Prosthetic valve endocarditis: superiority of surgical valve replacement versus medical therapy only

The objective of our study was to assess the long-term outcome of patients with prosthetic valve endocarditis. We used a multicenter, prospective, observational study design. Six university teaching hospitals with high volume cardiothoracic surgery participated. Seventy-four patients with prosthetic valve endocarditis as defined by explicit, objective criteria were selected for participation. All patients were followed up prospectively for 1 year. Thirty-one percent and 69% had development of endocarditis within 60 days of valve insertion ("early") and after 60 days ("late"), respectively. The most common causes were Staphylococcus epidermidis (40%), Staphylococcus aureus (20%), streptococcal species (18%), and aerobic gram-negative bacilli (11%). Physical signs of endocarditis (new or changing murmur, stigmata, emboli) were seen in 58%. At 6 months and 12 months, mortality was 46% and 47%, respectively. Surgical replacement of the infected valve led to significantly lower mortality (23%) as compared with medical therapy alone (56%), as assessed by both univariate and multivariate analyses (p < 0.05). Improved outcome was seen for the surgical group even when controlling for severity of illness at time of diagnosis. From these findings we conclude that accurate assessment of outcome in prosthetic valve endocarditis requires long-term follow-up of at least 6 months following diagnosis. Surgical therapy warrants greater scrutiny; evaluation in controlled clinical trials is appropriate.     

Expression and function of CTLA-4 in Th1 and Th2 cells

CTLA-4 is expressed on T cells after activation and shares homology with the CD28 costimulatory receptor. In contrast to CD28, CTLA-4 is thought to be a negative regulator of T cell activation. Cross-linking of CTLA-4 during activation of peripheral T cells reduces IL-2 production and arrests T cells in G1. Much less is known about the function of CTLA-4 in differentiated T cells. We have investigated the expression and function of CTLA-4 in established Th1 and Th2 clones and in bulk populations of Th1 and Th2 cells freshly derived in vitro from TCR transgenic splenocytes. We found that CTLA-4 was induced under similar conditions and with similar kinetics following activation of both Th1 and Th2 clones. However, CTLA-4 expression was much higher in Th2 than Th1 clones and lines. This was confirmed by flow cytometry, confocal microscopy, and Northern blot analysis. The ratio of surface to intracellular expression of CTLA-4 and its rate of endocytosis were similar in Th1 and Th2 clones. Inhibition of binding of CTLA-4 to its ligands using soluble anti-CTLA-4 mAb during stimulation with Ag increased the production not only of IL-2 by Th1 clones, but also that of IL-3 and IFN-gamma by Th1 clones and of IL-3, IL-4, IL-5, and IL-10 by Th2 clones. In contrast, when anti-CTLA-4 was coimmobilized with anti-CD3 and anti-CD28 mAbs, a decrease in the production of multiple cytokines was observed. We conclude that CTLA-4 can function to suppress the production of cytokines produced by both Th1 and Th2 cells.     

Montelukast, a potent leukotriene receptor antagonist, causes dose-related improvements in chronic asthma. Montelukast Asthma Study Group

The leukotrienes are known to be important mediators of bronchial asthma. The ability of montelukast, a potent and selective CysLT1 leukotriene receptor antagonist, to cause a dose-related improvement in chronic asthma was investigated in a placebo-controlled, multicentre, parallel-group study. After a two week placebo run-in period, chronic asthmatic patients with a forced expiratory volume in one second (FEV1) 40-80% predicted with > or = 15% increase (absolute value) after beta2-agonist were randomly assigned to one of four treatment groups (placebo or montelukast 2, 10, or 50 mg once daily in the evening) for a three week, double-blind treatment period. For patient-reported end-points (daytime symptom score, use of as needed inhaled beta2 agonist, asthma-specific quality of life) and frequency of asthma exacerbations, montelukast 10 and 50 mg caused similar responses, superior to 2 mg and significantly (p<0.05; linear trend test) different from placebo. All three doses caused improvements in FEV1 and morning and evening peak expiratory flow rate (PEFR) that were significantly (p<0.05) different from placebo. Differences (least square mean) between the pooled 10 and 50 mg montelukast treatment groups and placebo were: 7.1% change from baseline in FEV1, 19.23 L x min(-1) in morning PEFR, -0.29 in daytime asthma symptom score (absolute value), and -0.82 in beta2-agonist use (puff x day(-1)). The incidence of adverse experiences was neither dose-related nor different between montelukast and placebo treatments. We conclude that montelukast causes a dose-related improvement in patient-reported asthma end-points over the range 2-50 mg. Montelukast causes benefit to chronic asthmatic patients by improving asthma control end-points.     

