ventricular arrhythmias and sudden cardiac death. To determine predictive markers for future development of arrhythmia, we examined 101 resting ECGs in patients (age 12 +/- 6 years) with postoperative TOF and RBBB, 14 of whom developed late ventricular tachycardia (VT) or sudden death. These ECGs were also compared with an additional control group of 1000 age- and gender-matched normal ECGs. The mean QRS (+/- SD) in the VT group was 0.18 +/- 0.02 seconds versus 0.14 +/- 0.02 seconds in the non-VT group (P < 0.01). QTc and JTc in the VT group was 0.53 +/- 0.05 seconds and 0.33 +/- 0.03 seconds compared with 0.50 +/- 0.03 seconds and 0.32 +/- 0.03 seconds in the non-VT group (P = NS). There was no increase in QT dispersion among TOF patients with VT or sudden death compared with control patients or TOF patients without VT, although JT dispersion was more common in the TOF groups. A prolonged QRS duration in postoperative TOF with RBBB is more predictive than QTc, JTc, or dispersion indexes for identifying vulnerability to ventricular arrhythmias in this population, while retaining high specificity. The combination of both QRS prolongation and increased JT dispersion had very good positive and negative predictive values. These results suggest that arrhythmogenesis in children following TOF surgery might involve depolarization in addition to repolarization abnormalities. Prospective identification of high-risk children may be accomplished using these ECG criteria.

Child↗
PubMed1997

Nicotine: therapeutic potential for the treatment of ulcerative colitis.

Ulcerative colitis (UC) is predominantly a disease of non-smokers, and nicotine may be the agent responsible for this association. Transdermal nicotine has been shown to improve disease activity and sigmoidoscopic appearance in the active disease but in one study had no effect on maintenance of remission. Since side-effects with nicotine patches occur in up to two thirds of patients, attempts to reduce systemic levels and improve drug tolerance have been developed with colonic delivery systems of nicotine. Preliminary observations with nicotine enemas in UC have shown clinical benefit, but controlled trials are needed. Mechanisms responsible for the association of smoking with colitis and for the therapeutic effect of nicotine remain an enigma; possibilities include: modulation of the immune response, alterations of colonic mucus and eicosanoid production, changes in rectal blood flow, decreased intestinal permeability and the release of endogenous glucocorticoids. With current treatment for UC limited to corticosteroids and formulations of 5-aminosalicylic acid, alternative treatments are required and nicotine may fulfil this role.

Journal Article↗
PubMed1997

The immunomodulatory actions of E-type prostaglandins.

Prostaglandins (PGs) have been recognised as modulators of immune responses. This has been proved by both in vitro studies and from observations in animals and humans. Administration of prostaglandins for therapeutic purposes, however, has been hampered by their limited bioavailability and their pleiotropic effects, with resultant toxicological profile. Despite this, some success has been demonstrated in the clinic for the control of graft rejection, especially when used as part of a broader immunosuppressant regimen. Full realisation of the therapeutic potential of prostaglandins will depend on a better understanding of their mechanism of action at the cellular level. Recently, it has been appreciated that prostaglandins do not merely inhibit T-cell function, but appear to modulate the profile of lymphocyte sub-populations through regulation of cytokine synthesis and release. Recent efforts have also begun to focus on identifying prostaglandin receptor subtypes important for immune regulation and offer a means, together with targeted delivery, of utilising the immunosuppressant/anti-inflammatory effects of E-type prostaglandins in a safe and effective manner.

Journal Article↗
PubMed1997

Inflammatory bowel disease management. Some thoughts on future drug developments.

