Biomedical subjects
Publications and source records attributed to D R Meldrum.
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The prevalence of coronary artery disease renders myocardial ischemia a leading cause of morbidity and mortality. Both cardiac bypass operations and cardiac transplantation cause myocardial ischemia and reperfusion injury. Intracellular calcium transport and regulation are of paramount importance in both normal and pathologic myocardial states. Calcium regulation is integral to nearly every myocyte function, from early development to senescence. Normal intracellular calcium-mediated excitation-contraction coupling and abnormal patterns of calcium regulation leading to systolic/diastolic dysfunction are now therapeutically accessible to the cardiac surgeon. Additionally, altered Ca2+ transport protein gene expression is a mechanism of myocardial dysfunction. Therapeutic strategies involve receptor-mediated transduction of signals to intracellular metabolic sites. Evidence implicates protein kinase C as well as a potential therapeutic role for Ca2+. The potential for pharmacologic access to this protective state has abundant clinical appeal. The protective state (cardiac "preconditioning") is transient but is amenable as therapy against operation-related ischemic events.
Myocardial preservation techniques have evolved in conjunction with cardiac surgery and currently offer substantial protection against myocardial injury. We propose that cardiac preconditioning, a robust, endogenous mechanism of cardioprotection, is emerging as an important adjunct to current cardioplegic techniques. By reviewing the physiologic basis for current cardioplegic strategies, and understanding the cardioprotective benefits of preconditioning, we postulate that cardiac preconditioning may represent an important, clinically accessible component of myocardial protection.
OBJECTIVE: To examine the frequency of cornual pregnancy in patients with prior salpingectomy undergoing IVF. DESIGN: Review. SETTING: Private fertility practice. PATIENTS: Women undergoing IVF. MAIN OUTCOME MEASURE: Cornual ectopic pregnancy. RESULTS: Of 26 ectopic pregnancies detected after ET during a 7-year period, 7 were located in the cornu or tubal stump after prior salpingectomy. CONCLUSIONS: Patients with prior salpingectomy undergoing IVF are at particular risk for cornual pregnancy.
Cardiac preconditioning is mediated by protein kinase C. Although endogenous calcium is a potent stimulus of protein kinase C, it remains unknown whether preischemic administration of exogenous calcium can induce protein kinase C-mediated myocardial protection against ischemia-reperfusion injury. To study this, calcium chloride was administered retrogradely through the aorta at a rate 5 nmol/min for 2 minutes to isolated perfused rat hearts 10 minutes before a 20-minute ischemia and 40-minute reperfusion insult. Calcium-mediated cardioadaptation was then linked to protein kinase C by means of the protein kinase C inhibitor chelerythrine (20 mumol.L-1.2 min-1). To determine whether exogenous calcium administration induces protein kinase C translocation and activation, immunohistochemical staining for the calcium-dependent protein kinase C isoform alpha was performed on adjacent 5 microns myocardial sections with and without calcium chloride treatment. Results indicated that preischemic calcium chloride administration improved myocardial functional recovery, as determined by enhanced developed pressure, improved coronary flow, reduced end-diastolic pressure, and decreased creatine kinase leakage during reperfusion. Beneficial effects of calcium chloride were eliminated by concurrent protein kinase C inhibition. Immunohistochemical staining for the alpha isoform of protein kinase C demonstrated that calcium chloride induces translocation of this isoform from the cytoplasm to the sarcolemma, indicating that exogenous calcium administration activates this isoform. These results suggest that calcium chloride, a safe and routinely administered agent, can induce protein kinase C-mediated cardiac preconditioning. Calcium-induced cardioadaptation to ischemia-reperfusion injury may be promising as a clinically feasible therapy before planned ischemic events such as cardiac allograft preservation and elective cardiac operations.
