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Biomedical subjects

P B Thomas

Publications and source records attributed to P B Thomas.

At least 19 recordsLinked to original sources
PubMed2005

The effects of atorvastatin in experimental autoimmune uveitis.

AIM: To investigate the effect of atorvastatin (Lipitor), a commonly used drug for dyslipidaemia in experimental autoimmune uveitis (EAU). METHODS: 48 B10-RIII mice were immunised with human interphotoreceptor retinoid binding protein (IRBP) peptide p161-180. They were divided into three groups of 16 each and treated orally once daily for 14 days; group one received phosphate buffered saline (control group), group two received 1 mg/kg of atorvastatin (low dose group), and group three received 10 mg/kg (high dose). On day 14 lymph nodes, spleens, and right eyes were harvested. RNA was extracted from lymph nodes for RNase protection assay (RPA) to determine proinflammatory (IL-1 alpha and IL-1 beta), Th1 (TNF-alpha, IL-2, IL-12), and Th2 (IL-4, IL-5, and IL-10) cytokine levels. Protein was extracted from spleens for western blot to detect the expression of phosphorylated signal transducer and activator of transcription (STAT) 4 and STAT6. The severity of inflammation in enucleated eyes was graded by a masked observer. Paired t test was performed for the mean difference in histological scoring between treated groups and the immunised control group. RESULTS: Surprisingly, atorvastatin did not modulate the immune response. The proinflammatory cytokines, IL-1 alpha and IL-1 beta, and Th1 cytokines, TNF-alpha and IL-2, were upregulated equally in control and atorvastatin treated groups. IL-12 and Th2 cytokines were not upregulated in all three groups. Western blot analysis showed high levels of phosphorylated STAT4, but not STAT6 protein in the control and atorvastatin treated groups. Mean differences in histological scoring between treated groups and the immunised control group were not statistically significant. CONCLUSIONS: Atorvastatin treatment had no effect on Th1 and Th2 cytokine transcription. Although histological grading suggested mildly decreased inflammation in the high dose treated group, the equivalence of cytokine expression in all groups suggests that the statins may not modulate IRBP induced uveoretinitis.

Animals↗
PubMed2001

Mechanical properties of callus in human tibial fractures: a preliminary investigation.

OBJECTIVE: Investigate the mechanical properties of callus in tibial fractures treated with external fixation. In particular any time-dependent or non-linear characteristics. DESIGN: A clinical-based investigative study. BACKGROUND: A fracture bending stiffness in the sagittal plane of 15 N m/deg. has been stated as a satisfactory endpoint of clinical healing. However using this criterion in 76 previous tibial fractures, four continued to a malunion. METHODS: Fracture properties were measured in clinic. The fixator was removed for the tests and a specially designed system was used to measure displacement and load. Fracture stiffness was measured in different planes and at various loading rates. Passive stressing of the leg was performed whilst fracture displacement was recorded. A constant load was applied for a longer period to assess creep properties. RESULTS: Fracture stiffness was found to vary between different planes of measurement and on load rate. The visco-elastic characteristics of the callus changed with time. In early measurements, the callus absorbed a large proportion of energy when a load was applied. Later tests showed a progressive change with the callus absorbing less energy. This demonstrates that the properties of the callus changed with time, with the viscous element diminishing and the elastic element increasing. This sometimes occurred with no change in the measured fracture stiffness. CONCLUSIONS: Further investigation is needed, focusing on the visco-elastic properties of callus, to develop a more reliable method of determining clinical union. RELEVANCE: Improved understanding of the mechanical properties of callus could result in improved methods of measuring fracture healing.

Biomechanical Phenomena↗
PubMed2001

Nicotinic regulation of c-fos and osteopontin expression in human-derived osteoblast-like cells and human trabecular bone organ culture.