This article is intended to stimulate thought and focus on those areas where we feel advances in drug therapy for inflammatory bowel disease may occur. It is not an extensive review of current practice, although this is considered where it is thought to be pertinent to future developments. There are several excellent reviews of current practice which we do not attempt to repeat, nor do we give a comprehensive set of references, but cite well referenced reviews where necessary. New therapeutic developments should ideally stem from an understanding of the cause of pathogenesis of a condition; alternatively, established therapies may be modified or used as a basis for progress. Since the causes of both ulcerative colitis and Crohn's disease remain unknown, most forward thinking on drug development must come from current practice, but remain open to novel approaches. Our thoughts on possible future treatments for inflammatory bowel disease are somewhat selective, and because of their speculative nature are unlikely to coincide with those of others-only the future will reveal genuine advances as they become incorporated into established practice.

Adrenal Cortex Hormones↗
PubMed1997

Balloon Angioplasty for Native Coarctation of the Aorta: Acute and Mid-Term Results.

BACKGROUND: Balloon angioplasty is an accepted treatment for recurrent coarctation of the aorta. Application of this technique to patients with native coarctation is controversial. OBJECTIVE: To report on the immediate and mid-term results of this procedure in patients with native coarctation, including infants <6 months of age. METHODS AND RESULTS: Twenty-four children underwent balloon angioplasty of their coarctation at a median age of 2 yr. (range 2 weeksÐ14.7 yr.) and median weight of 13 kg (range 3Ð64 kg). The mean peak systolic gradient across the coarctation decreased from 40 +/- 14 to 9 +/- 6 mmHg (p < 0.001) and the mean diameter of the narrowest area improved from 4.1 +/- 2.1 to 7.5 +/- 2.5 mm (p < 0.001). Four patients had recurrence of their coarctation, 3 of whom were < 3 months of age. Two of these patients had successful repeat dilation. At a mean follow-up interval of 2.4 +/- 1.7 years, one patient (4%) developed an aneurysm. Three patients underwent surgical repair (two for recurrence and one for resection of the aneurysm). The remaining patients (87.5%) are normotensive with mean peak systolic gradient between the right arm and the lower extremity of 4 +/- 9 mmHg. CONCLUSION: Balloon angioplasty for native coarctation is an effective and safe method for most patients with coarctation. Repeat dilation is possible and surgical repair of an aneurysm is safe.

Journal Article↗
PubMed1996

Mapping of the ARIX homeodomain gene to mouse chromosome 7 and human chromosome 11q13.

The recently described homeodomain protein ARIX is expressed specifically in noradrenergic cell types of the sympathetic nervous system, brain, and adrenal medulla. ARIX interacts with regulatory elements of the genes encoding the noradrenergic biosynthetic enzymes tyrosine hydroxylase and dopamine beta-hydroxylase, suggesting a role for ARIX in expression of the noradrenergic phenotype. In the study described here, the mouse and human ARIX genes are mapped. Using segregation analysis of two panels of mouse backcross DNA, mouse Arix was positioned approximately 50 cM distal to the centromere of chromosome 7, near Hbb. Human ARIX was positioned through analysis of somatic cell hybrids and fluorescence in situ hybridization of human metaphase chromosomes to chromosome 11q13.3-q13.4. These map locations extend and further define regions of conserved synteny between mouse and human genomes and identify a new candidate gene for inherited developmental disorders linked to human 11q13.

Animals↗
PubMed1996

Interventional cardiac catheterization therapy for combined coarctation of the aorta and patent ductus arteriosus: successful outcome in two infants.

We report two infants each with coarctation of the aorta and small patent ductus arteriosus who had balloon angioplasty therapy for aortic obstruction at 3-6 months of age followed by anterograde placement of a single Gianturco coil to close the ductus at a separate catheterization. One infant developed recoarctation that resolved with repeat angioplasty prior to closure of the ductus. Follow-up evaluations have demonstrated a trivial aortic gradient, no aortic aneurysm, and no residual shunt.

Angioplasty, Balloon↗
PubMed1996

Schiff base forming drugs: mechanisms of immune potentiation and therapeutic potential.

