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Biomedical subjects

A M Malek

Publications and source records attributed to A M Malek.

17 recordsLinked to original sources
PubMed1998

Mannitol at clinical concentrations activates multiple signaling pathways and induces apoptosis in endothelial cells.

BACKGROUND AND PURPOSE: Hyperosmotic mannitol therapy is widely used in the clinical setting for acute and subacute reduction in brain edema, to decrease muscle damage in compartment syndrome, and to improve renal perfusion. Though beneficial rheological effects commonly are attributed to mannitol, its direct effects on endothelial cells are poorly understood. METHODS: We studied the effect of hypertonic and hypotonic stress on bovine aortic endothelial (BAE) cells, using mannitol, urea, and sodium chloride and medium dilution in vitro. RESULTS: Exposure to incremental osmolar concentrations of 300 mOsm of each osmotic agent increased apoptosis in BAE cells (mannitol congruent withNaCl>urea). Induced programmed cell death was detected by DAPI staining of intact cell nuclei, and by TUNEL and DNA fragmentation ladder assays. Mannitol-induced apoptosis exhibited dose dependence (42% of cells at 300 mOsm [P<0.0001] compared with 1.2% of control cells) and was also observed in bovine smooth muscle cells. Mannitol-induced apoptosis was attenuated approximately 50% in the presence of cycloheximide or actinomycin D. Hypertonic mannitol and NaCl, but not urea, increased tyrosine phosphorylation of the focal adhesion contact-associated proteins paxillin and FAK. Hypotonic medium, which did not lead to apoptosis, increased protein tyrosine phosphorylation of FAK but not of paxillin. Addition of mannitol or NaCl also produced sustained increases in c-Jun NH2-terminal kinase (JNK) activity. In addition, hypertonic mannitol increased intracellular free [Ca2+] in a dose-dependent manner. Chelation of intracellular Ca2+ with quin2-AM (10 micromol/L) inhibited mannitol-induced apoptosis approximately 50%, as to a lesser extent did inhibition of tyrosine kinase activity with herbimycin (1 micromol/L). CONCLUSIONS: We have shown that hypertonic mannitol exposure induces endothelial cell apoptosis, accompanied by activation of tyrosine and stress kinases, phosphorylation of FAK and paxillin, and elevation of intracellular free [Ca2+]. The apoptosis is attenuated by inhibition of transcription or translation, by inhibition of tyrosine kinases, or by intracellular Ca2+ buffering. These data suggest that clinical use of the osmotic diuretic mannitol may exert direct deleterious effects on vascular endothelium.

Animals↗
PubMed1998

Diagnosis and treatment of dural arteriovenous fistulas.

Dural arteriovenous fistulas (DAVFs) are abnormal vascular connections located within the dura mater which are thought to be promoted by venous hypertension and venous sinus thrombosis. The symptoms associated with DAVFs depend on the direction and adequacy of venous drainage pathways, the amount of arteriovenous shunting and specific location of the fistula. Our experience over a period of eight years with 268 patients suffering from cranial DAVFs in the transverse, sigmoid, superior sagittal, ethmoidal, inferior and superior petrosal, cavernous, and marginal sinuses are presented. The clinical presentation, radiographic evaluation, and treatment modalities for DAVFs in each of these locations are summarized.

Angiography↗
PubMed1997

Cervical spine fractures in the elderly.

BACKGROUND: Cervical spine fractures in the elderly are relatively common. The management of such injuries may be complicated by underlying medical debility and osteopenia as well as reduced tolerance to halo immobilization. METHODS: Over a 1-year period, 43 cervical spine fractures were treated at our institution. Ten (23%) were in persons 70 years of age or older. This retrospective analysis describe the clinical features, treatment, and outcome of these 10 elderly patients. All fractures in this patient population involved the atlantoaxial complex, including five combination C1-C2 fractures. Six patients were treated with early halo immobilization and three were initially managed with a rigid cervical collar. Three patients required posterior cervical fusion. RESULTS: Of the six patients undergoing halo immobilization, five progressed to osseous union. Three patients were immobilized in a Philadelphia collar resulting in one osseous union, one nonunion, and one death. Three patients underwent posterior cervical fusion with subsequent osseous union in all three. CONCLUSIONS: Although external immobilization with a halo device is our treatment of choice for most C1 and C2 fractures in elderly patients, a Philadelphia collar is useful in select cases when halo immobilization or early surgical fusion is contraindicated. Posterior cervical fusion can be safely and effectively performed in elderly patients and should be strongly considered for initial therapy in the elderly with fracture types unlikely to progress to osseous union with external immobilization alone.

