Effect of peri-operative red blood cell transfusion on 30-day and 1-year mortality following coronary artery bypass surgery.

OBJECTIVE: The purpose of this study was to examine the effect of peri-operative red blood cell (RBC) transfusion on 30-day and 1-year mortality following coronary artery bypass grafting (CABG). METHODS: We retrospectively analysed 3024 consecutive patients who underwent isolated CABG between January 1999 and December 2001. Patient records were linked to the National Strategic Tracing Service, which records all mortality in the UK. Thirty-day and 1-year mortality were derived from Kaplan-Meier curves. Confounding variables were controlled for by constructing a propensity score for the probability of receiving a transfusion from core patient characteristics including the lowest recorded laboratory haemoglobin (LL Hb) from a clinical chemistry database (C statistic 0.81). The propensity score and the comparison variable (transfusion versus no transfusion) were included in a Cox proportional hazards analysis, allowing calculation of adjusted hazard ratios (HR) and Kaplan-Meier survival curves. RESULTS: Nine hundred and forty (31.1%) patients received RBC transfusion during or within 72h of surgery. Predictors of the need for transfusion were LL Hb and lower body mass index, use of cardiopulmonary bypass, female sex, number of grafts, renal dysfunction, increased age, extent of disease, and prior CABG; these factors were all included in the propensity score. After 1-year of follow-up, 122 (4.03%) deaths occurred. The crude HR for 1-year mortality in patients transfused was 3.0 (P<0.001). After adjusting for the propensity score, re-operation for bleeding, peri-operative blood loss and post-operative complications, the adjusted 30-day mortality was 1.9% in transfused patients compared to 1.1% in patients not transfused (P<0.05). The adjusted HR for 1-year mortality in patients transfused was 1.88 (P<0.01). CONCLUSIONS: Peri-operative RBC transfusion after CABG is associated with an increased risk of mortality during a 1-year follow-up period, with a large proportion of deaths occurring within 30-days.     

Energy expenditure and body composition in children with Crohn's disease: effect of enteral nutrition and treatment with prednisolone

Background—Malnutrition and growth retardation arecommon complications of Crohn's disease in children. The contributionof resting energy expenditure (REE) to malnutrition is unclear.
Aims—To characterise the REE and body compositionin children with Crohn's disease and compare them with normal controlsand patients with anorexia nervosa; to compare the effects ofprednisolone and enteral nutrition on energy expenditure and body composition.
Subjects—Twenty four children with Crohn'sdisease, 19 malnourished females with anorexia nervosa, and 22 healthycontrol subjects were studied.
Methods—In children with Crohn's diseasemeasurements were done when the disease was acute and repeated at oneand three months after treatment with either prednisolone or enteralnutrition. Resting energy expenditure was measured by indirectcalorimetry and body composition by anthropometry, bioelectricalimpedance analysis, total body potassium,H₂¹⁸O, and bromide space studies.
Results—Body weight and ideal body weight weresignificantly lower in patients with Crohn's disease than in healthycontrols. Lean tissue was depleted and there was an increase inextracellular water. Per unit of lean body mass, there was nodifference between REE in patients with Crohn's disease and controls,whereas patients with anorexia nervosa had significantly reduced REE.With enteral nutrition all body compartments and REE increasedsignificantly (p<0.001). In a subgroup of age-matched men there was asignificant increase in height after three months of enteral nutritioncompared with prednisolone (p<0.01). Those treated with steroids didnot show a significant change in height but did show an increase in allbody compartments. However, intracellular water as well as lean bodymass accretion were significantly higher in the enteral nutrition groupthan in the prednisolone group.
Conclusions—Despite being malnourished, childrenwith Crohn's disease fail to adapt their REE per unit of lean bodymass. This might be a factor contributing to their malnutrition. Lean tissue accretion is higher in patients treated with enteral nutrition than in those treated with prednisolone.

Keywords:Crohn's disease; resting energy expenditure; bodycomposition; anorexia nervosa; prednisolone; enteral nutrition

     

CpG island methylation in aberrant crypt foci of the colorectum

Aberrant crypt foci (ACF) are postulated to be the earliest precursor lesion in colorectal carcinogenesis, and CpG island methylation has been described as an important molecular pathway. We therefore studied methylation in ACF from patients with familial adenomatous polyposis (FAP) or sporadic colorectal cancer. We assessed methylation status of the p16 tumor suppressor gene, MINT1 (methylated in tumor 1), MINT2, MINT31, O(6)-methylguanine-DNA methyltransferase gene, and hMLH1 mismatch repair gene. We compared methylation to ACF histopathology, K-ras proto-oncogene mutation, loss of heterozygosity at chromosome 1p, and microsatellite instability. Methylation was present in 34% (21 of 61) of ACF, including both FAP and sporadic types, but was more frequent in sporadic ACF [53% (18 of 34) versus 11% (3 of 27), P = 0.002], especially dysplastic sporadic ACF [75% (3 of 4) versus 8% (2 of 24), P = 0.004]. MINT31 was more frequently methylated in heteroplastic ACF than dysplastic ACF [35% (11 of 31) versus 7% (2 of 30), P = 0.01]. Strong associations of ACF methylation with K-ras mutation (P = 0.007) and with loss of chromosome 1p (P = 0.04) were observed, but methylation was the only molecular abnormality identified in 16% (10 of 61) of ACF. Our findings suggest that methylation in ACF is an early event in the pathogenesis of a subset of colorectal carcinomas, and that ACF from FAP patients and patients with sporadic colorectal cancer have distinct epigenetic changes that reflect differences in molecular pathogenesis.     