CD4 T-lymphocytes, which orchestrate immune responses, receive a cognitive signal when clonally distributed receptors are occupied by MHC class II bound peptides on antigen-presenting cells. The latter provide costimulatory or accessory signals through macromolecules such as B7.1 and B7.2 which interact with coreceptors on T-cells to regulate outcomes in terms of T-cell activation or specific non-responsiveness. Complementary studies at the chemical level have implicated Schiff base formation between specialised carbonyls and amines, constitutively expressed on antigen-presenting cell and T-cell surfaces, as an essential element in specific T-cell activation. The small xenobiotic Schiff base forming molecule tucaresol, which substitutes for the physiological donor of carbonyl groups to provide a costimulatory signal to CD4 T-helper lymphocytes (Th-cells), has been developed for testing as an immunopotentiatory drug. Tucaresol, which is orally bioavailable and systemically active, enhances CD4 Th-cell and CD8 cytotoxic T-cell responses in vivo and selectively favours a Th1-type profile of cytokine production. In murine models of virus infection and syngeneic tumour growth it has substantial therapeutic activity. Schiff base formation by tucaresol on T-cell surface amines provides a costimulatory signal to the T-cell through a mechanism that activates clofilium-sensitive K+ and Na+ transport. The signalling pathway utilised by tucaresol converges with T-cell receptor signalling at the level of MAP kinase, promoting the tyrosyl phosphorylation of ERK2 by MEK (mitogen-activated protein kinase kinase). The Schiff base forming class of immunopotentiatory drug provides the first orally active, mechanism-based immunopotentiatory agents for therapeutic testing. Tucaresol is currently undergoing pilot phase I/II clinical trials as an immunopotentiator in chronic hepatitis B virus infection, HIV infection and malignant melanoma.

Amines↗
PubMed1996

Screening protocol for Torulopsis (Candida) glabrata.

A screening test has been developed for the presumptive identification of Torulopsis (Candida) glabrata from other common clinical isolates of yeast-like fungi. An interlaboratory comparison of a protocol consisting of morphology on cornmeal Tween 80 agar and trehalose fermentation at 42 degrees C was successful in differentiating T. glabrata from other taxa that are frequent or possible clinical isolates. The screening results for 517 clinical yeast isolates, 241 of which were T. glabrata, were compared with their final identification via commercial systems (API20C Yeast Identification System [bioMERIEUX, Hazelwood, Mo.] and Rapid Yeast Identification Panel [Dade Microscan, Sacramento, Calif.]). The trehalose screening test has a sensitivity and a specificity of 97.8 and 95.8%, respectively, and a positive predictive value of 97.4% and a negative predictive value of 96.5%. Overall, the trehalose screen had an efficiency rating of 93.9% for ruling in or out T. glabrata. Since T. glabrata represents a substantial part of the workload in a clinical laboratory, a significant reduction in direct and indirect costs should be realized.

Candida↗
PubMed1996

Uptake, excretion and respiration of sucrose and amino acids in the pea aphid Acyrthosiphon pisum

Ingestion, excretion and respiration in aphids were studied using artificial diets labelled with radioactive sucrose or amino acids. The rate of ingestion of a 25 % w/v sucrose diet was 12.4 nl mg-1 h-1 and the honeydew excretion rate was 5.3 nl mg-1 h-1, about 43 % of the volume ingested during the same period. The concentration of sugars in the honeydew was equivalent to 0.53 mol l-1 sucrose and 69 % of the sucrose ingested was assimilated. The amino acid concentration of honeydew was 24.6 mmol l-1 and 94 % of the ingested amino acids were assimilated. Respiration was measured by collecting respired 14CO2 using a chamber which allowed the aphids to feed during the experiments on 14C-labelled artificial diets. While feeding on a 25 % w/v sucrose diet, sucrose was respired at the rate of 1.32x10(-6) mmol mg-1 h-1, equivalent to 0.354 &micro;l O2 mg-1 h-1, which was 14.6 % of the rate of ingestion. There was no evidence that reducing the dietary sucrose concentration from 22 to 11 % w/v had any effect on the rate at which sucrose was respired. Amino acids were respired at a rate of 0.14x10(-6) mmol mg-1 h-1, which was 6.4 % of the rate of ingestion. Dietary sucrose was oxidised in preference to amino acids.

