Persilylation of ferrocene: the ultimate discipline in sterically overcrowded metal complexes.

We report the preparation and structural characterization of the first persilylated metallocene via the metalation of decabromoferrocene. Although Grignard conditions turned out to be insufficient due to the steric and electronic effects of silyl groups causing a decreased nucleophilicity of the metalated intermediates, stepwise lithium-halogen exchange yields complex mixtures of polysilylated compounds FeC10DMSnH10-n (n = 10, 9, 8) including the targeted decasilylated ferrocene. These mixtures were successfully separated allowing a systematic study of silylation effects on ferrocene by XRD, CV, NMR and UV/vis spectroscopy supported by DFT calculations. The findings were used to develop a high-yielding and simple preparation method to generate a tenfold substituted overcrowded ferrocene, FeC10DMS8Me2.

Fluorescence of experimental atheromatous plaques with hematoporphyrin derivative.

Fluorescence of hematoporphyrin derivative (HPD) has been used clinically to localize malignant neoplasms because of its selective accumulation in these tissues. We tested the hypothesis that HPD may also be selectively concentrated within atheromatous plaques. 48 h after HPD injection in a variety of species, selective fluorescence of atheromatous plaques of the aorta was seen in each animal (rabbits and Patas monkey) exhibiting such lesions. No fluorescence could be demonstrated in aortic segments free of atheromatous involvement. Since the efficacy of photodynamic destruction of malignant tumors with HPD has been demonstrated in clinical studies, the observations of the present study may have therapeutic implications in atheromatosis.

Survey of domestic food handling practices in New Zealand.

The purpose of this survey was to obtain information on the domestic meat and poultry handling practices of New Zealanders in order to support the development of quantitative risk models, as well as providing data to underpin food safety campaigns to consumers. A sample of 1000 New Zealand residents, over 18 years of age, were randomly selected from the electoral roll and asked to participate in a national postal food safety study during 2005. Three hundred and twenty six respondents completed and returned questionnaires containing usable answers, and most of these respondents 'always' prepared the main meal within the household. The majority of meat (84.6%) and poultry (62.9%) purchased by New Zealanders was fresh (rather than frozen), and most consumers (94.4%) claimed that the time taken from food selection to reaching their home was 1 h or less. The majority (approximately 64%) of fresh meat and poultry was frozen in the home and the most favoured method of thawing was at room temperature for up to 12 h. The most common time period for storing cooked or raw meat and poultry in domestic refrigerators was up to 2 days. Most survey respondents preferred their meat and poultry to be cooked either medium or well done. The most popular cooking method for chicken was roasting or baking, while most respondents preferred to pan-fry steak/beef cuts, minced beef or sausages/hamburgers. The potential for undercooking was greatest with pan-fried steak with 19.8% of respondents preferring to consume this meat raw or rare. In answer to questions relating to food handling hygiene practices, 52.2% of respondents selected a hand washing sequence that would help prevent cross contamination. However, it was estimated that 41% and 28% of respondents would use knives and kitchen surfaces respectively in a manner that could allow cross contamination. The data in this survey are self-reported and, particularly for the hygiene questions, respondents may report an answer that they perceive as being correct rather than reflecting their actual behaviour. Nevertheless, the data on food processing, transport, storage and cooking preferences represent useful inputs into the assessment of food safety along the meat and poultry food chains.

Immunosuppressive drug-induced diabetes.

Post-transplant diabetes mellitus (PTDM) has emerged as a major adverse effect of immunosuppressive drugs (ISD). As recipients of organ transplants survive longer, the complications of diabetes mellitus have assumed greater importance. The predominant factor for causing PTDM by corticosteroids seems to be the aggravation of insulin resistance, however several studies have displayed deleterious effects on insulin secretion and beta-cells. Calcineurin inhibitors induce PTDM by a number of mechanisms, including decreased insulin secretion and a direct toxic effect on the pancreatic beta-cells. Recent in vitro studies stress on the increased apoptosis of beta-cells when exposed to these drugs. Studies involving other immunosuppressive agents (mycophenolate mofetil [MMF], sirolimus) are scarcer and lead to conflicting results, while daclizumab seems to have a neutral effect. Clinical studies have consistently shown a greater potential of tacrolimus to induce PTDM compared with cyclosporine. Reducing PTDM incidence is a feasible goal while using corticosteroid-sparing regimens and/or lower tacrolimus trough levels. In patients developing PTDM, conversion from tacrolimus to cyclosporine could improve or reverse glucose tolerance abnormalities. In the absence of well-designed studies in this specific indication, treatment of PTDM is based on the same principles as type 2 diabetes mellitus. Thiazolidinediones do not display any pharmacological interaction with calcineurin inhibitors, but their safety and efficacy in PTDM need to be confirmed in large-scale randomized trials. Use of sulfonylureas has to be cautious regarding the suspected interaction of some of them with calcineurin inhibitors. If needed, insulin regimens have to be adapted in patients who display the particular glycaemic profile of corticosteroid-induced diabetes. Incretin-based therapies, due to their specific action on beta-cell apoptosis and proliferation, raise promises that have to be confirmed in clinical studies. Until methods for inducing specific graft tolerance become available, immunosuppressive regimens should be tailored to the individual patient on the basis of predictive criteria for the development of PTDM.

