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Biomedical subjects

R G Walker

Publications and source records attributed to R G Walker.

At least 19 recordsLinked to original sources
PubMed2002

Factors influencing growth and final height after renal transplantation.

Growth retardation occurs commonly in children and adolescents with chronic renal insufficiency. While some children exhibit catch-up growth following renal transplantation, for many children growth remains sub-optimal. The aim of the current study was to review the factors influencing growth and final height following renal transplantation. Data from all children who had a renal transplant performed between 1985 and 1998 at the Royal Melbourne and Royal Children's Hospitals, Melbourne (n = 85), were examined retrospectively. Two children who died in the first year post-transplant and one patient lost to follow-up within 6 months of their transplant were excluded. Children with multiple grafts had only growth following their most recent graft analyzed. The mean height standard deviation score (Ht-SDS) at the time of transplantation was -2.11 (range: -5.05 to 0.27), improving to -1.50 (range: -3.67 to 1.27) at 7 yr post-transplant. On univariate analysis, the dose of cyclosporin at 6 months and at 1 and 3 yr, and the graft function at 1 yr, had a significant positive correlation with the change in Ht-SDS (DeltaHt-SDS) at each of those time-points post-transplant. At all time-points there was a strong correlation between pretransplant height and subsequent growth. A sub-group of children who were 16 yr of age or older at December 1999, and who were considered to have reached their final height, were examined to determine predictors of final height. Multiple regression analysis of clinical and laboratory parameters from the sub-group of patients > or = 16 yr of age showed that height at the time of transplant, age at the time of transplant, and final glomerular filtration rate, were significant independent predictors of growth (r2 = 0.82, p = 0.01). In addition, the immunosuppressive regimen at 1, 3, and 5 yr post-transplant had a significant effect on growth. This study confirms the importance of each of these factors for post-transplant growth.

Adolescent↗
PubMed2001

Molecular basis of mechanosensory transduction.

Mechanotransduction - a cell's conversion of a mechanical stimulus into an electrical signal - reveals vital features of an organism's environment. From hair cells and skin mechanoreceptors in vertebrates, to bristle receptors in flies and touch receptors in worms, mechanically sensitive cells are essential in the life of an organism. The scarcity of these cells and the uniqueness of their transduction mechanisms have conspired to slow molecular characterization of the ensembles that carry out mechanotransduction. But recent progress in both invertebrates and vertebrates is beginning to reveal the identities of proteins essential for transduction.

Animals↗
PubMed2001

Critically timed auxiliary shock to weak field area lowers defibrillation threshold.

INTRODUCTION: This study tested the hypothesis that the defibrillation threshold (DFT) can be lowered by delivering a weak auxiliary shock in conjunction with a stronger primary shock to the cardiac region where the primary shock electric field is weakest. METHODS AND RESULTS: Eight swine were studied in each of two study parts. In both parts, DFTs were determined for dual shocks delivered through two electrode pairs. The biphasic primary shock was delivered through electrodes in the right ventricle and superior vena cava. The auxiliary shock was delivered through a separate electrode in the superior vena cava and a left ventricular electrode placed where the primary shock field was presumed to be weakest. In part I, a monophasic auxiliary shock of 50, 100, or 150 V was delivered either simultaneously with or 1, 20, or 40 msec before primary shock. When auxiliary shock was delivered simultaneously with or 1 msec before primary shock, DFT energy was reduced by approximately 50% compared with primary shock alone. In part II, a 150-V monophasic or biphasic auxiliary shock of either polarity was delivered 1 msec before or after primary shock. Regardless of waveform or polarity, all auxiliary shock delivered before primary shock lowered DFT energy by approximately 30% compared with primary shock alone. Depending on waveform and polarity, auxiliary shock delivered after primary shock either did not significantly change the DFT or elevated the DFT compared with primary shock alone. CONCLUSION: Application of a small auxiliary shock, just before or simultaneously with a primary shock, to the cardiac region where the primary shock field is weakest significantly lowers DFT.

Animals↗
PubMed2001

The carriage of pro-inflammatory cytokine gene polymorphisms in recurrent pregnancy loss.