Long-term in vivo studies have highlighted smoking as a risk factor in postmenopausal osteoporosis, bone fracture incidence, and increased nonunion rates. In contrast, there are few data postulating the effects of smoking at the cellular level in human skeletal tissue. In this study, we present novel evidence demonstrating that the nicotinic receptor alpha4 subunit is present in human primary bone cells by using reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, we demonstrate direct cellular effects of nicotine on primary human bone cells and blockage of these effects with a nicotinic receptor antagonist, D-tubocurarine. Nicotine effects on cell proliferation were biphasic with toxic, antiproliferative effects at high levels of nicotine (>1 mmol/L) and stimulatory effects at very low levels (0.01-10 micromol/L) after 72 h. This nicotine-induced increase in cell proliferation was inhibited in a dose-dependent manner by the addition of D-tubocurarine. In addition, proliferation effects from low-level treatment correlated with an upregulation of expression of the AP-1 transcription factor, c-fos, within 1 h, which was blocked by incubation with D-tubocurarine. To determine in situ bone cell responses within their trabecular matrix, cores of human bone isolated from biopsies were perfused with 0.1 micromol/L nicotine for 24 h. Western analysis of proteins isolated from the cores highlighted an increase in osteopontin, a bone matrix protein implicated in regulating resorption, which was partially inhibited by the addition of D-tubocurarine. To conclude, our results suggest that nicotine has a direct effect on human bone cells in modulating proliferation, upregulation of the c-fos transcription factor, and the synthesis of the bone matrix protein, osteopontin.

Base Sequence↗
PubMed2001

A fracture movement monitoring system to aid in the assessment of fracture healing in humans.

This paper presents a new design for a device to monitor the motion of fracture fragments in diaphyseal tibial fractures. The device measures the motion that occurs at the fracture site when loaded by gait or by manipulation. It has undergone rigorous calibration and acceptance trials. The device has been used in ethically approved research clinics held at the North Staffordshire Hospital (40 patients). The paper presents a selection of results obtained using the new device. The results demonstrate several new ways of assessing fracture healing by examining fracture site motion. The following conclusions were drawn: 1. If fracture monitoring devices are to be attached to bone screws, it is essential to minimize bone screw errors. To do this, each patient must have similar bone screw lengths, orientations, alignment and siting. This is only achievable using a peroperative reduction device. 2. If fracture stiffness is to be used as a measure of fracture healing, load rate should be controlled; at the very least strain rate should be controlled. 3. It is imperative that fracture stiffness be measured in more than one plane by a biplanar device so that asymmetry may be accommodated. 4. Fracture stiffness, on its own, is probably not a sufficiently rigorous measure of healing end-point. The quantifiably viscoelastic properties of healing callus should be taken into account.

Bone Screws↗
PubMed2001

Fracture stiffness as a guide to the management of tibial fractures.

We have studied the progression of healing in 103 unstable fractures of the tibia. In 76 patients we removed the external fixator once the stiffness had reached 15 Nm/degrees in the sagittal plane. Deformity at the site of the fracture subsequently occurred in four patients. In a further 27, we measured stiffness in several planes and removed the fixator only when the stiffness reached 15 Nm/degrees in each. We found that stiffness in two orthogonal planes may differ widely (maximum difference 9.0 Nm/degrees, mean 4.1 Nm/degrees). There were no failures in the second group. We advocate that fracture stiffness be measured in two orthogonal planes when assessing tibial healing and suggest that values above 15 Nm/degrees in two planes give an indication that it is safe to remove the fixator.

Adolescent↗
PubMed2000

Selected contribution: regulatory pathways involved in mechanical induction of c-fos gene expression in bone cells.

