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Biomedical subjects

M E Berger

Publications and source records attributed to M E Berger.

At least 19 recordsLinked to original sources
PubMed2006

Medical management of radiation injuries: current approaches.

The current approach to medical management of irradiated patients begins with early diagnosis of radiation injury. Medical assessment of radiation dose is based on event history, symptomatology and laboratory results, with emphasis on time to emesis and lymphocyte depletion kinetics. Dose assessment provides a basis for early use of haematopoietic growth factors that can shorten the period of neutropaenia for patients with acute radiation syndrome. Assessments of haematopoietic, gastrointestinal and cutaneous syndromes have improved in recent years, but treatment options remain limited. Selected examples of current developments are presented.

Accidents, Occupational↗
PubMed2001

Long-term fructose feeding impairs vascular relaxation in rat mesenteric arteries.

To investigate the long-term influence of insulin resistance and hyperinsulinemia on vascular reactivity, both muscarinic and alpha2-receptor-mediated relaxations and the contribution of nitric oxide to these mechanisms were studied in the fructose-fed rat. Male Sprague-Dawley rats were fed either fructose-rich chow (FFR, n = 6) or normal chow (CNT, n = 6) for 40 weeks. Systolic blood pressure was measured by tail-cuff method. A 3-mm segment of mesenteric artery was excised, cannulated and pressurized, pretreated with prazosin (10(-6) mol/L) and propranolol (3 x 10(-6) mol/L), then precontracted with serotonin (10(-6) mol/L). Endothelium dependent relaxation was induced by addition of acetylcholine (10(-9) to 10(-4) mol/L), or a selective alpha2-agonist B-HT 920 (10(-9) to 10(-5) mol/L), with or without the nitric oxide synthase inhibitor L-NAME (10(-4) mol/L). Systolic blood pressure was significantly higher in FFR at the early period; however, there was no difference at the end of 40 weeks compared to CNT. Fasting plasma insulin was much higher in FFR than in CNT (110+/-62 v 41+/-11 microU/mL, P < .05), whereas plasma glucose was not different. Maximum relaxation to acetylcholine was attained at 10(-6) mol/L in FFR but at 3 x 10(-7) mol/L in CNT. The degree of maximum relaxation attained with acetylcholine was similar in FFR and CNT (89+/-9 and 94+/-4% of precontraction), although attenuated (P < .01) by the addition of L-NAME only in FFR (to 34+/-22%, P < .05) but not in CNT (to 82+/-25%). The half-maximal relaxation dose of acetylcholine was greater in FFR (P < .01) compared with CNT and was significantly increased (P < .05) by L-NAME in both groups. B-HT 920 at 10(-5) mol/L induced a greater relaxation in CNT (36+/-10% of serotonin constriction) than in FFR (19+/-14%, P < .05). These responses were significantly blunted by L-NAME. Thus, muscarinic receptor-mediated vascular relaxation is less sensitive and more nitric oxide dependent in FFR versus CNT. Alpha2-adrenergic-mediated relaxation, predominantly mediated by nitric oxide, is also impaired in FFR. It is possible that prolonged insulin resistance and hyperinsulinemia in FFR could alter endothelial-dependent vasodilatory mechanisms, thereby contributing to the increase in blood pressure seen in this model.

Acetylcholine↗
PubMed2001

Early dose assessment in criticality accidents.

Early estimation of dose is useful in the medical evaluation of severe radiation accidents. In a prior publication, lymphocyte depletion kinetics were shown to follow an exponential decline for gamma accidents in which the average whole-body dose was in the range 50 cGy < D < 8-10 Gy. In that study, the depletion rate constant was linearly related to dose, within the statistical variation of the historical hematological data. This simple technique has now been extended to include analysis of various types of criticality accidents (liquid process; water moderated systems; metallic systems). Lymphocyte depletion in high-level mixed gamma/neutron accidents is found to be approximately equal, at a given effective dose, to that for gamma accidents. This universality would indicate a neutron RBE for human lymphocytes close to unity. Furthermore, the technique appears to be insensitive to the shape of gamma and neutron spectra, therefore making it especially robust for initial, approximate dose estimation.

