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Biomedical subjects

J R Chapman

Publications and source records attributed to J R Chapman.

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

Analysis of cathepsin D forms and their clinical implications in human prostate cancer.

PURPOSE: To assess cathepsin D (Cat.D) status in the prostate, we analyzed the different Cat.D forms in human prostate tissues using Western immunoblots. MATERIALS AND METHODS: Cell extracts were prepared from prostate tissues (n = 42) obtained from radical prostatectomy, adopting the tissue homogenization method. Expression of the different Cat.D forms was analyzed using Western blots. The catalytic activity of Cat.D was assayed by acid treatment, in which cell extracts were incubated in acidic buffer (pH 3 to 4) at 37C for 1 hour. RESULTS: Pathologically confirmed normal (NML), benign prostatic hyperplasia (BPH) and cancer (CAP) specimens all expressed Cat.D, but as two distinct forms. Both NML and BPH predominantly expressed an inactive procathepsin D (Pro.Cat.D), while CAP notably exhibited an active mature Cat.D. The assessment of Cat.D activity, using PSA (prostate specific antigen) as a physiological substrate, showed that such activity was consistently higher in CAP than in NML/BPH specimens. Further studies revealed that the mode of Cat.D activation in CAP specimens appeared to be primarily due to acid-induced autoproteolysis (self-degradation) of mature Cat.D. CONCLUSION: This study demonstrates that expression and activity of Cat.D varies among prostate specimens. A greater expression of mature Cat.D with a higher catalytic activity in CAP specimens is the most notable difference from NML/BPH. Therefore, the differential expression/activity of Cat.D forms may be a useful indicator for assessing prostate cancer status.

Blotting, Western↗
PubMed1998

Maintenance therapy with oral ganciclovir after treatment of cytomegalovirus infection.

While oral ganciclovir (OGCV) has been used as primary prophylaxis in patients at high risk for cytomegalovirus (CMV) infection after solid organ transplantation, its value in secondary prophylaxis is unknown. We have examined the use of OGCV as maintenance therapy following confirmed CMV infection on 16 occasions in 15 patients, in kidney (n = 4), kidney-pancreas (n = 3) lung (n = 6) and heart-lung (n = 1) recipients. OGCV was used in two distinct clinical situations. One group (n = 7) received OGCV as consolidation therapy (mean duration of 21 +/- 5 d) following i.v. ganciclovir induction therapy (mean duration of 16 +/- 5 d) for acute CMV infection, and sustained remission was achieved in 6/7 patients for a median follow-up of 300 d. In the second scenario, OGCV suppressed clinical disease in all patients with relapsing CMV infection (n = 9), with minimal or absent toxicity with a median follow-up of 152 d. OGCV reduced morbidity by allowing removal of central lines used for long-term i.v. therapy in patients with poor peripheral access. Hence, this study demonstrates the safe and effective use of OGCV as consolidation therapy after standard induction treatment with i.v. ganciclovir, and as long-term suppressive therapy in transplant recipients with recurrent CMV infection.

Administration, Oral↗
PubMed1998

Glucose homeostasis standards for pancreas transplantation.

Simultaneous pancreas and kidney transplantation (SPK) is capable of achieving normoglycemia, as assessed by oral glucose tolerance tests (OGTT), in the majority of diabetic recipients with end-stage renal disease. Despite its success over the last decade, standard ranges for OGTT after SPK are not available for comparison between studies and techniques. We examined 327 prospectively performed OGTT, undertaken in insulin-free bladder-drained SPK recipients, between 1 month and 10 yr after transplantation. Ranges of values for glucose, insulin and C-peptide were derived and areas under the time concentration curves calculated. The normal range of 2-h glucose values from SPK recipients was comparable to WHO criteria for the diagnosis of diabetes mellitus in a normal population; however, the fasting glucose fell below these levels. Fasting and area-under-the-curve (AUC) glucose were remarkably stable with time after SPK, although insulin fell with time after pancreas transplantation. These ranges may allow clinical evaluation of the endocrine function in individual SPK recipients, provide standards for comparison between different centers and techniques, and provide targets for islet transplantation.

