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Biomedical subjects

H Sandler

Publications and source records attributed to H Sandler.

At least 37 records · Page 2Linked to original sources
PubMed1995

Effect of indomethacin on thrombin-induced pulmonary edema in the rat.

The preventive effect of indomethacin on thrombin-induced pulmonary edema was studied in rats. Administration of thrombin caused a significant increase in lung weight, wet weight to dry weight ratio (WW/DW), and relative lung water content. During infusion of thrombin, mean pulmonary artery pressure rose and mean systemic artery pressure fell, PaO2 decreased progressively and there was a continuous rise in pH and PaCO2. An inhibitor of cyclooxygenase, indomethacin, at a dose of 1 mg/kg body weight, induced a significant further increase in lung weight (p < 0.05), and a tendency towards an increase in WW/DW and water content compared with animals given thrombin alone. Treatment with indomethacin, however, counteracted the elevated pulmonary artery pressure occurring in the early phase after thrombin infusion, but not that in the late phase. Systemic artery pressure was not affected by indomethacin. The increases in pH and PaCO2 after thrombin infusion were attenuated and remained stable almost at baseline level after indomethacin administration. Indomethacin did not prevent the hypoxemia induced by thrombin infusion. In conclusion, although indomethacin prevented the early increase in pulmonary artery pressure due to thrombin and the decrease in pH and the increase in PaCO2, it caused lung vascular permeability to protein to increase more than with thrombin alone.

Animals↗
PubMed1994

Effect of ibuprofen on thrombin-induced pulmonary edema in the rat.

The effect of ibuprofen on thrombin-induced pulmonary edema was studied in rats. Thrombin infusion produced a significant increase in lung weight, wet weight/dry weight ratio and relative lung water content, a rise in mean pulmonary arterial pressure and a fall in mean systemic arterial pressure. It also caused a progressive decrease in PaO2 and a continuous increase in pH and PaCO2. Administration of either the S-isomer or R-isomer of ibuprofen at doses of 5 mg/kg body weight prior to thrombin infusion resulted in significant reduction in lung weight, wet weight/dry weight ratio and water content. The wet weight/dry weight ratio and the water content were somewhat lower after infusion of the S-isomer than of the R-isomer. Ibuprofen diminished the thrombin-induced increase in mean pulmonary arterial pressure and attenuated the early and late decrease in mean systemic arterial pressure caused by thrombin. Ibuprofen also stabilized thrombin-induced impairments in PaO2, PaCO2 and pH. The results thus indicate that ibuprofen effectively counteracts hemodynamic changes, stabilizes impairments in arterial blood gas variables and attenuates the increase in lung vascular permeability to protein with pulmonary edema caused by thrombin. The results also indicate a substantial R to S chiral inversion of ibuprofen in vivo in the rat.

Animals↗
PubMed1994

Radiosensitization with carotid intra-arterial bromodeoxyuridine +/- 5-fluorouracil biomodulation for malignant gliomas.

Bromodeoxyuridine (BUdR), a nonhypoxic radiosensitizing drug, is a halogenated pyrimidine analog that is incorporated into the DNA of dividing cells in a competitive process with thymidine. BUdR sensitizes cells to radiation therapy. 5-Fluorouracil (5-FU) inhibits the endogenous synthesis of thymidine, resulting in increased incorporation of the BUdR. Neurons and glial cells have a very low mitotic rate; they will not incorporate BUdR and will not be sensitized. BUdR and 5-FU are best delivered intra-arterially (IA) because of their regional advantage. We infused BUdR +/- 5-FU over 8 1/2 weeks, before and during 59.4-Gy focal conformal external beam radiation therapy, through a permanently implanted pump with a catheter placed retrograde through the external carotid artery to the carotid bifurcation. Sixty-two patients with grades III or IV glioma were entered into one of two trials, with 23 patients receiving BUdR alone and 39 patients receiving BUdR + 5-FU. The maximum tolerated dose (MTD) of BUdR alone was 400 mg/m2/d for 8 1/2 weeks. The Kaplan-Meier median survival (KMS) was 20 months. In the BUdR + 5-FU trial, the MTD of BUdR was also 400 mg/m2/d and 5-FU was 5 mg/m2/d with a KMS of 17 months. The KMS of all 62 patients in both trials 1 and 2 was 18 months. Pathologic grading used both the original World Health Organization (WHO) and 1993 modified WHO systems. The KMS of grade IV patients was 13.8 months (48 patients) with the original system and 17 months (58 patients) with the modified system.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Hemodynamic responses to seated and supine lower body negative pressure: comparison with +Gz acceleration.

