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Biomedical subjects

G Cohen

Publications and source records attributed to G Cohen.

At least 55 records · Page 3Linked to original sources
PubMed2001

Sheathless technique of Ash Split-Cath insertion.

A novel technique for insertion of the Ash Split-Cath without a peel-away sheath to decrease the potential for air embolism is described. A retrospective review of 62 attempted Ash Split-Cath insertions at three hospitals was made. Conversion to the usual technique using a sheath was necessary in four cases, mostly because of extensive scarring from previous catheters. There was no air embolus, hematoma, or immediate catheter malfunction. The authors believe that the occurrence of air embolism during placement of Ash Split-Cath may be lessened by eliminating the use of a peel-away sheath.

Catheterization, Central Venous↗
PubMed2001

Defining the disulphide stress response in Streptomyces coelicolor A3(2): identification of the sigmaR regulon.

In the Gram-positive, antibiotic-producing bacterium Streptomyces coelicolor A3(2), the thiol-disulphide status of the hyphae is controlled by a novel regulatory system consisting of a sigma factor, sigmaR, and its cognate anti-sigma factor, RsrA. Oxidative stress induces intramolecular disulphide bond formation in RsrA, which causes it to lose affinity for sigmaR, thereby releasing sigmaR to activate transcription of the thioredoxin operon, trxBA. Here, we exploit a preliminary consensus sequence for sigmaR target promoters to identify 27 new sigmaR target genes and operons, thereby defining the global response to disulphide stress in this organism. Target genes related to thiol metabolism encode a second thioredoxin (TrxC), a glutaredoxin-like protein and enzymes involved in the biosynthesis of the low-molecular-weight thiol-containing compounds cysteine and molybdopterin. In addition, the level of the major actinomycete thiol buffer, mycothiol, was fourfold lower in a sigR null mutant, although no candidate mycothiol biosynthetic genes were identified among the sigmaR targets. Three sigmaR target genes encode ribosome-associated products (ribosomal subunit L31, ppGpp synthetase and tmRNA), suggesting that the translational machinery is modified by disulphide stress. The product of another sigmaR target gene was found to be a novel RNA polymerase-associated protein, RbpA, suggesting that the transcriptional machinery may also be modified in response to disulphide stress. We present DNA sequence evidence that many of the targets identified in S. coelicolor are also under the control of the sigmaR homologue in the actinomycete pathogen Mycobacterium tuberculosis.

Amino Acid Sequence↗
PubMed2001

Uremic toxins modulate the spontaneous apoptotic cell death and essential functions of neutrophils.

Clearance of neutrophils via apoptosis from the site of infection is crucial for the coordinated resolution of inflammation. The balance between stimulating and attenuating as well as between pro- and anti-apoptotic factors is necessary for maintenance of an effective immune response without the harmful side effects of neutrophil action. This article describes the effect of glucose-modified serum proteins and of free immunoglobulin light chains (IgLCs) on neutrophil functions and apoptosis. Both groups of proteins are found at elevated levels in sera of uremic patients. Glucose-modified proteins increase both the chemotactic movement of neutrophils and the activation of glucose uptake. Spontaneous neutrophil apoptosis is increased in the presence of these modified serum proteins. On the other hand, the presence of free IgLCs, previously shown to diminish neutrophil chemotaxis and the activation of glucose uptake, increase the percentage of viable neutrophils by inhibiting spontaneous apoptotic cell death. We conclude that both glucose-modified proteins and free IgLCs can be considered to be uremic toxins and both contribute to the disturbed immune function in uremic patients. Their concentrations as well as the microenvironment in which they are acting seem to be important for their actual effects.

Apoptosis↗
PubMed2001

Reoperative coronary bypass surgery: effect of patent grafts and retrograde cardioplegia.

