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Biomedical subjects

J O'Toole

Publications and source records attributed to J O'Toole.

17 recordsLinked to original sources
PubMed2004

Improving the delivery of continuous renal replacement therapy using regional citrate anticoagulation.

AIMS: Regional citrate anticoagulation during acute renal replacement therapy (RRT) effectively prevents extracorporeal thrombosis and avoids bleeding risk. There have been a number of citrate anticoagulation protocols published; but a simple and predictable scheme with standardized components and procedures, as well as clearly defined citrate pharmacokinetics, is needed for continuous RRT (CRRT) that is now used frequently in the critical care setting. The present study sets forth methodology with standardized blood flow and dialysate composition, and with citrate and calcium infusions that are quantitatively linked to extracorporeal blood flow rate--a predictable and easily replicated CRRT paradigm. MATERIALS AND METHODS: CRRT using continuous venovenous hemofiltration with dialysis (CVVHD) was standardized using 150-200 ml/min blood flow, calcium-free dialysate with only moderate sodium (135 mEq/l) and bicarbonate (28 mEq/l) concentrations, and ultrafiltration limited to that needed for overall fluid balance in the intensive care unit. Citrate infusion (ACD-A solution) into the extracorporeal blood and calcium repletion in blood returned to the patient were proportional to blood flow. Anticoagulation was accomplished by keeping extracorporeal ionized calcium below 0.4 mM/l. Filter performance, citrate removal and changes in calcium, sodium and alkali were evaluated longitudinally. RESULTS: CVVHD using this protocol delivered urea clearance exceeding 2 l/h (48 l/d) when filter function was sustained. Filter longevity was markedly improved using citrate when compared with standard heparin anticoagulation, and nursing time spent on initiating and troubleshooting CRRT was approximately halved using this protocol. Sieving coefficients for urea, creatinine and citrate were approximately 0.9 and were sustained through nearly 3 days of filter use. Citrate clearance and removal were quantitatively linked to dialysate and ultrafiltration flow, resulting in 35-50% direct removal of the citrate-calcium chelate and reduced systemic citrate load. Serum tonicity and acid-base status were not problematic. The only notable side effect was modest calcium accumulation that necessitated reduction in calcium repletion rate. CONCLUSIONS: CVVHD is well suited to regional citrate anticoagulation. The present protocol is straightforward and predictable, with minor metabolic consequences that can be anticipated and adjusted. These results commend regional citrate anticoagulation to wider application.

Aged↗
PubMed1999

Induction and prevention of apoptosis in human HEp-2 cells by herpes simplex virus type 1.

Cultured human epithelial cells infected with an ICP27 deletion strain of herpes simplex virus type 1 (HSV-1) show characteristic features of apoptotic cells including cell shrinkage, nuclear condensation, and DNA fragmentation. These cells do not show such apoptotic features when infected with a wild-type virus unless the infections are performed in the presence of a protein synthesis inhibitor. Thus, both types of virus induce apoptosis, but the ICP27-null virus is unable to prevent this process from killing the cells. In this report, we show that this ICP27-deficient virus induced apoptosis in human HEp-2 cells through a pathway which involved the activation of caspase-3 and the processing of the death substrates DNA fragmentation factor and poly(ADP-ribose) polymerase. The induction of apoptosis by wild-type HSV-1 occurred prior to 6 h postinfection (hpi), and de novo viral protein synthesis was not required to induce the process. The ability of the virus to inhibit apoptosis was shown to be effective between 3 to 6 hpi. Wild-type HSV-1 infection was also able to block the apoptosis induced in cells by the addition of cycloheximide, staurosporine, and sorbitol. While U(S)3- and ICP22-deficient viruses showed a partial prevention of apoptosis, deletion of either the U(L)13 or vhs gene products did not affect the ability of HSV-1 to prevent apoptosis in infected cells. Finally, we demonstrate that in UV-inactivated viruses, viral binding and entry were not sufficient to induce apoptosis. Taken together, these results suggest that either gene expression or another RNA metabolic event likely plays a role in the induction of apoptosis in HSV-1-infected human cells.

Animals↗
PubMed1999

Treasure Weekend: supporting bereaved siblings.

The importance of allowing bereaved siblings the opportunity to be involved and mourn the loss of a sibling family member has gained increasing recognition. Child family members may need support in the same way that parents might need support to cope with a devastating loss. However, there are often few support services specifically focused to support bereaved children. Therefore, this article describes how a children's hospice provides specific support for bereaved siblings, by providing an opportunity for bereaved siblings to share a residential support weekend, known as the Treasure Weekend. The article describes the rationale, aims and the experience of the children's hospice, in facilitating this support service.

