In heart, NO is produced from L-arginine catalyzed by NO synthase, and CO is formed during the conversion of bilirubin from heme by the action of heme oxygenase. NO, which exerts its biological ...actions through cGMP and heme, has recently been implicated in myocardial protection during ischemia and reperfusion. We hypothesized that the intracellular signaling by NO may be modulated by heme oxygenase.
To test this hypothesis, isolated rat hearts were perfused for 10 minutes with one of the following: (1) buffer alone; (2) 3 mmol/L L-arginine, a precursor for NO; (3) 650 mumol/L zinc protoporphyrin, a heme oxygenase inhibitor; (4) 3 mmol/L L-arginine plus 650 mumol/L zinc protoporphyrin; (5) 15 mumol/L methylene blue, a cGMP inhibitor; or (6) 3 mmol/L L-arginine plus 15 mumol/L methylene blue. Hearts were then made ischemic for 30 minutes, followed by 30 minutes of reperfusion. L-Arginine afforded significant myocardial protection, as evidenced by increased developed pressure (DP) (53.3 +/- 4.3 versus 35.4 +/- 1.8 for control), dP/dtmax (2405 +/- 125 versus 1758 +/- 117 for control), aortic flow (23 +/- 1.5 versus 9.4 +/- 1.6 for control), and coronary flow (CF) (23.0 +/- 0.8 versus 19.0 +/- 1.6 for control) at the end of reperfusion. Protoporphyrin tended to reduce these values compared with L-arginine alone (DP, 27.5 +/- 1.4; dP/dtmax, 1400 +/- 78; CF, 17 +/- 0.5), suggesting a contribution of heme oxygenase in addition to NO for myocardial preservation. Increased mRNAs for the heme oxygenase were noticed in the ischemic reperfused myocardium. Contents of cGMP, the second messenger for NO signaling, increased in the L-arginine group (1.6 +/- 0.1 versus 1.1 +/- 0.1 for control) and were reduced by protoporphyrin. cGMP was completely inhibited by methylene blue, which also retarded postischemic myocardial functional recovery. Malonaldehyde formation, a presumptive marker for free radical generation, was decreased in the L-arginine group (0.053 +/- 0.003) compared with control (0.089 +/- 0.005) but was increased in the protoporphyrin group (0.09 +/- 0.003) compared with the L-arginine group. In vitro studies demonstrated that NO was able to reduce the reactive oxygen species produced by myoglobin, especially oxoferrylmyoglobin, which either are present in heart or are formed in high concentrations during the reperfusion of ischemic myocardium.
The results suggest that NO contributes to myocardial preservation by both cGMP-dependent and cGMP-independent mechanisms, the former being modulated by CO signaling and the latter by virtue of its antioxidant action.
A technique for the processing and quantitation of small volumes of plasma collected in heparinized capillary tubes is presented using a nomogram that determines the final amount of diluent needed ...for variable volumes of plasma.
We evaluated histologic changes associated with chronic impingement of the corpus callosum. Similar callosal impingement has been postulated to be responsible for some of the symptoms in people who ...have hydrocephalus.
Eight rats with callosal impingement produced by surgical implantation of a blunt blade in the interhemispheric fissure and four control animals with no callosal impingement were evaluated by magnetic resonance (MR) imaging and by direct histologic evaluation after autopsy. The histologic evaluations occurred 1 month after surgery in half the animals and 6 months after surgery in the other half.
MR imaging results showed that the implanted blade was in a good position in all animals. Histologically, the corpus callosum appeared normal 1 month after implantation of the impingement blade. Six months after surgery, the experimental group demonstrated decreased callosal thickness and a loss of axonal fibers in the corpus callosum both near and remote to the blade.
Chronic impingement of the corpus callosum was associated with callosal thinning and by loss of callosal axons. Further research will be required to investigate the possible relation of these histologic findings to the clinical findings in normal-pressure hydrocephalus.
A randomized, prospective, multicenter, double-blind, placebo-controlled, phase II clinical trial was performed to determine whether inhibition of leukocyte adherence by administration of monoclonal ...antibody directed against intercellular adhesion molecule-1 would improve burn wound healing.
One hundred ten patients with burn injury ranging from 10% to 30% total body surface area were enrolled. Fifty-six patients received placebo (saline) and 54 patients received murine monoclonal antibody to the human intercellular adhesion molecule-1 (enlimomab). Treatment was initiated within 6 hours of injury. Patients had three distinct partial-thickness wound sites assessed. Laser Doppler flowmetry was used to stratify wounds on the day of injury. Wounds were assessed for healing status on day 21 postburn and categorized as healed, nonhealed, or grafted.
Patients treated with enlimomab had a significantly increased percentage of wounds that healed spontaneously in less than 21 days overall and when stratified by burn wound laser Doppler blood flow readings for those wounds at greatest risk for nonhealing.
These results support the concept that leukocyte adherence is involved in the pathogenesis of burn wound necrosis and suggest a therapeutic mechanism for modulating the inflammatory response after the burn injury that may improve wound healing.
Three different neoplasms of B cell lineage, chronic lymphocytic leukemia, immunoglobulin A (IgA) myeloma and immunoglobulin G (IgG) myeloma were detected in three patients who had heavy occupational ...exposure to asbestos dust. Two of the patients had coexistent pulmonary asbestosis, whereas the third patient had a pleural mesothelioma subsequent to his initial presentation with myeloma. Defective cell-mediated immunity and hyperactivity of B cell function have previously been noted in patients with asbestosis. We suggest the possibility that these asbestos-related immunologic derangements may predispose to the development of immunoproliferative and lymphoproliferative neoplasms, since such tumors have been observed in a variety of other settings, characterized by protracted hyperactivity of the immune system.