Hemodynamic changes between upright and supine lower body negative pressure (LBNP) to levels of -70 mm Hg were compared in 8 subjects (5 males, 3 females) and correlated with their findings during simulated Shuttle reentry acceleration with a slow onset rate of 0.002 G/s (1,020 s to peak +2 Gz) and during gradual onset exposures (0.03 G/s) to +3 Gz and +4 Gz. Six of the 8 subjects were able to tolerate 2 min at peak +2 Gz, 2-5 min at +3 Gz, and 1-2 min at +4 Gz. Heart rate (HR) at any given level of upright LBNP regularly exceeded supine levels. HR change at -50 mm Hg in upright subjects (+47.7 bpm from 74.1 +/- 1.9 (M +/- S.E.) bpm, control) was 2.6 times greater than in supine subjects (+18.3 bpm from 64.8 +/- 2.8 bpm, control). HR values at -40 mm Hg supine (73.7 +/- 2.6) matched seated upright pre-LBNP control levels (74.1 +/- 1.9 bpm), while values at -70 mm Hg supine (102.5 +/- 4.4 bpm) were not significantly different from those at -40 mm Hg upright (103.1 +/- 4.0 bpm). Peak HR during +3 Gz (145.8 +/- 7.7 bpm) and +4 Gz (152.3 +/- 6.5 bpm) significantly exceeded recorded supine and upright LBNP levels, whereas values at +2 Gz (104.8 +/- 5.5 bpm) closely matched those at -40 mm Hg upright (103.1 +/- 4.0 bpm) and -70 mm Hg supine (102.5 +/- 4.4 bpm). Supine LBNP HR changes in this relatively small group of subjects closely matched those previously reported in the literature.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

The role of the H-ras oncogene in radiation resistance and metastasis.

The sensitivity of tumor cells to the killing effects of ionizing radiation is thought to be one of the major determinants of curability of tumors in patients treated with radiation therapy. This paper reviews the evidence from our laboratory and other groups which supports a role for oncogenes in the induction of radioresistance in cultured mammalian cells. Primary rat embryo cells (REC) were chosen as a model system in which the effects on radiation resistance of the H-ras oncogene could be studied on a uniform genetic background. These cells offered several useful advantages. The cells prior to transformation are diploid and because they have been in culture only for a few passages prior to transformation with the oncogene it is unlikely that any preexisting mutation affecting radiation response could be present. Additionally, the use of REC permitted the study of the effects of synergism between oncogenes on the induction of the radioresistant phenotype. The results show that the activated H-ras oncogene induces radiation resistance in primary rat cells after transformation, but that the effect of the oncogene itself is small. However, the myc oncogene, which has no effect on radiation resistance by itself, appears to have a synergistic effect on the induction of radiation resistance by H-ras. Radiation resistance induced by H-ras plus myc is characterized by an increase in the slope of the curve at high doses but there is also a large effect within the shoulder region of the radiation survival curve. The AdenoE1A oncogene which will also act synergistically with ras in transformation assays plays a less clear-cut role in assays of radiation resistance. The H-ras oncogene is also known not only to transform cells but also to induce metastatic behavior in the tumors which form after these transformed cells are injected into syngeneic animals or nude mice. We have also shown in our primary rat embryo cell system that the induction of metastatic behavior in transformed cells, like the induction of radioresistance depends on a complex interaction between oncogenes and the cellular background. This evidence will be reviewed to demonstrate some of the analogies between radiation resistance and metastasis as examples of the complex alterations in cellular phenotype which occur after oncogene transfection.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Haemodynamic and ADH responses to central blood volume shifts in cardiac-denervated humans.

