Biomedical subjects

Michael A Adams

Publications and source records attributed to Michael A Adams.

33 records · Page 2Linked to original sources

PubMed2004

Cyclic loading can denature type II collagen in articular cartilage.

We sought to explain previously reported associations between osteoarthritis, cartilage collagen denaturation, and repetitive mechanical loading. Eighty specimens of cartilage-on-bone were obtained from bovine patella grooves. After soaking in protease inhibitors, specimens were subjected to 3,600 cycles of compressive loading by means of a flat indenter. Loaded cartilage was supported by adjacent cartilage and subchondral bone. Peak stress ranged between 3.5 MPa and 14 MPa. Collagen denaturation was assessed by an inhibition ELISA assay using the col2-3/4 m antibody. Results showed that denaturation increased with loading severity, from 2% in control (unloaded) cartilage to 7.5% at 14 MPa (p < .0003). Collagen and glycosaminoglycan content of cartilage were unchanged after loading. Denaturation was largely unaffected by the absence of protease inhibitors or when chondrocytes were killed by repeated freeze-thaw cycles prior to loading. We conclude that vigorous cyclic mechanical loading causes an immediate dose-related increase in collagen denaturation in bovine articular cartilage.

Animals↗

PubMed2004

Depot local anesthetic in polymethylmethacrylate bone cement: a preliminary study.

Acrylic bone cement has been used successfully as a slow-release depot for antibiotics after orthopaedic surgery. The feasibility of administering local anesthetics in this way was examined in this preliminary in vitro study. Discs weighing approximately 4 g were prepared from five brands of acrylic cement (40 g) containing as much as 2 g of anesthetic base. Elution of the anesthetics into saline was measured during 72 hours. Prilocaine eluted the fastest and bupivacaine the slowest, with lidocaine between them. The elution rates were greatest in the first hour, declining thereafter. Rates also depended on the brand of cement with the quickest elution from CMW3 and the slowest from Surgical Simplex P. Using cement as a depot, therapeutic levels of a drug should be achievable in vivo at a negligible risk of toxicity. Before in vivo trials it is necessary to optimize elution of drugs in relation to the cement (brand, microstructure, method of preparation) and the concentration of a drug in the cement above which the cements' mechanical and adhesive properties are compromised.

Anesthetics, Local↗

PubMed2004

Biomechanics of back pain.

This paper offers a mechanistic account of back pain which attempts to incorporate all of the most important recent advances in spinal research. Anatomical and pain-provocation studies show that severe and chronic back pain most often originates in the lumbar intervertebral discs, the apophyseal joints, and the sacroiliac joints. Psychosocial factors influence many aspects of back pain behaviour but they are not important determinants of who will experience back pain in the first place. Back pain is closely (but not invariably) associated with structural pathology such as intervertebral disc prolapse and endplate fractures, although age-related biochemical changes such as those revealed by a 'dark disc' on MRI have little clinical relevance. All features of structural pathology (including disc prolapse) can be re-created in cadaveric specimens by severe or repetitive mechanical loading, with a combination of bending and compression being particularly harmful to the spine. Structural disruption alters the mechanical environment of disc cells in a manner that leads to cell-mediated degenerative changes, and animal experiments confirm that surgical disruption of a disc is followed by widespread disc degeneration. Some people are more vulnerable to spinal degeneration than others, largely because of their genetic inheritance. Age-related biochemical changes and loading history can also affect tissue vulnerability. Finally the concept of 'functional pathology' is introduced, according to which, back pain can arise because postural habits generate painful stress concentrations within innervated tissues, even though the stresses are not high enough to cause physical disruption.

Biomechanical Phenomena↗

PubMed2004

Priapism.

Explore the source record for details and available documents.

Adult↗

PubMed2003

Transplantation of enalapril-treated kidneys confers persistent lowering of arterial pressure in SHR.

