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Biomedical subjects

R Franks

Publications and source records attributed to R Franks.

At least 19 recordsLinked to original sources
PubMed1999

Expression and characterisation of human and rat CRF2alpha receptors.

Rat and human CRF2alpha receptors were expressed in CHO-pro5 cells and stable cell lines generated. Each receptor was characterised using [125I][tyr0]sauvagine and results compared to CRF1 receptors expressed in the same parental cell line. Under identical assay conditions, [125I][tyr0]sauvagine labelled both CRF1 and CRF2alpha receptors with high affinity. The level of expression varied from 103 fmol/mg membrane protein to 1842 fmol/mg membrane protein (rat CRF1 receptors and rat CRF2 receptors, respectively). It was possible to establish robust scintillation proximity assays (SPA) using wheat germ agglutinin (WGA) SPA beads to trap membrane protein. The success of the SPA assay format was dependent on the level of receptor expression observed. The rank order of affinities of a series of peptide CRF receptor agonists and antagonists was similar to that described in the literature for the two receptor subtypes as determined using radioligand binding and cAMP accumulation. No pharmacological differences were apparent between rat and human cloned receptors with the exception of alpha-helical CRF-(9-41). This peptide exhibited 10-fold higher affinity for rat CRF2alpha receptors as compared to human CRF2alpha receptors. PD 173307, PD 173602 and PD 174239 exhibited high affinity and selectivity for human CRF1 receptors, and as such represent useful tools for probing CRF receptor function.

Amphibian Proteins↗
PubMed1999

Human ubiquitous JCV(CY) T-antigen gene induces brain tumors in experimental animals.

JCV is a papovavirus which is widespread in the human population. The prototype Mad-1 variant of JCV induces a fatal demyelinating disease of the central nervous system (CNS) called Progressive Multifocal Leukoencephalopathy (PML) in immunosuppressed individuals. The unique tropism of JCV (Mad-1) to the CNS is attributed to the tissue-specific regulation of the viral early promoter which is responsible for the production of the viral regulatory protein, T-antigen. The archetype form of this virus, JCV(CY), which has been repeatedly isolated from the urine of PML and non-PML individuals, is distinct from JCV(Mad-1) in the structural organization of the regulatory sequence. To characterize the tissue specific expression of JCV(CY) and to investigate its potential in inducing disease, transgenic mice containing the early region of JCV(CY) were generated. Some of these mice between 9-13 months of age exhibited signs of illness as manifested by paralysis of rear limbs, hunched posture, and poor grooming. Neuropathological examination indicated no sign of hypomyelination of the brain, but surprisingly, revealed the presence of primitive tumors originating from the cerebellum and the surrounding brain stem. The tumor masses also infiltrated the surrounding tissue. Results from RNA and protein studies revealed a high level of T-antigen mRNA expression in hindbrains of clinically normal and affected transgenic mice. However, higher levels of T-antigen RNA and protein were detected in brains of the animals exhibiting severe illness. The close resemblance of JCV(CY) induced tumor in transgenic mice to the human medulloblastoma/primitive neuroectodermal tumor (PNETs) in location, histologic appearance, and expression of marker proteins strongly suggests the utility of this novel animal model for the study of human brain tumors.

Animals↗
PubMed1999

Intraaortic balloon pumping in children.

BACKGROUND: Intraaortic balloon pump (IABP) usage in young children remains a rarity because, first, there is a widespread misconception that the greater elasticity of the aorta in children may prevent effective augmentation, and second, children in low cardiac output states are more likely to have associated right ventricular failure and pulmonary problems. We report our experience with the use of IABP in children undergoing cardiac surgery in whom mechanical support was necessary for the treatment of refractory cardiac failure. METHODS: Over a 3-year period, 14 children were identified as requiring IABP support after cardiac surgery. Their median age was 3 years (range 7 days to 13 years) and their median weight was 13.3 kg (range 3.5-51 kg). Indications for IABP use were: failure to wean from cardiopulmonary bypass (5 patients), sudden deterioration in intensive therapy unit (ITU) (3 patients), progressive deterioration in ITU (4 patients), and prophylactic therapy for known poor preoperative ventricular function (2 patients). RESULTS: Ten of 14 patients (71%) were successfully weaned from the IABP, of whom 8 became long-term survivors (57%). Among the survivors, the mean duration of IABP usage was 127 h (range 12-260 h), while for those who died while on IABP, the mean duration was 15 h (range 8-24 h). The most major IABP-related complication encountered was mesenteric ischemia, which had a fatal outcome. CONCLUSIONS: IABP therapy, used as an adjunct to conventional medical treatment, can give properly selected young children in refractory low cardiac output states after heart surgery a greater than 50% chance of long-term survival.

