Critical role of P-selectin-dependent rolling in tumor necrosis factor-α-induced leukocyte adhesion and extravascular recruitment in vivo

Leukocyte-endothelium interactions are dependent on a coordinated expression and function of specific adhesion molecules. The objective of the present study was to examine the role of selectin function and leukocyte rolling in tumor necrosis factor-alpha (TNF-alpha)-induced leukocyte adhesion and extravasation in venules in vivo. For this purpose, we used intravital microscopy in the mouse cremaster muscle stimulated for 2-3 h with TNF-alpha intrascrotally. Pretreatment with fucoidan, which inhibits P- and L-selectin, and a P-selectin monoclonal antibody (RB40.34) abolished TNF-alpha-stimulated leukocyte rolling. This great reduction in rolling caused a marked attenuation of firm adhesion and extravascular accumulation of leukocytes. When fucoidan and RB40.34 were administrated after stimulation with TNF-alpha, it was found that leukocyte rolling was greatly reduced whereas the number of firmly adherent leukocytes was completely unchanged, suggesting that the inhibitory effect of blocking P-selectin function on firm leukocyte adhesion and recruitment was due to the reduction in leukocyte rolling along the endothelium. Moreover, pretreatment with a monoclonal antibody against intercellular adhesion molecule-1 (ICAM-1) and a platelet-activating factor (PAF)-receptor antagonist had no effect of TNF-alpha-induced leukocyte rolling and adhesion, indicating that molecules other than ICAM-1 and PAF mediate firm adhesion and recruitment of leukocytes in TNF-alpha-activated tissues. Taken together, our data demonstrate that P-selectin function plays an important role in TNF-alpha-induced inflammatory cell recruitment by mediating leukocyte rolling as a precondition for cytokine-provoked firm adhesion and transmigration in vivo. These findings, thus, suggest that inhibition of P-selectin may be a central target for pharmacological intervention in inflammatory diseases.     

Coping in relation to perceived threat of the risk of graft rejection and Health‐Related Quality of Life of organ transplant recipients

The most serious risk connected with transplantations besides infection is graft rejection. Organ transplant recipients (OTRs) perceive graft rejection as a stress factor and a threat. The primary aim of the present study was to examine types of coping used to handle the threat of the risk of graft rejection among OTRs and to investigate relations between coping and perceived threat as well as Health‐Related Quality of Life (HRQoL). A second aim was to test the General Coping Questionnaire (GCQ) for reliability in relation to the threat of the risk of graft rejection. Three different questionnaires, the Perceived Threat of the Risk of Graft Rejection (PTGR), GCQ and the SF‐36, were mailed to 229 OTRs between 19 and 65 years old. Patients were transplanted with a kidney, a liver or a heart and/or a lung. All patients with follow‐up time of 1 year ± 3 months and 3 years ± 3 months were included. With an 81% response rate, the study comprised of 185 OTRs. The differences between the transplanted organ groups in their use of coping were small. Likewise, coping related weakly with sex, age, time since transplantation and whether they had experienced graft rejections or not. The respondents tended in general to use more of the ‘positive’ coping (strategies related to positive well‐being). The measured coping in relation to the perceived threat of the risk of graft rejection seem to be relatively stable over time and quite independent of demographic and clinical variables.     

Effects of aldehyde dehydrogenase inhibitors on hexobarbital sensitivity and neuroamine metabolism in rat brain

