NCoR1-independent mechanism plays a role in the action of the unliganded thyroid hormone receptor.

Nuclear receptor corepressor 1 (NCoR1) is considered to be the major corepressor that mediates ligand-independent actions of the thyroid hormone receptor (TR) during development and in hypothyroidism. We tested this by expressing a hypomorphic NCoR1 allele (NCoR1ΔID), which cannot interact with the TR, in Pax8-KO mice, which make no thyroid hormone. Surprisingly, abrogation of NCoR1 function did not reverse the ligand-independent action of the TR on many gene targets and did not fully rescue the high mortality rate due to congenital hypothyroidism in these mice. To further examine NCoR1's role in repression by the unliganded TR, we deleted NCoR1 in the livers of euthyroid and hypothyroid mice and examined the effects on gene expression and enhancer activity measured by histone 3 lysine 27 (H3K27) acetylation. Even in the absence of NCoR1 function, we observed strong repression of more than 43% of positive T3 (3,3',5-triiodothyronine) targets in hypothyroid mice. Regulation of approximately half of those genes correlated with decreased H3K27 acetylation, and nearly 80% of these regions with affected H3K27 acetylation contained a bona fide TRß1-binding site. Moreover, using liver-specific TRß1-KO mice, we demonstrate that hypothyroidism-associated changes in gene expression and histone acetylation require TRß1. Thus, many of the genomic changes mediated by the TR in hypothyroidism are independent of NCoR1, suggesting a role for additional signaling modulators in hypothyroidism.

Plasma and urinary cytokine homeostasis and renal function during cardiac surgery without cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) significantly contributes to the plasma pro-inflammatory cytokine response at cardiac surgery. Complementary plasma and urinary anti-inflammatory cytokine responses have been described. The pro-inflammatory cytokines interleukin 8 (IL-8), tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) have lower molecular weights than the anti-inflammatory cytokines interleukin 10 (IL-10), interleukin 1 receptor antagonist (IL-1ra) and TNF soluble receptor 2 (TNFsr2) and thus undergo glomerular filtration more readily. In vitro work suggests that proximal tubular cells are vulnerable to pro-inflammatory cytokine mediated injury. Accordingly, this study investigated the hypothesis that cardiac surgery without CPB would not have significant changes in plasma and urinary cytokines and proximal renal dysfunction. Eight patients undergoing coronary artery bypass grafting (CABG) without CPB were studied. Blood and urine samples were analysed for pro- and anti-inflammatory cytokines. Proximal tubular dysfunction was measured using urinary Nu-acetyl-beta-D-glucosaminidase (NAG)/creatinine and alpha(1)-microglobulin/creatinine ratios. Plasma IL-8, IL-10, IL-1ra and TNFsr2 were significantly elevated compared with baseline. Urinary IL-1ra and TNFsr2 were significantly elevated, as were urinary NAG/creatinine and alpha(1)-microglobulin/creatinine ratios. Two hours following revascularization, urinary IL-1ra correlated with urinary alpha(1)-microglobulin/creatinine ratios (P<0.05). As previously reported in CABG surgery with CPB, we now report that non-CPB cardiac surgery also has significant changes in plasma and urinary cytokine homeostasis and early proximal tubular injury. The correlation between urinary IL-1ra and alpha(1)-microglobulin/creatinine ratios is consistent with earlier suggestions of a mechanistic link between cytokine changes and proximal tubular dysfunction. The relative roles of CPB and non-CPB processes in producing inflammation still require definition.

Endoscopic vein harvest: early results of a prospective trial with open vein harvest.

BACKGROUND: Conventional open long saphenous vein harvest (OVH) is often associated with significant wound pain and serious morbidity in some patients with a resultant extended treatment period. Endoscopic vein harvest (EVH) in theory should alleviate wound pain, be less predisposed towards leg wound infection and lead to greater patient satisfaction. This study aims to compare the two techniques on this basis and determine whether EVH is a viable technique within normal operative time. METHODS: During September and December 2000, 60 saphenous vein harvests were prospectively randomised to EVH (n=30) and OVH (n=30); all performed by one surgeon with the Clearglide(r) endoscopic vein harvest system (Ethicon Inc). End points were impaired wound healing (ASEPSIS score) and postoperative pain (Visual analogue scale) and operative variables. Statistical analysis done using Fisher s exact test and Mann-Whitney U test as appropriate. RESULTS: The groups were well matched demographically. Patients in the EVH group had significantly lower ASEPSIS scores (p<0.001) and postoperative pain (p<0.001). The vein was harvested at 0.96cm/min (0.43-1.5+/-0.33) in the OVH group compared to 0.81cm/min (0.41-1.13+/-0.19) in the EVH group (p=0.09). The new procedure did not prolong the overall operative time (p=0.53). Two patients needed to be converted to open technique. There was no difference found in the vein quality by histological analysis. CONCLUSIONS: These data clearly demonstrate that endoscopic vein harvest results in significantly reduced post-operative pain, better impaired wound healing, allows earlier ambulation and does not prolong the operative time significantly with no compromise in vein quality.