Cardiopulmonary Bypass↗
PubMed1997

Role of cell cycle regulators in tumor formation in transgenic mice expressing the human neurotropic virus, JCV, early protein.

Transgenic mice harboring the early genome from the human neurotropic JC virus, JCV, develop massive abdominal tumors of neural crest origin during 6-8 months after birth and succumb to death a few weeks later. The viral early protein, T-antigen, which possesses the ability to transform cells of neural origin, is highly expressed in the tumor cells. Immunoblot analysis of protein extract from tumor tissue shows high level expression of the tumor suppressor protein, p53, in complex with T-antigen. Expression of p21, a downstream target for p53, which controls cell cycle progression by regulating the activity of cyclins and their associated kinases during the G1 phase, is extremely low in the tumor cells. Whereas the level of expression and activity of cyclin D1 and its associated kinase, cdk6, was modest in tumor cells, both cyclin A and E, and their kinase partners, cdk2 and cdk4, were highly expressed and exhibited significant kinase activity. The retinoblastoma gene product, pRb, which upon phosphorylation by cyclins:cdk induces rapid cell proliferation, was found in the phosphorylated state in tumor cell extracts, and was detected in association with JCV T-antigen. The transcription factor, E2F-1, which dissociates from the pRb-E2F-1 complex and stimulates S phase-specific genes upon phosphorylation of pRb and/or complexation of pRb with the viral transforming protein, was highly expressed in tumor cells. Accordingly, high level expression of the E2F-1-responsive gene, proliferating cell nuclear antigen (PCNA), was detected in the tumor cells. These observations suggest a potential regulating pathway that, upon expression of JCV T-antigen, induces formation and progression of tumors of neural origin in a whole animal system.

Animals↗
PubMed1997

Transgenic mice with p53-responsive lacZ: p53 activity varies dramatically during normal development and determines radiation and drug sensitivity in vivo.

To analyze the involvement of p53-dependent transcriptional activation in normal development and in response to DNA damage in vivo, we created transgenic mice with a lacZ reporter gene under the control of a p53-responsive promoter. Five independent strains showed similar patterns of transgene expression. In untreated animals, lacZ expression was limited to the developing nervous system of embryos and newborn mice and was strongly decreased in the adult brain. gamma-irradiation or adriamycin treatment induced lacZ expression in the majority of cells of early embryos and in the spleen, thymus and small intestine in adult mice. Transgene expression was p53 dependent and coincided with the sites of strong p53 accumulation. The lacZ-expressing tissues and early embryos, unlike other adult tissues and late embryos, are characterized by high levels of p53 mRNA expression and respond to DNA damage by massive apoptotic cell death. Analysis of p53-null mice showed that this apoptosis is p53 dependent. These data suggest that p53 activity, monitored by the reporter lacZ transgene, is the determinant of radiation and drug sensitivity in vivo and indicate the importance of tissue and stage specificity of p53 regulation at the level of mRNA expression.

3T3 Cells↗
PubMed1997

Bilateral continuous paravertebral block used for postoperative analgesia in an infant having bilateral thoracotomy.

We describe the successful postoperative pain management in an 11-month-old infant who underwent bilateral thoracotomy, using continuous infusions of bupivacaine into two directly placed paravertebral catheters. Haemodynamic parameters and pain scores were measured 1-2 h for 60 h while the infusions were continued and, intermittently, blood samples were taken for subsequent measurement of serum bupivacaine concentrations. The technique provided effective pain relief and the infant required no other analgesia postoperatively. There were no adverse haemodynamic consequences or complications relating to either catheter placement or drug infusions. Serum concentrations of bupivacaine remained below toxic levels throughout the study period, though accumulation did occur.