Gamma Rays↗
PubMed1998

Evidence for increased functional vascular Na+/K+ pump activity in the obese Zucker rat.

Insulin is known to stimulate Na+/K+ ATPase and to relax vascular smooth muscle. We hypothesized that vascular tone in the obese Zucker (fa/fa) rat, a hyperinsulinemic model in which hypertension can develop, may be influenced by insulin's ability to stimulate Na+/K+ ATPase at the vascular level. We studied isometric preparations of tail and femoral arteries from 10-wk-old, male obese Zucker rats, which were hyperinsulinemic but still normotensive vs. lean controls. Sensitivity to potassium-induced relaxations, an index of vascular Na+/K+ ATPase activity was significantly greater in the obese Zucker rat than control. Sensitivity to transmural-nerve-stimulation-induced contractions was decreased in the femoral and tail arteries from obese rats as compared with lean controls. Insulin (50 to 200 mU/ml) mimicked potassium-induced relaxations in the femoral artery, an effect that was significantly greater in the obese group. These data suggest that in the young hyperinsulinemic Zucker rat, insulin has a stimulatory effect on the vascular Na+/K+ pump, which may be associated with a decreased presynaptic adrenergic influence on vascular tone. Development of resistance to these vascular relaxant effects of insulin with advancing age might contribute to the onset of hypertension in this model.

Animals↗
PubMed1998

Increased functional Na(+)-K+ pump activity in the vasculature of fructose-fed hyperinsulinemic and hypertensive rats.

We hypothesized that hyperinsulinemia may alter insulin's ability to stimulate vascular Na+/K(+)-ATPase pump activity and modulate changes in vascular responsiveness associated with hypertension. We measured potassium-induced relaxation as an indicator of Na+/K(+)-ATPase pump activity in isolated femoral arteries from fructose-fed (FF) hyperinsulinemic, Sprague-Dawley rats. FF rats had higher mean arterial blood pressures than did normal diet-fed (NF) rats (FF, 125 +/- 2.2, n = 20, vs. NF, 113.5 +/- 2.5 mmHg, n = 20, p < 0.05) and were hyperinsulinemic (FF, 64 +/- 4 vs. NF, 37 +/- 2, microU/ml insulin, p < 0.01). FF rats were more sensitive to KCl in the Na+/K+ pump bioassay (FF, 0.86 +/- 0.07, n = 21 vs. NF, 1.18 +/- 0.08, n = 17, p < 0.05, expressed as ED50 in mmol/l KCl). Exogenous insulin (100 mU/ml) increased Na+/K+ pump sensitivity in FF rats as compared with a boiled insulin control (insulin 45 +/- 6%, n = 11, vs. control, 11 +/- 7%, n = 13, p < 0.01, expressed as percent increase in sensitivity, i.e., ED50). There were no significant differences in Na+/K+ pump sensitivity between insulin and control responses in the NF animals (insulin 29 +/- 6%, n = 11, vs. control 46 +/- 5%, n = 10, NS). Dose-response curves were obtained in tail and femoral arteries from the same animals to norepinephrine and acetylcholine, basally and after exogenous insulin. FF vessels had reduced sensitivity to norepinephrine as compared with the NF group. Insulin increased sensitivity to acetylcholine-induced relaxations and increased AII-induced contractions in FF-rat vessels. These data suggest that in the FF rat insulin's influence on the vascular Na+/K+ pump is enhanced and may modulate the changes in vascular responsiveness seen in this model.

Acetylcholine↗
PubMed1997

Accidental radiation injury to the hand: anatomical and physiological considerations.