The kidney plays a critical role in regulating the level of arterial pressure and in the pathogenesis of hypertension. Important evidence has come from studies in which hypertension is generated by transplanting kidneys from genetically hypertensive rats into normotensive recipients, suggesting that the level of blood pressure is strongly influenced by the genetic background of the kidney. We hypothesized that pharmacotherapy could modify specific properties intrinsic to the kidney such that after transplantation, there would be persistent changes in the level of arterial pressure. We determined that angiotensin-converting enzyme inhibitor treatment (enalapril) in spontaneously hypertensive rats induced both a persistent 17% reduction of mean arterial pressure and a persistent change in the kidney. This persistent change in the circulation could be completely transferred to untreated spontaneously hypertensive rats by kidney transplantation; ie, mean arterial pressure in untreated spontaneously hypertensive rat recipients was persistently lowered after transplantation of a kidney from a previously treated spontaneously hypertensive rat donor. In addition, the persistent lowering of mean arterial pressure after enalapril treatment could be completely abolished by implanting an untreated kidney, thereby revealing the importance of the kidney-specific changes. Furthermore, after within-group transplantations, there were no changes in the level of arterial pressure; ie, a 16% difference in mean arterial pressure remained between the 2 groups. The findings revealed that drug-induced changes specific to the kidney determined the level of arterial pressure, thereby suggesting the kidney should be a key therapeutic target for pharmacotherapy.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2003

Time course of vascular structural changes during and after short-term antihypertensive treatment.

The present study characterized the persistent changes (ie, off-treatment) resulting from short-term antihypertensive treatments on mean arterial pressure (MAP) and structurally based vascular resistance. Rats were treated for 14 days with enalapril (30 mg x kg(-1) x d(-1)) with regular (ENAL, 0.4%) or low salt (ELS, 0.04%) diets, or a triple therapy (Triple: hydralazine 45 mg x kg(-1) x d(-1), hydrochlorothiazide 100 mg/L, and nifedipine 200 mg/d). MAP was continuously recorded via radiotelemetry. Structurally based hindlimb vascular resistance properties (resistance at maximum dilation [Max Dil]; resistance at maximum constriction [Max Con]) were assessed after 14-day enalapril treatment and 2 to 3 weeks after all drugs were withdrawn. Aortic urokinase plasminogen activator (uPA) activity was measured by zymography after 14 days of ELS. All treatments induced a significant, persistent decrease in the off-treatment MAP (ENAL downward arrow 12+/-4.6%, ELS downward arrow 16+/-2.6%, Triple downward arrow 5+/-4.17%). During treatment (14 days) the enalapril group had significant changes in the index of medial bulk (Max Con downward arrow 15+/-2.6%), but only minimal changes in lumen properties (Max Dil downward arrow 3+/-6.5%, NS). After stopping therapy, vascular properties at Max Dil were significantly decreased only in the 2 enalapril groups (ENAL downward arrow 15+/-7.9%, P<0.05; ELS downward arrow 9+/-6.0%, P<0.05; Triple downward arrow 2+/-9.8%, NS), whereas Max Con was significantly decreased in all groups (ENAL downward arrow 12+/-8.0%, ELS downward arrow 16+/-6.1%, Triple downward arrow 7+/-5.4%). At 14 days of ELS treatment, there was increased aortic uPA activity (1.6-fold). The findings reveal that various short-term antihypertensive treatments can produce persistent long-term changes in MAP and vascular structure. Further, the magnitude of the depressor response may be as important in inducing persistent changes as is the removal of angiotensin II.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2003

Propagation of surface fissures in articular cartilage in response to cyclic loading in vitro.

BACKGROUND: Mechanical overloading of synovial joints can damage the articular cartilage surface and may lead to osteoarthritis. However, causal links between mechanical and biological events in cartilage are poorly understood. OBJECTIVES: To test the hypothesis that surface fissures in cartilage can propagate mechanically if the joint surface is subjected to vigorous cyclic loading. METHODS: Thirty-five cartilage-on-bone specimens, 15-mm square, were removed from mature bovine knee and shoulder joints. Specimens were loaded by means of a 9-mm-diameter flat indenter with a beveled edge, and their compressive strength determined. Failure occurred in the cartilage surface at an average stress of 36 MPa. Cartilage fissures were marked with Indian ink, photographed, and their length and width measured using image analysis software. Each damaged specimen was subjected to cyclic loading at 40% of its compressive strength, at 0.5 Hz, for up to 5 h. Fissure length and width were measured at regular intervals. After testing, fissure depth was measured from histological sections, and compared with measurements from damaged cartilage which was not cyclically loaded. RESULTS: Cyclic loading caused cartilage fissures to increase in length (mean 353%, P<0.01) and width (360%, P<0.01) but not depth. Propagation was rapid at first, but approached equilibrium after several hundred cycles. Rehydration in saline had no effect on fissure length, but width returned to pre-cyclic loading values. CONCLUSION: Cartilage fissures can propagate mechanically when a joint surface is subjected to cyclic compressive loading in vitro. The transient opening-up of fissures to form wide surface "wounds" during cyclic loading could be of biological significance if it occurred in living people. RELEVANCE: In living joints, wide open fissures in the cartilage surface could promote degenerative changes in the tissue.