Differentiation of Mycoplasma hyopneumoniae, M flocculare, and M hyorhinis on the basis of amplification of a 16S rRNA gene sequence

Cell damage is caused by energy depletion or by direct membrane damage, or a combination when a direct membrane damage affects energy depleted cells. In this report it was investigated whether the extent of direct membrane damage induced by lysophosphatidyl choline (LPC) or phospholipase C (PhC) on quiescent fibroblasts depended on the metabolic state of the cells. When glycolysis was inhibited cell damage was always extensively increased, whereas cell damage was also increased to a minor degree when exposed to PhC during sole inhibition of oxidative phosphorylation. Acceleration of glycolysis in cells with a low rate of glycolysis resulted in a dramatic improvement of the membrane susceptibility within a few minutes. Thus, susceptibility of the cell membrane to direct membrane damage depends on the metabolic state. The results also emphasize previous findings that glycolysis has a special role in maintaining membrane function and integrity.     

A review of the readmissions of patients with tetraplegia to the Regional Spinal Injuries Centre, Southport, United Kingdom, between January 1994 and December 1995

Patients with chronic tetraplegia are prone to develop unique clinical problems which require readmission to specialised centres where the health professionals are trained specifically to diagnose, and treat the diseases afflicting this group of patients. An appraisal of the readmission pattern of tetraplegic patients will provide the necessary data for planning allocation of beds for treatment of chronic tetraplegic patients. Hospital records of patients with tetraplegia readmitted to the Regional Spinal Injuries Centre, Southport, UK between 1 January 1994 and 31 December 1995 were analyzed to find out the number of tetraplegic patients who required readmission, reasons for readmission, duration of hospital stay, and mortality among patients readmitted. During the 2-year period, 155 tetraplegic patients were readmitted and 44 of them (28.4%) required more than one readmission (total readmission episodes: 221); these patients occupied 4.5 beds which is equivalent to 11.5% of the total bed capacity of the spinal unit. Among the reasons for the readmissions, evaluation and care of urinary tract disorders topped the list with 96 readmission episodes (43.43%) involving 70 patients; the median hospital stay was 3 days, and 18 patients (26%) required more than one readmission during this period. One hospital bed was occupied by the tetraplegic patients requiring treatment/evaluation of urinary tract disorders. Assessment and treatment of cardio-respiratory diseases was the second most common reason for readmission with 51 readmission episodes pertaining to 27 patients having a median hospital stay of 6 days; 13 patients (48%) were readmitted more than once within this 2-year period. Treatment of cardio-respiratory diseases in chronic tetraplegic patients required 1.2 hospital beds yearly. Only five tetraplegic patients were readmitted for treatment of pressure sore(s); however they had a prolonged hospital stay (median duration: 101 days). Social reasons accounted for 13 readmission episodes concerning nine patients who stayed in the hospital for varying periods (median: 6.5 days; mean: 35 days). Four tetraplegic patients readmitted with acute chest infection expired. An 81 year-old tetraplegic died of myocardial infarction. Urinary sepsis, renal insufficiency, respiratory failure and intra-cerebral haemorrhage accounted for the demise of a 41 year-old tetraplegic patient following surgical removal of a large, impacted stone at the pelviureteric junction. A tetraplegic patient who was admitted with haematuria subsequently underwent cystectomy for squamous cell carcinoma of the urinary bladder; he developed secondaries and expired 5 months later. As more patients with high cervical spinal cord injury survive the initial period of trauma, and as the life expectancy of tetraplegic patients increases, it is likely that greater numbers of tetraplegic patients will be requiring readmission to spinal injuries centre. Although it may be possible to prevent some of the complications of spinal cord injury and hence the need for a readmission, progress in medicine and rehabilitation technology will create additional demands for readmissions of chronic tetraplegic patients in order to implement the newer therapeutic strategies. Thus a change in the pattern of readmission of chronic tetraplegic patients is likely to be the future trend and this should be taken into account while making plans for providing the optimum care to chronic tetraplegic patients.     