A case study describing an accident in Mexico caused by failure to de-energize an x-ray spectrometer prior to repair is presented. The evolution, medical management, and outcome of the radiation injury to the hand are briefly reviewed. A discussion follows, with radiation injury and thermal burns compared and contrasted. The anatomy and physiology of thick skin and the vascular system of the hand are reviewed so that the reader will have a better understanding of the role of vascular injury in the pathological process that leads to tissue atrophy and radiation necrosis. Hyperbaric oxygen therapy, sympathectomy, and other techniques for improving circulation in involved areas are reviewed.

Adult↗
PubMed1997

Early dose assessment following severe radiation accidents.

Early treatment of victims of high level acute whole-body x-ray or gamma exposure has been shown to improve their likelihood of survival. However, in such cases, both the magnitude of the exposure and the dosimetry profile(s) of the victim(s) are often not known in detail for days to weeks. A simple dose-prediction algorithm based on lymphocyte kinetics as documented in prior radiation accidents is presented here. This algorithm provides an estimate of dose within the first 8 h following an acute whole-body exposure. Early lymphocyte depletion kinetics after a severe radiation accident follow a single exponential, L(t) = L(o)e(-k(D¿t), where k(D) is a rate constant, dependent primarily on the average dose, D. Within the first 8 h post-accident, K(D) may be calculated utilizing serial lymphocyte counts. Data from the REAC/TS Radiation Accident Registry were used to develop a dose-prediction algorithm from 43 gamma exposure cases where both lymphocyte kinetics and dose reconstruction were felt to be reasonably reliable. The inverse relationship D(K) may be modeled by a simple two parameter curve of the form D = a/(1 + b/K) in the range 0 < or = D < or = 15 Gy, with fitting parameters (mean +/- SD): a = 13.6 +/- 1.7 Gy, and b = 1.0 +/- 0.20 d(-1). Dose estimated in this manner is intended to serve only as a first approximation to guide initial medical management.

Algorithms↗
PubMed1997

Impaired in vivo adrenergic responses in diet-induced hypertensive rats.

This study was conducted to investigate whether altered vascular responsiveness to vasoactive compounds contributes to the development of hypertension in diet-induced hyperinsulinemic rats. Male Sprague-Dawley rats were randomly assigned to receive high fructose, high sucrose, or standard rat chow for 13-18 wk. Blood pressure was monitored by indirect (tail-cuff) measurements at regular intervals during the diet treatment. Vascular responses to various vasoactive agents were studied both in vivo and in vitro. Blood pressure response, as assessed by direct (intra-arterial) measurement, to graded dose infusions of norepinephrine or angiotensin II or bolus infusion of acetylcholine were determined. In vitro vascular responses of the tail arteries to exogenous norepinephrine were also studied. The fructose- and the sucrose-fed rats had significantly higher blood pressure than controls. Serum insulin levels were also significantly higher in fructose- and sucrose-fed rats than in controls. The blood pressure responses to graded infusions of norepinephrine were significantly less in the fructose-fed rats than in controls. The blood pressure responses to angiotensin II and acetylcholine infusion were not significantly different among the three groups of rats. In vitro studies of vascular reactivity in the tail arteries revealed than the concentration of norepinephrine that produced half-maximal contraction (NE EC50) was significantly higher in the fructose group than control. Thus, impaired vascular responses to exogenous norepinephrine were observed in fructose-fed rats both in vivo and in vitro. This may be due to an adaptation to increased sympathetic nervous activity, or may be a compensatory response to other structural or functional changes that produce hypertension in this model.

Acetylcholine↗
PubMed1996

Platelet lipoxygenase inhibitors attenuate thrombin- and thromboxane mimetic-induced intracellular calcium mobilization and platelet aggregation.