Several authors have found that the aldehyde dehydrogenase (ALDH) inhibitor, disulfiram, prolongs hexobarbital-induced anaesthesia. It was suggested that this effect was caused by an alteration of the serotonergic system in brain, mediated by elevated levels of biogenic aldehydes. In the present study, disulfiram (300 mg/kg) was found to cause a 4-fold prolongation of hexobarbital-induced anaesthesia, while coprine (another potent ALDH-inhibitor) had no effect. This strongly suggested that biogenic aldehydes were not involved in this effect of disulfiram. The hexobarbital concentration in brain, at the electroencephalogram (EEG) criteria used for measuring hexobarbital sensitivity, was unaffected in rats given 75-300 mg/kg disulfiram, indicating that factors other than an increased brain hexobarbital sensitivity were responsible for the prolonged anaesthesia. Also 10-100 mg/kg coprine did not affect hexobarbital sensitivity measured this way. No alteration of the dopamine level in brain was found in rats given disulfiram, and in both disulfiram- and coprine-treated rats, similar changes in the serotonergic system were found. However, the level of norepinephrine was decreased in brains of disulfiram-treated rats, but it was unaffected by coprine. Thus, norepinephrine may have been involved in the prolongation of hexobarbital-induced anaesthesia caused by disulfiram.     

Pin-tract complications in external fixation of fractures of the distal radius

We analyzed retrospectively the rate and outcome of pin-tract complications in 314 unstable fractures of the distal radius, treated with the Hoffmann small-frame external fixator. The overall rate of complications was 27%. The commonest complication (21 %) was pin-tract infection, which was treated with oral antibiotics. There were no cases of osteitis. Complications led to premature removal of the fixator in 17 of the cases. Women over the age of 75 years had a significantly higher rate of pin loosening (17%), but not a higher rate of premature removal of the fixator due to complications. 4% of the cases had a pin-site fracture, all women. The rate of pin-tract complications was high, but severe complications were rare, even in old women.     

Red cell trapping and postischemic renal blood flow. Differences between the cortex, outer and inner medulla.

The distribution of blood flow in the rat kidney after 60 minutes of renal ischemia was studied by single-fiber laser-Doppler flowmetry. Blood flow in superficial cortex and inner medulla was measured with a probe directed towards the kidney surface and exposed papilla, respectively. Outer medullary blood flow was measured with a probe introduced through the renal core. After ischemia the blood flow decreased to 60% of the preischemic value (P less than 0.01) in superficial cortex and to 16% (P less than 0.01) in outer medulla, while inner medullary blood flow increased paradoxically to 125% (P less than 0.01). There was extensive trapping of red blood cells (RBC) in the outer medulla, but not in the inner medulla or cortex. The fractional RBC volume as measured by radiolabeled RBCs was 21% in the inner stripe of the outer medulla, but 2% in this area in a normal kidney. To investigate the influence of RBC trapping on intrarenal distribution of blood flow after ischemia, the hematocrit was reduced from 46% to 31% by isovolemic hemodilution. When performed before ischemia, this maneuver almost completely abolished RBC trapping. In this group blood flow in both outer and inner medulla was almost unchanged after ischemia, while superficial cortical blood flow decreased to 66% (P less than 0.01) of the pre-ischemic value. It is concluded that RBC trapping in the outer medulla causes a large decrease in blood flow in this area and, at the same time, shunting of blood to the inner medulla. In the absence of RBC trapping, blood flow of both outer and inner medulla is well preserved after ischemia.     

Overall Functioning and Criteria of Progress in Rehabilitation of Alcohol Abusers: Longitudinal Analyses of Changes

The aim was to compare alcohol consumption and vocational adjustment as criteria of rehabilitation progress of alcoholics, with regard to links to concomitant changes in functioning in other life areas. Thirty-four advanced alcohol abusers in rehabilitation were examined twice with an interval of 2 years between each examination. Change scores in alcohol consumption and work capacity were correlated with change scores in social network, activities, life-satisfaction, psychological well-being, psychiatric symptoms, and biomedical functioning. Improved drinking habits were connected with some changes in overall functioning, however not solely in a favorable direction. Negative mood changes were especially noteworthy. Improvements in vocational adjustment, on the other hand, appeared to be somewhat more unequivocally and encompassingly associated with amelioration in the wider range of functioning. The results indicate that drinking measures alone are not sufficient indicators of progress in rehabilitation and underscores the need of more global criteria of general adjustment.     