OBJECTIVE: To determine the effects of patent or diseased aorta-coronary bypass grafts and retrograde cardioplegia on mortality during reoperative coronary bypass surgery. METHODS: We conducted a retrospective review of prospectively gathered data, supplemented by systematic chart review, of all patients (n = 744) undergoing reoperative coronary bypass surgery at our institution between 1990 and 1997. Independent predictors of survival were determined by stepwise logistic regression analysis. RESULTS: At least one patent or stenosed graft to the left anterior descending artery was present in 50% of patients, to the circumflex territory in 27% of patients, and to the right coronary artery territory in 33% of patients. The previous left anterior descending graft was a saphenous vein in 82% and a left internal thoracic artery in 18% of patients. In-hospital mortality occurred in 42 (5.6%) patients. Patent or diseased grafts of any coronary artery territory did not significantly increase the risk of mortality. Retrograde cardioplegia use increased in more recent years, was more frequent in patients with stenosed grafts, and was associated with improved survival. Independent predictors of mortality were as follows (with odds ratios and 95% confidence intervals in parentheses): failure to use retrograde cardioplegia (odds ratio 2.81; 1.28-6.20), New York Heart Association class (odds ratio 2.69; 1.25-5.81), peripheral vascular disease (odds ratio 2.60; 1.25-5.41), and left ventricular grade (2.07; 1.31-3.27). CONCLUSIONS: In this series, patent or stenosed grafts were not associated with an increased risk of mortality during reoperative coronary bypass surgery, possibly because of increased use of retrograde cardioplegia in this patient group. We strongly recommend the routine use of retrograde cardioplegia during redo coronary bypass surgery.

Coronary Artery Bypass↗
PubMed2001

Late results of heart valve replacement with the Hancock II bioprosthesis.

OBJECTIVE: To review the late clinical outcomes of patients who had isolated aortic or mitral valve replacement with the Hancock II bioprosthesis. METHODS: From 1982 to 1994, 670 patients underwent isolated aortic valve replacement and 310 underwent isolated mitral valve replacement with the Hancock II bioprosthesis (Medtronic Inc, Minneapolis, Minn). Mean age was 65 +/- 12 years in both groups. Most patients were in New York Heart Association functional classes III or IV, and concomitant coronary artery disease was present in 44% of patients in the aortic valve group and 41% of patients in the mitral valve group. Patients were followed up prospectively at periodic intervals. Mean follow-up was 87 +/- 45 months in the aortic valve group and 83 +/- 50 months in the mitral valve group, and it was 99% complete. RESULTS: Actuarial survival at 15 years was 47% +/- 3% in the aortic valve group and 30% +/- 5% in the mitral valve group. Older age, advanced functional class, impaired left ventricular function, active endocarditis, and coronary artery disease were independent predictors of late death. The freedom from thromboembolic complications at 15 years was 83% +/- 3% in the aortic and 87% +/- 3% in the mitral valve group. The freedom from infective endocarditis at 15 years was 96% +/- 1% in the aortic and 91% +/- 1% in the mitral valve group. At 15 years, the actuarial and actual freedom from structural valve deterioration was 81% +/- 5% and 90% +/- 3%, respectively, in the aortic group and 66% +/- 6% and 83% +/- 3%, respectively, in the mitral group. Younger age, mitral valve position, and poor ventricular function were independent predictors of structural valve deterioration. The freedom from repeat valve replacement at 15 years was 77% +/- 5% in the aortic group and 69% +/- 6% in the mitral. The vast majority of patients had functional improvement after valve replacement. CONCLUSIONS: The Hancock II bioprosthesis has provided good clinical outcomes and is a durable valve, particularly in the aortic position in older patients.

Adolescent↗
PubMed2001

Is profound hypothermia required for storage of cardiac allografts?

BACKGROUND: Improved methods of cardiac allograft protection are required to expand the pool of potentially available organs and to enhance the recovery of grafts subjected to prolonged ischemia. We have previously demonstrated that limited coronary perfusion provided by donor blood harvested at the time of organ procurement can improve both metabolic and functional recovery after transplantation. In this study we evaluated the hypothesis that limited coronary perfusion may enable prolonged cardiac storage while avoiding the potentially detrimental effects of profound hypothermia. METHODS: Fourteen orthotopic cardiac transplants were performed in female Yorkshire pigs by using donor blood perfusion during 5 hours of either tepid (25 degrees C) or cold (4 degrees C) storage. Assessments of myocardial metabolism and function were performed at baseline and after 45 minutes of normothermic (37 degrees C) reperfusion. RESULTS: Hearts protected with tepid perfusion displayed improved recovery of myocardial function (89% +/- 18% vs 63% +/- 25%, P =.05). Diastolic compliance was adversely affected in both groups after transplantation. Aerobic myocardial metabolism was better preserved in the tepid group. CONCLUSIONS: Profound hypothermia results in depressed myocardial metabolic and functional recovery after transplantation. Limited coronary perfusion with shed donor blood can permit cardiac allograft storage at tepid temperatures, resulting in improved myocardial performance.