Journal Article↗
PubMed1996

Transdermal nicotine compared with oral prednisolone therapy for active ulcerative colitis.

BACKGROUND: Ulcerative colitis is largely a disease of non-smokers. Previous controlled trials have shown benefit with transdermal nicotine when given with 5-aminosalicylic acid in active disease but not when given alone as maintenance therapy. OBJECTIVE: To examine nicotine alone compared with prednisolone in active disease. PATIENTS AND METHODS: Sixty-one patients with active ulcerative colitis were treated with either transdermal nicotine patches or 15 mg prednisolone for 6 weeks in a randomized, double-blind study. Incremental doses of nicotine were given for the first 9 days; patients tolerated between 15 and 25 mg daily. Most patients were taking mesalazine at entry which was discontinued at day 10; a few were taking topical steroids which were discontinued at the onset. Clinical, sigmoidoscopic and histological assessments were made at baseline and 6 weeks, or at premature withdrawal. Symptoms were recorded on a diary card, and the clinician made a global clinical assessment. Side effects and serum nicotine and cotinine concentrations were monitored throughout the study. RESULTS: Forty-three patients completed the 6-week trial; of these, 6 of 19 in the nicotine group achieved full sigmoidoscopic remission compared with 14 of 24 with prednisolone (P = 0.08). In those who completed the 6-week study, there was significant improvement within both the nicotine and prednisolone group for the St Mark's score (P < 0.05 and P < 0.01, respectively), Global Clinical Grade (P < 0.01 for both), blood in the stool (P < 0.05 and P < 0.01), abdominal pain (P < 0.05 and P < 0.01) and sigmoidoscopic score (P < 0.01 and P < 0.001); differences between groups tend to favour prednisolone, but none reach statistical significance. However, on intention-to-treat analyses there is little clear evidence of improvement in either group apart from sigmoidoscopic score in which prednisolone was associated with a significantly greater improvement than nicotine (P < or = 0.05). The nicotine group had more withdrawals than the prednisolone group, 11 versus 7, respectively (P = 0.23), both for deterioration (6 vs. 5) and side effects (5 vs. 2, P = 0.15). Side effects were more frequently reported in the nicotine group (average 1.47 episodes per person) than the prednisolone group (average 0.61; P = 0.03), the most common of which were nausea, light-headedness and tremor. CONCLUSION: In those who managed to complete the 6-week study, nicotine alone appeared to be of only very modest benefit in acute colitis and was not as effective as 15 mg of prednisolone daily.

Administration, Cutaneous↗
PubMed1995

Therapeutic potentiation of the immune system by costimulatory Schiff-base-forming drugs.

Immune responses are orchestrated by CD4 T lymphocytes, which receive a cognitive signal when clonally distributed receptors are occupied by major histocompatibility complex (MHC) class II-bound peptides on antigen-presenting cells (APCs). The APCs provide costimulatory signals, through macromolecules such as CD80, that regulate outcomes in terms of T-cell activation or anergy. We have studied essential complementary chemical events in the form of Schiff base formation between carbonyls and amines that are constitutively expressed on presenting cell and T-cell surfaces and provide a new target for manipulation of immune responses. Here we show that small Schiff base-forming molecules can substitute for the physiological donor of carbonyl groups and provide a costimulatory signal to CD4 Th-cells through a mechanism that activates clofilium-sensitive K+ and Na+ transport. One such molecule, tucaresol, enhances CD4 Th-cell responses, selectively favouring a Th1-type profile of cytokine production. In vivo tucaresol potently enhances CD4 Th-cell priming and CD8 cytotoxic T-cell priming to viral antigens, and has substantial therapeutic activity in murine models of disease.

Adjuvants, Immunologic↗