Aged↗
PubMed1997

Solitary fibrous tumor presenting as a symptomatic intraspinal mass: case report.

OBJECTIVE AND IMPORTANCE: Mesenchymal, nonmeningeal tumors of the central and peripheral nervous systems are rare. Specifically, the solitary fibrous tumor, which occurs in both benign and malignant forms, was first described in the pleura and more recently in a number of sites, including the mediastinum, abdomen, upper respiratory tract, nasopharynx, and orbit. It has not, however, previously been known to involve the spine or to induce cord compression. CLINICAL PRESENTATION: We describe the case of a 33-year-old man who presented with back pain, progressive myelopathy, and lower extremity dysesthesias. Imaging studies demonstrated an intradural extramedullary mass at T7-T8. INTERVENTION: At surgery, the lesion was found to be firm, fibrous, intimately apposed to the T8 sensory nerve root but emanating from neither root nor dura. Histologically, the tumor was composed of spindle cells in a storiform pattern with extensive collagen deposition in the intercellular matrix. Immunohistochemistry showed diffuse positive staining of tumor cells for CD34 antigen but negative staining for S100 and EMA, a profile that is consistent with a histopathological diagnosis of solitary fibrous tumor and that effectively rules out meningioma and nerve sheath tumor. CONCLUSION: This is the first report of an intraspinal solitary fibrous tumor, a rare entity that should be included in the differential diagnosis of intradural extramedullary spinal neoplasms.

Adult↗
PubMed1997

Regulation of endothelin-1 gene expression by cell shape and the microfilament network in vascular endothelium.

Endothelial synthesis and release of endothelin-1 (ET-1) are exquisitely regulated by external shear and strain. We tested the hypothesis that manipulation of endothelial cell shape can regulate ET-1 gene expression. Treatment of bovine aortic endothelial cell (BAEC) monolayers with cytochalasin D disrupted F-actin and induced cell retraction and rounding, in parallel with time- and dose-dependent specific decreases in ET-1 mRNA levels. Treatments with forskolin, phorbol 12-myristate 13-acetate, staurosporine, and genistein also induced cell shape change and decreased F-actin staining and ET-1 mRNA levels. BAEC plated onto nonadhesive petri dishes coated with decreasing concentrations of synthetic RGD polymer showed RGD dose-dependent decreases in cell spreading and in F-actin microfilament elaboration. These changes were specifically accompanied by decreases in ET-1 peptide secretion (60%) and, via posttranscriptional mechanisms, ET-1 mRNA (94%) and were not due to decreased cell-cell contact. We conclude that the shape and microfilament network of endothelial cells are potent posttranscriptional regulators of ET-1 gene expression.

Actin Cytoskeleton↗
PubMed1997

Spontaneous rapid resolution of an epidural hematoma associated with an overlying skull fracture and subgaleal hematoma in a 17-month-old child.

Acute traumatic epidural hematomas (EDH) constitute one of the most critical emergencies in neurosurgical management. The rapid spontaneous resolution (<24 h) of EDH is an extremely rare phenomenon. A 17-month-old patient fell from a height of 1.5 m and presented with a 8-mm temporal EDH, an overlying linear skull fracture, and a subgaleal hematoma without evidence of intraparenchymal injury or edema. The patient complained only of mild headache, harbored no neurological deficits, and was, therefore, managed conservatively in the intensive care unit with provision to proceed to surgical decompression in the event of neurological change. A repeat CT study 18 h later revealed near-complete resolution of the EDH with a coincident increase in the volume and spread of the subgaleal hematoma. This is the fourth reported case of rapid spontaneously resolving EDH and the youngest one to date. All 4 cases have coincided with an overlying linear skull fracture. We propose that unlike classical EDH, rapidly resolving EDH in the absence of elevated intracranial pressure (ICP) originates from elevated interstitial pressure in the subgaleal compartment transiently decompressing into the epidural space through a skull fracture and resolving as the pressure in the subgaleal compartment decreases below ICP.