The regulatory pathways involved in the rapid response of the AP-1 transcription factor, c-fos, to mechanical load in human primary osteoblast-like (HOB) cells and the human MG-63 bone cell line were investigated using a four-point bending model. HOB and MG-63 cells showed upregulation of c-fos expression on fibronectin and collagen type I substrates; however, MG-63 cells did not respond on laminin YIGSR substrates. Addition of cytochalasin D and Arg-Gly-Asp peptides during loading did not inhibit the response, whereas addition of beta(1)-integrin antibodies inhibited the load response. The role of Ca(2+) signaling has been demonstrated by blocking upregulation with addition of 2 mM EGTA, which chelates extracellular Ca(2+), and gadolinium (10 microM), which inhibits stretch-activated channels. Addition of the Ca(2+) ionophore A-23187 induced upregulation without loading; however, addition of nifedipine (10 microM), the L-type channel blocker, failed to prevent the load response. Inhibitors of downstream pathways indicated the involvement of protein kinase C. Our results demonstrate a key involvement of Ca(2+) signaling pathways and integrin binding in the c-fos response to mechanical strain.

Bone and Bones↗
PubMed2000

A device for improved reduction of tibial fractures treated with external fixation.

A widely used method of treatment for unstable tibial shaft fractures is unilateral external fixation. The majority of fixators act as three distinct devices: an intra-operative reduction device, a device to maintain fracture alignment during healing and an aid to healing by allowing movement at the fracture site. Conventional operative techniques require the surgeon to manipulate a number of degrees of freedom at once, making reduction of the fracture difficult, and results in the fixator being out of alignment with the long axis of the bone. An operative method has been developed that separates reduction and fixation. A dedicated device has been designed to improve the per-operative control of fracture fragments during fracture reduction. The device has been used in clinical trials for the reduction of 22 diaphyseal tibial fractures. Compared with previous operative techniques there has been a saving of 53 per cent in fracture reduction time and an overall saving of 10 per cent in operating time. Fracture alignment has been improved compared with reductions achieved with a fixator which potentially improves healing and lowers the rate of malunion. In each case the fixator has been applied in alignment with the bone, improving dynamization and reducing the likelihood of malunion due to fixator cam slippage.

Biomechanical Phenomena↗
PubMed2000

Vertical transtalar Steinmann pin fixation for unstable ankle fractures.

Ankle fractures are common injuries and can usually be managed by either cast immobilisation or open reduction and internal fixation. Occasionally, both of these methods are contra-indicated. In such cases, one solution is the use of a vertical transtalar Steinmann pin to stabilise the fracture. Over the last 7 years, we have managed 8 patients with severe ankle fractures using vertical transtalar Steinmann pin fixation. The median age of these patients was 76 years (range, 35-94 years). This method was used in two patients with open contaminated wounds, in 5 with atrophic and blistered skin, and in one following failure of internal fixation in a patient with atrophic skin. In all patients, a satisfactory reduction was achieved and maintained after removal of the pin. Although all patients began to develop osteo-arthritic changes secondary to their original fractures, no complications were directly attributable to the use of the pin. In unstable ankle fractures where damage and contamination of soft tissues would preclude internal fixation, we recommend the use of vertical transtalar Steinmann pin fixation.

Adult↗
PubMed1999

Standardisation of radiographic views of the fractured tibia.

Serial radiographs are difficult to compare when the position of the shin is not accurately controlled in rotation. We have designed a device which can be used easily by the radiographer to produce accurately standardised radiographs of the tibia.

Equipment Design↗
PubMed1998

The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure.