Analgesia↗
PubMed1997

Gut mucosal perfusion in infants undergoing cardiopulmonary bypass: effect of preoperative captopril.

We have studied gut mucosal perfusion in 24 infants, aged 0.7-45 weeks, requiring cardiopulmonary bypass (CPB). Group 2 patients (n = 12) had received the angiotensin converting enzyme inhibitor captopril 0.8-0.9 mg kg-1 orally, 45 min before induction of anaesthesia. Group 1 infants were of similar age and size and required a similar duration of CPB, but did not receive any preoperative medication. An orogastric tonometer allowed intermittent calculations of gastric intramucosal pH (pHi), and rectal mucosal perfusion ("flux") was monitored using laser Doppler flowmetry. Measurements of arterial base deficit and lactate and pyruvate concentrations were made intermittently. We found no significant difference in femoral arterial pressure between the groups at any time before, during or after surgery. Similarly, we found no significant differences in our measures of regional or global tissue perfusion between the groups at any time before, during or after surgery. We conclude that preoperative administration of captopril produced no beneficial effect on gut mucosal perfusion in infants undergoing hypothermic, non-pulsatile CPB.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Serum concentrations of bupivacaine during prolonged continuous paravertebral infusion in young infants.

We have studied the efficacy of prolonged, continuous paravertebral infusion of bupivacaine for the management of post-thoracotomy pain in 22 infants with a median age of 1.5 weeks (range 1 day to 20.4 weeks). Immediately before chest closure, 0.25% bupivacaine 1.25 mg kg-1 was given into an extrapleural paravertebral catheter, inserted under direct vision. Subsequently, 0.125% bupivacaine with adrenaline 1:400000 was infused at a rate of 0.2 ml kg-1 h-1 for 48 h. We confirmed that extrapleural paravertebral catheter placement under direct vision was easy in neonates and infants. The technique provided effective post-operative pain relief in 86% of patients, with three patients requiring morphine in addition. Mean serum concentration of bupivacaine after 48 h was 1.60 (0.67) micrograms ml-1, but bupivacaine concentrations > 3 micrograms ml-1 were found in three patients at 30-48 h. There were no major complications relating to the technique, and paravertebral block was an effective method of providing prolonged post-thoracotomy analgesia in these young infants.

Analgesia↗
PubMed1996

Continuous extrapleural paravertebral infusion of bupivacaine for post-thoracotomy analgesia in young infants.

We have studied the efficacy of a continuous paravertebral infusion of bupivacaine for the management of post-thoracotomy pain in 20 infants with a median age of 5.3 weeks (range 2 days to 20 weeks). Immediately before chest closure, 0.25% bupivacaine 1.25 mg kg-1 was injected into an extrapleural paravertebral catheter, inserted under direct vision. A continuous infusion of 0.25% bupivacaine 0.5 mg kg-1 h-1 was commenced 1 h later and terminated after 24 h. We found that extrapleural paravertebral catheter placement under direct vision was easy in neonates and infants. The technique provided effective postoperative pain relief in 18 (90%) patients and the failure in two (10%) infants was attributed to catheter block. Mean maximum serum concentrations of bupivacaine after the loading dose and during infusion were 1.03 (SD 0.56) and 2.00 (0.63) microgram ml-1, respectively. There were no major complications relating to the technique and we conclude that extrapleural paravertebral block is a simple and effective method for post-thoracotomy analgesia in young infants.

Anesthesia, Spinal↗
PubMed1996

Effect of hypothermia on rectal mucosal perfusion in infants undergoing cardiopulmonary bypass.