Compartment Syndromes↗
PubMed1997

Elevation of cerebrospinal fluid levels of basic fibroblast growth factor in moyamoya and central nervous system disorders.

Moyamoya syndrome is a vaso-occlusive disease involving the intracranial vessels of the circle of Willis which is accompanied by an intense compensatory recruitment of new vessels. Angiogenic substances such as basic fibroblast growth factor (bFGF) present in the cerebrospinal fluid (CSF) have been proposed as possible mediators of the neovascular response. We analyzed CSF samples collected intraoperatively from predominantly pediatric patients with moyamoya and other conditions such as Chiari malformation (Ch), tethered cord (TC), arteriovenous malformation (AVM), brain tumor (BT) and hydrocephalus (HCP). We found that CSF bFGF was significantly elevated in patients with moyamoya (141 pg/ml, n = 37), Ch (56.7 pg/ml, n = 22), TC (55.1 pg/ml, n = 23), AVM (354 pg/ml, n = 5), and BT (208 pg/ml, n = 5) compared to patients with HCP (5.5 pg/ml, n = 7) and controls (1.6 pg/ml, n = 25; p < 0.05). There was no dependence of CSF bFGF on patient age or gender. Although CSF bFGF in the moyamoya group showed no correlation with the Suzuki radiographic stage at either pre- or post-operative (1-year follow-up) angiography, it showed a trend with the Matsushima angiographic score with increasing collateral vascularization from the synangiosis developing at higher levels of CSF bFGF. Our findings suggest that CSF bFGF may be playing a wide-ranging role in a number of central nervous system conditions associated with ischemia and hypervascularity. Although not a specific marker for moyamoya, elevated CSF bFGF may serve as a weak predictor of the extent of angiogenesis to be expected in indirect revascularization procedures.

Adolescent↗
PubMed1997

Quantitative densitometric analysis using a commercially available handheld CCD digital camera.

We describe here a novel method that relies on a digital imaging device to perform densitometric quantitation of radiographs in the laboratory setting. Using fluorescent back-illumination and appropriate exposure settings, a commercially available handheld charge-coupled device (CCD) digital camera is used to acquire the image of the radiograph. Following acquisition, the image is downloaded by means of a serial interface to a personal computer. There, it is analyzed to ensure that the series of pixel intensities lie within the linear range and then quantitated using two-dimensional integration with local background substraction. Using a linear dot blot established with serial dilution of 32P and imaging with standard radiographic film, we found that images acquired using the handheld digital camera were comparable to those input with a desktop scanner in transmittance mode. Quantitative densitometric analysis showed similar linear results between the digital camera and the desktop scanner over the 16-fold linear response of the radiographic film, both of which were comparable to phosphor imaging over that limited range. These findings demonstrate that the ever-improving technology of handheld digital imaging should be added to the repertoire of techniques for quantitative densitometry.

Animals↗
PubMed1996

Mechanism of endothelial cell shape change and cytoskeletal remodeling in response to fluid shear stress.

Endothelium exposed to fluid shear stress (FSS) undergoes cell shape change, alignment and microfilament network remodeling in the direction of flow by an unknown mechanism. In this study we explore the role of tyrosine kinase (TK) activity, intracellular calcium ([Ca2+]i), mechanosensitive channels and cytoskeleton in the mechanism of cell shape change and actin stress fiber induction in bovine aortic endothelium (BAE). We report that FSS induces beta-actin mRNA in a time- and magnitude-dependent fashion. Treatment with quin2-AM to chelate intracellular calcium release and herbimycin A to inhibit TK activity abolished BAE shape change and actin stress fiber induction by FSS, while inhibition of protein kinase C with chelerythrine had no effect. Altering intermediate filament structure with acrylamide did not affect alignment or F-actin induction by FSS. Examining the role of the BAE cytoskeleton revealed a critical role for microtubules (MT). MT disruption with nocodazole blocked both FSS-induced morphological change and actin stress fiber induction. In contrast, MT hyperpolymerization with taxol attenuated the cell shape change but did not prevent actin stress fiber induction under flow. Mechanosensitive channels were found not to be involved in the FSS-induced shape change. Blocking the shear-activated current (IK.S) with barium and the stretch-activated cation channels (ISA) with gadolinium had no effect on the shear-induced changes in morphology and cytoskeleton. In summary, FSS has a profound effect on endothelial shape and F-actin network by a mechanism which depends on TK activity, intracellular calcium, and an intact microtubule network, but is independent of protein kinase C, intermediate filaments and shear- and stretch-activated mechanosensitive channels.

