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Biomedical subjects

W Grossman

Publications and source records attributed to W Grossman.

At least 19 recordsLinked to original sources
PubMed2006

AAV serotype-1 mediates early onset of gene expression in mouse hearts and results in better therapeutic effect.

Adeno-associated viral vectors (AAV) are attractive tool for gene therapy for coronary artery disease. However, gene expression in myocardium mediated by AAV serotype 2 (AAV2) does not peak until 4-6 weeks after gene transfer. This delayed gene expression may reduce its therapeutic potential for acute cardiac infarction. To determine whether earlier gene expression and better therapeutic effect could be achieved using a different serotype, CMV promoter driving the EPO gene (AAV-EPO) was packaged into AAV serotypes 1-5 capsids and injected into mouse myocardium. EPO expression was studied by measuring the hematocrits and EPO mRNA. After we found that AAV1 mediates the highest gene expression after 4 days of gene transduction, AAV-LacZ (CMV promoter driving LacZ gene expression) and MLCVEGF (hypoxia-inducible and cardiac-specific VEGF expression) were packaged into AAV1 and 2 capsids. LacZ expression was detected in AAV1-LacZ but not in AAV2-LacZ-injected hearts 1 day after vector injection. Compared to AAV2-MLCVEGF that mediated no significant VEGF expression, AAV1-MLCVEGF mediated 13.7-fold induction of VEGF expression in ischemic hearts 4 days after gene transduction and resulted in more neovasculatures, better cardiac function and less myocardial fibrosis. Thus, AAV1 mediates earlier and higher transgene expression in myocardium and better therapeutic effects.

Animals↗
PubMed2001

LV systolic performance improves with development of hypertrophy after transverse aortic constriction in mice.

Transverse aortic constriction (TAC) is an effective technique for inducing left ventricular (LV) hypertrophy in mice. With the use of transthoracic echocardiography and Doppler measurements, we studied the effects of an acute increase in pressure overload on LV contractile performance and peak systolic wall stress index (WSI) at early time points after TAC and the time course of the development of LV hypertrophy in mice. The LV mass index was similar between TAC and sham-operated mice at postoperative day 1 but progressively increased in TAC mice by day 10. There was no further increase in the LV mass index between postoperative days 10 and 20. On day 1, whereas peak systolic WSI increased significantly, the LV ejection fraction (LVEF) and percent fractional shortening (%FS) decreased in TAC mice compared with sham-operated mice. By day 10, peak systolic WSI, LVEF, and %FS had recovered to baseline levels and were not significantly different between postoperative days 10 and 20. Thus LV systolic performance in mice declines immediately after TAC, associated with increased peak systolic WSI, but recovers to baseline levels with the development of compensatory LV hypertrophy over 10-20 days.

Animals↗
PubMed2001

An extract of Petasites hybridus is effective in the prophylaxis of migraine.

OBJECTIVE: Migraine is still an unsolved problem. This clinical trial investigates the efficacy and tolerance of Petasites hybridus in the prophylaxis of migraine. METHODS: A randomized, group-parallel, placebo-controlled, double-blind clinical study was carried out with a special CO2 extract from the rhizome of Petasites hybridus. Following a four-week run-in phase, 60 patients received either the special Petasites hybridus extract Petadolex or placebo at a dosage of two capsules (each capsule contains 25 mg) twice daily over 12 weeks. Outcome variables included the frequency, intensity and duration of migraine attacks as well as any accompanying symptoms. RESULTS: The frequency of migraine attacks decreased by a maximum of 60 percent compared to the baseline. This reduction in migraine attacks with Petadolex was significant (p < 0.05) compared to placebo. No adverse events were reported. Petasites was exceptionally well tolerated. CONCLUSIONS: The results suggest that migraine patients can benefit from prophylactic treatment with this special extract. The combination of high efficacy and excellent tolerance emphasizes the particular value that Petasites hybridus has for the prophylactic treatment of migraine.

Asteraceae↗
PubMed2000

Studies of the immortalizing activity of HTLV type 1 Tax, using an infectious molecular clone and transgenic mice.

