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PubMed2002

Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection.

Inflammatory processes can stimulate renal epithelial cells to release cytokines, chemoattractants and matrix proteins into the interstitium, thus contributing to interstitial injury during acute allograft rejection. To test the role of interleukin 17 (IL-17) in this process, cultured human renal epithelial cells (hRECs) were first established and treated with or without human IL-17 (hIL-17) for 2, 4, 8 and 10 h in vitro. Significant elevations of IL-6 and IL-8 levels were noted in the supernatants in a dose-dependent and time-dependent manner, as also for IL-6 mRNA expression. Secondly, using a rat acute allograft rejection model, the correlation between IL-17 expression and histopathological changes was serially studied. The results demonstrated that increased expression of IL-17 protein on infiltrating mononuclear cells (MNCs) was detectable on day 2. This corresponds to the borderline change of acute rejection according to the Banff classification, and it increased progressively to day 5. Serial study of IL-6, IL-8 and IL-17 mRNA expression of the renal allograft confirmed IL-17 mRNA expression in the allograft early on post-transplant day 2, whereas IL-6 and IL-8 expression started on day 3. Thirdly, IL-17 expression was observed in human renal allograft and urinary sediment. IL-17 protein expression was found in human subclinical (borderline) rejection renal allograft biopsy tissue and none in biopsy tissue not showing any evidence of rejection. There was also a 100% detectable rate of IL-17 mRNA expression in the MNCs of urinary sediment of patients with subclinical borderline rejection. These results demonstrate that hRECs exposed to IL-17 can produce inflammatory mediators with the potential to stimulate early alloimmune responses, which may also serve to give warning of acute renal allograft rejection.

Analysis of Variance↗
PubMed1986

Safety and efficacy of long-term diet and diet plus bile acid-binding resin cholesterol-lowering therapy in 73 children heterozygous for familial hypercholesterolemia.

Our specific aim was to examine the efficacy and safety of long-term cholesterol-lowering diet and bile acid-binding resin therapy in 73 children heterozygous for familial hypercholesterolemia (FH). We prospectively followed accretion of height and weight in 40 FH children for 5.8 years on diet alone and in 33 FH children for 4.3 years on diet and bile acid-binding resins (8 to 20 g/d). In 67 of these 73 children, sequential data on plasma cholesterol lowering was obtained, including 32 children on diet plus bile acid-binding resins and 35 on diet alone. For all 73 children, median age, sex, and race-specific percentiles for height and weight at entry were 50 and 50, respectively, and 5.7 years later, were unchanged at 50 and 50. Initial and final percentiles for height (r = .76, P less than .001) and weight (r = .70, P less than .001) were closely correlated. Percentile distributions for height and weight at entry into the study did not differ from those at the end of follow-up (P greater than .1), in both the 40 FH children on diet alone and the 33 on diet plus bile acid-binding resins. Tracking of height and weight did not differ in the 40 children on diet alone v the 33 on diet plus bile acid-binding resins (P greater than .1). During 6 years of follow-up there were no significant differences in the percentage of serial, postbaseline measurements for height which were either less than or greater than or equal to baseline percentiles, comparing 40 FH children on diet alone, 33 FH children on diet plus resin, and 39 normal children (on ad libitum diet). FH children on diet or plus resin had a smaller percentage of weight measurements equal to or more than baseline percentiles than normals on follow-up (P less than .01), probably reflecting restriction of total fat intake to less than 35% of calories. On diet alone, 32 FH children had total plasma cholesterol of 307 +/- 8 mg/dL (mean +/- SE); bile acid-binding resins were added to diet in these children at an average age of 11.5 years, with this regimen maintained for 4.6 +/- 0.4 years, leading to a mean reduction in total plasma cholesterol of 12.5% +/- 2% beyond the effects of diet alone (P less than .01).(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1985

Effects of beta-adrenergic blockade on the natural progression of myocardial infarct size and compensatory hypertrophy.

Using contrast-enhanced computed tomography, the effects of beta-adrenergic blockade were assessed on experimentally produced myocardial infarcts in dogs evaluated serially over the course of approximately 1 month. Infarct size, initial perfusion defect (jeopardized segment) and noninfarcted muscle mass were studied in two groups of conditioned mongrel dogs. Group 1 (n = 11) served as the control group and Group 2 (n = 10) was pretreated with propranolol (2 mg/kg). Each animal in the propranolol-treated group was given identical amounts of the agent twice daily for 7 days after coronary occlusion. Both groups developed increases in the noninfarcted muscle mass of the left ventricle (compensatory hypertrophy). The mean increase averaged 19.8% over 30 days when the two groups were included together. Infarct size was smaller in the propranolol-treated group, and averaged 28% less (p less than 0.05) than that of the control group 30 days after initial myocardial infarction. Thus, pharmacologic interventions were shown by computed tomography to alter the size of an acute experimental myocardial infarct, particularly when examined over the time course of infarct healing. Moreover, compensatory hypertrophy occurred in both the control and propranolol-treated groups.