Animals↗
PubMed2001

Analysis of transcription of the Staphylococcus aureus aerobic class Ib and anaerobic class III ribonucleotide reductase genes in response to oxygen.

Staphylococcus aureus is a gram-positive facultative aerobe that can grow in the absence of oxygen by fermentation or by using an alternative electron acceptor. To investigate the mechanism by which S. aureus is able to adapt to changes in oxygen concentration, we analyzed the transcriptional regulation of genes that encode the aerobic class Ib and anaerobic class III ribonucleotide reductase (RNR) systems that are responsible for the synthesis of deoxyribonucleotides needed for DNA synthesis. The S. aureus class Ib RNR nrdIEF and class III RNR nrdDG genes and their regulatory regions were cloned and sequenced. Inactivation of the nrdDG genes showed that the class III RNR is essential for anaerobic growth. Inhibition of aerobic growth by hydroxyurea showed that the class Ib RNR is an oxygen-dependent enzyme. Northern blot analysis and primer extension analysis demonstrated that transcription of class III nrdDG genes is regulated by oxygen concentration and was at least 10-fold higher under anaerobic than under aerobic conditions. In contrast, no significant effect of oxygen concentration was found on the transcription of class Ib nrdIEF genes. Disruption or deletion of S. aureus nrdDG genes caused up to a fivefold increase in nrdDG and nrdIEF transcription under anaerobic conditions but not under aerobic conditions. Similarly, hydroxyurea, an inhibitor of the class I RNRs, resulted in increased transcription of class Ib and class III RNR genes under aerobic conditions. These findings establish that transcription of class Ib and class III RNR genes is upregulated under conditions that cause the depletion of deoxyribonucleotide. Promoter analysis of class Ib and class III RNR operons identified several inverted-repeat elements that may account for the transcriptional response of the nrdIEF and nrdDG genes to oxygen.

Aerobiosis↗
PubMed2001

Uremic toxicity: present state of the art.

The uremic syndrome is a complex mixture of organ dysfunctions, which is attributed to the retention of a myriad of compounds that under normal condition are excreted by the healthy kidneys (uremic toxins). In the area of identification and characterization of uremic toxins and in the knowledge of their pathophysiologic importance, major steps forward have been made during recent years. The present article is a review of several of these steps, especially in the area of information about the compounds that could play a role in the development of cardiovascular complications. It is written by those members of the Uremic Toxins Group, which has been created by the European Society for Artificial Organs (ESAO). Each of the 16 authors has written a state of the art in his/her major area of interest.

Cardiovascular Diseases↗
PubMed2000

Postimplantation dosimetric analysis of permanent transperineal prostate implantation: improved dose distributions with an intraoperative computer-optimized conformal planning technique.