PROBLEM: Recurrent pregnancy loss (RPL) affects 2-4% of couples, and remains largely unexplained. Recent studies have examined the role of cytokines in the maintenance of normal pregnancy, which is linked with an increased expression of Th2 cytokines. Overexpression of Th1 cytokines is associated with RPL. Knowing that functional polymorphisms exist for certain cytokines, it has therefore been suggested that women with RPL may have a genetic predisposition to overexpress Th1 cytokines. METHOD OF STUDY: The genes for interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) carry functional gene polymorphisms. In both cases these are biallelic polymorphisms that can be detected by polymerase chain reaction followed by restriction fragment length polymorphism. The aim of this pilot study was to assess whether carriage of the rarer alleles (TNF*2 and IL-1B*2) could act as independent risk factors in recurrent miscarriage. RESULTS: We found an increased incidence in the carriage of TNF*2, more pronounced in those women with two or more miscarriages. Carriage of the IL-1B*2 either alone or in association with TNF*2 was not associated with recurrent miscarriage. CONCLUSION: There may be a role for these cytokine gene polymorphisms in RPL.

Abortion, Habitual↗
PubMed2000

A notch-independent activity of suppressor of hairless is required for normal mechanoreceptor physiology.

Suppressor of Hairless [Su(H)]/Lag-1/RBP-Jkappa/CBF1 is the only known transducing transcription factor for Notch receptor signaling. Here, we show that Su(H) has three distinct functions in the development of external mechanosensory organs in Drosophila: Notch-dependent transcriptional activation and a novel auto-repression function, both of which direct cell fate decisions, and a novel auto-activation function required for normal socket cell differentiation. This third phase of activity, the first known Notch-independent activation function for Su(H) in development, depends on a cell type-specific autoregulatory enhancer that is active throughout adult life and is required for proper mechanoreception. These results establish a direct link between a broadly deployed cell signaling pathway and an essential physiological function of the nervous system.

Animals↗
PubMed2000

A Drosophila mechanosensory transduction channel.

Mechanosensory transduction underlies a wide range of senses, including proprioception, touch, balance, and hearing. The pivotal element of these senses is a mechanically gated ion channel that transduces sound, pressure, or movement into changes in excitability of specialized sensory cells. Despite the prevalence of mechanosensory systems, little is known about the molecular nature of the transduction channels. To identify such a channel, we analyzed Drosophila melanogaster mechanoreceptive mutants for defects in mechanosensory physiology. Loss-of-function mutations in the no mechanoreceptor potential C (nompC) gene virtually abolished mechanosensory signaling. nompC encodes a new ion channel that is essential for mechanosensory transduction. As expected for a transduction channel, D. melanogaster NOMPC and a Caenorhabditis elegans homolog were selectively expressed in mechanosensory organs.

Action Potentials↗
PubMed2000

Evaluation and long-term outcome of pediatric renovascular hypertension.

Seventeen children with renovascular hypertension were managed at the Royal Children's Hospital, Melbourne, over the 20-year period from 1975 to 1996. The age at presentation ranged from 10 days to 18 years. All children presented with severe hypertension with mean systolic blood pressure 7 standard deviations above age-matched averages and mean diastolic blood pressure 5.5 standard deviations above age-matched averages. Neurofibromatosis was the most common etiology (58% of patients) and there were no cases of Takayasu's arteritis. Patients underwent a variety of biochemical and imaging investigations but in all cases renal angiography was necessary for definitive diagnosis and for planning therapy. Ten of the 17 patients had surgical procedures performed. Percutaneous transluminal angioplasty was performed in four patients but led to cure in only one patient following thrombosis of the affected artery producing segmental renal infarction. Other vascular reconstructive procedures, including the use of autologous or synthetic bypass grafts and autotransplantation, produced cure of hypertension in 50% of children with improvement in a further 30%. The long-term outlook for children treated with surgical reconstructive procedures was excellent. One patient underwent surgery for avulsion of an arterial graft following a pubertal growth spurt. No other patient originally cured by surgery has required reoperation with no cases of restenosis at a mean follow-up of 11 years 3 months.

Adolescent↗
PubMed2000

Influence of anti-rejection therapy on the timing of cytomegalovirus disease and other infections in renal transplant recipients.