Repeat heart valve surgery: risk factors for operative mortality.

BACKGROUND: Patients undergoing repeat heart valve operations are a diverse population. We assessed risk factors for operative mortality in patients undergoing a first heart valve reoperation. METHODS: A retrospective review of hospital records was performed for 671 patients who underwent first repeat heart valve operations between 1969 and 1998. Univariable and multivariable analyses were performed. RESULTS: Operative mortality was 8.6%. Mortality fell each decade to 4.8% in the most recent period (adjusted chi(2) for linear trend P <.0005). Mortality increased from 3.0% for reoperation for a failed repair or reoperation at a new valve site to 10.6% for prosthetic valve dysfunction or periprosthetic leak and to 29.4% for endocarditis or valve thrombosis. Concomitant coronary artery bypass grafting was associated with a mortality of 15.4% compared with 8.2% when it was not required. Mortality for aortic valve replacement was 6.4%, mitral valve replacement 7.4%, aortic and mitral valve replacement 11.5%, tricuspid valve replacement 25.6%, periprosthetic leak repair 9.1%, and isolated valve repair 2.2%. Among 336 patients requiring replacement of prosthetic valves, mortality was 26.1% for replacement of a mechanical valve compared with 8.6% for replacement of a tissue valve (P <.0005). Multivariable analyses identified year of reoperation, age, coronary artery bypass grafting, indication, and replacement of a mechanical valve rather than a tissue valve as significant explanatory variables for operative mortality. CONCLUSIONS: Heart valve reoperations can be performed with an acceptable operative mortality. However, we have identified several categories of patients in whom reoperation carries an increased risk.

Glue aortoplasty repair of aortic dissection after coronary angioplasty.

Aortic dissection complicating percutaneous transluminal coronary angioplasty is rare. We report the case of a 45-year-old man who after right coronary artery angioplasty with stenting, dissected that vessel to involve the aorta to the bifurcation. Surgical repair with Gelatin-Resorcinol-Formaldehyde (GRF) glue as opposed to prosthetic graft replacement of the ascending aorta was successful. The use of GRF glue is effective in the surgical treatment of aortic dissection after coronary angioplasty.

Mechanical or bioprosthetic valves in the elderly: a 20-year comparison.

BACKGROUND: Our objective was to compare long-term results of mechanical and bioprosthetic valve replacement in patients older than 70 years. METHODS: Patients older than 70 years who had either a St. Jude Medical (SJM) mechanical prosthesis or any bioprosthesis (BP) implanted between January 1977 and December 1997 were identified. Alive patients were interviewed by telephone during a closing interval of 130 days. RESULTS: Complete follow-up was achieved with a total follow-up of 2,264 patient years. A total of 547 patients had 448 aortic valve replacements (199 SJM and 249 BP) and 99 had mitral valve replacements (76 SJM and 23 BP). A further 30 patients had double valve replacement. One hundred ninety of the 577 patients (33%) had coronary artery bypass grafting in addition to the valve replacement. Survival analysis showed no advantage for either mechanical or bioprosthetic valves. There was also no difference in thromboembolic rates, paravalvular leaks, structural dysfunction, and endocarditis rates. However, patients with mechanical valves had a significantly greater risk of major (p < 0.0001) and minor bleeding (p = 0.002) events. CONCLUSIONS: Bioprosthetic valves do not offer a survival advantage over mechanical valves among the elderly. However, anticoagulant-related mortality and morbidity is statistically higher for patients with mechanical valves.

Plasma and urinary cytokine homeostasis and renal dysfunction during cardiac surgery.