First-pass nuclear magnetic resonance imaging studies using gadolinium-DTPA in patients with coronary artery disease.

Nuclear magnetic resonance (NMR) imaging has been shown to accurately portray cardiac anatomy and function. To investigate the potential of NMR imaging for the assessment of coronary stenosis in patients with chest pain, ultrafast NMR imaging in conjunction with a T1 (longitudinal relaxation time) contrast agent was performed in 17 patients with chest pain who had undergone cardiac catheterization. These included 12 patients with significant coronary artery stenoses and 4 who underwent repeat NMR study after myocardial revascularization. Cardiac images at rest were obtained during rapid intravenous injection of gadolinium-DTPA (0.04 mM/kg). Electrocardiographic-gated images were acquired over 380 ms, with repetitive images obtained every 3 to 4 s. After contrast injection, there was pronounced signal enhancement in the right ventricular cavity, followed by enhancement in the left ventricular cavity and myocardium. Regional myocardium perfused by a diseased vessel demonstrated a lower peak signal intensity (p = 0.001) and lower rate of signal increase (p = 0.001) than did myocardium perfused by coronary arteries without stenosis. Repeat NMR study after revascularization showed an increase in peak signal intensity (p less than 0.002). These results demonstrate the clinical potential of dynamic gadolinium-DTPA-enhanced NMR imaging for the assessment of coronary artery disease in patients with chest pain. In combination with anatomic and functional NMR imaging, this technique has the potential to provide a comprehensive noninvasive cardiac evaluation of patients with suspected coronary artery disease.

Intracoronary thallium-201 scintigraphy after thrombolytic therapy for acute myocardial infarction compared with 10 and 100 day intravenous thallium-201 scintigraphy.

Thallium-201 imaging has been utilized to estimate myocardial salvage after thrombolytic therapy for acute myocardial infarction. However, results from recent animal studies have suggested that as a result of reactive hyperemia and delayed necrosis, thallium-201 imaging may overestimate myocardial salvage. To determine whether early overestimation of salvage occurs in humans, intracoronary thallium-201 scans 1 hour after thrombolytic therapy were compared with intravenous thallium-201 scans obtained approximately 10 and 100 days after myocardial infarction in 29 patients. In 10 patients with angiographic evidence of coronary reperfusion, immediate improvement in thallium defects and no interim clinical events, there was no change in imaging in the follow-up studies. Of nine patients with coronary reperfusion but no initial improvement of perfusion defects, none showed worsening of defects in the follow-up images. Six of these patients demonstrated subsequent improvement at either 10 or 100 days after infarction. Seven of 10 patients with neither early evidence of reperfusion nor improvement in perfusion defects had improvement of infarct-related perfusion defects, and none showed worsening. In conclusion, serial scanning at 10 and 100 days after infarction in patients with no subsequent clinical events showed no worsening of the perfusion image compared with images obtained in acute studies. Therefore, there is no evidence that thallium-201 imaging performed early in patients with acute myocardial infarction overestimates improvement.

In vivo coronary angioscopy.

The feasibility of in vivo coronary angioscopy was tested utilizing a 1.8 mm angioscope in vessels where blood had been replaced by optically clear liquids, including a new perfluorocarbon emulsion. After trials in postmortem canine and human coronary arteries, in vivo intraluminal visualization was accomplished in the dog with a catheterization technique and in patients during open heart surgery. The results demonstrate the feasibility and potential clinical usefulness of direct visualization of intravascular anatomy and disease, analogous to endoscopy of other organ systems.

Medically refractory unstable angina pectoris. II. Hemodynamic and angiographic effects of intraaortic balloon counterpulsation.

Of 60 patients receiving intraaortic balloon counterpulsation for angina refractory to maximal medical therapy, a subgroup of 10 patients underwent left ventricular angiography both with and without counterpulsation. Severe stenosis of the left anterior descending coronary artery was present in all 10 patients. Counterpulsation resulted in a significant decrease in systolic and end-diastolic left ventricular pressures and no increase in cardiac index. Left ventricular diastolic and systolic volume, ejection fraction and regional contraction patterns, often abnormal, were unchanged. However, mean normalized systolic ejection rate was improved by the addition of counterpulsation. It is concluded that intraaortic balloon counterpulsation has relatively little effect on the left ventricular volume of patients with medically refractory angina pectoris. The symptomatic improvement that takes place seems to occur mainly through the effect of counterpulsation on preload and afterload.