Haemodynamic responses and antidiuretic hormone (ADH) were measured during body position changes designed to induce blood volume shifts in 10 cardiac transplant recipients to assess the contribution of cardiac and vascular volume receptors in the control of ADH secretion. Each subject underwent 15 min of a control period in the seated posture, then assumed a lying posture for 30 min at 6 degrees head-down tilt (HDT) followed by 30 min of seated recovery. Venous blood samples and cardiac dimensions (echocardiography) were taken at 0 and 15 min before HDT, 5, 15 and 30 min of HDT, and 5, 15 and 30 min of seated recovery. Blood samples were analysed for haematocrit, plasma osmolality, plasma renin activity (PRA) and ADH. Resting plasma volume (PV) was measured by Evans blue dye and per cent changes in PV during posture changes were calculated from changes in haematocrit. Heart rate (HR) and blood pressure (BP) were recorded every 2 min. In the cardiac transplant subjects, mean HR decreased (BP less than 0.05) from 102 b.p.m. pre-HDT to 94 b.p.m. during HDT and returned to 101 b.p.m. in seated recovery while BP was slightly elevated (P less than 0.05). PV was increased by 6.3% (P less than 0.05) by the end of 30 min of HDT but returned to pre-HDT levels following seated recovery. Plasma osmolality was not altered by posture changes. Mean left ventricular end-diastolic volume increased (P less than 0.05) from 90 +/- 5 ml pre-HDT to 105 +/- 4 ml during HDT and returned to 88 +/- 5 ml in seated recovery. Plasma ADH was reduced by 28% (P less than 0.05) by the end of HDT and returned to pre-HDT levels with seated recovery. PRA was also reduced by 28% (P less than 0.05) with HDT. These responses were similar to those of six normal cardiac-innervated control subjects and one heart-lung recipient. Therefore, cardiac volume receptors are not the only mechanism for the control of ADH release during acute blood volume shifts in man.

Adult↗
PubMed1990

Intrapericardial denervation: radial artery blood flow and heart rate responses to LBNP.

Eight rhesus monkeys were used to study responses of radial artery blood flow velocity (RABFV) and heart rate (HR) to low (0 to -20 mmHg) and high (0 to -60 mmHg) ramp exposures during supine lower body negative pressure (LBNP). These levels were chosen to separate peripheral vascular responses associated with stimulation of low- and high-pressure baroreceptors. Four monkeys had efferent and afferent cardiac denervation by use of the Randall procedure with pharmacological (phenylephrine and atropine) verification. Animals were studied 3 wk after surgery to avoid reinnervation. Findings were compared with those of four identically treated intact animals. Denervated animals showed no change in RABFV or HR during low-level LBNP; however, HR increased significantly (P less than 0.05) when LBNP reached -50 mmHg and blood flow velocity also fell (P less than 0.05) starting at -30 mmHg pressure. In contrast, intact animals showed steady decreases in RABFV during both high- and low-pressure protocols, with HR showing a 6-beat/min increase (P less than 0.05) starting at -20 mmHg pressure. As with denervated animals, intact animals showed a more pronounced increase in HR after reaching a level of -60 mmHg suction. Cardiac output (electromagnetic flowmeter, ascending aorta) fell significantly in both groups starting at -30 mmHg pressure. Left ventricular pressure (Konigsberg pressure cell) in three intact animals showed a progressive fall in systolic pressure starting at -10 mmHg suction, which became significant at -55 mmHg pressure. These results demonstrate that cardiac denervation by use of the Randall technique significantly affects RABFV and HR responses to LBNP in rhesus monkeys. The lack of RABFV change during LBNP in denervated animals suggests that these changes coupled with HR response can be used as an effective method to verify the completeness of denervation of low-pressure baroreceptors in animals that have undergone intrapericardial denervation.