OBJECTIVES: We sought to identify the effects of endothelin (ET) subtype-A (ET(A))) receptor blockade during the development of congestive heart failure (CHF) on left ventricle (LV) function and contractility. BACKGROUND: Congested heart failure causes increased plasma levels of ET and ET(A) receptor activation. METHODS: Yorkshire pigs were assigned to four groups: 1) CHF: 240 beats/min for 3 weeks; n=7; 2) CHF/ET(A)-High Dose: paced for 2 weeks then ET(A) receptor blockade (BMS 193884, 50 mg/kg, b.i.d.) for the last week of pacing; n=6; 3) CHF/ET(A)-Low Dose: pacing for 2 weeks then ET(A) receptor blockade (BMS 193884, 12.5 mg/kg, b.i.d.) for the last week, n=6; and 4) CONTROL: n=8. RESULTS: Left ventricle fractional shortening decreased with CHF compared with control (12+/-1 vs. 39+/-1%, p < 0.05) and increased in the CHF/ET(A) High and Low Dose groups (23+/-3 and 25+/-1%, p < 0.05). The LV peak wall stress and wall force increased approximately twofold with CHF and remained increased with ET(A) receptor blockade. With CHF, systemic vascular resistance increased by 120%, was normalized in the CHF/ET(A) High Dose group, and fell by 43% from CHF values in the Low Dose group (p < 0.05). Plasma catecholamines increased fourfold in the CHF group and were reduced by 48% in both CHF/ET(A) blockade groups. The LV myocyte velocity of shortening was reduced with CHF (32+/-3 vs. 54+/-3 microm/s, p < 0.05), was higher in the CHF/ET(A) High Dose group (39+/-1 microm/s, p < 0.05), and was similar to CHF values in the Low Dose group. CONCLUSIONS: ET(A) receptor activation may contribute to the progression of LV dysfunction with CHF.

Animals↗
PubMed1997

Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure: II. Effects on myocyte contractile processes.

BACKGROUND: The goal of this study was to determine the effects of ACE inhibition alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade in a model of congestive heart failure (CHF) on isolated LV myocyte function and fundamental components of the excitation-contraction coupling process. METHODS AND RESULTS: Pigs were randomly assigned to one of five groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant ACEI (benazeprilat, 0.187 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (3) concomitant AT1 Ang II receptor blockade (valsartan, 3 mg/kg/d) and rapid pacing (n=9), (4) concomitant ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg x kg(-1) x d(-1)) and rapid pacing (n=9), and (5) sham controls (n=10). LV myocyte shortening velocity was reduced with chronic rapid pacing compared with control (27.2+/-0.6 versus 58.6+/-1.2 microm/s, P<.05) and remained reduced with AT1 Ang II receptor blockade and rapid pacing (28.0+/-0.5 microm/s, P<.05). Myocyte shortening velocity increased with ACEI or combination treatment compared with rapid pacing only (36.9+/-0.7 and 42.3+/-0.8 microm/s, respectively, P<.05). Myocyte beta-adrenergic response was reduced by >50% in both the rapid pacing group and the AT1 Ang II blockade group and improved by 25% with ACEI and increased by 54% with combined treatment. Both L-type Ca2+ channel density and the relative abundance of sarcoplasmic reticulum Ca2+ ATPase density were reduced with rapid pacing and returned to control levels in the combined ACEI and AT1 Ang II blockade group. CONCLUSIONS: The unique findings of this study were twofold. First, basic defects in specific components of the myocyte excitation-contraction coupling process that occur with CHF are reversible. Second, combined ACEI and AT1 Ang II blockade may provide unique benefits on myocyte contractile processes in the setting of CHF.

Analysis of Variance↗
PubMed1997

Pulmonary hemodynamics and endothelin levels in pacing-induced heart failure: during rest and exercise.