Adult↗
PubMed1997

The cytokine and histological response in islet xenograft rejection is dependent upon species combination.

BACKGROUND: Islet xenografts have clinical potential, may avoid hyperacute rejection, and therefore are a good place to examine the cellular xenograft immune response. The aim of this study was to examine the cellular, humoral, and cytokine response in islet xenograft rejection and to determine the difference in the immune response with a different donor species. METHODS: Two islet xenograft models (DA rat islets to B6AF1 mouse and canine islets to B6AF1 mouse) and a mouse syngeneic control model were examined histologically and by a semiquantitative polymerase chain reaction method. RESULTS: There was significant up-regulation of all intragraft cytokines tested (interleukin [IL]-2, IL-4, IL-5, IL-10, and interferon-gamma) in both xenograft models compared with the controls. However, the dog islet grafts had higher levels of IL-4 and IL-5 gene expression than the rat islet grafts, which, conversely, had higher levels of interferon-gamma gene expression. These differences correlated with the histological and anti-donor antibody production differences between the two models. The dog to mouse model had an intense eosinophilic infiltrate and an early up-regulation of anti-donor antibody, whereas there was little eosinophilic infiltrate and a delayed anti-donor antibody up-regulation in the rat to mouse model. CONCLUSIONS: The mouse used different mechanisms to reject the rat and canine islets, suggesting that the immune response in islet xenograft rejection may be dependent on the species combination. It may not be possible to characterize the cellular xenograft rejection response in a bipolar manner as has been the case with humoral rejection response. Caution therefore needs to be taken before extrapolating the cellular immune responses seen in animal models to the clinical setting.

Animals↗
PubMed1997

Diabetic neuropathy after pancreas transplantation: determinants of recovery.

Although simultaneous pancreas and kidney transplantation (SPK) achieves normoglycemia and correction of uremia in type I diabetic patients with renal failure, little data are available on long-term outcome and clinical determinants of recovery of peripheral neuropathy. In this prospective study, 219 electrophysiological studies using a standardized protocol were performed before and up to 8 years after SPK in 44 patients. Nine control diabetic recipients with functioning kidney but nonfunctioning pancreas transplants were studied on 35 occasions. Patients were 38.5+/-7.9 years old (mean+/-SD) with pretransplant diabetes present for 25.2+/-7.6 years. Significant polyneuropathy (total nerve conduction scores [NCS] <-1.0) was present in 89% before transplantation, which correlated with body weight (r=0.628, P<0.001). Two distinct patterns of neurological recovery were observed after SPK. Conduction velocity (CV) improved in a biphasic pattern, with a rapid initial recovery followed by subsequent stabilization. In contrast, the recovery of nerve amplitude was monophasic, and continued to improve for up to 8 years. Initial improvement in NCS was primarily due to an increase in CV (P=0.002 vs. baseline), and was best in shorter and younger patients. Recovery of total NCS at 6 months after SPK, assessed by multivariate analysis, was least in obese recipients and when performed in patients who had started dialysis before SPK, and was associated with lower transplant kidney isotopic glomerular filtration rate and HLA mismatch (P<0.05 to 0.001). Subsequent improvement was associated with less severe initial neuropathy, smaller body weight, and longer duration of diabetes (P<0.01 to 0.001). Fasting hyperinsulinemia was associated with impairment of initial recovery and subsequent NCS after SPK, but was worse in the control group. Recovery of nerve action potential amplitudes was predicted by better initial amplitudes and HLA mismatch, lower body weight, and the use of nifedipine (P<0.05 to 0.001). Nifedipine was used for hypertension in 33% of SPK and was associated with better CV and amplitudes, particularly in the upper limbs, where there was less neuropathy. The use of angiotensin-converting enzyme inhibitors also appeared beneficial, but this was confined to the lower limbs. SPK resulted in a gradual, sustained, and late improvement in nerve action potential amplitudes, consistent with axonal regeneration and partial reversal of diabetic neuropathy. These data suggest that early transplantation of uremic diabetic patients before onset of severe neuropathy, minimizing obesity and optimizing renal transplant function, maximizes neurological recovery after SPK. Furthermore, the preliminary data support randomized clinical trials for evaluation of nifedipine and angiotensin-converting enzyme inhibitors in diabetic neuropathy.