Pharmacokinetics of cyclophosphamide and its metabolites in bone marrow transplantation patients

Classical swine fever virus infection of pigs causes a severe leukopenia and immunosuppression. In the present study, the kinetics of virus infection, and identification of target cells for the virus in peripheral blood were analysed. Virus infection was often not detectable before 5-7 days p.i. A minority of animals yielded detectable infected cells at 3 days p.i., but < 5% PBMC. It was not until 10 days p.i. that this figure increased-to 35-70% PBMC depending on the animal. Detailed analysis of Ficoll-Hypaque-purified PBMC identified the major population to be SWC3+SWC8+CD14+MHCII- granulocytic cells. Microscopic observations determined that these low density granulocytic cells in the PBMC from CSFV infected animals were indeed immature cells. Both the low density granulocytic cells and monocytes were major targets for CSFV infection in the peripheral blood. This is the first demonstration that low density granulocytic cells dominate the blood leukocyte population during CSF, and that such cells are targets for virus infection. The present work also demonstrates that the leukocyte population changes, such as B lymphocyte depletion and the relative dominance of myeloid cells in the blood during CSF, occur before virus infection of the affected cells. Thus, the pathological mechanism therein is not a direct consequence of virus infection.     

Peripheral nerve insult induces NMDA receptor-mediated, delayed degeneration in spinal neurons

Injury of a peripheral nerve gives rise to adaptive functional and structural alterations in spinal neurons. We report that the rearrangement of the spinal circuitry in response to sciatic nerve transection in adult rats involves a delayed mode of degeneration of lumbar spinal cord neurons. Nuclear fragmentation was detected by the TUNEL technique 7 days after sciatic neurectomy but not after 3 or 14 days. Dying cells were preferentially located in the ipsilateral superficial dorsal horn and expressed the neuronal cytoskeletal marker SMI-31. Degeneration was prevented by continuous systemic treatment with the NMDA receptor-antagonist MK-801. These data are supportive that apoptosis is induced in spinal neurons in a transsynaptic manner by an early signal from injured afferent fibres via activation of spinal NMDA receptors.     

PET instrumentation: what are the limits?

This report has emphasized the attributes of positron emission tomography (PET) through a discussion of the historical development with attention to limitations or factors that are of importance in using and further developing this technology. As is the case for all nuclear detector developments, the factors that require consideration are spatial resolution, uniformity of resolution, sensitivity, distortions (attenuation), background noise (scatter and randoms), image volume, data acquisition capabilities (count-rate saturation), and limitations based on allowable radiation doses to the subject. Forty years ago, the fact that dual gamma-cameras could not handle the count-rates from the short half-life radionuclides that had clinical applications at that time (ie, 15O, 11C, 13N) precluded their acceptance in nuclear medicine. With the advent of 18F applications particularly with FDG in oncology, this limitations was no longer a barrier. Twenty years ago and until recently, the promise of time-of-flight PET has been stifled by the fact that the appropriately fast scintillator BaF2 had too low an efficiency (low density) to be useful in improving the signal to noise of a time-of-flight tomograph over contemporary systems. With the development of dense scintillators with high light output and high speed such as LSO30 the time-of-flight potentials are now once again worth pursuing. Twenty years ago systems that theoretically would have improved sensitivity by minimal or no septa with spherical geometric arrangements of detectors were ignored because it appeared that scatter backgrounds would lead to a signal to noise less than 1. But in the last 5 years, cylindrical systems without speta have shown that noise effective sensitivity improvements of a factor of 4 can be realized. With time-of-flight additional improvements in sensitivity will be realized. Horizons for detector development include discovery of new scintillators, new methods of registering scintillation light, deployment of larger field of view systems and methods of compensating for scatter, randoms, attenuation, and irregular sampling associated with new geometries which can encircle most of the body. The expected limit for PET is 2 mm isotropic resolution for the head and appendages including joints and breasts. Clinical realization of this resolution for the thorax and abdomen requires compensation for motion and even in this area strategies are underdevelopment which rely on the improvement in sensitivity being realized by 3D systems.