Elevated plasma levels of endothelin (ET) have been reported to accompany the development of heart failure (HF), and therefore, this potent vasoconstrictive peptide has been postulated to contribute to the altered pulmonary hemodynamics that occur in this disease process. The overall goal of this study was to examine more carefully the relationship between ET levels in the pulmonary system and pulmonary hemodynamics in the normal and HF states, during both rest and exercise. This study used a porcine model of chronic rapid pacing that has been shown in previous studies to produce left ventricular dysfunction and neurohormonal system activation consistent with the syndrome of HF. Pigs (n = 10) were chronically instrumented to measure pulmonary and systemic hemodynamics, parenchymal flow, and ET content and to obtain blood samples from the pulmonary circuit in the conscious state. Measurements were performed in the normal control state and again following the development of pacing-induced HF (240 beats/min per 21 days), both at rest and during treadmill exercise (3 mph, 15 degrees incline, 12 minutes). With HF, under ambient resting conditions, a threefold increase in pulmonary plasma ET occurred and was accompanied by a fivefold increase in pulmonary vascular resistance. During treadmill exercise, pulmonary plasma ET and pulmonary vascular resistance remained elevated in the HF group when compared with the normal state and were associated with a sixfold decrease in pulmonary parenchymal flow. Pulmonary parenchymal ET content was increased with HF when compared with values for normal control subjects (8.5 +/- 0.6 vs 5.6 +/- 0.8 fmol ET/mg protein, P < .05). Thus, the findings of this study suggest that in this model of HF, increased ET within the pulmonary circuit contributed to abnormalities in resistive properties and parenchymal flow.

Animals↗
PubMed1997

A data-logging system to monitor bone fracture movement continuously.

A compact system is presented, which can continuously monitor the occurrence of fracture site movement in patients with tibial shaft fractures treated with an Orthofix external fixator allowing limited axial movement. The system comprises a microswitch and data logger board, which are both attached to the fixator. Each time the switch is closed by the movement of the fixator, the data logger records it as an event. The number of events per half hour is stored to the board's memory. The data logger can record the frequency of movement for at least a four-week period, at which time, the data can be transferred to a computer via a serial link. The system has been proven in a limited patient trial. The results highlight the variation in patient mobility. The significance of continuously monitoring the fracture site movement during the healing period is discussed.

Biomedical Engineering↗
PubMed1996

Exogenous effects and endogenous production of endothelin in cardiac myocytes: potential significance in heart failure.

Increased plasma concentrations of endothelin have been identified in patients and animals with severe congestive heart failure (CHF). However, whether and to what extent increased endothelin (ET) concentrations influence left ventricular (LV) myocyte contractility, ET-receptor subtype density, and endogenous ET production with the development of CHF remains unclear. Accordingly, myocyte contractile function, response to ET, sarcolemmal ET-receptor density, and myocyte ET production were examined in pigs following the development of pacing-induced CHF (240 beats/min, 3 wk, n = 8) and in controls (n = 8). With CHF, plasma ET increased over threefold. In the presence of ET (10-500 pM), myocyte contractility increased in a dose-dependent manner in control myocytes but decreased in CHF myocytes. For example, in the presence of 200 pM ET, velocity of shortening increased by 32.8 +/- 2.3 microns/s in controls but decreased by 8.3 +/- 2.2 microns/s with CHF. LV sarcolemmal ET-receptor density was primarily of the ETA-receptor subtype in controls (96 +/- 1.0%) and was unchanged with CHF. In quiescent myocyte preparations, control myocytes secreted ET (2.29 +/- 0.45 amol.cell-1.h-1), which was similar in CHF myocytes. These findings suggest that the production of ET may have important and potentially differential effects on contractile function with the development of CHF.

Animals↗
PubMed1995

Reduction of post-traumatic osteoporosis after external fixation of tibial fractures.

Disuse osteoporosis following tibial fractures is associated with pain and prolonged rehabilitation. In a prospective study, 22 patients with stable tibial fractures treated in plaster of Paris were compared with 15 patients in whom unstable tibial fractures were treated by external fixation. All patients were allowed to bear full weight from the day after the injury. The patients treated with plaster of Paris had the less severe fractures but still had a greater number of the higher grades of osteoporosis. We found a significantly lower degree of osteoporosis in the external fixator group. A comparison of the median percentage bearing weight in the two groups of patients showed greater percentage bearing weight in the external fixator group at four and eight weeks after the injury. We suggest that the reduction of post-traumatic osteoporosis is due to improved early function and weight bearing in patients treated by external fixation.

Adolescent↗