Animals↗
PubMed2004

Effect of formulary policy decisions on antimicrobial drug utilization in British Columbia.

BACKGROUND: Formularies are used routinely for management of drug expenditures yet evaluations of their impact remain rare. The objective of this study was to analyse the impact of addition or deletion of antimicrobials from the provincial formulary on drug utilization. METHODS: We obtained data from the British Columbia PharmaNet database on all outpatient oral antimicrobial prescriptions from 1996 to 2000 and converted them to their defined daily dose (DDD) equivalents according to the ATC system. Trends in utilization associated with a changing formulary status of new antimicrobial agents were analysed. Maximum likelihood estimation was used to determine the rate of increase in utilization resulting from addition to the formulary. Models were adjusted for seasonal and temporal trends as well as serial correlation. RESULTS: During this time period, clarithromycin was on formulary, later delisted, and then relisted again. Valaciclovir and famciclovir were also added to the formulary. During the time clarithromycin was off the formulary, the rate of change in its monthly consumption was 0.0061 DDD/1000 population/day; following its relisting, the rate of change increased by 818% to 0.0560 DDD/1000 population/day (P=0.002). After the listing of valaciclovir on the formulary, the rate of change in its monthly consumption increased 57% from a baseline of 0.0014 to 0.0022 DDD/1000 population/day (P=0.07). A similar effect was seen with the addition of famciclovir to the formulary whereby the rate of change in monthly consumption increased from 0.0008 (before addition to the formulary) to 0.0018 (after addition to the formulary) (P </= 0.001). CONCLUSIONS: Listing of antimicrobials on provincial or countrywide formularies is followed temporally with increased utilization. However, before governmental agencies can institute reference-based pricing or co-payment programmes, the effect of such a programme on the emergence of antimicrobial resistance and on patient outcomes needs further study.

Anti-Bacterial Agents↗
PubMed2002

Survivin expression correlates with clinical stage, histological grade, invasive behavior and survival rate in endometrial carcinoma.

Survivin is a new member of the inhibitor of apoptosis family of anti-apoptotic proteins. It has been reported that survivin is expressed during fetal development and in cancer tissues. Because suppression of apoptosis is important for carcinogenesis and tumor growth, we investigated the expression of survivin in human endometrial carcinomas. We analyzed serial frozen sections for survivin protein expression in 31 cases of endometrial carcinoma and 20 cases of normal endometria by fluorescent immunohistochemistry. We analyzed the relationship between the percentages of survivin-stained cells and the patient's characteristics, including clinical stage, histological grade, presence of invasion to >1/2 myometrium, clinical outcome, and survival rate. Survivin was weakly detected in some normal endometria in the proliferative phase (0-5.1%) and in the secretory phase (0-15.8%). There was, however, abundant survivin immunoreactivity in the nucleus and/or cytoplasm of the endometrial carcinoma cells. Scoring on the basis of the percentage of positive cells indicated that survivin expression was significantly associated with proliferating cell nuclear antigen-labeling index, clinical stage, histological grade, the presence of invasion to >1/2 myometrium, clinical outcome, and survival rate (P<0.01, respectively). We conclude that the survivin protein is a defining diagnostic marker for endometrial carcinomas that may also yield prognostic information.

Adenocarcinoma↗
PubMed2001

Hypertension exacerbates coronary artery disease in transgenic hyperlipidemic Dahl salt-sensitive hypertensive rats.