Animals↗

PubMed2003

Expression of the translational repressor NAT1 in experimental models of cardiac hypertrophy.

The development of hypertension-induced cardiac hypertrophy is a complex process involving a number of biochemical pathways. In particular, the translation initiation pathway has been postulated to play an important role in controlling cellular growth and proliferation in the cardiovascular system. Recently, a fundamental translational repressor, NAT1 (novel APOBEC target 1), has been identified. We have previously shown that NATI is developmentally-regulated in the heart of neonatal rats and its expression correlates with periods of rapid cardiac growth. The present investigation was designed to determine whether the expression of NAT1 is modified in the left ventricle of spontaneously hypertensive rats and 2-kidney-1-clip (2K1C) hypertensive rats. Northern blot analysis revealed an increase in NAT1 mRNA expression which correlates with the onset of cardiac hypertrophy. Unlike its pattern of mRNA expression, however, NAT1 protein level did not differ significantly from their respective controls throughout the time course. Interestingly, several protein species ranging in size from approximately 40-70 kDa were detected by Western blotting, in addition to the full length 97 kDa NAT1. Since the NAT1 transcript is a known substrate for the enzyme APOBEC-1 and possibly APOBEC-2, we speculate that these proteins may represent truncated fragments of NAT1 resulting from the formation of premature translation termination codons along the NAT1 transcript by APOBEC editing. Together, these results show that the ventricular expression of NAT1 is regulated at the transcriptional level during the early stages of genetic and 2K1C-induced hypertension and may be involved in the onset of left ventricular hypertrophy.

Acetyltransferases↗

PubMed2003

Persistent lowering of arterial pressure after continuous and intermittent therapy.

OBJECTIVE: The present study investigates the impact of antihypertensive treatment on persistent reduction of arterial pressure after cessation of drug treatment. DESIGN AND METHODS: Specifically, adult spontaneously hypertensive rats (SHR) were treated for 6 weeks with inhibitors of the renin-angiotensin system (RAS), or combination therapy (hydralazine, nifedipine, hydrochlorothiazide) and following a 14-week 'drug holiday', were re-treated for 4 weeks. Mean arterial pressure (MAP) was continuously monitored via radiotelemetry. RESULTS: Comparison in the first off-treatment period revealed that RAS inhibitor drugs produced a 16-18% persistent lowering of arterial pressure, whereas the triple therapy induced a 10% lowering of MAP relative to untreated SHR. The drug re-challenge induced a further 9% reduction in the 'off'-treatment level of MAP such that in all treatment groups MAP was reduced by more than 30 mmHg compared with controls. CONCLUSIONS: This study provides new evidence that combination therapy, not directly targeting the RAS, can be efficacious in persistently reducing MAP off-treatment. Furthermore, we demonstrated that the 6-week treatment with RAS inhibitors induced equivalent persistent changes as a 10-week treatment. That is, the additional 4 weeks of continuous therapy was ineffective in further altering the off-treatment MAP. In contrast, with the intermittent treatment protocol (the 14-week 'drug holiday') a further effect on persistent lowering of MAP was regained. These findings suggest continuous long-term treatment with antihypertensive drugs may not be the most effective means of reversing underlying circulatory abnormalities and that the introduction of a drug holiday may be beneficial.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2003

Hypoxia induced resistance to doxorubicin in prostate cancer cells is inhibited by low concentrations of glyceryl trinitrate.

