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G Koski

Publications and source records attributed to G Koski.

At least 19 recordsLinked to original sources
PubMed2001

Calcium signaling inhibits interleukin-12 production and activates CD83(+) dendritic cells that induce Th2 cell development.

Mature dendritic cells (DCs), in addition to providing costimulation, can define the Th1, in contrast to the Th2, nature of a T-cell response through the production of cytokines and chemokines. Because calcium signaling alone causes rapid DC maturation of both normal and transformed myeloid cells, it was evaluated whether calcium-mobilized DCs polarize T cells toward a Th1 or a Th2 phenotype. After human monocytes were cultured for 24 hours in serum-free medium and granulocyte-macrophage colony-stimulating factor to produce immature DCs, additional overnight culture with either calcium ionophore (CI) or interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and soluble CD40L resulted in phenotypically mature DCs that produced interleukin-8 (IL-8) and displayed marked expression of CD80, CD86, CD40, CD54, CD83, DC-LAMP, and RelB. DCs matured by IFN-gamma, TNF-alpha, and soluble CD40L were additionally distinguished by undetectable CD4 expression, marked secretion of IL-12, IL-6, and MIP-1beta, and preferential ability to promote Th1/Tc1 characteristics during T-cell sensitization. In contrast, DCs matured by CI treatment were distinguished by CD4 expression, modest or absent levels of IL-12, IL-6, and MIP-1beta, and preferential ability to promote Th2/Tc2 characteristics. Calcium signaling selectively antagonized IL-12 production by mature DCs activated with IFN-gamma, TNF-alpha, and soluble CD40L. Although the activation of DCs by calcium signals is largely mediated through calcineurin phosphatase, the inhibition of IL-12 production by calcium signaling was independent of this enzyme. Naturally occurring calcium fluxes in immature DCs, therefore, negatively regulate Dc1 differentiation while promoting Dc2 characteristics and Th2/Tc2 polarization. Calcium-mobilized DCs may have clinical usefulness in treating disease states with excessive Th1/Tc1 activity, such as graft-versus-host disease or autoimmunity.

Antigens, CD↗
PubMed2001

Variation in institutional review board responses to a standard protocol for a multicenter clinical trial.

UNLABELLED: Multicenter clinical trials require approval by multiple local institutional review boards (IRBs). The Multicenter Airway Research Collaboration mailed a clinical trial protocol to its U.S. investigators and 44 IRBs ultimately reviewed it. OBJECTIVE: To describe IRB responses to one standard protocol and thereby gain insight into the advantages and disadvantages of local IRB review. METHODS: Two surveys were mailed to participants, with telephone follow-up of nonrespondents. Survey 1 was mailed to 82 investigators across North AMERICA: Survey 2 was mailed to investigators from 44 medical centers in 17 U.S. states. Survey 1 asked about each investigator's local IRB (e.g., frequency of meetings, membership), whereas survey 2 asked about IRB queries and concerns related to the submitted clinical trial. RESULTS: Both surveys had 100% response rate. Investigators submitted applications a median of 58 days (interquartile range [IQR], 40--83) after receipt of the protocol, and IRB approval took an additional 38 days (IQR, 26--62). Although eight applications were approved with little or no changes, IRBs requested an average of 3.5 changes per site. Changes involved study logistics and supervision for 45%, the research process for 43%, and the consent form for 91%. Despite these numerous requests, all eventually approved the basic protocol, including inclusion criteria, intervention, and data collection. CONCLUSIONS: The IRBs showed extreme variability in their initial responses to a standard protocol, but ultimately all gave approval. Almost all IRBs changed the consent form. A national, multicenter IRB process might streamline ethical review and warrants further consideration.

Androstadienes↗
PubMed2001

Greg Koski, MD, PhD.

Explore the source record for details and available documents.

Clinical Trials as Topic↗
PubMed2000

Protecting human subjects in research--occasional views along a road less traveled.

Public trust in biomedical research is eroding rapidly because too many investigators participating in human subjects research have failed to take personal responsibility for their actions. In this essay, taken partly from an address to the 66th Annual Research Colloquium of the Massachusetts General Hospital, January 2001, and a presentation to the research community of the Washington University School of Medicine in September, 2000, in St. Louis, Missouri; Greg Koski shares his views about protecting human subjects in biomedical research.

Clinical Trials as Topic↗
PubMed1995

Norepinephrine infusion following cardiopulmonary bypass: effect of infusion site.