BACKGROUND: Cardiac preconditioning is an adaptation of cardiomyocytes that promotes tolerance to a subsequent ischemic insult. Adenosine receptor signaling is proposed as a mediator of preconditioning, but its mechanism of protection remains unknown. We hypothesized that protection against hypoxia-reoxygenation (H/R) injury could be conferred in a rat ventricle by adenosine-mediated protein kinase C (PKC) activation and that adenosine-mediated cardioprotection could be extended to human ventricular muscle. METHODS: Isolated rat and human ventricular muscle (VM) strips were subjected to 30 minutes of hypoxia and 60 minutes of reoxygenation (H/R control). The VM was pretreated with 125 mumol/L adenosine, an adenosine antagonist ((p-Sulfophenyl) theophylline [SPT] 50 mumol/L) and adenosine (adenosine + SPT), or with a PKC inhibitor (chelerythrine, 10 mumol/L) and adenosine (adenosine + chelerythrine) before H/R Developed force (DF) and tissue creatine kinase (CK) activity were assessed at end reoxygenation. Human trabeculae were obtained from diseased explanted hearts at cardiac transplantation and were also subjected to H/R injury. Human VM was pretreated with adenosine (125 mumol/L) before H/R injury. Results are expressed as mean +/- standard error of mean. RESULTS: In the rat, adenosine pretreatment conferred protection of DF against H/R injury (adenosine, 62% +/- 6%; H/R control, 27% +/- 2%, p < 0.05). Adenosine + SPT or adenosine + chelerythrine eliminated the functional recovery conferred by adenosine. This recovery of contractile function was associated with greater tissue CK activity (adenosine, 415 +/- 40 units/gm; H/R control, 78 +/- 13 units/gm, p < 0.05). The protective effects of adenosine against H/R were present in the human ventricle and with recovery of DF in adenosine (66% +/- 5%) and H/R control (24% +/- 4%), p < 0.05. CONCLUSIONS: Adenosine, a clinically accessible agonist, induces protection against H/R injury through a PKC-mediated mechanism in the rat ventricle. Further, the protection conferred by adenosine against H/R extends to the human ventricle.
We tested the hypothesis that neutrophils contribute to endotoxin-induced impairment of endothelium-dependent and -independent cyclic guanosine monophosphate (cGMP)-mediated pulmonary vascular smooth muscle relaxation. Rats were studied 6 h after endotoxin (20 mg/kg, intraperitoneal) or saline (1 cc, intraperitoneal). Neutrophil-depleted rats were studied 4 days after administration of vinblastine (750 micrograms/kg, intravenous). Concentration-response curves were generated for acetylcholine and sodium nitroprusside in isolated pulmonary arterial rings (10(-9) M to 10(-6) M). The absolute neutrophil count of controls was 1050 +/- 206 neutrophils/mL, and the absolute neutrophil count of vinblastine-treated rats was 100 +/- 41 neutrophils/mL (p < .05 versus controls) and 25 +/- 25 neutrophils/mL in vinblastine-treated rats receiving endotoxin (p < .05 versus control and endotoxin). Endotoxin-induced impairment of endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation was significantly attenuated by prior treatment with vinblastine. We conclude that neutrophils contribute to the pathogenesis of endotoxin-induced impairment of cGMP-mediated pulmonary vascular smooth muscle relaxation.
Ischemia and ischemic stress hormones induce endogenous cardiac protection against ischemia-reperfusion (I/R) injury. Although ischemia and ischemic stress hormones are accompanied by increased [Ca2+], it is unknown whether either opening of the sarcoplasmic reticular ryanodine Ca2+ channel (SR RyR) or inhibition of Ca2+ uptake by the sarcoendoplasmic reticular Ca(2+)-ATPase (SERCA) prior to I/R can similarly induce post-I/R functional protection. To study this, isolated, crystalloid perfused Sprague-Dawley rat hearts were used to assess the effects of inducing a pre-ischemic [Ca2+]i load by either priming the SR RyR with ryanodine (Ry, 5 nM/2 min) or by transient blockade of the SERCA 10 min prior to global I/R (20 min). A pre-ischemic Ca2+ load by either SR RyR activation or SERCA blockade improved post-ischemic myocardial functional recovery (developed pressure, end diastolic pressure, coronary flow, heart rate, and left ventricular creatine kinase activity). We conclude that 1) Ca(2+)-induced myocardial functional protection involves the SR Ca2+ source, 2) a pre-ischemic Ca2+ load induced with either Ry or thapsigargin constructively primes against myocardial I/R injury, and 3) Ca(2+)-induced cardioadaptation to I/R injury may have important therapeutic implications prior to planned ischemic events such as cardiac allograft preservation and cardiac bypass surgery.