Acrylamide↗
PubMed1995

Control of endothelial cell gene expression by flow.

The vessel wall is constantly subjected to, and affected by, the stresses resulting from the hemodynamic stimuli of transmural pressure and flow. At the interface between blood and the vessel wall, the endothelial cell plays a crucial role in controlling vessel structure and function in response to changes in hemodynamic conditions. Using bovine aortic endothelium monolayers, we show that fluid shear stress causes simultaneous differential regulation of endothelial-derived products. We also report that the downregulation of endothelin-1 mRNA by flow is a reversible process, and through the use of uncharged dextran supplementation demonstrate it to be shear stress- rather than shear rate-dependent. Recent work on the effect of fluid shear stress on endothelial cell gene expression of a number of potent endothelial products is reviewed, including vasoactive substances, autocrine and paracrine growth factors, thrombosis/fibrinolysis modulators, chemotactic factors, surface receptors and immediate-early genes. The encountered patterns of gene expression responses are classified into three categories: a transient increase with return to baseline (type I), a sustained increase (type II) and a biphasic response consisting of an early transient increase of varying extent followed by a pronounced and sustained decrease (type III). The importance of the dynamic character of the flow stimulus and the magnitude dependence of the response are presented. Potential molecular mechanisms of shear-induced gene regulation, including putative shear stress response elements (SSRE), are discussed. These results suggest exquisite modulation of endothelial cell phenotype by local fluid shear stress and may offer insight into the mechanism of flow-dependent vascular remodeling and the observed propensity of atherosclerosis formation around bifurcations and areas of low shear stress.

Animals↗
PubMed1994

Endothelial expression of thrombomodulin is reversibly regulated by fluid shear stress.

The vascular endothelium, by virtue of its position at the interface between blood and the vessel wall, is known to play a critical role in the control of thrombosis and fibrinolysis. Thrombomodulin (TM) is a surface receptor that binds thrombin and is a potent activator of the protein C anticoagulant pathway. Although TM expression is known to be regulated by various cytokines, little is known about its response to ever-present biomechanical stimuli. We have explored the role of fluid shear stress, imparted on the luminal surface of the endothelial cell as a result of blood flow, on the expression of TM mRNA and protein in both bovine aortic endothelial (BAE) and bovine smooth muscle (BSM) cells in an in vitro system. We report in the present study that TM expression is regulated by flow. Subjecting BAE cells to fluid shear stress in the physiological range of magnitude of 15 (moderate shear stress) and 36 (elevated shear stress) dynes/cm2 resulted in a mild transient increase followed by a significant decrease in TM mRNA to 37% and 16% of its resting level, respectively, by 9 hours after the onset of flow. In contrast, shear stress at the low magnitude of 4 dynes/cm2 did not affect TM mRNA levels. The sensitivity of TM mRNA expression by flow was found to be specific to endothelium, since it was not observed in BSM cells exposed to steady laminar shear stress of 15 dynes/cm2. Furthermore, unlike BAE cells, BSM cells did not exhibit altered cell shape nor align in the direction of flow after 24 hours of shear stress at 15 dynes/cm2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Regulation of endothelin 1 gene by fluid shear stress is transcriptionally mediated and independent of protein kinase C and cAMP.

