Intestinal injury after thoracic aortic cross-clamping in the pig

BACKGROUND: The mucosal surface epithelium is an essential part of the functional intestinal barrier, but its structural response to ischemia/reperfusion is only partly characterized. The purpose of this study was to provide a detailed morphological evaluation of intestinal surface epithelium after aortic cross-clamping. MATERIAL AND METHODS: Pigs were subjected to thoracic aortic cross-clamping for 60 min and subsequent reperfusion for 120 min. Tissue blood flow and high-energy phosphates were measured with microspheres and HPLC, respectively. Urinary excretion of (14)C polyethylene glycol (MW 4000 Da) (PEG-4000), loaded into an intestinal loop, provided an index of intestinal permeability. RESULTS: Jejunal blood flow was restored at 10 min after aortic declamping. Denudation of the basement membrane of the intestinal villi tips, as a consequence of epithelial shedding, increased markedly during the initial 60 min of reperfusion (P = 0.002). During the following 45 min, the denuded basement membrane was partly covered with low cuboidal and squamous-shaped cells extending lamellipodia over a wavy basement membrane. Restoration of ATP at 60 min after aortic declamping correlated inversely to the extent of denuded basement membrane (r = 0.75, P = 0.032). Permeability of PEG-4000 increased markedly after aortic declamping and was linearly correlated to the area of denuded basement membrane (r = 0.87, P = 0.01). CONCLUSIONS: Reperfusion for 2 h after aortic cross-clamping is associated with initial aggravation of ischemia-induced injury in the porcine jejunum, but thereafter with restitution of the surface epithelium. Restoration of ATP may be important to avoid intestinal injury after ischemia. Increased permeability of a macromolecule in response to reperfusion is closely correlated to injury of the surface epithelium.     

Long term survival and costs per life year gained after out-of-hospital cardiac arrest

PURPOSE: To study long-term survival and estimate the costs per year of survival after out-of-hospital cardiac arrest of cardiac origin. MATERIALS AND METHODS: Cardiac arrest patients treated by the physician-manned ambulance in Oslo from January 1971 to June 1992. The condition of the patient when discharged from hospital was noted and survival followed until June 2002. Costs of the Emergency Medical Service (EMS), hospital treatment, rehabilitation and nursing homes and psychiatric institutions after discharge from hospital were included in a cost-effectiveness analysis. RESULTS: 1300 (42%) of 3065 patients receiving ALS were admitted to hospital after return of spontaneous circulation (ROSC). 1066 of these patients had a cardiac cause of the arrest, full hospital report and were found in the National Registry. Median age was 68 years (60-74) and 802 (75%) were men. 269 of the 1066 patients were discharged from hospital alive, 239 to their homes and 30 patients to rehabilitation/nursing homes or psychiatric institutions. The mean survival of the 1066 patients was 532 days. They spent mean 3.4 days in a CCU, 6.8 days in a general ward and 11.2 days in nursing/rehabilitation homes or psychiatric institutions. 30 patients were discharged to rehabilitation/nursing homes or psychiatric institutions. The mean survival time for the 269 patients discharged from hospital alive was 6.13 years. 110 patients were alive after five and 61 after 10 years. The cost per patient discharged alive was 40,642 or 6,632 per life year gained. CONCLUSIONS: Cardiac arrest patients do not occupy intensive care beds too long, and few end up in a vegetative state. Methodological differences in different studies makes meaningful comparisons of costs difficult, but the costs per life year saved are not high compared to other publications.     

Rational design of potent and selective VLA-4 inhibitors and their utility in the treatment of asthma