Expression of Tax in the mature lymphoid compartment of transgenic mice resulted in a lymphoproliferative malignancy of natural killer cells and cytotoxic T lymphocytes. Transgenic mouse tumors exhibited mutations in the p53 tumor suppressor gene, and functional inactivation of wild-type p53 protein. Tax transgenic mice heterozygous for the p53 gene exhibited more rapid tumor dissemination and accelerated mortality. Studies of Tax trans-activation in an infectious clone of HTLV-1 demonstrated a critical role for nuclear factor B activation in lymphocyte immortalization. A mutant disrupting Tax activation of the cAMP response element binding (CREB) protein resulted in preferential immortalization of CD8(+) lymphocytes, rather than preferential immortalization of CD4(+) lymphocytes seen with the wild-type infectious clone. A mutation disrupting Tax interaction with CREB-binding protein, CBP, did not affect lymphocyte immortalization by the infectious molecular clone. These models provide new insights into the molecular details of HTLV-1 leukemogenesis.

Animals↗
PubMed1999

EXP3174, the AII antagonist human metabolite of losartan, but not losartan nor the angiotensin-converting enzyme inhibitor captopril, prevents the development of lethal ischemic ventricular arrhythmias in a canine model of recent myocardial infarction.

OBJECTIVES: The antiarrhythmic efficacies of the competitive angiotensin II (AII) antagonist losartan, losartan's more potent noncompetitive AII antagonist human metabolite EXP3174 and the angiotensin-converting enzyme inhibitor captopril were assessed in a canine model of recent myocardial infarction. BACKGROUND: Multiple hemodynamic and electrophysiologic effects of AII may contribute to cardiac electrical instability. In the recent Losartan Heart Failure Study, Evaluation of Losartan in the Elderly (ELITE), a 722-patient trial primarily designed to assess effects on renal function, an unexpected survival benefit was observed with losartan compared with captopril, with the lower mortality using losartan primarily confined to a reduction in sudden cardiac death. METHODS: Intravenous losartan (1 mg/kg + 0.03 mg/kg/min), EXP3174 (0.1 mg/kg + 0.01 mg/kg/min), captopril (1 mg/kg + 0.5 mg/kg/h) or vehicle were infused in anesthetized dogs with recent (8.1 +/- 0.4 days) anterior myocardial infarction. Electrolytic injury of the left circumflex coronary artery to induce thrombotic occlusion and posterolateral ischemia was initiated 1 h after the start of treatment. RESULTS: Losartan, EXP3174 and captopril elevated plasma renin activities and comparably and significantly reduced mean arterial pressure. No significant electrocardiographic or cardiac electrophysiologic effects were noted with any treatment. Incidences of acute posterolateral ischemia-induced lethal arrhythmias were: vehicle, 7/9 (77%); losartan, 6/8 (75%); EXP3174, 2/8 (25%; p < 0.05 vs. vehicle control); captopril, 7/10 (70%). There were no among-group differences in time to onset of acute posterolateral ischemia or underlying anterior infarct size. CONCLUSIONS: EXP3174, but not losartan nor captopril, reduced the incidence of lethal ischemic ventricular arrhythmia in this preparation. The antiarrhythmic efficacy of EXP3174 may be due to an attenuation of deleterious effects of local cardiac AII formed during acute myocardial ischemia or, alternatively, a non-AII-related activity specific to EXP3174. These findings suggest that in humans, metabolic conversion of losartan to EXP3174 may afford antiarrhythmic protection.

Analysis of Variance↗
PubMed1998

Combined effects of angiotensin converting enzyme inhibition and angiotensin II receptor antagonism in conscious pigs with congestive heart failure.