Animals↗
PubMed1988

Role of cardiac atria in the human renal response to changing plasma volume.

We examined the role of cardiac atria in the renal response to sequential volume expansion and contraction, during and directly following water immersion. In immersed healthy volunteers (group 1, n = 9) atrial diameter, plasma levels of atrial natriuretic peptide (ANP), and natriuresis increased, whereas renal vascular resistance (RVR) and filtration fraction declined. Each parameter changed in an opposite direction postimmersion. An analysis of transglomerular dextran transport suggests that transglomerular hydraulic pressure difference (delta P) changed in parallel with filtration fraction. Baseline atrial diameter, plasma ANP, RVR, and filtration fraction were significantly elevated in nine recipients of denervated cardiac allografts (group 2). Atrial diameter and plasma ANP changed in parallel with group 1 during and after immersion. However, corresponding reciprocal changes in RVR were smaller and filtration fraction remained constant throughout. From transglomerular dextran transport, we compute that delta P increased progressively during and after immersion, suggesting predominant efferent arteriolar tone. The postimmersed state was associated also with enhanced sodium retention despite sixfold higher plasma ANP than in group 1. These findings are consistent with an effect of cardiac denervation to leave unopposed efferent sympathetic nervous traffic to the kidney. They suggest that the latter is an important modulator of the renal response to changing plasma volume in humans.

Atrial Function↗
PubMed1988

The hemodynamic effects of repeated bed rest exposure.

Hemodynamic changes were measured during stepwise exposure to lower-body negative pressure (LBNP) (5 min, -20, -30, and -40 mm Hg) in a group of seven physically active subjects before and after consecutive exposure to three 2-week bed rest periods. Bed rest exposures were separated by 3-week periods of ambulatory recovery. Dynamic exercise (68% max O2, 30 min each day) and isometric exercise (21% max leg extension, 30 min each day) performed during bed rest and reambulation failed to prevent deconditioning or accelerate the recovery process between bed rest exposures. Heart rate (HR) and end-diastolic volume index (EDVI) proved to be parameters showing greatest changes during LBNP. Heart rate increases at -40 mm Hg LBNP (compared to respective pre-LBNP levels) were 13.3%, 35.1%, and 51.0% for each of the pre-bed rest exposures, while respective changes after bed rest were 57.8%, 57.2%, and 75.5%. The significantly elevated HR responses during subsequent pre-bed rest (control) periods indicated incomplete recovery despite mild exercise and ambulation. Comparison of EDVI and HR revealed a similar linear regression relationship during LBNP before and after bed rest so that EDVI = 112.5-0.85 x HR, r = -0.97. We conclude from these findings that cardiovascular deconditioning for physically active individuals involves factors other than simple loss of plasma volume, requires at least 3 weeks or longer to return to the pre-bed rest state, and is not counteracted by the levels of aerobic and/or isometric exercise used in the present study.

Adult↗
PubMed1987

The effect of plasma volume expansion on the response to carotid occlusion in the non-human primate.

The purpose of this study was to investigate the effects of plasma volume expansion on the cardiac and peripheral components of the baroreceptor reflex. Nine male Rhesus monkeys were chronically instrumented to measure arterial pressure and aortic blood flow. The aortic arch was denervated at the time of surgery. Bilateral carotid artery occlusion (BCO) was used to elicit the carotid sinus reflex both before and after 25% plasma volume expansion with an iso-osmotic dextran solution. The BCO elicited significant increases in heart rate (HR, 29.8 +/- 5.3 bpm) mean arterial pressure (MAP, 55.0 +/- 8.2 mm Hg) and total peripheral resistance (TPR, 0.076 +/- 0.01 mm Hg/ml/min) coupled with a significant reduction in mean aortic flow (AF, -246.9 +/- 55.3 ml/min) and stroke volume (SV, -2.86 +/- 0.36 ml). Volume expansion significantly attenuated the HR (15.2 +/- 5.8 bpm), MAP (30.4 +/- 4.4 mm Hg) and TPR (0.036 +/- 0.006 mm Hg/ml/min) response to carotid sinus hypotension. The changes in mean AF and SV elicited by BCO, however, were not significantly different between the control and volume expansion conditions. These data suggest that plasma volume expansion significantly attenuates the baroreceptor reflex control of circulation with a similar reduction in both the peripheral resistance and heart rate components of the response.