BACKGROUND: Cardiac surgery induces changes in plasma cytokines. Proinflammatory cytokines have been associated with a number of renal diseases. The proinflammatory cytokines interleukin 8 (IL-8), tumor necrosis factor alpha (TNFalpha), and interleukin 1beta (IL-1beta) are smaller than the antiinflammatory cytokines interleukin 10 (IL-10), interleukin 1 receptor antagonist (IL-1ra), and TNF soluble receptor 2 (TNFsr2), and thus undergo glomerular filtration more readily. Accordingly, this study investigated the relation between plasma and urinary cytokines and proximal renal dysfunction during cardiac surgery. METHODS: Twenty patients undergoing coronary artery bypass grafting with cardiopulmonary bypass (CPB) were studied. Blood and urine samples were analyzed for proinflammatory and antiinflammatory cytokines. Proximal tubular dysfunction was measured using urinary N-acetyl-beta-d-glucosaminidase (NAG)/creatinine and alpha1-microglobulin/creatinine ratios. RESULTS: Plasma IL-8, IL-10, IL-1ra, and TNFsr2 values were significantly elevated compared with baseline. Urinary IL-1ra and TNFsr2 were significantly elevated. Urinary NAG/creatinine and alpha1-microglobulin/creatinine ratios were also elevated. Plasma TNFalpha at 2 h correlated with urinary NAG/creatinine ratio at 2 and 6 h (P < 0.05) and with urinary IL-1ra at 2 h (P < 0.05). Plasma IL-8 at 2 h correlated with NAG/creatinine at 6 h (P < 0.05). Urinary IL-1ra correlated with urinary NAG/creatinine ratio after cross-clamp release and 2 and 6 h after CPB (P < 0.05). CONCLUSIONS: Cardiac surgery using CPB leads to changes in plasma and urinary cytokine homeostasis that correlate with renal proximal tubular dysfunction. This dysfunction may be related to the renal filtration of proinflammatory mediators. Renal autoprotective mechanisms may involve the intrarenal generation of antiinflammatory cytokines.

Association of interleukin-1 gene polymorphisms with Alzheimer's disease.

Interleukin-1 (IL-1) is markedly overexpressed in Alzheimer's disease. We found the IL-1A 2,2 genotype in 12.9% of 232 neuropathologically confirmed Alzheimer's disease patients and 6.6% of 167 controls from four centers in the United Kingdom and United States (odds ratio, 3.0; controlled for age and for ApoE [apolipoprotein E] genotype). Homozygosity for both allele 2 of IL-1A and allele 2 of IL-1B conferred even greater risk (odds ratio, 10.8). IL-1 genotypes may confer risk for Alzheimer's disease through IL-1 overexpression and IL-1-driven neurodegenerative cascades.

The -491A/T polymorphism of the Apolipoprotein E gene is associated with the ApoEepsilon4 allele and Alzheimer's disease.

Several studies have attempted to confirm the association between the recently reported polymorphism located at position -491 in the transcriptional regulatory region of the Apolipoprotein E (ApoE) gene and Alzheimer's disease (AD). Results have been inconclusive, possibly due to the use of clinically diagnosed subjects and controls only. In this retrospective case-control study of 149 (96 AD and 53 controls) brain samples we show that homozygosity for the -491A variant is associated with an increased risk of development of AD. The genotype is also strongly associated with the presence of at least one epsilon4 allele (an established risk factor for AD) in women but not in men.

Aorto-atrial fistula without aneurysm formation in Behçet's disease.

Cardiac disease is known to occur in patients with the multisystemic inflammatory disorder Behçet's disease. An aorto-atrial fistula secondary to Behçet's disease without a sinus of Valsalva aneurysm has not been previously reported. A 30 year old man with a four year history of symptoms and signs consistent with Behçet's disease presented with an aorto-atrial fistula and a large left to right shunt. At operation the defect was repaired with a bovine pericardial patch. There was no evidence of aneurysm formation. The patient made a good recovery and was well at one year follow up.

Are genetic factors important in the aetiology of leukoaraiosis? Results from a memory clinic population.

OBJECTIVE: To discover whether polymorphism in either the apolipoprotein E (ApoE) or angiotensin-converting enzyme (ACE) genes is associated with leukoaraiosis, white matter lesions visible on neuroimaging of the brain, which is commonly seen in dementia as well as some normal elderly subjects. DESIGN: Prospective study of consecutive patients attending our memory disorders clinic, to examine the relationship between leukoaraiosis and polymorphism of the ApoE and ACE genes. SETTING: Memory disorders clinic in Bristol, UK. PATIENTS: 182 patients attending the memory disorders clinic for investigation of possible dementia of whom 75% were suffering from dementia, 20% from memory impairment but no dementia and in 5% of whom a dementing illness was thought to be unlikely; 38% of all patients had visible white matter lesions and 16% had cerebral infarcts. MEASURES: Patients and/or carers who agreed to participate in the study had their ACE and ApoE genotype determined and their brain CT/MRI scans were assessed by a neuroradiologist, blind to the result of the genotyping, for the presence or absence of white matter low attenuation. RESULTS: There was a significant association between white matter lesions and the DD genotype (p < 0.05), but not the ApoE genotype. However, this relationship with the DD genotype was only significant for patients with a previous infarct. CONCLUSION: Homozygosity of ACE gene deletion polymorphism is a risk factor for white matter lesions when it is associated with cerebral infarction. This suggests that it may be possible to identify subjects who are at greater risk of developing white matter lesions and are at risk of cognitive impairment and possibly dementia.

Effect of gender and apolipoprotein E genotype on response to anticholinesterase therapy in Alzheimer's disease.