Medically refractory unstable angina pectoris. I. Long-term follow-up of patients undergoing intraaortic balloon counterpulsation and operation.

Of 82 patients with medically refractory unstable angina pectoris seen between October 1972 and January 1978, 60 patients underwent a combination of intraaortic balloon pump counterpulsation, cardiac catheterization and coronary revascularization. Most patients had atherosclerotic involvement of the vessels of the anterior left ventricular wall, 48 patients (80 percent) had abnormalities of left ventricular wall contraction and 22 patients (36 percent) had evidence of acute myocardial injury. One operative and one late death occurred. The perioperative infarction rate was 5 percent. Survivors, followed up for 3 to 63 months (mean 31 months), have done remarkably well; 77 percent are considered employable,and more than 90 percent are in functional class I or II.

Cyanosis in uncomplicated atrial septal defect with normal right cardiac and pulmonary arterial pressures.

A patient with cyanosis in an uncomplicated ostium secundum atrial septal defect without pulmonary hypertension is described. There were no anatomic abnormalities in right-sided cardiac valves or venous return and no evidence of right ventricular hypoplasia or hypertrophy; however, the diastolic pressure curve suggested a decreased compliance. We suggest that this unusual finding may be a result of intrinsically abnormal right ventricular compliance.

Effect of angiographic contrast agents on the mechanical performance of the isolated rat papillary muscle preparations.

The effects of the radiographic contrast agents Renografin, Isopaque, and Hypaque on the mechanical performance of isometrically contracting rat papillary muscle was compared to a new contrast agent, Amipaque. It was found that exposure to Amipaque resulted in significantly less depression of contractile activity than any of the other agents. Changes in mechanical performance associated with exposure to Renografin, Isopaque, or Hypaque could not be attributed to either hypocalcemia or hypoxia. The decrease in developed tension and increase in resting tension was similar to that produced by Krebs-Henseleit containing hypertonic (1420 mmol) glucose or sucrose. Thus, the data support the concept that hyperosmolarity of the radiographic contrast agents may be primarily responsible for the adverse effects on mechanical performance of the myocardium associated with angiography.

Comparative effects of three radiographic contrast agents in isolated normal and ischemic canine hearts.

Investigators have sought to improve contrast agents by changing the ionic content or decreasing osmolarity. This study compared the effects of meglumine sodium diatrizoate, sodium meglumine calcium metrizoate, and metrizamide on coronary blood flow, myocardial contractile force, and perfusion pressure under normal and ischemic conditions in eight isolated canine hearts. Diatrizoate had an initial negative inotropic effect, but contractile force returned to baseline within 1 minute during normal perfusion and within 2 minutes under ischemic conditions. Calcium-enriched metrizoate and metrizamide had only a positive inotropic effect under normal perfusion (127 +/- 3.9% and 116 +/- 2.9% of baseline, respectively). During ischemia, however, the positive inotropic effect of sodium meglumine calcium metrizoate was followed by a decrease in contractile force to 93 +/- 5% of baseline after 2 minutes. Metrizamide showed only a positive inotropic effect during ischemia. The myocardial depression that follows the initial positive inotropic effect of calcium may further alter the instability between normal and ischemic areas of the heart, thus increasing the risk of coronary arteriography in patients with severe coronary artery disease.

Intracoronary thallium-201 assessment of thrombolysis in acute myocardial infarction. Validation of the method of imaging before and after therapy.

In order to study acute changes in perfusion with intracoronary thrombolytic therapy, we have used ten times the pretherapy intracoronary thallium-201 dose for the posttherapy study. Because of the larger posttherapy dose, the posttherapy images had ten times as many counts as the pretherapy images. Since the change in image quality between the pretherapy and posttherapy studies might affect interpretation, we studied the effect of image statistics on interpretation of perfusion scintigraphy. The pretherapy and posttherapy images were scored on a four-point scale in five segments on each of three views. In 31 patients, Poisson-distributed pseudorandom noise was added to the posttherapy study in order to match the statistical accuracy of the pretherapy study. A blinded interpretation of the pretherapy and posttherapy noise-added images was performed in the same way as the initial unblinded interpretation. The mean difference between the unblinded pretherapy and posttherapy scores (the improvement in thallium distribution with therapy) was 2.5+/-0.8 (standard error) compared with the difference between the blinded pretherapy and posttherapy noise-added scores which was 2.6+/-1.0. The correlation between readings of similar pairs of data was higher than the correlation between pretherapy and posttherapy studies. Thus, the difference in statistic quality of the pretherapy and posttherapy studies did not affect the interpretation of these studies. Therefore, our evaluation of pretherapy and posttherapy studies using a ten-fold increase in thallium-201 dosage is valid.