Anesthesia↗
PubMed1987

Echocardiographic evaluation of space shuttle crewmembers.

Echocardiographic measurements were obtained before and after space flight from 17 members of four shuttle crews. Measurements obtained 1 h after landing (L+0) compared with preflight values (n = 7) demonstrated an increase in heart rate (HR) (16 beats/min, 30.5%, P less than 0.05), mean arterial pressure (12%, P less than 0.05), and systemic vascular resistance (34%, P less than 0.05). End-diastolic volume index (EDVI) fell 17 ml/m2 (-23%, P less than 0.005) and stroke volume index (SVI) fell 15 ml/m2 (-28%, P less than 0.05). Repeat measurements taken 1-2 wk later (n = 17) demonstrated that HR had returned to normal (4 beats/min, P less than 0.05); however, EDVI remained significantly below preflight levels (-11%, P less than 0.005). End-systolic volume index (ESVI) was also still significantly lower (-23%, P less than 0.01). This delayed recovery occurred despite ability of the subjects to fully ambulate and exercise during the postflight period. These results indicate that spaceflight induces significant changes in heart volume affecting left ventricular function. The exact reasons for these specific changes remain unknown and will require additional measurements before, during, and after flight. The prolonged recovery period for the present subject group probably relates to their high level of aerobic conditioning.

Adult↗
PubMed1987

Cardiovascular results from a rhesus monkey flown aboard the Cosmos 1514 spaceflight.

Pressure and flow relationships to the head were measured before and during spaceflight by means of a chronically implanted cuff placed about the left common carotid artery in one of two rhesus monkeys flown aboard Cosmos 1514. Measurements were obtained daily for 4 min every 2 h during the 5-d spaceflight and compared to identical recordings obtained during a 35-h pre-flight control period 9 d before flight and a 12-h period while on the launch pad. Mean arterial pressure demonstrated a 10% increase compared to control levels immediately on insertion into orbit and maintained a 16-27% increase over the first few hours of flight before returning to baseline levels. Blood flow velocity showed a marked increase (approximately 8 cm/s) compared to pre-flight control while on the launch pad which was maintained over the duration of the flight. Blood flow showed reciprocal changes to pressure on orbital insertion. Cardiovascular system changes persisted into the second day of flight and were most clearly indicated by a decrease in relative differences between blood flow to the head and total cardiac output as measured by impedance plethysmography. Signs of adaptation appeared on days 3-5 of flight.

Animals↗
PubMed1987

Logistic risk model for the unique effects of inherent aerobic capacity on +Gz tolerance before and after simulated weightlessness.