Adult↗
PubMed1997

The mechanism of cyclosporine toxicity induced by clarithromycin.

AIMS: Recently a number of case reports have described the interaction of clarithromycin with cyclosporine A, resulting in cyclosporine toxicity. This interaction is presumed to take place via the hepatic cytochrome P450 enzyme system. METHODS: Following a case of cyclosporine toxicity and acute renal failure in a transplant patient started on clarithromycin, we investigated the effect of oral clarithromycin on the hepatic P450 system in five healthy normal male volunteers, by means of the erythromycin breath test. RESULTS: Cytochrome P4503A (CYP3A) activity was reduced in all subjects by a mean level of 26% following clarithromycin treatment. This would result in a significant reduction in cyclosporine clearance in patients receiving clarithromycin. CONCLUSIONS: As clarithromycin was shown to inhibit CYP3A activity in all subjects tested, we recommend that a high degree of caution be exercised when clarithromycin is administered to patients receiving cyclosporine therapy or other drugs known to be eliminated by CYP3A-mediated metabolism.

Anti-Bacterial Agents↗
PubMed1997

Biomechanical comparison of internal fixation techniques for the treatment of unstable basicervical femoral neck fractures.

OBJECTIVES: The optimal method of internal fixation of basicervical femoral neck fractures is controversial. This area represents a transition zone between the intracapsular femoral neck fracture, usually fixed with multiple cancellous screws, and the extracapsular interochanteric fracture, fixed with a sliding screw device [sliding hip screw (SHS)] and derotation screw (DRS) device. The authors' specific aim was to biomechanically compare these two methods of fixation in a cadaveric model of a basicervical femoral neck fracture with posteromedial comminution. DESIGN: The authors compared the average peak force during cyclic loading and the maximum axial force sustained by matched pairs of specimens stabilized with either fixation and subjected to axial and torsional loading while flexing and extending the hip. The average peak force was defined as the mean of the peak force values measured in each loading cycle with the maximum displacement of the materials tester actuator the same for each cycle (displacement control) as opposed to the maximum force being held constant (load control). RESULTS: The cancellous screw group maintained a significantly lower average peak force, 470 Newtons (SD = 145 Newtons), compared with 868 Newtons (SD = 186 Newtons) for the SHS and DRS composite group (p < 0.01). Similarly, the cancellous screw group demonstrated a lower ultimate load to failure, 1,863 Newtons (SD = 475 Newtons) compared with 3,557 Newtons (SD = 215 Newtons) for the SHS and DRS composite group (p < 0.01). CONCLUSION: The results support the use of an SHS and DHS composite compared with three cancellous screws in the treatment of unstable basicervical femoral neck fractures.

Aged↗
PubMed1996

Experimental hyperacute rejection in pancreas allotransplants.

A model of sensitization by intraperitoneal lymph node inoculation was developed to test the hypothesis that hyperacute rejection (HAR) could occur in sensitized recipients of vascularized pancreas allografts. Ten pairs of outbred mongrel dogs that were lymphocytotoxic cross-match assay negative were inoculated with homogenized lymph nodes on either three or four occasions at fortnightly intervals before renal transplantation. A renal allograft from the same donor was used to test the HAR response and to further enhance sensitization by rejection of a vascularized organ. Pancreas transplants were performed 2 weeks later, with biopsies of the graft and blood samples taken at 0, 10, 20, and 30 min and then at 30-min intervals until the grafts were no longer viable. All renal and pancreas grafts were rejected in a classical hyperacute pattern. Within 4 min of revascularization of the pancreas, central lobular hemorrhage and vascular congestion appeared, followed by general edema. Histology demonstrated parallel changes of edema, vascular congestion, necrosis, hemorrhage, and leukocytic infiltrate, which all preceded graft infarction. A sharp decline in both arterial and venous white blood cell count and platelets occurred within 10 min of revascularization with initial sequestration and subsequent release of platelets from the graft (P=0.02). In summary, HAR of the allografted pancreas can be observed by the surgeon within minutes of revascularization, with predictable macroscopic and microscopic changes. This study supports the use of routine lymphocytotoxic cross-match tests for all recipients of pancreas transplants and implies that particular care is warranted in regraft pancreas allograft recipients.