A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes

Heritable diseases are caused by germ-line mutations that, despite tissuewide presence, often lead to tissue-specific pathology. Here, we make a systematic analysis of the link between tissue-specific gene expression and pathological manifestations in many human diseases and cancers. Diseases were systematically mapped to tissues they affect from disease-relevant literature in PubMed to create a disease–tissue covariation matrix of high-confidence associations of >1,000 diseases to 73 tissues. By retrieving >2,000 known disease genes, and generating 1,500 disease-associated protein complexes, we analyzed the differential expression of a gene or complex involved in a particular disease in the tissues affected by the disease, compared with nonaffected tissues. When this analysis is scaled to all diseases in our dataset, there is a significant tendency for disease genes and complexes to be overexpressed in the normal tissues where defects cause pathology. In contrast, cancer genes and complexes were not overexpressed in the tissues from which the tumors emanate. We specifically identified a complex involved in XY sex reversal that is testis-specific and down-regulated in ovaries. We also identified complexes in Parkinson disease, cardiomyopathies, and muscular dystrophy syndromes that are similarly tissue specific. Our method represents a conceptual scaffold for organism-spanning analyses and reveals an extensive list of tissue-specific draft molecular pathways, both known and unexpected, that might be disrupted in disease.     

Striatal kinetics of [11C]-(+)-nomifensine and 6-[18F]fluoro-L-dopa in Parkinson''s disease measured with positron emission tomography

The kinetics in brain of the dopamine reuptake blocking agent [11C]-(+)-nomifensine and the L-dopa analogue 6-[18F]fluoro-L-dopa were compared in 3 patients with idiopathic Parkinson's disease and age-matched healthy volunteers using positron emission tomography. Regional uptake was analyzed and quantified according to a 3-compartment model. Retention of both tracers in striatal regions of the parkinsonian patients were reduced compared with the healthy volunteers mainly in the putamen, while the caudate nucleus was only mildly affected. The reductions were considerably less than the decrease previously reported postmortem for striatal dopamine content in the basal ganglia of patients with Parkinson's disease. A fairly constant ratio between 6-[18F]fluoro-L-dopa utilization and [11C]-(+)-nomifensine binding in the caudate nucleus and the putamen were found in both groups unrelated to the size of the estimated parameters. This indicates that a limiting factor for the utilization of exogenous levodopa in Parkinson's disease may be a reduced transport capacity for the amino acid into the dopaminergic terminals.     

Analysis of the influence of elective nodal irradiation on postirradiation pulmonary function

Irradiation (RT) field selection for bronchogenic carcinoma is based on such factors as extent of disease, pulmonary function, and the perceived need for elective nodal irradiation (ENI). A technique of superimposing a patient's RT treatment film onto his quantitative perfusion lung scan can predict the fractional volume of perfused lung receiving RT and has been shown to reliably estimate the minimum post-RT pulmonary function as measured by the forced expiratory volume in one second (FEV1). This technique has been applied to 20 patients with nonresected clinically staged T1-4N0M0 lesions to quantify the pulmonary impact of varying degrees of ENI. The five treatment volumes selected were as follows: (1) tumor volume plus a 2-cm margin; (2) volume 1 plus ipsilateral hilum; (3) volume 2 plus mediastinum; (4) volume 3 plus supraclavicular fossae; and (5) volume 4 plus contralateral hilum. The median pre-RT FEV1 was 2.0 l, and the median predicted minimal post-RT FEV1 for each proposed field was field 1, 1.7 l; field 2, 1.5 l; field 3, 1.3 l; field 4, 1.1.; and field 5, 1.0 l. The decline in median predicted FEV1 with each increase in field size ranged from 2% to 12%, with a broad range of declines for each field. Such quantification can aid in decisions regarding ENI for patients with impaired pulmonary function.