OBJECTIVE: The goal of this study was to determine if the hemodynamic effects of the combined administration of an angiotensin converting enzyme (ACE) inhibitor and angiotensin II type 1 (AT1) receptor antagonist are greater than those produced by either of these agents administered individually during heart failure. METHODS: Ten farm pigs were chronically instrumented with aortic, left atrial and right atrial catheters, a left ventricular (LV) pressure gauge, LV dimension crystals, coronary occluders, an ascending aortic flow probe and pacing leads. Heart failure was induced by serial myocardial infarctions followed by repeated rapid ventricular pacing. RESULTS: Heart failure was manifested by significant (p < 0.01) decreases in LV dP/dt (-38 +/- 5%, from 2943 +/- 107 mmHg/s) and cardiac output (-27 +/- 4%, from 4.1 +/- 0.2 l/min) and increases in left atrial pressure (+18 +/- 1 mmHg, from 4 +/- 1 mmHg) and total peripheral resistance (TPR)(+40 +/- 8%, from 23 +/- 2 mmHg/l/min). The effects of an ACE inhibitor (enalaprilat) and an AT1 receptor antagonist (L-158,809), administered in maximally effective doses, either individually or concomitantly, were examined on different days in conscious pigs with heart failure. There were no differences in any of the baseline hemodynamic measurements among the groups studied. Thirty minutes after administration, enalaprilat (4 mg/kg i.v.) increased (p < 0.05) cardiac output by 8 +/- 2% and reduced (p < 0.05) mean arterial pressure and TPR by 5 +/- 1 and 12 +/- 1%, respectively, while the changes in LV dP/dt (0 +/- 2%), LV fractional shortening (+4 +/- 3%) and heart rate (+1 +/- 1%) were not statistically significant. Similarly, L-158,809 (4 mg/kg, i.v.) increased cardiac output by 9 +/- 2% and reduced mean arterial pressure and TPR by 4 +/- 1 and 11 +/- 3%, respectively, while the changes in LV dP/dt (+3 +/- 3%), LV fractional shortening (+3 +/- 1%) and heart rate (0 +/- 1%) were not significant. However, enalaprilat (1 mg/kg, i.v.) and L-158,809 (1 mg/kg, i.v.), administered concomitantly, reduced TPR by 21 +/- 3%, an effect greater (p < 0.05) than when either of these agents was administered individually at a dose of 4 mg/kg, i.v. The changes in mean arterial pressure (-9 +/- 2%), cardiac output (+15 +/- 4%) and LV fractional shortening (+11 +/- 3%) also tended to be greater with concomitant administration. In addition, in a sequential dosing protocol, when L-158,809 (1 mg/kg, i.v.) was administered 30 min after enalaprilat (1 mg/kg, i.v.), TPR was reduced by 20 +/- 4% compared to only a 6 +/- 3% reduction (p < 0.05) when the enalaprilat was followed 30 min later by a second dose of enalaprilat (1 mg/kg, i.v.). The changes in mean arterial pressure and cardiac output for the combined treatment group also tended to be greater than those for the group given two sequential doses of enalaprilat. CONCLUSION: In conscious pigs with heart failure, the combined vasodilatory effects of an ACE inhibitor and AT1 receptor antagonist are greater than those produced when only one of these agents is administered, suggesting that independent mechanisms of ACE inhibition and AT1 receptor antagonism could be partly responsible for the improved vascular dynamics during heart failure.

Analysis of Variance↗
PubMed1996

Rationale, background, and design of the randomized angiotensin receptor antagonist--angiotensin-converting enzyme inhibitor study (RAAS).

The randomized angiotensin receptor antagonist--angiotensin converting enzyme (ACE)--Inhibitor Study (RAAS) was designed to test the hypothesis that the addition of an angiotensin II type 1 receptor blocking agent, losartan 50 mg/day, to an ACE-inhibitor, enalapril 10 mg twice a day (group 1), will be more effective than standard-dose enalapril 10 mg twice a day (group 2) or high-dose enalapril alone 20 mg twice a day (group 3), in blocking the activation of the renin angiotensin aldosterone system in patients with heart failure and left ventricular systolic dysfunction. The addition of an angiotensin II type 1 receptor blocking agent to an ACE inhibitor would theoretically block ACE as well as non-ACE-dependent angiotensin II formation while maintaining the potential beneficial effect of ACE inhibitor-induced bradykinin formation. One hundred twenty patients with left ventricular systolic dysfunction and moderate to severe heart failure despite treatment with an ACE inhibitor will be randomized to 1 of the 3 groups and followed for 6 weeks, with an optional long-term week extension to determine the safety and tolerability of the combination of losaratan and enalapril, its effectiveness in preventing rest and exercise-induced neurohumoral activation (plasma norepinephrine, N-terminal proatrial natriuretic factor, angiotensin II, and aldosterone), as well as quality of life and exercise performance (6-minute walk test).