Small sample size (n less than 10) and inappropriate analysis of multivariate data have hindered previous attempts to describe which physiologic and demographic variables are most important in determining how long humans can tolerate acceleration. Data from previous centrifuge studies conducted at NASA/Ames Research Center, utilizing a 7-14 d bed rest protocol to simulate weightlessness, were included in the current investigation. After review, data on 25 women and 22 men were available for analysis. Study variables included gender, age, weight, height, percent body fat, resting heart rate, mean arterial pressure, VO2max, and plasma volume. Since the dependent variable was time to greyout (failure), two contemporary biostatistical modeling procedures (proportional hazard and logistic discriminant function) were used to estimate risk, given a particular subject's profile. After adjusting for pre-bed-rest tolerance time, none of the profile variables remained in the risk equation for post-bed-rest tolerance greyout. However, prior to bed rest, risk of greyout could be predicted with 91% accuracy. All of the profile variables except weight, MAP, and those related to inherent aerobic capacity (VO2max, percent body fat, resting heart rate) entered the risk equation for pre-bed-rest greyout. A cross-validation using 24 new subjects indicated a very stable model for risk prediction, accurate within 5% of the original equation. The result for the inherent fitness variables is significant in that a consensus as to whether an increased aerobic capacity is beneficial or detrimental has not been satisfactorily established. We conclude that tolerance to +Gz acceleration before and after simulated weightlessness is independent of inherent aerobic fitness.

Acceleration↗
PubMed1987

Antiserum-induced neutropenia in the rat: characterization of a rabbit anti-rat neutrophil serum.

A heterologous rabbit anti-rat neutrophil serum (ANS) based on peptone-stimulated peritoneal exudate neutrophils (PMNLs) from Sprague Dawley rats was prepared. Leucoagglutination and indirect immunofluorescence assays revealed high titres of antibodies to rat PMNLs (1/2560), lower titre of antibodies to rat lymphocytes (1/160) and a very low titre against rat platelets (1/20). ANS given intravenously (i.v.) to rats in doses of up to 42 mg of protein/kg b.w. caused transient neutropenia, lasting about 10 min after administration, and thrombocytopenia, lasting about 5 min. Two minutes after an i.v. injection of 21 mg of ANS/kg b.w. there was profound uptake of 51Cr-labelled PMNLs in the lung, increased release of 51Cr to plasma, an increased amount of 51Cr in the spleen and consumption of greater than 98% of total complement (CH50). Two hours later there was high activity of 51Cr in the plasma, spleen and liver, while lung radioactivity had decreased to below baseline and CH50 had recovered to 55% of baseline. An intraperitoneal (i.p.) injection of ANS was followed by prolonged neutropenia with a maximum after 12 h. Simultaneously peripheral mononuclear cells slightly decreased. There was no change in the number of peripheral platelets in the blood or in the plasma concentration of fibrinogen, alpha 2-antiplasmin, plasminogen or plasminogen activators. Intraperitoneal administration of ANS did not affect CH50. It was concluded that the raised ANS had good specificity against rat PMNLs and was able to induce prolonged neutropenia after i.p. injection without affecting the complement of fibrinolytic system.

Agranulocytosis↗
PubMed1986

Studies on the role of thromboxane in thrombin-induced pulmonary insufficiency in the rat.

During infusion of thrombin in rats pulmonary arterial pressure rose from 15 +/- 2 to 35 +/- 3 mmHg and mean arterial pressure fell from 120 +/- 6 to 49 +/- 27 mmHg. Plasma thromboxane B2 (TxB2) increased from 0.3 +/- 0.04 to 3.6 +/- 0.5 ng/ml. Ninety minutes later the lung weight and albumin concentration in the lung were increased (2.21 +/- 0.13 g and 22.7 +/- 4.7 mg/g) compared with controls (1.12 +/- 0.14 g and 8.5 +/- 0.9 mg/g). An inhibitor of thromboxane synthetase, Dazoxiben R, reduced the elevated pulmonary arterial pressure and the elevated plasma TxB2 concentration following infusion of thrombin. Ninety minutes after infusion of thrombin, the in vitro synthesis of TxB2 in lung tissue was increased. Dazoxiben and antineutrophil serum reduced this synthesis of TxB2 in vitro. The lung weight (2.18 +/- 0.20 g) and lung albumin concentration (21.4 +/- 3.4 mg/g) was not affected by Dazoxiben. The results indicate that TxA2 is an important mediator of the pressure changes in the early phase after infusion of thrombin and that neutrophils are associated with thromboxane formation in the lung tissue.

6-Ketoprostaglandin F1 alpha↗