PURPOSE: To compare the target coverage and dose to normal tissues after I-125 transperineal permanent implantation (TPI) of the prostate in 90 patients treated with one of three different transperineal techniques. METHODS AND MATERIALS: Detailed postimplant dosimetric evaluations of permanent I-125 implantation procedures were performed on 30 consecutive patients treated between 1995-1996 who underwent TPI using a preplanning CT-based technique, on 30 consecutive patients treated in 1997-1998 who underwent an ultrasound-guided approach with intraoperative determination of seed distribution based on an I-125 nomogram, and on 30 consecutive patients in 1998-1999 who underwent TPI with intraoperative computer-based 3-dimensional conformal optimization. For all three techniques, postimplant CT scans were obtained 4-6 hours after TPI. Dosimetric parameters included V(100), V(90), V(150), D(100), D(90), D(80), as well as maximal and average doses to the urethra and rectal wall. These parameter outcomes are reported as a percentage of the prescription dose. RESULTS: The intraoperative 3D-optimized technique (I-3D) provided superior target coverage with the prescription dose for all dosimetric variables evaluated compared to the other treatment techniques. The median V(100), V(90), and D(90) values for the I-3D technique were 96%, 98%, and 116%, respectively. In contrast, the V(100), V(90), and D(90) values for the CT preplan and ultrasound manual optimization approaches were 86%, 89%, and 88%, respectively and 88%, 92%, and 94%, respectively (I-3D versus other techniques: p < 0.001). The superior target coverage with the I-3D technique was also associated with a higher cumulative implant activity required by the optimization program. A multivariate analysis determined that the treatment technique (I-3D versus other approaches) was an independent predictor of improved target coverage for each parameter analyzed (p < 0.001). In addition, higher cumulative implant activities and smaller prostate target volumes were independent predictors of improved target coverage. The maximum and average urethral doses were significantly lower with the I-3D technique compared to the other techniques; a modest increase in the average rectal dose was also observed with this approach. CONCLUSION: Three-dimensional intraoperative computer optimized TPI consistently provided superior target coverage with the prescription dose and significantly lower urethral doses compared to two other techniques used. These data provide proof-of-principle that improved therapeutic ratios can be achieved with the integration of more sophisticated intraoperative planning for TPI and may potentially have a profound impact on the outcome of patients treated with this modality.

Algorithms↗
PubMed2000

Structure-function studies of the non-heme iron active site of isopenicillin N synthase: some implications for catalysis.

Isopenicillin N synthase (IPNS) is a non-heme ferrous iron-dependent oxygenase that catalyzes the ring closure of delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to form isopenicillin N. Spectroscopic studies and the crystal structure of IPNS show that the iron atom in the active species is coordinated to two histidine and one aspartic acid residues, and to ACV, dioxygen and H2O. We previously showed by site-directed mutagenesis that residues His212, Asp214 and His268 in the IPNS of Streptomyces jumonjinensis are essential for activity and correspond to the iron ligands identified by crystallography. To evaluate the importance of the nature of the protein ligands for activity, His214 and His268 were exchanged with asparagine, aspartic acid and glutamine, and Asp214 replaced with glutamic acid, histidine and cysteine, each of which has the potential to bind iron. Only the Asp214Glu mutant retained activity, approximately 1% that of the wild type. To determine the importance of the spatial arrangement of the protein ligands for activity, His212 and His268 were separately exchanged with Asp214; both mutant enzymes were completely defective. These findings establish that IPNS activity depends critically on the presence of two histidine and one carboxylate ligands in a unique spatial arrangement within the active site. Molecular modeling studies of the active site employing the S. jumonjinensis IPNS crystal structure support this view. Measurements of iron binding by the wild type and the Asp214Glu, Asp214His and Asp214Cys-modified proteins suggest that Asp214 may have a role in catalysis as well as in iron coordination.

Amino Acid Substitution↗
PubMed2000

Treatment planning for prostate implants using magnetic-resonance spectroscopy imaging.

PURPOSE: Recent studies have demonstrated that magnetic-resonance spectroscopic imaging (MRSI) of the prostate may effectively distinguish between regions of cancer and normal prostatic epithelium. This diagnostic imaging tool takes advantage of the increased choline plus creatine versus citrate ratio found in malignant compared to normal prostate tissue. The purpose of this study is to describe a novel brachytherapy treatment-planning optimization module using an integer programming technique that will utilize biologic-based optimization. A method is described that registers MRSI to intraoperative-obtained ultrasound images and incorporates this information into a treatment-planning system to achieve dose escalation to intraprostatic tumor deposits. METHODS: MRSI was obtained for a patient with Gleason 7 clinically localized prostate cancer. The ratios of choline plus creatine to citrate for the prostate were analyzed, and regions of high risk for malignant cells were identified. The ratios representing peaks on the MR spectrum were calculated on a spatial grid covering the prostate tissue. A procedure for mapping points of interest from the MRSI to the ultrasound images is described. An integer-programming technique is described as an optimization module to determine optimal seed distribution for permanent interstitial implantation. MRSI data are incorporated into the treatment-planning system to test the feasibility of dose escalation to positive voxels with relative sparing of surrounding normal tissues. The resultant tumor control probability (TCP) is estimated and compared to TCP for standard brachytherapy-planned implantation. RESULTS: The proposed brachytherapy treatment-planning system is able to achieve a minimum dose of 120% of the 144 Gy prescription to the MRS positive voxels using (125)I seeds. The preset dose bounds of 100-150% to the prostate and 100-120% to the urethra were maintained. When compared to a standard plan without MRS-guided optimization, the estimated TCP for the MRS-optimized plan is superior. The enhanced TCP was more pronounced for smaller volumes of intraprostatic tumor deposits compared to estimated TCP values for larger lesions. CONCLUSIONS: Using this brachytherapy-optimization system, we could demonstrate the feasibility of MRS-optimized dose distributions for (125)I permanent prostate implants. Based on probability estimates of anticipated improved TCP, this approach may have an impact on the ability to safely escalate dose and potentially improve outcome for patients with organ-confined but aggressive prostatic cancers. The magnitude of the TCP enhancement, and therefore the risks of ignoring the MR data, appear to be more substantial when the tumor is well localized; however, the gain achievable in TCP may depend quite considerably on the MRS tumor-detection efficiency.