Angiotensin Receptor Antagonists↗
PubMed1996

Decreased inotropic but relatively preserved relaxation response to cyclic adenosine monophosphate-dependent agents in myopathic human myocardium.

BACKGROUND: Increased intracellular concentrations of cyclic adenosine monophosphate (AMP) stimulate a positive inotropic and lusitropic response in healthy myocardial tissue. Heart failure results in an attenuated inotropic response to cyclic AMP-dependent agents. This study compares the inotropic versus relaxation response to cyclic AMP-dependent and cyclic AMP-independent agents in myocardium from patients with end-stage heart failure and control patients without heart failure. METHODS AND RESULTS: Fifty-four control and 59 myopathic human ventricular trabeculae, 1 mm or less in diameter were placed in physiologic saline, 2.5 mM Ca2+, and stretched to the length at which maximal isometric force developed at 30 degrees C, 0.33 Hz. Dose-response curves plotted as percentage change from baseline versus concentration of drug were determined for acetylstrophanthidin, isoproterenol, isobutylmethylxanthine, and milrinone. Acetylstrophanthidin, a cyclic AMP-independent agent, showed similar increases in peak tension relative to baseline over the entire dose range tested for both control and myopathic heart muscle; its effect on relaxation of control and failing cardiac muscle was equivalent over the dose range tested. In contrast, the inotropic actions of the cyclic AMP-dependent agents, isoproterenol and the phosphodiesterase inhibitors, were significantly decreased in myopathic muscle compared with control muscle, but effects on relaxation in the control and myopathic groups remained relatively preserved. CONCLUSIONS: A relatively preserved relaxant effect is associated with the cyclic AMP-dependent agents, despite significant diminution of their inotropic effects. Thus, in advanced heart failure, patients may continue to benefit from the lusitropic effects of the cyclic AMP-dependent agents, even when the inotropic effects of these agents are severely attenuated.

1-Methyl-3-isobutylxanthine↗
PubMed1996

GH replacement fails to improve ventricular function in hypophysectomized rats with myocardial infarction.

To determine whether growth hormone (GH) replacement improves cardiac function, GH-deficient hypophysectomized rats with moderate myocardial infarction (MI) were studied after 3 wk of treatment with either recombinant rat GH (3.2 mg.kg-1.day-1 sc) or vehicle. The serum insulin-like growth factor I level in rats after GH treatment was approximately 10-fold greater than in vehicle-treated rats. GH replacement prevented a decrease in body weight at 1 wk (+5 +/- 6 vs. -26 +/- 4 g in vehicle group, P < 0.01) and increased body weight at 3 wk (+40 +/- 5 vs. -30 +/- 4 g in vehicle group, P < 0.01) after MI. Infarct size, expressed as a percentage of left ventricular (LV) perimeter, was similar for GH-treated (21 +/- 3%) and vehicle-treated (23 +/- 3%) rats. Basal LV systolic pressure, LV end-diastolic pressure, LV dP/dt, mean arterial pressure and heart rate, and the changes in these parameters in response to isoproterenol and norepinephrine were similar for these two groups. Although GH replacement tended to prevent depression in myocardial contractility during the recovery period after maximal stimulation either by the largest dose of isoproterenol (0.8 microgram/kg iv) or by acute volume loading, differences between the two groups were not statistically significant. In addition, to determine the effects of excess GH treatment in a severe state of cardiac dysfunction, nonhypophysectomized rats with larger infarcts (i.e., > 45% of the LV) were studied after 4 wk of treatment. There were no differences either in hemodynamic indexes or in infarct size between the GH- and vehicle-treated groups, whereas body weight had increased (P < 0.01) in the GH-treated group. Thus, although GH treatment effectively prevents the loss of body weight after MI, neither GH replacement nor excess GH treatment plays an important role in preserving cardiac function in rats with moderate or large MI.

Animals↗
PubMed1995

Amlodipine in chronic stable angina: results of a multicenter double-blind crossover trial.