The signal transduction of ischemic preconditioning involves activation of endogenous receptor-based systems, including alpha 1-adrenoceptors and adenosine receptors. Whereas preconditioning protects against ischemia-reperfusion injury, it is unknown whether this protective strategy might be useful clinically. Furthermore, human atrium has been successfully preconditioned, but it is unknown whether human ventricle can be functionally protected against hypoxia-reoxygenation. To study these questions, isolated rat ventricle and human ventricular trabeculae were suspended in an organ bath and subjected to 30 min of hypoxia and 60 min of reoxygenation. In the rat ventricle, preconditioning was induced by 5 min of rapid pacing at 3 Hz in hypoxic buffer without glucose (simulated ischemia), alpha 1-adrenoceptor stimulation (phenylephrine), or adenosine receptor stimulation (adenosine). In the human trabeculae the effects of preceding simulated ischemia and alpha 1-adrenoceptor and adenosine receptor stimulation were examined against hypoxia-reoxygenation. In the rat, pretreatment with simulated ischemia and alpha 1-adrenoceptor and adenosine receptor stimulation improved recovery of developed tension (56 +/- 3, 56 +/- 4, and 58 +/- 2%, respectively) compared with control trabeculae (25 +/- 2%) after hypoxia-reoxygenation (P < 0.05). In human trabeculae, simulated ischemic preconditioning and alpha 1-adrenoceptor and adenosine receptor stimulation augmented recovery of developed tension (65 +/- 5, 59 +/- 6, and 60 +/- 3%, respectively) compared with control (29 +/- 2%) after hypoxia-reoxygenation (P < 0.05). We conclude that functional cardioadaptation (preconditioning) against hypoxia-reoxygenation injury in rat and human myocardium exists and that alpha 1-adrenergic and adenosine receptor signaling participate in conferring this protection.
The effect of neutrophil depletion on endotoxin-induced dysfunction of guanosine 3',5'-cyclic monophosphate (cGMP)-mediated pulmonary vasorelaxation was studied in rats. Two mechanisms of neutrophil depletion were used: vinblastine (0.75 mg/kg iv) and rabbit anti-rat neutrophil antiserum (0.15 ml iv). Concentration-response curves were generated (10(-9) to 10(-6) M) for acetylcholine (ACh), A-23187, and sodium nitroprusside (SNP) in isolated pulmonary arterial rings preconstricted with phenylephrine 6 h after endotoxin (20 mg/kg ip). Absolute neutrophil count was significantly lowered from 1,050 +/- 206 (neutrophils/ml; mean +/- SE) in controls to 100 +/- 41 by vinblastine and to 50 +/- 29 by antiserum. Endotoxin produced histological evidence of pulmonary vascular endothelial damage and significantly increased lung neutrophil accumulation (myeloperoxidase assay, 5.1 +/- 0 vs. 1.2 +/- 0.1 in controls; 0.1 +/- 0.1 and 0.8 +/- 0.0 U/g lung wt after endotoxin in neutrophil-depleted rats by vinblastine and antiserum, respectively). Endotoxin produced significant impairment of endothelium-dependent cGMP-mediated pulmonary vasorelaxation by receptor-dependent (ACh) and -independent (A-23187) pathways as well as endothelium-independent relaxation (SNP). Neutrophil depletion significantly attenuated the endotoxin-induced impairment of all three of these mechanisms. We conclude that neutrophils contribute to endotoxin-induced impairment of GMP-mediated pulmonary vasorelaxation.