Cell-type-specific excitatory and inhibitory circuits involving primary afferents in the substantia gelatinosa of the rat spinal dorsal horn in vitro

The substantia gelatinosa (SG) of the spinal dorsal horn shows significant morphological heterogeneity and receives primary afferent input predominantly from Aδ- and C-fibres. Despite numerous anatomical and physiological studies, correlation between morphology and functional connectivity, particularly in terms of inhibitory inputs, remains elusive. To compare excitatory and inhibitory synaptic inputs on individual SG neurones with morphology, we performed whole-cell recordings with Neurobiotin-filled-pipettes in horizontal slices from adult rat spinal cord with attached dorsal roots. Based on dendritic arborization patterns, four major cell types were confirmed: islet, central, radial and vertical cells. Dorsal root stimulation revealed that each class was associated with characteristic synaptic inputs. Islet and central cells had monosynaptic excitatory inputs exclusively from C-afferents. Islet cells received primary-afferent-evoked inhibitory inputs only from Aδ-fibres, while those of central cells were mediated by both Aδ- and C-fibres. In contrast, radial and vertical cells had monosynaptic excitatory inputs from both Aδ- and C-fibres and inhibitory inputs mediated by both fibre types. We further characterized the neurochemical nature of these inhibitory synaptic inputs. The majority of islet, central and vertical cells exhibited GABAergic inhibitory inputs, while almost all radial cells also possessed glycinergic inputs. The present study demonstrates that SG neurones have distinct patterns of excitatory and inhibitory inputs that are related to their morphology. The neurotransmitters responsible for inhibitory inputs to individual SG neurones are also characteristic for different morphological classes. These results make it possible to identify primary afferent circuits associated with particular types of SG neurone.     

Epitope mapping and characterization of a novel CD4-induced human monoclonal antibody capable of neutralizing primary HIV-1 strains

Human immunodeficiency virus (HIV-1) enters target cells by binding its gp120 exterior envelope glycoprotein to CD4 and one of the chemokine receptors, CCR5 or CXCR4. CD4-induced (CD4i) antibodies bind gp120 more efficiently after CD4 binding and block the interaction with the chemokine receptor. Examples of CD4i antibodies are limited, and the prototypes of the CD4i antibodies exhibit only weak neutralizing activity against primary, clinical HIV-1 isolates. Here we report the identification of a novel antibody, E51, that exhibits CD4-induced binding to gp120 and neutralizes primary HIV-1 more efficiently than the prototypic CD4i antibodies. The E51 antibody blocks the interaction of gp120-CD4 complexes with CCR5 and binds to a highly conserved, basic gp120 element composed of the beta 19-strand and surrounding structures. Thus, on primary HIV-1 isolates, this gp120 region, which has been previously implicated in chemokine receptor binding, is accessible to a subset of CD4i antibodies.     

Characterisation of axon terminals in the rat dorsal horn that are immunoreactive for serotonin 5-HT3A receptor subunits

Serotonin 5-HT₃ receptors are abundant in the superficial dorsal horn and are likely to have an involvement in processing of nociceptive information. It has been shown previously that 5-HT₃ receptors are present on primary afferent terminals and some dorsal horn cells. The primary aim of the present study was to determine what classes of primary afferent possess 5-HT₃A receptor subunits. We performed a series of double- and triple-labelling immunofluorescence experiments. Subunits were labelled with an anti-peptide antibody and primary afferent axons were identified by the presence of calcitonin gene-related peptide (CGRP) and binding of the lectin IB4. Quantitative confocal microscopic analysis revealed that approximately 10% of axons displaying 5-HT₃A immunoreactivity were also labelled for CGRP but that only 3% of these fibres bind IB4. We also investigated the relationship between immunoreactivity for the subunit and descending serotoninergic systems, axons originating from inhibitory neurons that contain glutamic acid decarboxylase, and axons of a subpopulation of excitatory neurons that contain neurotensin. None of these types of axon was associated with immunoreactivity for receptor subunits. Ultrastructural studies confirmed that punctate immunoreactive structures observed with the light microscope were axon terminals. These terminals invariably formed asymmetric synaptic junctions with dendritic profiles and often contained a mixture of granular and agranular vesicles. Some terminals formed glomerular-like arrangements. Immunoreactive cells were also examined and were found to contain intense patches of reaction product within the cytoplasm. We conclude that the majority (about 87%) of dorsal horn axons that are immunoreactive for 5-HT₃A receptor subunits do not originate from the subtypes of primary afferent fibres that bind IB4 or contain CGRP. It is likely that most of these axons have an excitatory action and they may originate from dorsal horn interneurons and/or fine myelinated primary afferent fibres. Electronic Publication     

Small cell (oat cell) carcinoma of the trachea with endocrine features. Report of a case and results of ultrastructural and immunohistochemical study

Primary small cell (oat cell) carcinoma of the trachea is very rare. We report a case with ultrastructural evidence of endocrine differentiation. Immunoperoxidase staining demonstrated carcinoembryonic antigen and bombesin in the tumor cells.