Asthma, a chronic inflammatory disease of the airways, is a significant burden on our healthcare system. There is high unmet need for treatments directed towards the underlying causes of the disease. The cell surface integrin VLA-4 (very late antigen-4; alpha4beta1; CD49d/CD29) plays an important role in the trafficking of white blood cells to sites of inflammation and represents an exciting target for the development of novel anti-inflammatory drugs for the treatment of asthma. Here, we review our efforts to use rational design to identify potent, selective inhibitors of VLA-4. We describe the discovery of a series of potent VLA-4 inhibitors through the addition of a novel N-terminal organic cap to a tetrapeptide VLA-4 binding motif 4-((N'-2-methylphenyl)uriedo)phenylacetyl-Leu-Asp-Val-Pro ; Kd = 70 pM), and rationalize their structure-activity relationships using 3D-QSAR. Also, we show our rational peptidomimetic design strategy using "template hopping" from the gpIIb/IIIa integrin antagonist field, and also a novel virtual screening strategy. Two series have been developed, one that has high selectivity for the activated over the non-activated state of the receptor, and the other which is non-selective inhibiting both activated and non-activated VLA-4. Both series are highly selective for VLA-4 versus against other integrin family members. These inhibitors show promise in the treatment of asthma, based upon efficacy in a sheep model of asthma, where they inhibit both the early and late-phase responses to asthma and also block hypersensitivity.     

The role of stressful life events in the development of depressive symptoms in adolescence--a longitudinal community study

Depressive symptoms were measured in a cohort of community-based adolescents (n = 163) at two time-points, with 1 year intervening. At Time 2, participants also answered a scale about past-year stressful life events. Depressive symptoms increased from Time 1 to Time 2, the effect being stronger for girls than for boys. Depressive symptoms were significantly correlated with concurrent measures of recent stressful life events, but this relationship disappeared after controlling for previous depressive symptoms. Rather, previous level of depressive symptoms predicted stressful life events. This demonstrates that a unidirectional model of stressful life events as the cause of depressive symptoms in adolescents is too simplistic.     

Retention of basic life support skills 6 months after training with an automated voice advisory manikin system without instructor involvement

AIM: To evaluate the retention of skills 6 months after training in ventilation and chest compressions (CPR) on a manikin with computer based on-line voice advisory feedback and the possible effects of initial overtraining. METHODS: Thirty five volunteers had 20 min provisional CPR training on a manikin with computer based voice advisory feedback but without an instructor. The appropriate feedback was taken from a pre-recorded list depending on performance measured by the manikin--computer system versus set limits for ventilation and compression variables. One group in addition was randomised to receive 10 similar 3 min training sessions during 1 week in the following month (overtrained group). All ventilation and compression variables were measured without feedback before and after the initial training session, with feedback immediately thereafter, and both without and with feedback 6 months after the initial training session. RESULTS: The initial training improved all variables. Compressions with correct depth increased from a mean of 33 to 77%, and correct inflations from a mean of 9 to 58%. After 6 months, the results for the controls were not significantly different from pre-training, except for a higher of correct inflations (18%), while the overtrained group had better retention of skills including the correct compression depth (mean 61%) and inflations (mean 42%). When verbal feedback was added both the compressions and ventilations immediately improved both when tested immediately and 6 months after the initial training session. CONCLUSIONS: The computer-based voice advisory manikin (VAM) feedback system can improve immediate performance of basic life support (BLS) skills, with better long-term retention with overtraining.     

Are expert panel judgments of medical benefits reliable? An evaluation of emergency medical service programs

OBJECTIVE: We have used multidisciplinary expert panels to assess the health benefits from two different emergency medical service programs in Norway. This gave the opportunity to study the reliability of the expert panel method. METHODS: Two panels assessed case reports for 18 children, and two other panels assessed case reports for 64 adult patients. The assessments of each case report were compared. These assessments were also compared with assessments of the same case reports, done by the same panels 1 and 9 years earlier. RESULTS: Two different panels agreed on the benefit/no benefit conclusion in at least 75% of the patients, both for children and adult patients (kappa 0.88-0.50). For groups of patients assessed to have some health benefit, the magnitude of the benefit estimates differed by 25% between the panels. When the same panels assessed the same patient groups twice, 1 and 9 years apart, their estimates of total benefit differed up to 30%. However, estimates for single patients, as well as estimates from single panel members, varied considerably more. CONCLUSIONS: Use of multidisciplinary expert panels is a useful method for estimating health benefits on program level or for groups of patients. But assessments from single panelists, and for single patients may be seriously biased.     