Although protein kinase C (PKC)-mediated cardioadaptation to ischemia-reperfusion (IR) is accompanied by increased intracellular Ca2+ concentration, it is unknown whether a preischemia sarcoplasmic reticulum (SR) Ca2+ release affects PKC-mediated post-IR functional protection. To study this, crystalloid-perfused (Langendorff) Sprague-Dawley rat hearts were used to assess the effects of a ryanodine (Ry)-induced preischemia Ca2+ load (Ry, 5 nM/2 min, retrograde coronary) 10 min before global IR (20 min). Ry was administered with and without each of two different PKC inhibitors (20 microM chelerythrine and 150 nM bisindolylmaleimide I-HCl). Ry improved myocardial functional recovery (developed pressure, end-diastolic pressure, coronary flow, and creatine kinase activity), which was eliminated after PKC inhibition. Immunohistochemical staining for PKC isoforms demonstrated that Ry induces specific PKC translocation of alpha-, delta-, and zeta-isoforms. We conclude that 1) a preischemia Ca2+ load from the SR results in post-IR myocardial functional protection 2) Ca(2+)-induced functional protection is PKC regulated via the translocation of specific isoforms, and 3) Ca(2+)-induced cardioadaptation to IR injury may have important therapeutic implications prior to planned ischemic events such as cardiac allograft preservation and cardiac bypass surgery.
Regimens for ovarian stimulation that result in increased circulating follicle-stimulating hormone with low levels of luteinizing hormone produce adequate follicular growth and improved oocyte quality and cycle outcome. Recombinant follicle-stimulating hormone for subcutaneous use and antagonists of gonadotropin-releasing hormone promise to simplify ovarian stimulation in the future.
BACKGROUND: Perihepatic packing has been shown to result in pathologic intra-abdominal hypertension. Although now recognized as impairing abdominal organ perfusion, the extent to which perihepatic packing affects cardiopulmonary function has not been elucidated. METHODS: We analyzed a 3-year experience with 11 patients who sustained major hepatic injuries requiring perihepatic packing to control hemorrhage. Pertinent hemodynamic indices consisting of pulmonary capillary wedge pressure (PCWP), cardiac index (CI), oxygen delivery index (DO2), and systemic vascular resistance (SVR), and pulmonary indices consisting of peak airway pressure (PAP), mean airway pressure (MAP), static compliance (CST), and PaO2/FiO2 were measured in the surgical intensive care unit immediately before and after packs were removed. RESULTS: Unpacking resulted in a significant increase in CI (3.1 +/- 0.4 to 4.2 +/- 0.6 L/min/m2), DO2 (539 +/- 41 to 689 +/- 43 mL min/m2), CST (26 +/- 6 to 36 +/- 4 mL/cm H2O), and PaO2/FiO2 (162 +/- 44 to 237 +/- 53 cm H2O), as well as a significant decrease in PAP (47 +/- 9 to 29 +/- 6 cm H2O), MAP (34 +/- 4 to 27 +/- 3 cm H2O), PCWP (21 +/- 4 to 13 +/- 3 mm Hg), and SVR (1,239 +/- 162 to 887 +/- 130 dyne/cm5). CONCLUSIONS: Abdominal compartment syndrome following temporary perihepatic packing can result in significant cardiopulmonary compromise. While perihepatic packing can be an early life-saving procedure, timely alleviation of the secondary syndrome may be critical to the ultimate salvage of patients with marginal cardiopulmonary reserve.
OBJECTIVE: To evaluate follicular FSH and LH requirements during suppression of endogenous gonadotropins with the GnRH antagonist Nal-Glu and whether LH-like activity could be supplied by administering subcutaneous hCG. DESIGN: Randomized clinical trial. PARTICIPANTS: Thirty-two normally cycling females in the late follicular phase (dominant follicle mean diameter > or = 14 mm). INTERVENTION: Twelve normal women were randomized to receive 150 IU IM FSH with or without 75 IU SC hCG; 11 subjects were randomized to receive 225 IU FSH with or without 50 IU SC hCG; 9 women received 150 or 225 IU IM hMG. Subjects returned the next day for repeat blood sample and ultrasound. RESULTS: Continued follicular maturation, as evidenced by rising E2 levels, correlated with serum immunoactive and bioactive FSH levels and was unrelated to bioactive LH-hCG. Two hundred twenty-five international units of exogenous FSH consistently supported follicular maturation. There was a similar increase in mean follicular diameter in women with an E2 rise versus those with a plateau or fall. In subjects receiving SC mini-dose hCG, serum bioactive LH-hCG levels were increased significantly and were similar to levels before Nal-Glu. CONCLUSIONS: During administration of a GnRH-a, the maturing follicle appears to require only FSH support. In markedly hypogonadotropic women, mini-dose hCG may be a more practical alternative to recombinant LH to promote normal follicle maturation.