Platelets metabolize arachidonic acid via cyclooxygenase and lipoxygenase (LO) enzymatic pathways. Although platelets produce large amounts of arachidonic acid metabolites via the LO pathway, little is known regarding the physiological significance of these products. We used three structurally dissimilar LO inhibitors, 5,8,11-eicosatriynoic acid (ETI), baicalein and phenidone, and found that LO inhibition attenuated thrombin- and U46619 (a thromboxane mimetic)-induced increases of platelet intracellular calcium ([Ca++]i) in washed human platelets. LO inhibitors also reduced platelet aggregation induced by thrombin and U46619. The effect of ETI on reducing the thrombin-induced [Ca++]i elevation persisted even when cation channels were blocked, suggesting that LO inhibitors modify release of Ca from intracellular stores. Stimulating endogenous LO product formation potentiated thrombin-induced [Ca++]i responses and aggregation, and these effects were eliminated by ETI. ETI did not alter inositol 1,4,5-trisphosphate production in stimulated platelets, but increased platelet cyclic AMP production in thrombin- or forskolin-stimulated platelets. These results suggest that LO products are regulators of platelet [Ca++]i mobilization and aggregation in response to some agonists, and that LO inhibitors may work in part by modifying platelet cyclic AMP metabolism.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1995

Desensitization of vascular tissue to parathyroid hormone and parathyroid hormone-related protein.

Although PTH and PTH-related protein (PTHrP) are vasodilators, prolonged exposure to elevated levels of PTH is often associated with hypertension. We investigated the effects of prolonged incubation with PTH or PTHrP on arterial segments and cultured vascular smooth muscle cells (VSMC). PTH or PTHrP transiently relaxed precontracted arterial segments within 10 min. Additional PTH or PTHrP added after 40-min exposure to these peptides had little effect on vascular tone, whereas forskolin, isoproterenol, isobutylmethyl-xanthine, or acetylcholine were still potent. In fura 2-loaded VSMC, 5-min incubation with PTH or PTHrP attenuated angiotensin II (Ang II)-induced calcium mobilization, an effect that was reduced by preincubation of VSMC with PTH for 1.5 h. Similarly, 1.5-h preincubation with PTH or PTHrP decreased the cAMP response to these peptides but not to forskolin or NaF. Ang II potentiated the cAMP response to PTH and PTHrP but was also subject to desensitization. Nle8, 18Tyr34 bovine PTH(3-34) amide did not desensitize vascular tissue to PTH or PTHrP. Our results suggest that homologous desensitization to PTH or PTHrP in vascular tissue requires receptor stimulation, occurs proximal to G stimulatory protein, and impairs attenuation of calcium mobilization by PTH or PTHrP. This may be a mechanism by which vasodilator effects of these peptides are decreased with prolonged elevation of PTH levels.

Angiotensin II↗
PubMed1992

Flavonoid potentiation of contractile responses in rat blood vessels.

Certain bioflavonoids and phenolic compounds have long been known to enhance catecholamine responses, in vivo and in vitro. In the present studies the flavone, baicalein, potentiated nerve-stimulated contractions in vitro in rat tail and femoral artery isometric ring preparations. Inhibition of catecholamine reuptake with cocaine or catecholamine metabolism with tropolone and parglyine (monoamine oxidase and catecholamine-O-methyl transferase inhibitors, respectively) did not alter baicalein's ability to potentiate contractile responses to nerve stimulation. Baicalein (10(-5) M), the prototype flavone, also increased sensitivity to exogenous norepinephrine, serotonin, arginine vasopressin and to the noncatecholamine alpha-1 and alpha-2 adrenergic agonists, cirazoline and tramazoline. Structure-function studies indicated that flavone potentiation required three contiguous A or B ring hydroxylations. Several nonflavone phenol derivatives with three contiguous hydroxyls also potentiated nerve stimulation responses. As baicalein is a potent lipoxygenase inhibitor, comparisons were made between potentiating ability and lipoxygenase inhibitory activity in a series of flavonoids. There was no direct correlation between inhibition of 12-hydroxy-5,8,10,14-eicosatetraenoic acid levels in thrombin stimulated human platelets and potentiation of contractile responses in the femoral artery. Additionally, the specific substrate analog lipoxygenase inhibitor, 5,8,11-eicosatriynoic acid, and the cyclooxygenase inhibitor, ibuprofen, were nonpotentiating. Ibuprofen pretreatment did not alter the potentiating action of baicalein. It is concluded that flavonoids with three contiguous hydroxyls on either the A or B ring increase in vitro vascular responsiveness via a post-synaptic process, independent of cyclooxygenase, lipoxygenase, monoamine oxidase or catecholamine-O-methyl transferase activity.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1989

Altered vascular responses in cyclosporine-treated rats.