Computer reconstruction of luminal cross-sectional shape from multiple cineangiographic views.

Knowledge of coronary luminal shape, in addition to diameter information as routinely obtained from a cineangiogram, may be useful in assessing lesions which deviate from circular symmetry. We have developed an image analysis system for automated tracking of luminal edges and measurement of diameter form cine frames digitized by a video camera/digitizer interfaced to a Vax 11/780 computer. Between vessel edges, cinedensitometric profiles across the vessel long axis are used to provide a rotationally invariant measure of relative luminal cross-sectional area. A maximum entropy iterative algorithm is used to reconstruct the lumen cross section from a set of projection data consisting of the cinedensitometric profiles from multiple radiographic views. Nonaxisymmetric model coronary lumena, such as a crescent shape and a double lumen simulating a coronary artery dissection, were filmed under cineradiographic conditions similar to clinical exposures. Radiographic views at 10 degrees increments about the model lumen long axis over 360 degrees were available for analysis. Graphic display of reconstructed model lumena indicate that as few as three to five radiographic views may be useful in reconstructing coronary luminal shape.

Sips, Sops, and SPIs but not stn influence Salmonella enteropathogenesis.

The virulence factors influencing Salmonella-induced enteropathogenesis remain poorly characterised. The interactions of different serotypes of Salmonella with bovine ileal mucosa have been characterised in the ligated ileal loop model. In a quantitative intestinal invasion assay Salmonella dublin, S. choleraesuis, S. gallinarum, and S. abortusovis strains were all recovered from ileal mucosa, either with or without Peyer's patches in similar numbers. This observation suggests that the magnitude and route of intestinal invasion does not mediate Salmonella serotype host specificity. Despite being equally invasive there was a clear hierarchy in the enteropathogenicity of these serotypes. The magnitude of the enteropathogenic responses did not correlate to serotype host specificity. These observations implicate undefined serotype specific factors in influencing enteropathogenicity independently of intestinal invasion. Disruption of genes in Salmonella Pathogenicity Island (SPI) 1 of S. typhimurium and S. dublin blocked the secretion of Salmonella Invasion Proteins (Sips) and Salmonella Outer Proteins (Sops). These mutants were significantly less invasive and enteropathogenic then the wild type strain in ligated ileal loops. Disruption of sopB and sopD significantly reduced enteropathogenesis, but without influencing intestinal invasion. These two genes appear to act in concert. Surprisingly, disruption of stn, the Salmonella enterotoxin gene cloned on the basis of its homology to cholera toxin, did not influence enteropathogenesis. SopB was mapped to the 20 centisome of S. typhimurium and is flanked by 5 genes that are organised in a manner typical of a pathogenicity island, which we have termed SPI-5. Mutation of the other genes in SPI-5 also attenuated enteropathogenesis but not virulence for mice, suggesting SPI-5 is a key locus specifically influencing Salmonella enteropathogenesis.

Intravenous infusion of donor apoptotic leukocytes before transplantation delays allogeneic islet graft rejection through regulatory T cells.

AIM: This study describes the ability of intravenous donor apoptotic leukocyte infusion before islet transplantation to delay allogeneic graft rejection and implicates regulatory T cells (T(reg)) in the effect. METHODS: Allogeneic FVB (Friend virus B-type) islet transplants were placed under the kidney capsule of BALB/c recipient mice rendered diabetic by streptozotocin. Apoptotic donor leukocytes were infused intravenously 7 days before transplantation. Foxp3/DTR/GFP transgenic C57BL/6 mice were used as recipients to show depletion of T(reg) after apoptotic cell infusion. Control mice received islet transplants without apoptotic cells. RESULTS: The graft median survival time (MST) in recipient mice was 15±1.5 days when apoptotic cells were infused 7 days prior to transplantation of a 1000-islet-containing allograft and 6±0.5 days in the control mice (P<0.01). The same effect was observed using a 500-islet allograft, with an MST of 9±1.1 days vs. 3±0.8 days with and without (controls) apoptotic cells, respectively (P<0.01). This immunomodulatory effect was not observed when apoptotic cell administration was performed on the day of transplantation. Specific T(reg) depletion in Foxp3/DTR/GFP recipient mice inhibited the beneficial effect of apoptotic cell infusion with an MST of 8±1.5 days after apoptotic cell infusion vs. 2±0.2 days when T(reg) were depleted (P<0.01). Furthermore, T(reg) were specifically detected in the islet grafts of mice infused with apoptotic cells prior to islet transplantation. CONCLUSION: Infusion of donor apoptotic cells 7 days before allogeneic transplantation delays islet allograft rejection through a process involving T(reg).