OBJECTIVE: To determine whether leuprolide acetate (LA), given subcutaneously at the time of follicular maturity in stimulated cycles, can result in ovulation and in vivo fertilization. STUDY DESIGN: Sixty-seven women underwent 91 cycles of ovarian stimulation (OS) and received a single subcutaneous injection of 1 mg of LA when follicular maturity was reached. Only clomiphene citrate (CC) was used for 15 cycles, CC/FSH for 66 cycles and human menopausal gonadotropin only for 10 cycles. Thirty-four cycles were in oligoovulatory women. Eighty-two cycles were combined with intra-uterine insemination. RESULTS: Viable pregnancies occurred in 21/91 cycles (23%). Forty-two women testing with home urinary luteinizing hormone (LH) kits noted a surge. Seventy-one or 71 cycles demonstrated a biphasic curve. Sixty-eight of 75 cycles demonstrated follicular collapse (91%). Six women had serum LH levels of 12 +/- 4, 136 +/- 22 and 17 +/- 3 mIU/mL before and 12 and 36 hours after LA, respectively. CONCLUSION: LA successfully induced ovulation, fertilization and luteinization in women receiving OS. The pituitary LH response to LA appeared to be normal in women having OS. The pregnancy rate was similar to that generally observed with human chorionic gonadotropin (hCG). A large, prospective, randomized study may be warranted to compare LA to hCG since the subcutaneous route of LA administration and potential for reduced hyperstimulation could be significant advantages, making OS more practical and safe.
Although it is known that decreased high-energy phosphates contribute to organ dysfunction following shock, it remains unknown whether changes in lymphocyte energetics contribute to the profound immune dysfunction that occurs in late septic shock. Moreover, while studies have shown that ATP-MgCl2 treatment after hemorrhagic shock improves tissue ATP levels and organ function, it remains unknown whether lymphocyte high-energy phosphates and immune functions are similarly affected by this agent after sepsis. To study this, sepsis was induced in C3H/HeN (endotoxin sensitive) mice by cecal ligation and puncture (CLP) and they were then treated intraperitoneally with ATP-MgCl2 or saline vehicle. Sham animals received laparotomy, but not CLP. Splenic lymphocytes were harvested 24 hr after treatment and ATP levels were determined by ultraresolution 31P NMR. Lymphocyte proliferative capacity was determined by [3H]-thymidine incorporation following mitogenic stimulation. Host survival was assessed following CLP with and without ATP-MgCl2 treatment. Prolonged sepsis caused a significant decrease (decreases 67 +/- 12% vs Sham) in lymphocyte ATP levels which were correlated with decreased lymphocyte proliferative capacity in response to mitogenic stimulation (64 +/- 17 x 10(3) vs. 232 +/- 43 x 10(3) counts per minute (cpm) in Sham; P < 0.05). Treatment with ATP-MgCl2 at the onset of sepsis significantly increased lymphocyte ATP levels (increases 32 +/- 15% vs CLP) and proliferative response to mitogenic stimuli (218 +/- 37 x 10(3) cpm, CLP/ATP-MgCl2; P < 0.05). Improved lymphocyte function in this group correlated with a significant increase in overall survival (20% CLP vs 70% CLP/ATP-MgCl2; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
We achieved two ongoing pregnancies in five older recipients with natural cycle oocyte donation from five young donors using a GnRH antagonist, with hMG and hCG to complete oocyte maturation. This provides a new alternative to ovarian stimulation for both oocyte donation and routine IVF.