Fluid shear stress induces a number of morphological and functional changes in vascular endothelium, including a rapid and significant down-regulation of endothelin 1 (ET-1) mRNA and peptide release in bovine aortic endothelial cells. We show here that both the cell alignment and ET-1 down-regulation depend on on-going protein synthesis, and that the latter is the result of a decrease in transcription, as shown by nuclear run-off assay, and not the result of changes in ET-1 mRNA half-life. The treatment of endothelial cells with either phorbol 12-myristate 13-acetate (100 nM) to activate protein kinase C (PKC) or forskolin (10 microM) to stimulate adenylate cyclase sharply decreased ET-1 mRNA. However, the phorbol-induced ET-1 decrease was, unlike the shear-induced down-regulation, independent of active protein synthesis. Physiological shear stress (20 dynes/cm2) did not significantly activate PKC, as assessed by PKC translocation and enzymatic activity assay and failed to increase intracellular cAMP content. Furthermore treatment with calphostin C (1 microM) did not prevent the shear-induced down-regulation of ET-1. DNA transfection experiments suggest that the shear stress-responsive element of the ET-1 gene is contained in the sequence between -2.5 kb and -2.9 kb of the 5'-upstream region. Neither the transcription factor AP-1 binding site nor the GATA-2-factor binding site, necessary for the basal level of transcription of ET-1 gene, is sufficient to confer shear-responsiveness to the reporter gene. These results suggest that shear stress regulates the transcription of the ET-1 gene via an upstream cis element by a distinct mechanism not dependent on the PKC or cAMP pathways.

Animals↗
PubMed1993

Fluid shear stress differentially modulates expression of genes encoding basic fibroblast growth factor and platelet-derived growth factor B chain in vascular endothelium.

Fluid shear stress has been shown to be an important regulator of vascular structure and function through its effect on the endothelial cell. We have explored the effect of shear stress on the expression of the heparin-binding growth factors platelet-derived growth factor B chain (PDGF-B) and basic fibroblast growth factor (bFGF) in bovine aortic endothelial cells using a purpose-built cone-plate viscometer. Using morphometric analysis, we have mimicked the endothelial cell shape changes encountered in vivo in response to shear stress and correlated these with changes in gene expression. Steady laminar shear stress of 15 and 36 dyn/cm2 both resulted in endothelial cell shape change, but the higher shear stress induced greater and more uniform alignment in the direction of flow and nuclear protrusion after 24 h. Steady laminar shear stress of both 15 and 36 dyn/cm2 induced a significant 3.9- and 4.2-fold decrease, respectively, in PDGF-B mRNA at 9 h. In contrast, steady laminar shear of 15 dyn/cm2 induced a mild and transient 1.5-fold increase in bFGF mRNA while shear of 36 dyn/cm2 induced a significant 4.8-fold increase at 6 h of shear which remained at 2.9-fold at 9 h. Pulsatile and turbulent shear stress showed the same effect as steady laminar shear stress (all at 15 dyn/cm2 time-average magnitude) on PDGF-B and bFGF mRNA content. Cyclic stretch (20% strain, 20/min) of cells grown on silicone substrate did not significantly affect either PDGF-B or bFGF mRNA levels. These results suggest that expression of each peptide growth factor gene is differentially regulated by fluid shear stress in the vascular endothelial cell. These results may have implications on vascular structure and function in response to hemodynamic forces and present a model for the study of transduction of mechanical stimuli into altered gene expression.

Animals↗
PubMed1991

Clinically enhancing nursing practice. Improving feeding skills.

1. The aim of nurses assisting elders with eating is to maintain the resident's existing abilities or recover, as much as possible, lost abilities. 2. The findings of this study indicated that nurses did not understand the importance of sitting while feeding elderly residents. 3. More than one quarter (28%) of the nursing staff surveyed were unable to identify age-related changes that may increase the possibility of choking.

Activities of Daily Living↗
PubMed1989

Functional electrical stimulation of the latissimus dorsi muscle for use in cardiac assist.

Direct and nondirect nerve stimulation modes of the thoraco-dorsal nerve (TDN) leading to the latissimus dorsi muscle (LDM) were evaluated by using nerve cuff electrodes (NCE) and intramuscular electrodes (IME), respectively. Following electrode implantation, the LDM was chronically stimulated for two months to induce muscle transformation to oxidative, fatigue-resistant type I muscle fibers. Threshold and impedance values were measured regularly to establish the stability of the implants. The LDM was then dissected, shaped into a ventricle, subjected to a hydraulic load and stimulated using a controlled-voltage pulse-train stimulator with adjustable parameters. Electrical input and hydraulic output variables were measured to obtain the recruitment characteristics and to compare the efficiency of the two types of electrodes. Results indicate a tradeoff between the NCE's lower threshold, higher recruitment, and lower energy consumption at saturation, and the IME's greater mechanical stability and better long-term reproducibility.

Animals↗