We have examined the effect of profound hypothermia on gut mucosal perfusion in 20 infants, aged 1.4-45 weeks, requiring cardiopulmonary bypass (CPB). After induction of anaesthesia, a laser Doppler probe was inserted 8 cm into the patient's rectum to allow monitoring of rectal mucosal perfusion ("flux") throughout operation. Steady-state observation periods (5 min with no change in temperature or mean arterial pressure (MAP) were achieved after 10 min on CPB at 35 degrees C, after CPB-induced cooling to 15-25 degrees C, immediately before rewarming and after rewarming to 35 degrees C. Throughout these periods flow rate was 100 ml kg-1 min-1, packed cell volume was kept constant and Paco2 maintained at 5.3 +/- 0.5 kPa. No vasoactive drugs were used. Initial warm and rewarm MAP values (46 mm Hg) were significantly lower (P = 0.008) than during the cold CPB periods (63 and 64 mm Hg). Mean flux in the first cold period (152) was significantly lower (P = 0.001) than that in the first warm CPB period (211). Post-rewarm flux (127) was significantly lower than all other CPB flux values (P = 0.004). We conclude that although hypothermia significantly reduced mucosal blood flow, rewarming produced even greater reductions in mucosal perfusion that may prove crucial in the development of mucosal hypoxia.

Blood Pressure↗
PubMed1996

Gut mucosal perfusion in neonates undergoing cardiopulmonary bypass.

We studied gut mucosal perfusion in 24 neonates requiring cardiopulmonary bypass (CPB). Group A patients (n = 12) had obstruction to their aorta such that gut perfusion before operation was dependent on flow through a ductus arteriosus (DA). Group B neonates were of similar age and size and required a similar duration of CPB, but did not have a DA. An orogastric tonometer allowed intermittent calculations of gastric intramucosal pH (pHi), and rectal mucosal perfusion ("flux") was monitored using laser Doppler flowmetry. Measurements of arterial base deficit, and lactate and pyruvate concentrations were made intermittently. Before CPB, mean femoral arterial pressure (MAP) and base deficit in group A were not significantly different from those in group B. However, mean flux before CPB was significantly lower and the lactate/pyruvate (L/P) ratio was significantly higher in group A compared with group B. Mean pHi was below normal (< 7.26) throughout the operative period in group A, although it remained normal (> 7.33) in group B. After corrective surgery, both during warm CPB and after CPB, we found no significant difference in MAP, L/P ratio or base deficit between the groups, but both flux and pHi were significantly lower in group A compared with group B. We conclude that neonates requiring aortic arch surgery may be at particular risk of gut mucosal hypoxia both before and after operation.

Aortic Arch Syndromes↗
PubMed1995

Comparison of the haemodynamic effects of dopamine and dobutamine in young children undergoing cardiac surgery.

Nineteen children, aged 2-54 months, requiring high-dose inotropic support after cardiac surgery, were given either dopamine or dobutamine in a blinded, double crossover, study. Using a pulmonary artery thermistor, right and left atrial cannulae, and pulmonary and femoral arterial catheters, conventional haemodynamic variables were measured hourly over three consecutive 4 h dopamine-dobutamine-dopamine or dobutamine-dopamine-dobutamine exchanges. No significant differences in haemodynamics occurred during dopamine therapy compared with the same dose of dobutamine in 14 patients receiving phenoxybenzamine 2 mg kg-1, four of whom had also received enoximone. In five patients, neither enoximone nor phenoxybenzamine was used and significant increases in pulmonary artery pressure and pulmonary vascular resistance (P = 0.04) occurred when patients were given dopamine rather than dobutamine. We conclude that dobutamine and dopamine are equipotent inotropes in children and that dopamine in doses > 7 micrograms kg-1 min-1, caused pulmonary vasoconstriction, an effect mediated by alpha adrenergic receptors.

Cardiac Surgical Procedures↗
PubMed1995

The expandable metal stent for tracheal obstruction.

A 10 month old boy with stridor persisting from birth was found to have tracheal narrowing secondary to myofibromatosis of the tracheal wall. An expandable metal stent was positioned across the tracheal stenosis with immediate clinical improvement. There were no complications relating to stent insertion. The child remained clinically asymptomatic and repeat bronchoscopy at nine months' follow up showed that the stent had become completely endothelialised with no evidence of granuloma formation.

Follow-Up Studies↗
PubMed1995

Transgenic models of HIV-1.