Acute Disease↗
PubMed1996

Reversal of cyclosporine malabsorption in diabetic recipients of simultaneous pancreas and kidney transplant using a microemulsion formulation.

In view of the known problems that diabetic recipients have with drug absorption and of the potential advantages of the microemulsion formulation of cyclosporine (Neoral), 17 previously diabetic recipients of simultaneous pancreas and kidney allografts were studied before and after conversion from Sandimmune (SIM) to Neoral (NEO) formulations of cyclosporine a mean of 4.75 +/- 2.0 years after transplantation. The aims of this study were to determine whether there were changes in the absorption profiles using the 2 formulations and to analyze the safety of conversion from SIM to NEO on a 1:1 ratio. Pharmacokinetic, clinical, and renal function parameters were measured 2 weeks before, and 2 and 4 weeks after conversion. Pharmacokinetics demonstrated that, when taking SIM, only 5 patients had "good absorption" (maximal concentration >500 ng/ml and time to maximal concentration < / = 2 hr), but after conversion to NEO, 14 at week +2, and 13 at week +4 were good absorbers (P<0.02 and <0.01, respectively). There was a 50% reduction in the time to maximal blood concentration (from 3.2 +/- 1.9 hr with SIM, to 1.8 +/- 1.3 hr on NEO [P<0.007]) and a 36% increase in trough and a 143% increase (P<0.01) in maximal blood concentrations, although the 9-hr cyclosporine AUC showed an 89% increase (P<0.01). There was an 18% mean reduction in dose per kilogram prescribed 4 weeks after conversion. Renal function, measured by serum creatinine and technecium-99m diethylenetriamine pentaacetic acid glomerular filtration rate, was not altered and no adverse events were attributed to NEO. This study confirmed that previously diabetic recipients of simultaneous renal pancreas allografts had variable and poor absorption of cyclosporine using conventional Sandimmune and that this absorption was improved by conversion to Neoral.

Absorption↗
PubMed1996

Clinical determinants of glucose homeostasis after pancreas transplantation.

Although successful simultaneous pancreas and kidney transplantation (SPK) achieves normoglycemia in the majority of diabetic recipients with end-stage renal disease, little is known about the factors that influence long-term endocrine function. In this prospective study of 48 bladder-drained SPK patients, 209 oral glucose tolerance tests were performed between 3 months and 6 years after transplantation. Normal fasting glucose levels and systemic hyperinsulinemia were stable for up to 6 years after SPK. Multivariate analysis revealed that increased area-under-curve (AUC) levels of C-peptide 3 months after transplantation were predicted by short surgical pancreas anastomosis time, greater recipient body weight, and total HLA mismatch score. Episodes of acute pancreas rejection were not associated with reduced allograft insulin output in the long term. Insulin output, stimulated by oral glucose tolerance tests and assessed by the ratio of AUC insulin to AUC glucose, fell gradually after transplantation and was decreased by an elevated serum calcium level and high cyclosporine dose. The ratio of fasting insulin to glucose, which acts as a marker of peripheral insulin resistance, fell with time after transplantation and was increased by greater body weight, higher prednisolone dose, and lower cyclosporine dose. The inhibitory effect of cyclosporine on both fasting and postprandial insulin output was, however, minor when quantified by multivariate analysis. Endocrine function of the transplanted pancreas was not correlated with its exocrine function measured by urinary amylase excretion, nor was there a correlation with change in renal function measured by isotopic glomerular filtration rate. In summary, simultaneous pancreas and kidney transplantation leads to excellent long-term glucose homeostasis maintained at the expense of systemic hyperinsulinemia. The key factors adversely affecting peripheral resistance in SPK were corticosteroid therapy, body weight, and time after transplantation. The susceptibility of islets to ischemia-reperfusion injury, as quantitated by surgical anastomosis time, may have implications for islet transplantation programs, as may the relative resistance of islets to allograft rejection. Glucose homeostasis after SPK, while remaining abnormal, may be used as the standard against which islet transplantation must be measured.