The efficacy and safety of amlodipine, 10 mg, a new long-acting calcium antagonist, was compared with placebo in 103 patients with stable angina pectoris in a multicenter double-blind crossover study. The trial consisted of an initial 2-week single-blind placebo period followed by a first period of 4 weeks of double-blind therapy, which was followed by a 1 week washout period and then a second 4-week double-blind period after treatments were crossed over. Twenty-four-hour Holter electrocardiographic monitoring was carried out in 12 patients at three centers. In the first double-blind period amlodipine produced a significantly greater increase in symptom-limited exercise duration (amlodipine 478.5 to 520.6 vs placebo 484.6 to 485.2 seconds; change +8.8% vs +0.1%, respectively; p = 0.0004) and total work (amldipine 2426 to 2984 vs placebo 2505 to 2548 kilopondmeters; change +24% vs +1.7%, respectively; p = 0.0006) and a decrease in angina attack frequency (from 3 to 1 per week; p = 0.016) and nitroglycerin consumption (from 2 to 0.5 tablets/wk; p = 0.01) compared with placebo. Holter monitoring revealed significant reductions in numbers (amlodipine 4.65 to 2.22 vs placebo 1.84 to 1.54; change -52% vs +84%, respectively; p = 0.06), absolute total area (amlodipine 87.66 to 11.43 vs placebo 5.76 to 35.24; change -87% vs +513%, respectively; p = 0.02), and duration (amlodipine 12.29 to 2.95 vs 1.66 to 7.74 seconds; change -76% vs +367%, respectively; p = 0.008) of ST-segment depressions after treatment with amlodipine compared with placebo. After the treatments were crossed over changes continued to favor amlodipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Soft-tissue injury as an indication of child abuse.

We reviewed the hospital records of 371 children who were suspected of having been physically abused. Our purpose was to determine specific features that might be used to distinguish injuries resulting from abuse from accidental injuries. Soft-tissue injuries were found in 341 (92 per cent) of these children. Ecchymoses were most common, accounting for 555 (62 per cent) of 892 soft-tissue injuries, and very few had a suspicious pattern. Only thirty-four (9 per cent) of the children had a radiographically documented fracture, but radiography was performed for only thirty-seven (10 per cent) of the patients and it rarely was done unless a fracture was clinically obvious. The patterns of injury were age-specific. The forty-four children who were nine months old or less had an average of only one soft-tissue injury; thirty soft-tissue injuries involved the head or face, and seven (16 per cent) of the children had a burn. These children were the most severely injured: two (5 per cent) died and twenty (45 per cent) had a fracture. The sixty-one children who were ten months to two years and eleven months old had an average of two soft-tissue injuries; fifty-four soft-tissue injuries involved the head or face, and nine (15 per cent) of the children had a burn. A fracture was found in eight (13 per cent) of these children.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1994

Ca2+ handling and myofibrillar Ca2+ sensitivity in ferret cardiac myocytes with pressure-overload hypertrophy.

Experiments were performed in aequorin-loaded left ventricular myocytes isolated from hypertrophied hearts and age-matched controls. Five to six months after postvalvular aortic banding, left ventricular hypertrophy was present, as indicated by a 97% (P < 0.001) increase in the left ventricular weight-to-body weight ratio and a 24% (P < 0.001) increase in cell width. In comparison with controls, the hypertrophied myocytes demonstrated that 1) contraction duration was prolonged by 37% (P < 0.001) and was associated with a 44% (P < 0.001) prolongation of the intracellular Ca2+ transient; 2) peak systolic shortening was decreased by 31% (P < 0.001) and was associated with a 21% (P < 0.001) decrease in peak systolic intracellular Ca2+ concentration; 3) both the peak systolic intracellular Ca2+ concentration-to-peak shortening relationship and the intracellular Ca2+ concentration-to-cell shortening relationship at the time of the peak twitch were shifted downward, suggesting a decrease in myofilament Ca2+ responsiveness; and 4) isoproterenol (5 x 10(-8) M) produced equal increases in the peak systolic intracellular Ca2+ of control and hypertrophied myocytes (88 vs. 90%; P > 0.05) in contrast to much smaller increases in the peak cell shortening (170 vs. 73%; P < 0.02) of the hypertrophied myocytes, suggesting a decrease in myofilament Ca2+ responsiveness. These data demonstrate that the hypertrophy-related abnormalities in intracellular Ca2+ handling and mechanical function, previously reported in aequorin-loaded multicellular muscle preparations, are present in isolated myocytes, arguing against changes in the interstitium as essential causative factors.

Aequorin↗