Adolescent↗
PubMed1998

Anti-B4-blocked ricin: a phase II trial of 7 day continuous infusion in patients with multiple myeloma.

This phase II trial was undertaken to determine the toxicities, response rate, pharmacokinetics and frequency of human anti-mouse antibody (HAMA) and anti-ricin antibody (HARA) when the B-cell restricted immunotoxin anti-B4-bR was administered to patients with previously treated multiple myeloma (MM). Five patients with MM were scheduled to receive a 7 d continuous infusion of anti-B4-bR. The initial four patients received therapy at 40 microg/kg lean body weight (LBW)/d. Two patients received a 7 d infusion, one patient received 6 d, and another patient 5 d of therapy. The fifth patient was treated for 7 d at a lower dose of 30 microg/kg LBW/d because of the side-effects observed in the initial patients. Pharmacokinetic studies demonstrated a peak serum level >2.6 nM in three of the patients. Side-effects of therapy included hepatic transaminase elevations, myalgias, thrombocytopenia, nausea, vomiting, decrease in performance status, and capillary leak syndrome. One patient developed HAMA and two patients HARA. One patient developed neurologic toxicity with akinetic mutism, and died following therapy. No patient demonstrated a significant decline in M-component during therapy. We concluded that anti-B4-bR can be administered by continuous infusion to patients with multiple myeloma, although immunotoxin levels >3 nM were associated with increased incidence of toxicity and required dose adjustment. Future trials using anti-B4-bR in MM will be needed to determine the optimal dose and administration schedule in this patient population, and to determine whether there is evidence of biologic activity.

Adult↗
PubMed1998

Metabotropic glutamate receptor agonists potentiate cyclic AMP formation induced by forskolin or beta-adrenergic receptor activation in cerebral cortical astrocytes in culture.

The metabotropic glutamate receptor (mGluR) agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) potentiated the accumulation of cyclic AMP induced by either beta-adrenergic receptor stimulation (isoproterenol) or direct activation of adenylyl cyclase (AC) with forskolin in rat cerebral cortical astrocytes grown in a defined medium. In contrast, ACPD inhibits the cyclic AMP response in astrocytes cultured in a serum-containing medium. Pharmacological characterization indicated that a group I mGluR, of which only mGluR5 is detectable in these cells, is involved in the potentiation of cyclic AMP accumulation. Potentiation was elicited by mGluR I agonists [e.g., (R,S)-3,5-dihydroxyphenylglycine (DHPG)], but not by mGluR II or III agonists; it was pertussis toxin resistant and abolished by procedures suppressing mGluR5 function (phorbol ester pretreatment or DHPG-induced receptor down-regulation). Nevertheless, it appears that products generated through the mGluR5 transduction pathway, such as elevated [Ca2+]i or activated protein kinase C (PKC), are not involved in the potentiation as it was not influenced by either the intracellular calcium chelator BAPTA-AM or the PKC inhibitor Ro 31-8220. An inhibitor of phospholipase C, U-73122, markedly attenuated mGluR5-activated phosphoinositide hydrolysis but did not significantly affect the DHPG potentiation of the cyclic AMP response. A mechanism is proposed in which the potentiating effect on AC could be mediated by free betagamma complex that is liberated after the agonist-bound mGluR5 interacts with its coupled G protein.

Adenylyl Cyclases↗
PubMed1994

Rational design of high affinity tachykinin NK1 receptor antagonists.

The rational design of a non-peptide tachykinin NK1 receptor antagonist, [(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)P h (28, PD 154075) is described. Compound 28 has a Ki = 9 and 0.35 nM for the NK1 receptor binding site in guinea-pig cerebral cortex membranes and human IM9, cells respectively (using [125I] Bolton-Hunter-SP as the radioligand). It is a potent antagonist in vitro where it antagonises the contractions mediated by SPOMe in the guinea-pig ileum (KB = 0.3 nM). Compound 28 is active in vivo in the guinea-pig plasma extravasation model, where it is able to block the SPOMe-induced protein plasma extravasation (monitored by Evans Blue) in the bladder with an ID50 of 0.02 mg kg-1 iv.