Adult↗
PubMed1996

Comparative biomechanical evaluation of different external fixation sidebars: stainless-steel tubes versus carbon fiber rods.

Carbon fiber rods were developed to provide radiolucent sidebars for external fixation. In the present study, a single-plane, half-pin, double-bar external fixator construct with either stainless-steel tubes or carbon fiber rods was applied on the anteromedial surface of an osteotomized synthetic human tibia and evaluated for fixation rigidity. Testing was performed with the bone fragments in cortical contact and with a 5-mm midshaft gap between the fragments. The sidebars then were loaded to failure in bending. The results of this study show (a) that the carbon fiber rods were 15% stiffer than the stainless-steel tubes (p = 0.009) and (b) that the external fixator with carbon fiber rods achieved approximately 85% of the fixation stiffness of the external fixator with stainless-steel tubes. The loss of stiffness of the external fixator with carbon fiber rods is most likely due to the clamps being less effective in connecting the carbon fiber rods rigidly to the Schanz screws.

Biomechanical Phenomena↗
PubMed1996

A comparative biomechanical evaluation of a noncontacting plate and currently used devices for tibial fixation.

The appearance of porous bone under fixation plates during fracture healing, attributed to disturbance of blood supply by the plate, has led to new plate designs with reduced plate to bone contact. The fixation stability afforded by these devices, in comparison to implants commonly used for fixation, is not well known. Therefore, the construct stiffnesses of osteotomized synthetic tibiae fixed with dynamic compression plates, external fixators, or two configurations of noncontact plates were compared in axial compression, bending, and torsion with and without cortical contact at the osteotomy site. The results of this study show that (1) the noncontact plated constructs achieve comparable fixation rigidity to constructs using dynamic compression plates or external fixators, if applied at a distance no greater than 5 mm from the surface of the tibia, and (2) the fixation rigidity of the noncontact plate decreases as the distance between plate and bone surface increases.

Biomechanical Phenomena↗
PubMed1996

Factors affecting the pullout strength of cancellous bone screws.

Screws placed into cancellous bone in orthopedic surgical applications, such as fixation of fractures of the femoral neck or the lumbar spine, can be subjected to high loads. Screw pullout is a possibility, especially if low density osteoporotic bone is encountered. The overall goal of this study was to determine how screw thread geometry, tapping, and cannulation affect the holding power of screws in cancellous bone and determine whether current designs achieve maximum purchase strength. Twelve types of commercially available cannulated and noncannulated cancellous bone screws were tested for pullout strength in rigid unicellular polyurethane foams of apparent densities and shear strengths within the range reported for human cancellous bone. The experimentally derived pullout strength was compared to a predicted shear failure force of the internal threads formed in the polyurethane foam. Screws embedded in porous materials pullout by shearing the internal threads in the porous material. Experimental pullout force was highly correlated to the predicted shear failure force (slope = 1.05, R2 = 0.947) demonstrating that it is controlled by the major diameter of the screw, the length of engagement of the thread, the shear strength of the material into which the screw is embedded, and a thread shape factor (TSF) which accounts for screw thread depth and pitch. The average TSF for cannulated screws was 17 percent lower than that of noncannulated cancellous screws, and the pullout force was correspondingly less. Increasing the TSF, a result of decreasing thread pitch or increasing thread depth, increases screw purchase strength in porous materials. Tapping was found to reduce pullout force by an average of 8 percent compared with nontapped holes (p = 0.0001). Tapping in porous materials decreases screw pullout strength because the removal of material by the tap enlarges hole volume by an average of 27 percent, in effect decreasing the depth and shear area of the internal threads in the porous material.