BACKGROUND: The mechanisms underlying the known interaction of two complex polygenic traits, hypertension and hyperlipidemia, resulting in exacerbation of coronary artery disease have not been elucidated. Identification of critical pathways underlying said exacerbation could identify mechanism-based targets for intervention and prevention. MATERIALS AND METHODS: To investigate hypertension- atherosclerosis interaction, we studied the inbred transgenic atherosclerosis-polygenic hypertension Dahl salt-sensitive (S) rat model (Tg53), which over-expresses human cholesteryl ester transfer protein (hCETP) in the liver, and exhibits coronary artery disease and decreased survival compared with control non-transgenic Dahl S rats. Using serial-section histopathological and immunohistochemical analyses, we analyzed the coronary artery disease phenotype of Tg53 rats at end-stage marked by cardio-respiratory compromise as the experimental equivalent of acute coronary syndromes, and determined the effects of reduction of blood pressure through low salt diet (0.008% NaCl) on the coronary artery disease phenotype and survival. RESULTS: End-stage Tg53 rats exhibit coronary artery lesions in the proximal right coronary artery system which exhibit "culprit plaque" features such as plaque inflammation, matrix degradation, apoptosis, neovascularization, thrombosis and hemorrhage recapitulating said features and heterogeneity of human coronary "culprit plaques". Comparative analysis of 6 month vs end-stage lesions reveals distinct lesion development profiles of proximal coronary lesions which quickly progress from eccentric non-occlusive foam-cell rich lesions at 6 months to occlusive "culprit plaques", compared with more distal coronary lesions which exhibit occlusive thick-cap atheroma that remain relatively unchanged from 6 months to end stage. Reduction of hypertension through a low-salt (0.008% NaCl) diet increased survival (P < 0.0001) of Tg53 rats and significantly attenuated the coronary artery disease phenotype detected at 10 months of age marked by diminished apoptosis, neovascularization, matrix degradation compared with end-stage lesions detected at <8 months of age. CONCLUSIONS: End stage coronary lesions in the Tg53 rats recapitulate many, albeit not all, features of "culprit plaques" in humans supporting proposed paradigms of plaque vulnerability implicating lesion macrophage enrichment, apoptosis, matrix degradation and pathological neovascularization. Comparative time course analysis of coronary lesions reveals that plaques which develop into end-stage "culprit plaques" are distinct from "stable plaques" by location and early lesion morphology, suggesting distinct lesion development and progression pathways. The significant effects of low-salt diet-induced decrease in hypertension on right coronary disease phenotype provides compelling evidence that polygenic hypertension accelerates coronary plaque progression and complication independent of cardiac hypertrophy, and more importantly provides paradigmatic support for public health policy.

Animals↗
PubMed1999

Continuous heparinization and circulating adhesion molecules in the critically ill.

Endothelial activation and damage are common endpoints of a complex process that may result in multiple organ dysfunction syndrome (MODS). The influence of continuous intravenous heparinization on plasma levels of circulating adhesion molecules was studied in 28 trauma patients (injury severity score between 15 and 25 points) and 28 sepsis patients secondary to abdominal surgery. According to a prospective, randomized sequence the patients received either unfractionated heparin (aim: activated partial thromboplastin time (aPTT) approximately 2 x normal) (trauma-heparin (n = 14); sepsis-heparin (n = 14)) or not (trauma (n = 14); sepsis (n = 14)). Plasma levels of circulating soluble endothelial leukocyte adhesion molecule-1 (sELAM-1), vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (slCAM-1), and granule membrane protein-140 (sGMP-140) were serially measured from arterial blood samples for 5 days. Approximately 600 U/h of heparin were given to increase aPTT to approximately 60 s. Plasma levels of all adhesion molecules increased in all groups. This increase was significantly (p < .05) highest in both sepsis groups (sepsis: sELAM-1: from 50+/-11 to 84+/-19 ng/mL; slCAM-1: 410+/-68 to 700+/-95 ng/mL), but did not differ significantly between the treated and nontreated patients (sepsis-heparin: sELAM-1: from 60+/-131 to 88+/-20 ng/mL; slCAM-1: from 398+/-99 to 686+/-119 ng/mL). Trauma patients showed a less pronounced increase in all adhesion molecules without differences between the two subgroups. Only sGMP-140 increased significantly (p < .05) more in the trauma (from 102+/-20 to 169+/-16 ng/mL) than in the trauma-heparin group (from 109+/-19 to 132+/-17 ng/mL). It is summarized that continuous heparinization with approximately 600 U/h did not attenuate the rise in circulating adhesion molecules in sepsis and trauma patients. The study findings suggest that heparin in this dose regimen may be unlikely to influence endothelial inflammation or endothelial function in critically ill patients.

Adult↗
PubMed2005

Continuous intra- and postoperative thoracic epidural analgesia attenuates brain natriuretic peptide release after major abdominal surgery.