Transgenic technology has been very successful at providing insights into possible processes involved in HIV-induced pathogenesis. The availability of these small animal models for the study of HIV-related syndromes including KS, epidermal proliferative lesions, HIV-associated nephropathy, AIDS-related growth failure and cachexia may well facilitate the development of novel therapies for these complications. Other phenotypes created in mice, such as cataracts and hepatic cancer [59], may not have human analogies but may still provide insight into pathogenesis. Thus, transgenic models have already provided resources to study many manifestations of AIDS and others are likely to be developed. The optimal strategy for designing future transgenic animals, however, is less clear. No transgenic mouse model has been generated to date that will provide an avenue for vaccine development. This advance awaits the further discovery of the host factors that facilitate the virus replicative cycle in humans and a better understanding of these pathways in the mouse. For the development of molecular-based therapy, however, the currently available models may well be adequate to test molecular inhibitors of transcription [7,60,61] and post-transcriptional processing of viral mRNA [62]. Whether single or multigenic constructs under the control of the LTR are better or worse for this purpose is a debatable issue. Transgenic technology may yet make an additional contribution to the development of molecular therapy for AIDS. The best method of demonstrating that a gene therapeutic strategy is safe to administer to patients has not been determined. By introducing potentially therapeutic constructs into mice as transgenes, their safety can be assessed in many different cell types in vivo, analogous to toxicological testing in rodents for systemically administered drugs. Thus, transgenic technology has already provided insights into the pathogenesis of HIV-1. While it has not yet proven its utility for vaccine development, transgenic technology holds the promise of being an active participant in the development of both safe and effective gene therapy approaches for the treatment of AIDS.

AIDS Dementia Complex↗
PubMed1994

Comparison of the haemodynamic effects of dobutamine with enoximone after open heart surgery in small children.

We have studied 28 children (mean age 13.6 months) undergoing elective cardiac surgery involving a myocardial ischaemic time greater than 60 min. Thirteen received phenoxybenzamine 1 mg kg-1 before cardiopulmonary bypass (CPB) and dobutamine 10 micrograms kg-1 min-1 before discontinuation of CPB; 15 received enoximone 0.5 mg kg-1 followed by an infusion of 10 micrograms kg-1 min-1 before discontinuation of CPB. Haemodynamic variables were measured at intervals for 6 h after CPB. Two patients in each group required additional inotropic support with adrenaline. Heart rates, right and left atrial pressures, mean pulmonary artery pressures and systemic and pulmonary vascular resistance indices were similar in the two groups. Mean arterial pressure was significantly greater in those receiving dobutamine (61.3 (SD 7.6) mm Hg) compared with enoximone (56.2 (5.3) mm Hg) (P < 0.05). Differences in cardiac index (thermodilution) (dobutamine group 2.92 (0.62) litre min-1 m-2; enoximone group 2.55 (0.55) litre min-1 m-2) and left ventricular stroke work index (dobutamine group 13.1 (4.7) g m beat-1 m-2; enoximone group 10.4 (2.7) g m beat-1 m-2) were not statistically significant. Enoximone may be used successfully in these patients to assist discontinuation of CPB and maintain an acceptable haemodynamic state in the early postoperative period but, when used alone, conferred no advantage compared with the combination of dobutamine and phenoxybenzamine.

Blood Pressure↗
PubMed1994

The hidden curriculum, ethics teaching, and the structure of medical education.

The authors raise questions regarding the wide-spread calls emanating from lay and medical audiences alike to intensify the formal teaching of ethics within the medical school curriculum. In particular, they challenge a prevailing belief within the culture of medicine that while it may be possible to teach information about ethics (e.g., skills in recognizing the presence of common ethical problems, skills in ethical reasoning, or improved understanding of the language and concepts of ethics), course material or even an entire curriculum can in no way decisively influence a student's personality or ensure ethical conduct. To this end, several issues are explored, including whether medical ethics is best framed as a body of knowledge and skills or as part of one's professional identity. The authors argue that most of the critical determinants of physician identity operate not within the formal curriculum but in a more subtle, less officially recognized "hidden curriculum." The overall process of medical education is presented as a form of moral training of which formal instruction in ethics constitutes only one small piece. Finally, the authors maintain that any attempt to develop a comprehensive ethics curriculum must acknowledge the broader cultural milieu within which that curriculum must function. In conclusion, they offer recommendations on how an ethics curriculum might be more fruitfully structured to become a seamless part of the training process.

Bioethical Issues↗