PURPOSE: Tumor hypoxia has been correlated with metastasis and resistance to chemotherapy. Hypoxia is also associated with human prostate cancers, which are highly resistant to chemotherapy. We hypothesized that hypoxia contributes to chemoresistance in prostate cancer cells and this hypoxia induced chemoresistance can be inhibited by low concentrations of nitric oxide (NO) mimetics. MATERIALS AND METHODS: Human PC-3 and mouse TRAMP-C2 prostatic adenocarcinoma cells were incubated in 20% or 0.5% O(2) for 12 hours with or without glyceryl trinitrate (GTN) (0.1 nM). This treatment was followed by a 1-hour incubation with doxorubicin and survival was assessed by clonogenic assays. Western blot analysis was used to measure NO synthase levels. The effect of hypoxia and GTN on cell cycle distribution was determined by flow cytometry. RESULTS: Hypoxic pre-incubation of the 2 cell lines resulted in increased survival following exposure to doxorubicin. Co-incubation of PC-3 and TRAMP-C2 cells with GTN (0.1 nM) inhibited the hypoxia induced resistance to doxorubicin. Each cell line expressed all 3 NO synthase isoforms at levels that were not significantly affected by O(2) concentrations. Cell cycle analysis revealed that there was no significant difference in the distribution of PC-3 cells at each stage of the cycle. However, incubation under hypoxia resulted in a small decrease in the number of TRAMP-C2 cells in S-phase. CONCLUSIONS: These findings indicate that NO may have an important role in the regulation of chemosensitivity in prostate cancer cells. Furthermore, the results suggest that GTN administration may represent a means of chemosensitizing prostatic carcinomas.

Adenocarcinoma↗

PubMed2002

Oxygen-mediated regulation of tumor cell invasiveness. Involvement of a nitric oxide signaling pathway.

Tumor hypoxia is associated with a poor prognosis for patients with various cancers, often resulting in an increase in metastasis. Moreover, exposure to hypoxia increases the ability of breast carcinoma cells to invade the extracellular matrix, an important aspect of metastasis. Here, we demonstrate that the hypoxic up-regulation of invasiveness is linked to reduced nitric oxide signaling. Incubation of human breast carcinoma cells in 0.5% versus 20% oxygen increased their in vitro invasiveness and their expression of the urokinase receptor, an invasion-associated molecule. These effects of hypoxia were inhibited by nitric oxide-mimetic drugs; and in a manner similar to hypoxia, pharmacological inhibition of nitric oxide synthesis increased urokinase receptor expression. The nitric oxide signaling pathway involves activation of soluble guanylyl cyclase (sGC) and the subsequent activation of protein kinase G (PKG). Culture of tumor cells under hypoxic conditions (0.5% versus 20% oxygen) resulted in lower cGMP levels, an effect that could be prevented by incubation with glyceryl trinitrate. Inhibition of sGC activity with a selective blocker or with the heme biosynthesis inhibitor desferrioxamine increased urokinase receptor expression. These compounds also prevented the glyceryl trinitrate-mediated suppression of urokinase receptor expression in cells incubated under hypoxic conditions. In contrast, direct activation of PKG using 8-bromo-cGMP prevented the hypoxia- and desferrioxamine-induced increases in urokinase receptor expression as well as the hypoxia-mediated enhanced invasiveness. Further involvement of PKG in the regulation of invasion-associated phenotypes was established using a selective PKG inhibitor, which alone increased urokinase receptor expression. These findings reveal that an important mechanism by which hypoxia increases tumor cell invasiveness (and possibly metastasis) requires inhibition of the nitric oxide signaling pathway involving sGC and PKG activation.

Cyclic GMP↗

PubMed2002

Oxygen as a regulator of cellular phenotypes in pregnancy and cancer.

Cellular phenotype is determined by genetic and microenvironmental factors. There is evidence that tissue oxygenation status is one of the microenvironmental factors regulating cellular behaviour. Both normal and pathological processes such as blastocyst implantation in the uterus, placentation, and rapidly growing tumours occur under conditions characterized by relatively low oxygen levels. In this review, we address the effects of low oxygen concentrations on the phenotype of trophoblast and cancer cells. We provide evidence that oxygenation levels play an important role in the regulation of normal and pathological cellular invasiveness as it occurs during trophoblast invasion of the uterus and in tumour progression and metastasis, drug resistance in cancer, and antitumour activity of natural killer cells of the immune system.