Animals↗
PubMed1996

Twin- versus single-bag disconnect systems: infection rates and cost of continuous ambulatory peritoneal dialysis.

Although twin-bag disconnect fluid-transfer systems for continuous ambulatory peritoneal dialysis (CAPD) have a lower rate of catheter-related infection than single-bag systems, their greater monetary purchase cost has prevented universal adoption. Therefore, a single-center randomized study was performed in 63 adult patients to compare the efficiency and total cost of Freeline Solo (FS, twin-bag) and Basic Y (BY, single-bag) systems. Patients were new to CAPD (N = 39), or had a new CAPD catheter, or had had no episodes of peritonitis or exit-site infection in the previous 12 months (N = 24). Total follow-up was 631 patient months (pt.mon), and 53 patients were still on the trial at its termination. Patients rated FS as easier to use than BY (P < 0.001). Peritonitis occurred on 23 occasions in 12 out of 30 patients using BY, and on seven occasions in five of 33 patients using FS. Time to first infection was less with BY than FS (hazard ratio, 2.4; 95% confidence interval (CI), 1.0 to 5.3; P < 0.04). Cumulative incidence of peritonitis was 1 per 14.0 pt.mon with BY and 1 per 46.5 pt.mon with FS (odds ratio, 3.6; 95% CI 1.5 to 8.5; P = 0.004). Length of hospitalization for peritonitis or exit-site infection was 98 days in six patients with BY, versus 17 days in two patients with FS. With BY, four catheters were removed because of infection, but none with FS (P < 0.05). With BY, the total cost of infection was $AUD127,079 ($5033 per pt.yr) versus $19,250 ($704 per pt.yr) with FS, which offset the higher purchase cost of FS. The total cost of CAPD was $AUD956 per pt.yr less with FS than BY. In conclusion, the higher purchase cost of the FS twin-bag system is more than offset by savings from its lower incidence of peritonitis.

Adolescent↗
PubMed1996

Posterior instrumentation of the unstable cervicothoracic spine.

Fractures, tumors, and other causes of instability at the cervicothoracic junction pose diagnostic and treatment challenges. The authors report on 23 patients with instability of the cervicothoracic region, which was treated with posterior plate fixation and fusion between the lower cervical and upper thoracic spine. During operation AO reconstruction plates with 8- or 12-mm hole spacing were affixed to the spine using screws in the cervical lateral masses and the thoracic pedicles. Postoperative immobilization consisted of the patient's wearing a simple external brace for 2 months. The following parameters were analyzed during the pre- and postoperative treatment period: neurological status, spine anatomy and reconstruction, and complications. Follow up consisted of clinical and radiographic examinations (mean duration of follow up, 15.4 months; range, 6-41 months). No neurovascular or pulmonary complications arose from surgery. All patients achieved a solid arthrodesis based on flexion-extension radiographs. There was no significant change in angulation during the postoperative period, but one patient had an increase in translation that was not clinically significant. There were no hardware complications that required reoperation. One patient requested hardware removal in hopes of reducing postoperative pain in the cervicothoracic region. One postoperative wound infection required debridement but not hardware removal. The authors conclude that posterior plate fixation is a satisfactory method of treatment of cervicothoracic instability.

Adult↗
PubMed1996

MRI in acute knee dislocation. A prospective study of clinical, MRI, and surgical findings.

We treated 17 knees in 15 patients with severe ligament derangement and dislocation by open repair and reconstruction. We assessed the competence of all structures thought to be important for stability by clinical examination, MRI interpretation, and surgery. Our findings showed that in these polytrauma patients clinical examination was not an accurate predictor of the extent or site of soft-tissue injury (53% to 82% correct) due mainly to the limitations of associated injuries. MRI was more accurate (85% to 100% correct) except for a negative result for the lateral collateral ligament and posterolateral capsule. The detail and reliability of MRI are invaluable in the preoperative planning of the surgical repair and reconstruction of dislocated knees.

Acute Disease↗