Infections are an important cause of mortality and morbidity in renal transplant recipients. To study the impact of anti-rejection therapy on the timing of infections, the records of 599 consecutive renal transplants, performed prior to 31 December 1996 at the Royal Melbourne Hospital, were reviewed. Patients were grouped according to acute rejection (AR) episode and treatment during the first 6 months after transplantation. Group 1 [n = 168 (35%)] patients did not experience any episode of AR. Group 2 [n = 169 (35%)] patients had one or more episodes of AR and received high doses of steroids. Group 3 [n = 141 (30%)] patients had more than one episode of AR and received anti-lymphocyte antibodies in addition to high doses of steroids. Infections were more common in Groups 2 and 3 but only cytomegalovirus (CMV) disease occurred earlier in patients treated with lympholytics. Given the high incidence and early onset of CMV disease in patients receiving lympholytics and considering that an effective prophylactic protocol remains undetermined, pre-emptive treatment with ganciclovir in this high risk group appears justified.

Acute Disease↗
PubMed2000

Fibrillation is more complex in the left ventricle than in the right ventricle.

INTRODUCTION: The mechanisms that maintain ventricular fibrillation (VF) are not completely understood. It has been proposed that increased ventricular wall thickness destabilizes VF wavefronts and therefore is an important determinant of VF activation patterns. We hypothesized that if this is the case, then VF patterns on the thin-walled right ventricle (RV) should be simpler than those on the thick-walled left ventricle (LV). METHODS AND RESULTS: In seven open chest pigs, we mapped VF simultaneously from two epicardial recording arrays, one on the RV and one on the LV. Each array contained 504 unipolar electrodes (in a 21 x 24 grid) spaced by 2 mm. We used specialized pattern analysis methods to compute quantitative descriptors of RV and LV activation patterns. Our data show that VF is more organized in the RV than the LV, containing fewer, larger wavefronts that follow fewer distinct pathways and are less likely to fragment or collide with other wavefronts. The incidence, size, and cycle length of reentrant circuits were similar in the two ventricles, but RV reentry persisted for more cycles. These results are not predicted by the differences in electrophysiologic properties between LV and RV that have been reported in mammalian hearts. CONCLUSION: The geometry of the ventricular wall, particularly wall thickness, is an important determinant of VF activation patterns.

Action Potentials↗
PubMed2000

Marked reduction of ventricular defibrillation threshold by application of an auxiliary shock to a catheter electrode in the left posterior coronary vein of dogs.

INTRODUCTION: For endocardial shocks near the defibrillation threshold (DFT), postshock activity originates from the lateral left ventricular apex, where the shock field is weak. This study tested the hypothesis that an auxiliary shock (AS) delivered between an electrode at this site and a superior vena cava (SVC) electrode before the primary endocardial shock (PS) would reduce the DFT. METHODS AND RESULTS: In six pentobarbital-anesthetized dogs (26 to 36 kg), catheter electrodes were placed in the right ventricular (RV) apex and the SVC. To simulate transvenous introduction, a small electrode was inserted into the posterior cardiac vein using an epicardial approach. For dual shock treatments, AS (2-msec monophasic) was applied to the coronary vein electrode at different time intervals before a biphasic PS (4 msec/3 msec) to the RV-SVC electrodes. The mean DFT energy for dual shocks treatments were significantly reduced (P < 0.05) in comparison to the control treatment (no AS, 26.5+/-8.8 J). Mean DFT energy after 10 seconds of electrically induced ventricular fibrillation for dual shocks, in which AS and PS were separated by 1, 5, 10, and 20 msec, were 10.2+/-4.1 J, 10.9+/-5.5 J, 11.3+/-6.3 J, and 15.4+/-7.2 J, respectively. These values were all significantly lower than the PS alone (26.5+/-8.8 J). CONCLUSION: Addition of an AS from the posterior cardiac vein before an endocardial PS reduces DFT energy by more than 50%. Such DFT reduction could improve therapeutic safety margin or permit reduction in volume of implantable cardioverter defibrillators.

Animals↗
PubMed1999

Impact of acute rejection therapy on infections and malignancies in renal transplant recipients.