Algorithms↗
PubMed2000

Stress does not enable pyridostigmine to inhibit brain cholinesterase after parenteral administration.

The peripherally acting cholinesterase inhibitor pyridostigmine was widely used during the Gulf War as a pretreatment against possible chemical warfare attack. Following consistent reports on long-term illness among Gulf War veterans, pyridostigmine was examined for its possible long-term effects. These effects were suggested to be induced by the combination of pyridostigmine administration and stress exposure that allowed this quaternary compound to enter the brain through stress induced changes in blood-brain barrier (BBB) permeability. Recently, pyridostigmine administration was demonstrated to inhibit brain cholinesterase following acute stress in mice. However, the effect was not replicated under similar conditions in guinea pigs. Because of the significant implication of these findings, we tested brain cholinesterase (ChE) inhibition following the administration of pyridostigmine, or the tertiary carbamate physostigmine, with or without stress in mice. Different experiments were performed to examine the contribution of gender, age (young and adults), stress (type and intensity), or strain (CD-1 and FVB/n) parameters. No inhibition of brain ChE was detected in any of these experiments. At the same time, physostigmine induced the expected decrease in brain ChE in all the experiments. Thus, we could not replicate the findings that suggest pyridostigmine can affect brain cholinesterase following stress.

Animals↗
PubMed2000

Predictive accuracy study: comparing a statistical model to clinicians' estimates of outcomes after coronary bypass surgery.

BACKGROUND: The purpose of this study was to compare clinicians' prior probability estimates of operative mortality (OM) and prolonged intensive care unit stay (ICU) length of stay greater than 48 hours after coronary artery bypass graft surgery (CABG) with estimates derived from statistical models alone. METHODS: Nine clinicians estimated the predicted probability of OM and ICU stay greater than 48 hours from an abstract of information for each of 100 patients selected from the 1996 to 1997 database of 1,904 patients who underwent isolated CABG. Logistic regression models were used to calculate the predicted probability of OM and ICU stay greater than 48 hours for each patient. The study sample was split into two parts; clinicians were randomly given access to a predictive rule to guide their judgements for one part of the study. RESULTS: Clinicians' estimates were similar with or without access to the rule, and both parts of the study were therefore pooled. Clinicians significantly overestimated the probability of OM (model 6.3% +/- 1%, clinicians 7.6% +/- 3%, p = 0.0001) and ICU stay greater than 48 hours (model 25% +/- 2%, clinicians 28% +/- 1%, p = 0.0012). Clinicians' estimates of OM were not significantly higher than the model's for nonsurvivors (0.8% +/- 0.7%, p = 0.2), but were significantly higher for survivors (1.4% +/- 0.3%, p = 0.039). CONCLUSIONS: Clinicians trusted their own empiric estimates rather than a predictive rule and overestimated the probability of OM and ICU stay greater than 48 hours.

Aged↗
PubMed2000

Neutrophil beta(2)-microglobulin and lactoferrin content in renal failure patients.