The placement of left atrial catheters following cardiopulmonary bypass (CPB) allows accurate monitoring of left ventricular filling pressures, as well as access for the infusion of vasoactive drugs. While the left atrial administration of norepinephrine (NE) is thought to provide higher systemic arterial NE levels while minimizing any pulmonary vasoconstriction, no study critically compares central venous and left atrial NE infusion following cardiopulmonary bypass. A canine model was used to compare central venous and left atrial NE infusion at three dosages (0.2, 0.4, and 0.6 microgram/kg/min) both prior to CPB and following 2 hr of hypothermic CPB at 27 degrees C. Prior to CPB, there was no difference in the hemodynamic efficacy of central venous and left atrial NE infusion at any dosage. The pulmonary circulation metabolized 16-29% of circulating NE. Only at the 0.2 microgram/kg/min dose was there a difference in the arterial NE level between central venous (3474 +/- 486 pg/ml) and left atrial (5504 +/- 751 pg/ml, P = 0.019) NE administration. Above this dose, no difference in the arterial NE level was identified. Following 2 hr of CPB, the pulmonary endothelium metabolized a significantly higher percentage of circulating NE (35-42%). Despite this increased extent of pulmonary metabolism, there was no difference in the hemodynamic efficacy or the resulting arterial NE level of central venous and left atrial NE infusion at a given dose. In conclusion, the results demonstrate: (1) increased pulmonary NE uptake following CPB, and (2) no difference in hemodynamic efficacy between central venous and left atrial NE infusion over a wide range of three doses in a model with normal lungs.

Animals↗
PubMed1995

Calcium administration augments pancreatic injury and ectopic trypsinogen activation after temporary systemic hypotension in rats.

BACKGROUND: Calcium infusion and hypotension have been described as the most important risk factors for pancreatic injury after cardiopulmonary bypass. METHODS: Rats were randomly allocated to three experimental groups undergoing either sham operation and saline infusion (Control, n = 30), hemorrhagic reduction of mean arterial pressure to 30 mmHg for 30 min alone (hypotension, n = 51), or hypovolemic hypotension followed by bolus infusion of CaCl2 (200 mg.kg-1; hypercalcemia, n = 85). Serum ionized calcium, amylase activity, trypsinogen activation peptide in pancreatic tissue homogenates, pancreatic wet/dry weight ratio, histologic changes, and mortality were assessed for 24 h. RESULTS: Control rats showed no significant changes of any parameter throughout the experiments. In contrast, hypotension significantly increased serum amylase (P < 0.001), tissue trypsinogen activation peptide (P < 0.01), wet/dry weight ratio (P < 0.001), and histologic scores for edema (P < 0.001) and pancreatic necrosis (P < 0.05). Subsequent CaCl2 administration transiently increased [Ca2+] (P < 0.001) with the concentration rapidly returning to baseline within 3 h. That infusion of CaCl2 further increased amylase (P < 0.05), tissue trypsinogen activation peptide (P < 0.05), wet/dry weight ratio (P < 0.001), and histologic evidence of pancreatic edema (P < 0.05) and acinar necrosis (P < 0.05) when compared with hypotension alone. Whereas all Control animals survived the experiments, 22% (P < 0.05) and 47% (P < 0.05 vs. hypotension) of animals died in the hypotension and hypercalcemia groups, respectively. CONCLUSIONS: Temporary hypotension alone causes ectopic trypsinogen activation and lethal acute pancreatitis. Super-imposed hypercalcemia significantly aggravates hypotension-induced pancreatic injury and mortality in rats.

Animals↗
PubMed1995

Heparin-enhanced plasma phospholipase A2 activity and prostacyclin synthesis in patients undergoing cardiac surgery.

Although eicosanoid production contributes to physiological and pathophysiological consequences of cardiopulmonary bypass (CPB), the mechanisms accounting for the enhanced eicosanoid production have not been defined. Plasma phospholipase A2 (PLA2) activity, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TXB2) levels were measured at various times during cardiac surgery. Plasma PLA2 activity increased after systemic heparinization, before CPB. This was highly correlated with concurrent increases in plasma 6-keto-PGF1 alpha, TXB2 concentrations did not increase with heparin administration but did increase significantly after initiation of CPB. High plasma PLA2 activity, 6-keto-PGF1 alpha, and TXB2 concentrations were measured throughout the CPB period. Protamine, administered to neutralize the heparin, caused an acute reduction of both plasma PLA2 activity and plasma 6-keto-PGF1 alpha, but no change in plasma TXB2 concentrations. Thus the ratio of TXB2 to 6-keto-PGF1 alpha increased significantly after protamine administration. Enhanced plasma PLA2 activity was also measured in patients with lower doses of heparin used clinically for nonsurgical applications. Human plasma PLA2 was identified as group II PLA2 by its sensitivity to deoxycholate and dithiothreitol, its substrate specificity, and its elution characteristics on heparin affinity chromatography. Heparin addition to PMNs in vitro resulted in dose-dependent increases in cellular PLA2 activity and release of PLA2. The PLA2 released from the PMN had characteristics similar to those of post-heparin plasma PLA2. In conclusion, plasma PLA2 activity and 6-keto-PGF1 alpha concentrations are markedly enhanced with systemic heparinization. Part of the anticoagulant and vasodilating effects of heparin may be due to increased plasma prostacyclin (PGI2) levels. In addition the pulmonary vasoconstriction sometimes associated with protamine infusion during cardiac surgery might be due to decreased plasma PLA2 activity, with an associated increased TXB2/6-keto-PGF1 alpha ratio.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Intrathecal magnesium sulfate protects the spinal cord from ischemic injury during thoracic aortic cross-clamping.