Automatic "respirator/weaning" with adaptive support ventilation: the effect on duration of endotracheal intubation and patient management

Adaptive support ventilation (ASV) provides an automatic adaptation of the ventilator settings to patient's passive and active respiratory mechanics. In a randomized controlled study, we evaluated automatic respiratory weaning in ASV for early tracheal extubation after cardiac surgery. Eligible patients were assigned to either an ASV protocol or a standard one consisting of synchronized intermittent ventilation followed by pressure support. Eighteen patients completed the ASV protocol, and 16 completed the standard one. There were no differences between groups in perioperative characteristics, lengths of tracheal intubation and intensive care unit stay, and ventilatory variables, except less peak inspiratory pressure during the initial phase in ASV (17.5 +/- 0.8 versus 22.2 +/- 0.8 cm H(2)O; P < 0.01). ASV patients required fewer ventilatory settings manipulations (2.4 +/- 0.7 versus 4.0 +/- 0.8 manipulations per patient; P < 0.05) and endured less high-inspiratory pressure alarms (0.7 +/- 2.4 versus 2.9 +/- 3.0; P < 0.05). These results suggest that in this specific population of patients, automation of postoperative ventilation with ASV resulted in an outcome similar to the control group. The internal logic of the new device resulted in less manipulation of the setting and alarms that could simplify respiratory management. IMPLICATIONS: Adaptive support ventilation (ASV), a ventilatory mode providing automatic adjustment of the settings was compared with standard management for rapid tracheal extubation after cardiac surgery. The two approaches were equal in terms of outcome. In ASV, we observed fewer ventilator settings manipulations and a smaller amount of alarms, suggesting that this automatic mode may simplify postoperative respiratory management without delaying extubation.     

A longitudinal study of long-term quality of life after ileal pouch-anal anastomosis

BACKGROUND: There is a lack of longitudinal long-term studies of quality of life (QOL) after surgery with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis, where cohorts of patients are used as their own controls. METHODS: Forty ulcerative colitis patients who had undergone IPAA were prospectively assessed while they had a temporary ileostomy, and at a median of 18 months and 7 years after ileostomy closure. QOL was measured with the Psychosocial Adjustment to Illness Scale and the Well-Being Profile. RESULTS: QOL was good at all three time points and, with some exceptions, did not change significantly between the assessments. There was a high degree of stability in the patients' evaluation of their QOL over time. CONCLUSIONS: QOL was already good when the patients had a temporary ileostomy and generally did neither improve nor deteriorate during 7 years after ileostomy closure. QOL was also quite stable in terms of individual differences.     

Morphology,phenotype and ultrastructure of fibroblastic cells from normal and neuropathic human detrusor: absence of myofibroblast characteristics

PURPOSE: Fibroblasts are functionally diverse and fibroblastic cells with smooth muscle-like characteristics (myofibroblasts) regulate smooth muscle activity in certain tissues. The presence of myofibroblasts has been reported in the bladder with important implications for normal function and detrusor overactivity. We assessed fibroblastic cell characteristics to discern features suggesting a myofibroblast phenotype in normal or neuropathic human detrusor. MATERIALS AND METHODS: A total of 25 control samples were obtained from cadaveric organ donors or patients with a mean age of 42.3 years investigated for hematuria and compared with samples from 18 patients with a mean age of 37.4 years with neurogenic detrusor overactivity. Morphology, phenotypic expression of various markers and the ultrastructure of each fibroblastic cell visible in multiple sections from each specimen was evaluated by 2 independent assessors. RESULTS: Fibroblastic cells were observed throughout the smooth muscle and connective tissue. They were located peripherally on muscle fascicles and had a polar stellate appearance with processes ramifying in interfascicular planes and muscle. They possessed vimentin-like immunoreactivity and weak c-kit-like immunoreactivity but not desmin or alpha-smooth muscle actin-like immunoreactivity. Ultrastructurally they showed dilated rough endoplasmic reticulum with a moderately electron dense amorphous content and prominent golgi complexes. Nuclei had clumped peripheral heterochromatin. There were extensive flattened processes that lacked basal laminae. There was no specific contact with nerve fibers or smooth muscle. Neuropathic bladder samples did not differ overtly from those of controls. CONCLUSIONS: The detrusor possesses an extensive network of fibroblastic cells and processes. No evidence of myofibroblast differentiation was discerned in normal or neuropathic detrusor, although a minority subpopulation or regional variability in cellular phenotype could not be excluded.