Disease Progression↗

PubMed2002

Effect of in vivo nitrate tolerance on hypersensitivity to NO donors after NO-synthase blockade.

Animals treated with nitric oxide synthase (NOS) inhibitors exhibit marked hypersensitivity to the blood pressure lowering effects of exogenous nitric oxide (NO) donors. We used this model as a sensitive index to evaluate the relative importance of reduced biotransformation of glyceryl trinitrate (GTN) to NO in the development of nitrate tolerance. NOS-blockade hypertension using N(G)-nitro-L-arginine methyl ester (L-NAME) caused a marked enhancement of the mean arterial pressure (MAP) decrease mediated by GTN in nontolerant rats. However, even large doses of GTN were unable to change the MAP in GTN-tolerant, NOS-blockade hypertensive animals. In contrast, the MAP responses to the spontaneous NO donor sodium nitroprusside (SNP) were completely unaltered in either tolerant rats or tolerant NOS-blockade hypertensive animals, indicating that NO-dependent vasodilatory mechanisms remain intact despite the development of GTN tolerance. The MAP-lowering effects of GTN in NOS-blockade hypertensive animals were restored 48 h after cessation of chronic GTN exposure. These alterations in the pharmacodynamic response to GTN during tolerance development and reversal were associated with parallel changes in the pattern of GTN metabolite formation, suggesting that the activity of one or more enzymes involved in nitrate metabolism was altered as a consequence of chronic GTN exposure. These findings suggest that the vasodilation resulting from the vascular biotransformation of GTN to NO (or a closely related species) is severely compromised in nitrate-tolerant animals, and that although other mechanisms may contribute to the vascular changes observed following the development of GTN tolerance, decreased GTN bioactivation is likely the most important.

Animals↗

PubMedDate not supplied

Causes of erectile dysfunction.

Erectile dysfunction (ED) arises as a result of a collision of circumstances among any of a number of factors (e.g., risk factors, causes, probable associations), each with its own primary power to affect the outcome. Furthermore, each of the components has its own timing as part of a complex effort of compensation and adjustment that often obscures the individual details. In the end, ED results from a failure of local tissues or systemic supply and control structures. The power of any individual "cause" to degrade erectile function is an important but as-yet unquantified property. The power of a small abnormality over a long or critical period (e.g., organogenesis), or many small contributions, or multiple risk factors will certainly be greater than the sum of the individual elements. Without a full quantitation of pathways and their potential influence, one can compare the importance of causative factors only in limited ways. Not surprisingly, it is the presence of a multiplicity of unidentified or poorly understood causative factors that accounts in large measure for the current inability to cure and prevent ED. There are two other important properties of a putatively causative factor for ED--reversibility and preventability--and these are strongly influenced by the time of onset and the duration of impact. Thus, a critical understanding that comes from recognizing the importance of the temporal associations of component factors is that the causes of ED in an individual may be guessed at but cannot be fully disclosed by an analysis of a "snapshot" of the disease taken at the time of diagnosis.

Erectile Dysfunction↗

PubMedDate not supplied

The mechanical environment of chondrocytes in articular cartilage.

There is a growing literature concerning chondrocyte responses to mechanical loading, but relatively little is known about the mechanical environment these cells experience in a living joint. Calculations indicate that high forces are applied to limb joints whenever the joints are flexed, because flexion can cause body weight to act on long lever arms compared to the joint centre, whereas the muscles which extend the joint act on much shorter lever arms. As a result, joint reaction forces (which compress the cartilage) can rise to 3-6 times body weight during activities such as stair climbing. Articular cartilage tends to spread this load evenly over the joint surface, but is too thin to do this well, and compressive stresses can rise to 10-20 MPa. Within cartilage, matrix stresses vary locally, possibly as a result of variation in composition or undulations in the subchondral bone, and further modifications of stress occur within each chondron. Articular cartilage is a fibrous solid and cells within it are deformed by mechanical loading rather than subjected to a hydrostatic pressure. The mechanical environment of chondrocytes can best be reproduced in vitro by direct compression of the articular surface of cartilage which is supported naturally by adjacent cartilage and subchondral bone.

Cartilage, Articular↗