BACKGROUND: Paraplegia is a known complication after surgery on the descending thoracic aorta. Thoracic aortic cross-clamping causes an increase in proximal aortic and cerebrospinal fluid pressures. Sodium nitroprusside, though effectively decreasing proximal aortic pressure, has been implicated in worsening the incidence of paraplegia by further increasing cerebrospinal fluid pressure and decreasing distal blood pressure, thereby reducing spinal cord perfusion pressure. Intravenous administration of magnesium sulfate has been shown to offer some spinal cord protection when used with mild hypothermia. This study investigated the effect of intrathecal magnesium on the prevention of paraplegia when sodium nitroprusside is used to control proximal hypertension during thoracic aortic cross-clamping in a dog model of spinal cord ischemia. METHODS: Two groups of eight dogs underwent thoracic aortic cross-clamping via a small thoracotomy incision for 45 min. Proximal, distal, and central venous pressures and cerebrospinal fluid pressures were monitored. Temperature was maintained at 36 degrees C. Sodium nitroprusside was used to control proximal hypertension. The control group received no magnesium sulfate, and a second group received 3 mg/kg intrathecal magnesium sulfate before thoracic aortic cross-clamping. The dogs were neurologically evaluated 24 h later by an observer blinded to the dogs' group. Spinal cord segments were obtained for histologic examination. RESULTS: Proximal mean arterial pressure, cerebrospinal fluid pressure, spinal cord perfusion pressure, and central venous pressure were not statistically different between the two groups. Neurologic outcome, however, was statistically different between the groups. None of the eight dogs in the magnesium group had any measurable neurologic injury, in contrast to the control group, in which seven of the eight dogs had severe neurologic injury (P < 0.005). Post mortem histologic data supported these findings. CONCLUSIONS: Intrathecal magnesium can prevent spinal cord injury despite markedly negative spinal cord perfusion pressure during thoracic aortic cross-clamping in a canine model of spinal cord ischemia.

Animals↗
PubMed1993

Effect of chronic ethanol on calcium currents and calcium uptake in undifferentiated PC12 cells.

Undifferentiated pheochromocytoma (PC12) cells were chronically exposed to 200 mM ethanol for six days. Parallel cultures were maintained without ethanol. Cells chronically exposed to ethanol had significantly larger voltage-gated calcium currents than those grown in the absence of ethanol. Concurrent radioisotopic flux assays confirm that calcium influx is, indeed, increased in the chronically treated cells. However, acute exposure to ethanol at the same concentration as those used for the chronic studies greatly reduced the magnitude of the currents and net calcium influx.

Animals↗
PubMed1993

Epileptiform activity during opioid anesthesia.

The proconvulsant properties of exogenously administered opioids in man are not established. We prospectively evaluated relationships between epileptiform activity and opioid dose in 20 patients undergoing coronary artery revascularization. Baseline electroencephalograms were performed before surgery. Ten subjects were given fentanyl and 10 sufentanil, at 100 micrograms/kg and 10 micrograms/kg, respectively, in 4 divided doses, 3 min apart. Midazolam (4 mg) was given 3 min after the last dose of narcotic. Serum opioid concentrations were measured by radioimmunoassay. Within 3 min of the first opioid dose, 19 of 20 patients developed epileptiform activity, characterized by generalized single and multiphasic, low-to-moderate voltage spike discharges, similar in appearance to benign epileptiform transients of sleep (BETS). Despite continuously increasing serum concentrations of opioid, the number of spike discharges initially increased during the first and second dose intervals and then declined during the third and fourth dose intervals. This dissociation between epileptiform discharges and measured serum opioid concentration was unexpected and remained unexplained. Spike activity was consistently attenuated (P = 0.000003) within 20 sec of midazolam administration. Abrupt cessation of discharges after administration of the anticonvulsant, midazolam, suggests an epileptogenic mechanism for the opioid-induced activity.

Anesthesia, General↗
PubMed1991

Risk factors for pancreatic cellular injury after cardiopulmonary bypass.