BACKGROUND: Infections and malignancies are important causes of mortality and morbidity in renal allograft recipients. Their risk increases with increasing immunosuppression. METHODS: In an attempt to quantitate the increase in the risk of these complications in association with antirejection therapy, we reviewed the records of all renal allograft recipients of our center transplanted during the cyclosporin era. We sub-divided the patients into three groups based on acute rejection episodes during the first 6 months posttransplant, and the treatment for acute rejection: those who did not develop AR--group 1 (n=168); those who had one or more episodes of acute rejection and were treated with high dose corticosteroids --group 2 (n=169); those who in addition to corticosteroids required cytolytics (OKT3) and/or other drugs--group 3 (n=141). RESULTS: 52% patients in group 1, 71% patients in group 2 and 86% patients in group 3 had one or more episodes of infection during the first 6 months posttransplantation. Relative risk for group 2 and 3 were 1.56 (P=0.0002) and 2.98 (P<0.00001), respectively. Infection/patient rates at 6 months were 0.67, 1.23, and 2.79 in groups 1, 2, and 3 respectively. Groups 1 and 2 had a similar number of cases with squamous and basal cell carcinoma, however, there were few cases with these malignancies in group 3. No case of lymphoma was seen in group 1; there were four cases in group 2 and nine in group 3. There was no significant difference in patient survival in group 1 and 2, however, patients in group 3 had a reduced patient survival (1 vs. 3 P<0.001, 2 vs. 3 P=0.067). Graft survival was best in group 1 and worst in group 3 (1 vs. 2 P<0.05; 1 vs. 3 P<0.00001; 2 vs. 3 P<0.01). CONCLUSIONS: In renal transplant recipients the risk of infections and lymphoma increases with increasing immunosuppression and hence mortality and morbidity associated with it. When adding a potent immunosuppressive agent to rescue a kidney one needs to consider the serious and at times fatal side effects given the modest beneficial effect on long-term outcome.

Acute Disease↗
PubMed1998

Locally propagated activation immediately after internal defibrillation.

BACKGROUND: Electrical mapping studies indicate an interval of 40 to 100 ms between a defibrillation shock and the earliest activation that propagates globally over the ventricles (globally propagated activation, GPA). This study determined whether activation occurs during this interval but propagates only locally before being blocked (locally propagated activation, LPA). METHODS AND RESULTS: In five anesthetized pigs, the heart was exposed and a 504-electrode sock with 4-mm interelectrode spacing was pulled over the ventricles. Ten biphasic shocks of a strength near the defibrillation threshold (DFT) were delivered via intracardiac catheter electrodes, and epicardial activation sequences were mapped before and after attempted defibrillation. Local activation was defined as dV/dt < or =-0.5 V/s. Postshock activation times and wave-front interaction patterns were determined with an animated display of dV/dt at each electrode in a computer representation of the ventricular epicardium. LPAs were observed after 40 of the 50 shocks. A total of 173 LPA regions were observed, each of which involved 2+/-2 (mean+/-SD) electrodes. LPAs were observed after both successful and failed shocks but occurred earlier (P<.0001) after failed (35+/-8 ms) than successful (41+/-16 ms) shocks, although the times at which the GPA appeared were not significantly different. On reaching the LPA region, the GPA front either propagated through it (n=135) or was blocked (n=38). The time from the onset of the LPA until the GPA front propagated to reach the LPA region was shorter (P<.01) when the GPA front was blocked (32+/-12 ms) than when it propagated through the LPA region (63+/-20 ms). CONCLUSIONS: LPAs exist after successful and failed shocks near the DFT. Thus, the time from the shock to the GPA is not totally electrically silent.

Animals↗
PubMed1998

Suppression of the humoral immune response by mycophenolate mofetil.