We report observations of the Cabibbo suppressed decays B-->D((*))K- using a 10.4 fb(-1) data sample accumulated at the Upsilon(4S) resonance with the Belle detector at the KEKB e(+)e(-) storage ...ring. We find that the ratios of Cabibbo suppressed to Cabibbo favored branching fractions are B(B--->D0K-)/B(B--->D0pi(-)) = 0.079+/-0.009+/-0.006, B(B(0)-->D+K-)/B(B(0)-->D+pi(-)) = 0.068+/-0.015+/-0.007, B(B--->D(*0)K-)/B(B--->D(*0)pi(-)) = 0.078+/-0.019+/-0.009, and B(B(0)-->D(*+)K-)/B(B(0)-->D(*+)pi(-)) = 0.074+/-0.015+/-0.006. These are the first observations of the B-->D+K-, D(*0)K-, and D(*+)K- decay processes.
Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of ...15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca
-independent phospholipase A
β (iPLA
β, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA
β averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPD
) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9
mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant Snca
mice, with decreased iPLA
β expression and a PD-relevant phenotype. Thus, iPLA
β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.
California Assembly Bill AB487 mandates that all practicing physicians are required to obtain 12 h of Continuing Medical Education in Pain Management and End of Life Care before the year 2006 in ...order to renew their state license to practice medicine. In order to determine the effectiveness of this bill in influencing the practice of medicine, we conducted the first of five planned annual Pain Management seminars and utilized physician questionnaires to determine possible practice changes as a result of this seminar. Eighty-one physicians representing 17 multiple specialties of medicine enrolled in this seminar. The topics included: management of malignant and non-malignant pain, pharmacology and management of side effects of opiate and non-opiate analgesics, and adjunctive therapies including depression management and spirituality issues. Physicians were asked to respond to an immediate post-seminar questionnaire and were subsequently queried 4 months following the conference. Fifty-one out of 81 physician registrants responded to an immediate post-attendance questionnaire, and 31 responded to the 4-month follow-up questionnaire. Responses included:
Early
Late
I will change/have changed my practice
34
28
I see no need to change my practice
6
2
I will await further information
7
1
No response regarding practice change
4
Responses of those who changed their practices included:
Increased use of known modalities for pain control
21
Earlier referrals to specialists
14
More attention to psychosocial aspects
14
Use of new drugs/modalities of care
11
This audience represents the most motivated group of practitioners electing to receive Pain Management Education long before the mandated deadline. Sixty-seven percent expressed an interest in changing their practice following this intensive educational experience. Ninety percent responding to the follow-up evaluation indicated that their practices had changed, suggesting that this seminar series is effective in altering physician practice patterns (supported by Cancer Center Support Grant CA 33572 and Sarnat Foundation).
DRG (diagnosis related group) 504 is utilized for patients with extensive burn injuries with skin grafts along with the recent inclusion of patients with nonextensive full-thickness burns with skin ...grafts who require >or=4 days of mechanical ventilation. Since patients with extensive burns and/or inhalation injuries often required ventilator support, we elected to compare demographics, length of stay variables, and hospital charges for patients assigned to DRG 504 based upon the length of ventilator support. The American Burn Association's National Burn Repository was queried for all inpatients admitted from January 2000 through December 2001 and who were assigned to DRG 504. Demographic, resource utilization, and financial data were analyzed based upon the need for >or=96 hrs of mechanical ventilation. One hundred seven patients were identified of which 94 (87.9%) required >or=96 hrs of mechanical ventilation. While patients with inhalation injuries required significantly more days of ventilator support, length of stay and hospital charges were nearly identical. Patients who required >or=96 hrs of ventilator support, had a 10-fold greater number of ventilator and intensive care unit days (P < 0.0001) and twice the length of hospitalization (P < 0.005) and hospital charges (P < 0.05) for their care compared to those requiring <96 hrs of ventilator support. Burn patients requiring endotracheal intubation and >or=96 hrs of ventilator support during their acute hospitalization consume significantly greater resources than those who do not require such treatment. The Center for Medicare & Medicaid Services should consider modifying DRG 504 for patients with extensive burns to permit a more appropriate resource-based reimbursement to burn center hospitals.
Alzheimer’s disease (AD) is a complex neurodegenerative disorder marked by numerous causative factors of disease progression, termed pathologies. We report here the synthesis of a small library of ...novel sym-triazine compounds designed for targeted modulation of multiple pathologies related to AD, specifically human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and Aβ aggregation. Rational targeting of AChE was achieved by the incorporation of acetylcholine substrate analogues into a sym-triazine core in either a mono-, di-, or trisubstituted regime. A subset of these derivatives demonstrated improved activity compared to several commercially available cholinesterase inhibitors. High AChE/BuChE selectivity was characteristic of all derivatives, and AChE steady-state kinetics indicated a mixed-type inhibition mechanism. Further integration of multiple hydrophobic phenyl units allowed for improved β-sheet intercalation into amyloid aggregates. Several highly effective structures exhibited fibril inhibition greater than the previously reported β-sheet-disrupting penta-peptide, iAβ5p, evaluated by thioflavin T fluorescence spectroscopy and transmission electron microscopy. Highly effective sym-triazines were shown to be well tolerated by differentiated human neuronal cells, as demonstrated by the absence of adverse effects on cellular viability at a wide range of concentrations. Parallel targeting of multiple pathologies using sym-triazines is presented here as an effective strategy to address the complex, multifactorial nature of AD progression.
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