Multiple dysfunctions of polymorphonuclear leukocytes (PMNLs) contribute significantly to the increased morbidity and mortality among patients with end-stage renal disease. In the present study, we measured the PMNL content of beta(2)-microglobulin (beta(2)m) and lactoferrin in different states of renal insufficiency and after kidney transplantation. PMNLs were lysed ultrasonically and, after centrifugation, both proteins were assayed in the supernatant by enzyme-linked immunosorbent assay technique. Despite marked differences in plasma beta(2)m levels, no significant difference in PMNL content of beta(2)m and lactoferrin could be shown among the groups analyzed. There was also no correlation between plasma beta(2)m level and PMNL beta(2)m content. In control subjects, as well as in renal allograft recipients with a well-functioning graft, PMNL beta(2)m level correlated positively with PMNL lactoferrin level (pooled data, r = 0.55; P < 0.001; n = 55). Both proteins are considered to colocalize in peroxidase-negative PMNL granules. However, no correlation was found in the azotemic and uremic patient groups. Standard immunofluorescence staining of control PMNLs showed a cytoplasmic granular distribution of both granule proteins. However, in PMNLs of uremic patients, lactoferrin shifted to a perinuclear localization. PMNLs obtained from uremic individuals failed to elicit an increase in lactoferrin release after stimulation with the chemotactic peptide f-Met-Leu-Phe compared with PMNLs obtained from healthy volunteers. These data indicate abnormalities in uremic patients of PMNL granule lactoferrin content and release that are reversible after successful renal transplantation.

Adult↗
PubMed2000

Insulin cardioplegia for elective coronary bypass surgery.

BACKGROUND: Improved methods of myocardial preservation are required to reduce the morbidity and mortality of coronary bypass surgery for high-risk subgroups. Metabolic stimulation with insulin, glucose solutions, or both has been proposed as a method to preserve the ischemic myocardium. We performed a prospective, double-blind, randomized trial to evaluate the effects of insulin and glucose as cardioplegic additives when used as part of a tepid continuous blood cardioplegic strategy. METHODS: We randomized 56 male patients undergoing elective isolated coronary bypass surgery to 1 of 4 cardioplegic groups containing either 42 or 84 mmol/L glucose with or without 10 IU/L of insulin. Perioperative assessments of myocardial metabolism and left ventricular function were performed. RESULTS: Insulin-enhanced cardioplegia was associated with beneficial effects on both myocardial metabolic and functional recovery after cardioplegic arrest. Insulin's effect was independent of the ambient glucose concentration. CONCLUSIONS: Cardioplegic formulations containing a 42 mmol/L concentration of glucose and a 10 IU/L concentration of insulin provide significant benefit to patients undergoing isolated coronary bypass surgery. The clinical effect of these formulations will need to be assessed in high-risk subgroups of patients, such as those with unstable angina, recent myocardial infarction, or poor left ventricular function.

Coronary Artery Bypass↗
PubMed2000

Rabeprazole, 20 mg once daily or 10 mg twice daily, is equivalent to omeprazole, 20 mg once daily, in the healing of erosive gastrooesophageal reflux disease.

BACKGROUND: Proton pump inhibitors are the most potent pharmacologic inhibitors of gastric acid secretion currently available, and have proven effective in the treatment of gastro-oesophageal reflux disease (GERD). The object of this study was to compare the efficacy and tolerability of a new proton pump inhibitor, rabeprazole at two different dosages, with that of omeprazole in the healing of erosive GERD. METHODS: Rabeprazole 20 mg once daily (QD) and 10 mg twice daily (BID) were compared with omeprazole 20 mg QD in a double-blind, multicentre, parallel group study involving 310 patients with erosive GERD. The primary efficacy endpoint was oesophageal mucosal healing determined by endoscopy. Secondary endpoints included reduction in symptoms and improvements in quality-of-life scores. RESULTS: The healing rates between both rabeprazole groups and the omeprazole group were equivalent in both the per-protocol and intent-to-treat populations. In the per-protocol population, rabeprazole 20 mg was noted to have a numerical trend toward more rapid daytime heartburn relief. However, by 4 and 8 weeks of treatment, no significant differences were found between groups for secondary endpoints, adverse events, or laboratory abnormalities including elevation of serum gastrin levels. CONCLUSIONS: Rabeprazole 20 mg in two different dosing schedules is as effective as omeprazole 20 mg QD with regard to efficacy and tolerability in patients with erosive GERD.

2-Pyridinylmethylsulfinylbenzimidazoles↗