BACKGROUND: Pancreatitis is a known complication of cardiac surgery with cardiopulmonary bypass. Although ischemia is believed to be a factor, the cause of pancreatitis after cardiopulmonary bypass remains unknown. METHODS: We prospectively studied 300 consecutive patients undergoing cardiac surgery with cardiopulmonary bypass. Serum amylase, pancreatic isoamylase, and serum lipase were measured on postoperative days 1,2,3,7, and 10. Pancreatic cellular injury was defined as the presence of hyperamylasemia (greater than 123 U per liter) with an increase in either the serum level of lipase (greater than 24 U per liter) or the peak level of pancreatic isoamylase. Trypsinogen-activation peptides, which indicate intrapancreatic enzyme activation, were measured in the urine of the last 101 patients studied. RESULTS: Evidence of pancreatic cellular injury was detected in 80 patients (27 percent), of whom 23 had associated abdominal signs or symptoms and 3 had severe pancreatitis (2 with pancreatic abscess and 1 with necrotizing hemorrhagic pancreatitis). Two of 19 postoperative deaths were secondary to pancreatitis. In multivariate analyses, the development of pancreatic cellular injury was significantly associated with preoperative renal insufficiency, valve surgery, postoperative hypotension, and perioperative administration of calcium chloride. The administration of more than 800 mg of calcium chloride per square meter of body-surface area was an independent predictor of pancreatic cellular injury, and the increase in risk was dose-related. No differences were found in the level of trypsinogen-activation peptides between patients who had pancreatic cellular injury and those who did not. CONCLUSIONS: Pancreatic cellular injury, as indicated by hyperamylasemia of pancreatic origin, is common after cardiac surgery. The administration of large doses of calcium chloride is an independent predictor of pancreatic cellular injury and may be a cause of it.

Aged↗
PubMed1991

Ethanol-induced inhibition of carbachol-stimulated uptake of calcium in PC12 pheochromocytoma cells.

Using a rapid-quench technique the effects of ethanol on the uptake of 45Ca2+ into PC12 pheochromocytoma cells were studied in suspension. At concentrations achieved during acute intoxication in man (25-100 mM), ethanol inhibited both the carbachol-stimulated and K(+)-induced uptake of calcium. Inhibition of carbachol-stimulated uptake of Ca2+ occurred rapidly, within seconds at 27 degrees C, whereas inhibition of K(+)-induced uptake of Ca2+ developed more slowly. This disparity between the kinetics of these ethanol-induced inhibitions was unexpected, because the uptake of Ca2+, evoked by either stimulus, is thought to occur predominantly through a common pathway, namely voltage-sensitive Ca2+ channels. This difference may reflect differential effects of ethanol on multiple carbachol-activated pathways for entry of Ca2+. Alternatively, carbachol may facilitate the inhibitory action ethanol on voltage-dependent channels. This apparent facilitation was manifested principally by a more rapid onset of inhibition, although the extent of inhibition by ethanol, in the presence of carbachol, was also increased. In preincubation experiments, ethanol did not enhance the apparent agonist-induced desensitization of carbachol-evoked uptake of Ca2+. Nevertheless, an acute interaction between cholinergic agonists and ethanol, affecting homeostasis of Ca2+ may play a role in the pathophysiology of alcohol intoxication.

Calcium↗
PubMed1991

Induction and localization of Plasmodium falciparum stress proteins related to the heat shock protein 70 family.

Induction of heat shock-related stress proteins Pfhsp and Pfgrp, similar in sequence to hsp70 (heat shock protein) and grp78 (glucose-regulated protein), respectively, was studied in culture-derived parasite Plasmodium falciparum. Elevation in temperature from 26 degrees C to 37 degrees C and higher caused significant induction of Pfhsp with a moderate effect on the synthesis of Pfgrp also. Synthesis of Pfgrp, however, was not induced by partial glucose deprivation. On the contrary, lack of glucose in the medium resulted in cessation of protein synthesis in the parasites. Other known inducers of grp synthesis in mammalian cells, i.e., calcium ionophore A23187 and inhibitors of glycosylation (tunicamycin, 2-deoxy glucose) were also without any apparent effect on the synthesis of Pfgrp. Heat shock-induced responses were transient in nature: removal of stress caused repression of these responses. The effect of glucose deprivation was only partially reversible with better recovery if parasites were subjected to glucose starvation at 26 degrees C than at 37 degrees C. Northern blot analysis and in vitro translation of mRNA revealed a parallel increase in the levels of mRNA for Pfhsp upon heat shock. Immuno-gold electron microscopy with cultured parasites revealed nuclear location of Pfhsp and primarily cytoplasmic (probably endoplasmic reticulum) location of Pfgrp. These findings suggest that SDEL (carboxy terminal sequence of Pfgrp) might play a similar role in the cellular localization of Pfgrp as does the sequence KDEL in mammalian cells and HDEL in yeast.

Amino Acid Sequence↗