Animals↗
PubMed1993

The synthesis of 2,3-dideoxy-2-fluoro-3-C-methylpentose-containing nucleosides via [3,3]-sigmatropic rearrangements.

[3,3]-Sigmatropic rearrangement of in situ-formed [O,O]-silyl ketene acetals of butenyl fluoroacetates was used as the key step in the synthesis of racemic 2,3-dideoxy-2-fluoro-3-C-methylpentofuranoses. The product pentofuranoses were transformed further into pyrimidine and purine nucleosides. The conformations of the synthetic carbohydrates were confirmed by single-crystal X-ray diffraction studies and indicated that previous structural assignments made by NMR were in error.

Crystallography, X-Ray↗
PubMed1991

Parental education and child mortality in Burundi.

This paper examines the relationship between parental education and child mortality in Burundi using data collected in the 1987 Demographic and Health Survey. Proportional hazards models are estimated to examine this relationship, while holding constant other known child mortality determinants. Parental education proves to be a key factor in explaining differences in child mortality, the effect of maternal education being particularly strong compared to paternal education.

Birth Order↗
PubMed1990

Initial report of the National Registry of Elective Cardiopulmonary Bypass Supported Coronary Angioplasty.

Relative contraindications to coronary angioplasty have been large amounts of jeopardized myocardium and poor left ventricular function. To prevent possible hemodynamic collapse after balloon occlusion or acute vessel closure in such high risk patients, a cardiopulmonary bypass system capable of providing up to 6 liters/min output was employed prophylactically. This technique, termed supported angioplasty, results in reductions of preload and afterload and allows prolonged balloon inflations in critical coronary vessels. A National Registry of 14 centers performing elective supported angioplasty was formed to collate the initial experience with high risk patients. Suggested indications were ejection fraction less than 25% or a target vessel supplying more than half the myocardium, or both. During 1988, the data from 105 patients (mean age 62 years) undergoing supported angioplasty were entered into the Registry. This group included 20 patients whose disease was deemed too severe to permit bypass surgery and 30 patients who had dilation of their only patent coronary vessel. Seventeen patients had stenosis of the left main coronary artery and 15 underwent dilation of that vessel. Chest pain and electrocardiographic changes occurred uncommonly despite prolonged balloon inflations. During the trial, there was a progressive change from cutdown insertion to percutaneous insertion of the circulatory support cannulas. The angioplasty success rate was 95% for the 105 patients, who underwent an average of 1.7 dilations per patient. Morbidity was frequent (41 patients), in most cases due to arterial, venous or nerve injury associated with cannula insertion or removal, or both.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon, Coronary↗
PubMed1988

Endocarditis due to six entrapped pacemaker leads and concomitant recurrent coronary arteriosclerosis.

A case of endocarditis associated with six entrapped endocardial pacer leads is presented. Because of many failed attempts at removing them by conservative measures, cardiopulmonary bypass was needed; concomitant redo coronary bypass grafts were done. To our knowledge, this represents a unique case, the like of which has not been reported previously. Salient features of management are discussed.

Cardiopulmonary Bypass↗
PubMedDate not supplied

Don't hire the wrong CEO.

A disturbing trend is going on in corporate America--CEO churning. Top executives are rapidly coming and going, keeping their jobs for increasingly shorter periods of time. The reason? Most boards are so unclear about the definition of leadership, they are picking the wrong people. CEO churning needn't be, say leadership experts Warren Bennis and James O'Toole. Boards can reverse the trend by following several guidelines. First, boards must come to a shared, accurate definition of leadership. Simply put, leaders must be able to move human hearts--to challenge people and make them want to scale steep peaks. Second, boards should strengthen the CEO selection process by resolving strategic and political conflicts amongst themselves. An agreed-upon strategic direction will make choosing the CEO with the right vision for the company that much easier and can clarify the job for the new CEO. Third, the board needs to measure every CEO candidate's soft qualities. Economic measures are important, but integrity, the ability to provide meaning, and the talent for creating other leaders are critical. Fourth, boards should beware of candidates who act like CEOs. Charisma and glossy pitches can be enticing, but they're rarely the stuff of true leadership. Fifth, boards should accept that real leaders will more than likely overturn the status quo. Sixth, boards need to know that insider heirs usually aren't apparent, and finally, boards should always avoid making a hasty decision. Hiring the right CEO is a slow process at best. Ultimately, the surest way for boards to pick the right CEO is to cultivate and nurture talent in the making.

Administrative Personnel↗