BACKGROUND: Anticholinesterase therapies offer modest benefit to subgroups of AD sufferers. However, there has previously been no way of predicting which patients will respond to any of the drugs. OBJECTIVE: To discover if gender and/or apolipoprotein E genotype can be used as predictors of response in the clinical setting. DESIGN: 107 patients from the Bristol Memory Disorders Clinic took part in a double-blinded or open label trial of tacrine therapy for between 3 and 12 months or an open label trial of galanthamine therapy for 3 months. RESULTS: After 3 months of therapy, gender was found to be the only significant influence on the number of responders to anticholinesterase therapy. Men had a 73% greater chance of responding than women (p = 0.012). While ApoE genotype did not modify response to therapy in the short term, there are indications that it may affect response over the longer term (up to 12 months), and also that the initial advantage of male gender may not be maintained after 3 months. CONCLUSION: Gender is likely to be a more powerful determinant of outcome of anticholinesterase treatment than apolipoprotein E status in the short term.

Reduced cholinergic function in normal and Alzheimer's disease brain is associated with apolipoprotein E4 genotype.

Apolipoprotein E (ApoE) is a potent risk factor for Alzheimer's disease. Since the loss of cholinergic function in Alzheimer's disease is known to occur at an early stage in the disease we have examined this function in normal subjects with an Apoepsilon4 allele to see if the deficit occurs in the absence of Alzheimer pathology or symptoms. We report that brain tissue obtained post-mortem from normal subjects and Alzheimer patients with an Apoepsilon4 allele has a lower cholinergic activity than tissue from those subjects without this allele. This has important significance for the interpretation of the cholinergic deficits found in Alzheimer's disease.

Superoxide radical and xanthine oxidoreductase activity in the human heart during cardiac operations.

BACKGROUND: The results of clinical trials of xanthine oxidoreductase inhibition in cardiac surgery are encouraging, although studies have failed to localize the enzyme to the human heart and to localize free radical activity to fresh human heart. METHODS: We adapted a histochemical staining technique based on the reduction of nitro blue tetrazolium to formazan by superoxide radical. In six samples of right atrium graded blindly on a scale of 0 through 4, strong staining (median grade, 3) of the microvasculature was seen. This was blocked by allopurinol in paired sections (median grade, 1; p < 0.01). Chemiluminescence can be used as an index of superoxide radical activity. Atrial samples were taken from 13 patients at five time points during coronary bypass grafting and placed in buffered luminol. Then chemiluminescence was measured. RESULTS: A 15-fold rise in chemiluminescence (295.93 +/- 39.47 mV) was demonstrated during reperfusion compared with the control value (19.06 +/- 0.47 mV). Chemiluminescence at 1 minute after release of the cross-clamp was significantly higher (p < 0.05) by analysis of variance versus values obtained before bypass and 1 minute before and 30 minutes after reperfusion. CONCLUSIONS: In this study we have identified superoxide radical activity and a possible generating system (xanthine oxidoreductase) in the human heart.

Cloning of a non-catalytic form of human trkB and distribution of messenger RNA for trkB in human brain.

A truncated form of the human trkB gene has been cloned and sequenced. This gene is related to the trk family of tyrosine kinases, the products of which act as receptors for the neurotrophins. Of these, brain-derived neurotrophic factor and mammalian neurotrophin-4 are the known ligands for the TrkB receptor. Catalytic and non-catalytic (or truncated) forms of the trkB gene have been cloned for rat and mouse. In this study, using in situ hybridization, we describe the distribution of trkB messenger RNA in fetal and adult human brain.

Atrial myxoma: national incidence, diagnosis and surgical management.

Despite being the most common benign intracardiac tumour with an excellent prognosis after surgical excision the incidence of atrial myxoma (except at autopsy) is unknown. We reviewed all patients admitted to the National Cardiac Surgery Unit (n = 26) with an atrial myxoma over a fifteen year period (1977-1991) to compile national incidence data and assess pre-operative diagnosis, management, surgical technique, and outcome. Preoperative symptoms were: congestive cardiac failure (12 patients), embolism (8 patients), constitutional (3 patients), asymptomatic (2 patients) and tachyarrhythmia (1 patient). The diagnosis was confirmed by 2D echocardiography alone in thirteen patients and by a combination of echocardiography and angiography in thirteen patients. At operation the site of the tumour was left atrial in 24 patients and bi-atrial in two patients. All cases were confirmed by histology. All patients made a good post-operative recovery, although one patient survived a pulmonary embolus and one patient developed a deep venous thrombosis. There has been one late death (five months after surgery) from a cerebrovascular accident. Serial echocardiography has revealed one recurrence to date (8 years after surgery). The surgical incidence of these tumours in the Republic of Ireland over the study period was 0.5 atrial myxomas/million population/year. Although rare atrial myxomas are the most important cardiac tumours to diagnose as the results from surgery are excellent.