Administration of cyclosporine to allograft recipients and patients with immunologically mediated disorders is associated with a high incidence of the development of hypertension. We studied the effect of CsA on blood pressure and on the in vitro tail artery contractile response to transmural nerve stimulation (TNS) and exogenous norepinephrine (NE) in the spontaneously hypertensive rat (SHR). Fourteen days of p.o. administration of CsA 5 mg/kg/day (CsA5) or CsA 20 mg/kg/day (CsA20) resulted in significant increases in blood pressure. The effective level of TNS that resulted in a 50% of maximal response (ED50) was significantly (P less than 0.05) decreased in the CsA5 and CsA20 animals compared to controls. The values for controls (n = 7), CsA5 (n = 10), and CsA20 (n = 9) were 4.3 +/- 0.3, 3.2 +/- 0.3, and 3.1 +/- 0.4 pulses/sec, respectively. In the CsA20 group, the dose-response curve to NE was significantly shifted to the left, and the ED50 was significantly (P less than 0.01) decreased compared to controls (5.7 +/- 0.8 x 10(-5) mol/L, n = 11, vs. 8.9 +/- 0.6 x 10(-5) mol/L, n = 12). We conclude that the in vitro contractile response to nerve stimulation is augmented by CsA. Some of the increase may be related to an enhancement of NE response, but a direct effect on neurovascular function is also suggested. This effect of CsA may be important in the development of hypertension and the changes in neurovascular tone seen with the clinical administration of this immunosuppressant.

Animals↗
PubMed1987

Decreased vascular reactivity to norepinephrine in Fischer rats with neoplasia-induced hypercalcemia.

The effect of a hypercalcemia-producing Leydig cell tumor on vascular reactivity in Fischer rats was studied. Seven to eight days after tumor implantation, there was no difference between tumor (T) and control (C) animals in serum calcium, serum phosphate, plasma catecholamine levels, mean arterial pressure (MAP), or blood pressure responses to norepinephrine (NE) infusion. At day 12-13 of tumor growth, the serum calcium in the tumor-bearing rats was significantly higher (12.2 +/- 0.8 vs. 9.7 +/- 0.3 mg%, P less than .01) and their serum phosphate significantly lower (4.5 +/- 0.3 vs. 5.7 +/- 0.4 mg%, P less than .01) than controls. Plasma epinephrine (E) (497 +/- 154 vs. 62 +/- 13 pg/ml, P less than .05), and norepinephrine (NE) (686 +/- 85 vs. 329 +/- 75 pg/ml, P less than .01) were markedly elevated in the tumor rats. MAP and the blood pressure responses to graded NE infusions were significantly lower in tumor animals at Day 12-13, whereas there was no change in sensitivity to angiotensin II (AII) infusions. In vitro contractile responses of tail artery segments to transmural nerve stimulation (TNS) in animals with tumors were lower than in controls but there were no differences in sensitivity to exogenous NE in vitro. These results suggest that the tumor stimulates production of a circulating factor which desensitizes NE receptors and that this tumor also decreases neurovascular function by an undefined mechanism.

Animals↗
PubMed1987

Direct augmentation by cyclosporin A of the vascular contractile response to nerve stimulation.