BACKGROUND: No conventional immunosuppressive agent preferentially inhibits antibody production. Studies in experimental animals and in human cells in vitro suggested mycophenolate mofetil (MMF) might have such an effect. If this was the case in vivo it could have significant implications in terms of both MMF toxicity and the rational design of immunotherapeutic regimens. METHODS: Subjects were renal transplant recipients (25 patients treated with prednisolone, cyclosporine and azathioprine, and 13 treated with prednisolone, cyclosporine and MMF) and 20 normal controls. The three groups received influenza vaccination, and the antibody response to it was measured 4-6 weeks later using a standard haemagglutination assay. RESULTS: MMF profoundly suppressed the humoral immune response to influenza vaccination when added to prednisolone and cyclosporine. This effect could be seen when comparing the rise in the mean titre of antibody after vaccination. It was also reflected in the number of patients mounting responses deemed to be clinically protective by either demonstrating a 4-fold rise in titre or an increase in titre to > or = 40. CONCLUSIONS: Suppression of the humoral immune response by MMF has implications for the design of immunization protocols to protect the immunosuppressed, and raises the possibility that MMF use may be accompanied by more or different infections than complicate more conventional immunosuppression. More importantly, consideration should be given to harnessing the relatively specific effect of MMF on antibody production to treat antibody-mediated diseases.

Adolescent↗
PubMed1997

Myofibroblast involvement in chronic transplant rejection.

BACKGROUND: Chronic rejection remains the major cause of late graft failure. We studied the renal tissue of 10 renal transplant patients with chronic rejection in whom biopsies had been performed at various time points over a 15-year posttransplant period to ascertain whether myofibroblasts (MF) have a role in this process. METHODS: Biopsies were grouped into five categories with respect to time after vascular anastomosis: 0 (n=10); 1 day to 3 months (n=7); 6-24 months (n=5); 36-72 months (n=7); and >72 months (n=5). A control group consisted of patients who had undergone routine biopsies at 0 (n=10), 3 (n=10), 12 (n=6), 60 (n=5), and >60 months (n=6) with no rejection. MF were identified by morphology and alpha-smooth muscle actin immunostaining. T cells and macrophages (MF) were identified using an antisera to CD3 and CD68, respectively. Collagen III deposition was similarly quantified by immunohistochemistry. Interstitial fractional area was measured by point counting. RESULTS: At all time points studied beyond time 0, there were significant increases in interstitial fractional area, collagen III staining, MF, and T-cell staining in patients with chronic rejection compared with the controls. Staining for alpha-smooth muscle actin increased with time in conjunction with worsening fibrosis and collagen deposition. CONCLUSIONS: In this study, MF were a major component of the interstitial infiltrate of the 10 patients with chronic transplant rejection. Abnormal persistence of these cells in the interstitium is one of the events that contributes to pathologic scarring of the kidney.

Actins↗
PubMed1997

Computerized documentation of activities of Pharm.D. clerkship students.

A method for documenting the contributions of entry-level Pharm.D. clerkship students at a teaching hospital is described. Between mid-September 1995 and April 1996, students were asked to use a cost-accounting software program to document time spent on various activities associated with inpatient pharmacy services. The system was already being used for documenting the clinical activities of staff pharmacists; pharmacists entered activities in the same way that they entered medication orders, using a mnemonic for a clinical activity in place of a drug name and time spent on the activity in place of a dosage. Pharmacist preceptors verified the students' entries. Eleven students reported 3,466 clinical events. Thirty-five pharmacists reported 54,299 clinical events during the same period. Students were responsible for 42.5% of the initial patient work-ups reported, 34.0% of the patient information and education episodes, and 24.6% of the inservice programs for physicians. On the basis of documented student contributions to the clinical workload, the pharmacy department requested additional clerkship students. The following year, 16 clerkship students were assigned to the department and the program was expanded to year-round clerkships. Pharmacy clerkship students contributed to the productivity data of a teaching hospital. Documentation of the students' contributions led to an expansion of the clerkship program.

California↗
PubMed1997

Transabdominal cervico-isthmic cerclage in the management of cervical incompetence.

The use of transabdominal cervico-isthmic cerclage is described in 13 patients with a diagnosis of cervical incompetence. The patients were recruited from seven Scottish Maternity Units over a period of 10 years. The 13 patients have had a successful pregnancy in 86.6% of pregnancies with this procedure compared with a success rate of 16% in their previous pregnancies. In carefully selected cases transabdominal cervico-isthmic cerclage is a worthwhile procedure in patients with cervical incompetence when the cervix is so damaged that it would be impossible to insert a vaginal suture or when a vaginal suture has previously failed.

Adult↗