Cyclosporin A administration is associated with an increased incidence of hypertension. To evaluate the direct effects of the drug on the contractile responses of vascular tissue to adrenergic stimuli, rat caudal artery ring segments were studied before and after the addition of cyclosporin A or its ethanol vehicle in vitro. In a dose-related manner, cyclosporin A augmented the contractile response to transmural nerve stimulation, with a highly significant (p less than 0.001 relative to that produced by the vehicle) lowering of the stimulation rate, a 50% of maximum contractile response (ED50) that elicited. The difference between pretreatment and treatment maximal responses to transmural nerve stimulation was also significantly greater (p less than 0.01) in the cyclosporin A-treated preparations than in those receiving the vehicle. In similar experiments, the responses to exogenous norepinephrine were not significantly affected. The effect of cyclosporin A on transmural nerve stimulation was demonstrated at several extracellular calcium concentrations. The results suggest that cyclosporin A enhances nerve stimulation responses by a presynaptic mechanism.

Animals↗
PubMed1985

Adrenergic stimulation of prostacyclin production in the rat tail artery. I. Response to agonists and antagonists.

The release of prostacyclin (PGI2) as measured by the production of 6-keto-PGF1 alpha was assessed in vitro in rat tail artery segments after exposure to norepinephrine (NE). Time course studies demonstrated a three fold increase in 6-keto-PGF1 alpha production in response to 6 X 10(-5) M NE that persisted for approximately one hour. This production was almost completely prevented by the cyclooxygenase inhibitors indomethacin and ibuprofen and the phospholipase inhibitor mepacrine. Vigorous rubbing of the vessel intima did not prevent the response to NE. Previously stimulated tissues were unresponsive to further addition of NE. However, the addition of arachidonic acid following NE resulted in further increases in PGI2 production which exceeded that of the addition of arachidonic acid alone. NE stimulation was significantly inhibited by phentolamine and prazosin pretreatment of the tissues but was not affected by yohimbine or propranolol. Alpha-1 adrenergic agonists (cirazoline, methoxamine, and phenylephrine) were stimulatory whereas alpha-2 agonists in high doses (tramazoline, BHT-920, xylazine, and UK-14304) were without effect. It is concluded that norepinephrine stimulates PGI2 production in the rat tail artery via an alpha-1 adrenergic receptor. NE also enhances the conversion of arachidonic acid to PGI2. Exhaustion of the response appears to be due to consumption of available arachidonic acid. The fact that procedures which generally remove most of the endothelium did not prevent NE-induced stimulation points to the vascular smooth muscle as the likely source of adrenergically mediated prostacyclin generation in this tissue.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Adrenergic stimulation of prostacyclin production in the rat tail artery. II. The role of calcium.

This investigation studied the role of extracellular and intracellular calcium in the stimulation of prostacyclin (PGI2) production by norepinephrine (NE) in the rat tail artery in vitro. Incubation of the artery in zero calcium medium inhibited the response to NE as well as the response to the calcium ionophore A23187. Increasing the extracellular calcium concentration had no effect on basal or NE-stimulated PGI2 (measured by radioimmunoassay of the stable metabolite, 6-keto-PGF1 alpha). Several different calcium entry blocking drugs had a partial inhibitory effect on the NE response, but it was noted that the dihydropyridine derivatives, nifedipine and nimodipine, also decreased the stimulatory effect of added exogenous arachidonic acid (AA). This effect on AA conversion was also seen with W-7, a calcium-calmodulin inhibitor, and with TMB-8, an inhibitor of intracellular calcium mobilization. However, two phenothiazine calmodulin inhibitors, trifluoperazine and pimozide, did not affect AA conversion and were effective in reducing the stimulatory response to NE. Trifluoperazine, particularly at a high dose of 10(-4) M, had an independent stimulatory effect on PGI2 production in this tissue. The data suggests that many of the antagonist probes of extracellular-intracellular calcium metabolism may have variable effects on more than one point in the prostaglandin synthetic pathway. Nevertheless, the results are consistent with the hypothesis that NE stimulates PGI2 in the rat tail artery by activation of a calcium-calmodulin dependent phospholipase and that at least some of the calcium is of extracellular origin.

6-Ketoprostaglandin F1 alpha↗