We investigated whether blocking afferent nociceptive inputs by continuous intra- and postoperative thoracic epidural analgesia (TEA) would decrease plasma concentrations of brain natriuretic peptide (BNP) in patients who were at risk for, or had, coronary artery disease. Twenty-eight patients undergoing major abdominal surgery received either general anesthesia supplemented with a continuous thoracic epidural infusion of 1.25 mg/mL bupivacaine and 1 microg/mL sufentanil (n = 14; TEA) or general anesthesia followed by IV patient-controlled analgesia (n = 14; IV PCA). Visual analog scale pain scores, hemodynamics, plasma catecholamines, cardiac troponin T, atrial natriuretic peptide (ANP), and BNP were serially measured preoperatively, 90 min after skin incision, at arrival in the intensive care unit, and in the morning of the first, second, and third postoperative day. Dynamic visual analog scale scores were significantly less in the TEA group. TEA reduced the postoperative heart rate without affecting other hemodynamic variables. Plasma epinephrine increased perioperatively in both groups but was significantly lower in the TEA group. Baseline ANP and BNP concentrations were similar between groups (TEA 3.4 +/- 1.8 and 27.0 +/- 12.3 pg/mL; IV PCA 3.1 +/- 2.0 and 25.9 +/- 13.0 pg/mL, respectively). ANP and BNP increased perioperatively in both groups, with significantly lower postoperative BNP levels in TEA patients (TEA 92.1 +/- 31.9 pg/mL; IV PCA 161.2 +/- 44.7 pg/mL). No such difference was observed in plasma ANP concentrations. Plasma cardiac troponin T concentrations were within normal limits in both groups at all times. We conclude that continuous perioperative TEA using local anesthetics and opioids attenuated the release of BNP in patients undergoing major abdominal surgery who were at risk for, or had, coronary artery disease.

Abdomen↗
PubMed2006

Brain magnetic resonance imaging abnormalities after the Norwood procedure using regional cerebral perfusion.

OBJECTIVES: Neurologic deficits are common after the Norwood procedure for hypoplastic left heart syndrome. Because of the association of deep hypothermic circulatory arrest with adverse neurologic outcome, regional low-flow cerebral perfusion has been used to limit the period of intraoperative brain ischemia. To evaluate the impact of this technique on brain ischemia, we performed serial brain magnetic resonance imaging in a cohort of infants before and after the Norwood operation using regional cerebral perfusion. METHODS: Twenty-two term neonates with hypoplastic left heart syndrome were studied with brain magnetic resonance imaging before and at a median of 9.5 days after the Norwood operation. Results were compared with preoperative, intraoperative, and postoperative risk factors to identify predictors of neurologic injury. RESULTS: Preoperative magnetic resonance imaging (n = 22) demonstrated ischemic lesions in 23% of patients. Postoperative magnetic resonance imaging (n = 15) demonstrated new or worsened ischemic lesions in 73% of patients, with periventricular leukomalacia and focal ischemic lesions occurring most commonly. Prolonged low postoperative cerebral oximetry (<45% for >180 minutes) was associated with the development of new or worsened ischemia on postoperative magnetic resonance imaging (P = .029). CONCLUSIONS: Ischemic lesions occur commonly in neonates with hypoplastic left heart syndrome before surgery. Despite the adoption of regional cerebral perfusion, postoperative cerebral ischemic lesions are frequent, occurring in the majority of infants after the Norwood operation. Long-term follow-up is necessary to assess the functional impact of these lesions.

Brain Ischemia↗
PubMed2005

The incidence and natural history of Raynaud's phenomenon in the community.

OBJECTIVE: Raynaud's phenomenon (RP) is a common disorder, yet its incidence and natural history are unknown. Our objective was to determine the incidence and natural history of RP not associated with a connective tissue disease in a large, community-based population. METHODS: Using serial examinations of the Framingham Heart Study offspring cohort, we collected data regarding RP symptoms for 717 women and 641 men over a 7-year period. We used validated criteria for RP classification and categorized participants as having incident, persistent, or remitted RP. We performed sex-specific analyses of RP status by age, body mass index, vibratory tool use, season of examination, state of residence, use of antihypertensive medications, and smoking status. RESULTS: The mean +/- SD age of participants was 53.5 +/- 10 years. The incidence of RP was 2.2% in women (n = 14) and 1.5% in men (n = 9). Of the 78 women and 50 men who had RP at baseline, 36% of women (n = 28) and 36% of men (n = 18) had persistent RP. RP remitted in 64% of women (n = 50) and 64% of men (n = 32), with 41 women and 25 men meeting no or only 1 RP criterion at followup. RP episodes were infrequent and rarely interfered with daily activities. CONCLUSION: This is the first prospective study to determine the incidence and natural history of RP in a community-based cohort. Our data demonstrate that RP not associated with a connective tissue disease is frequently a transient phenomenon and rarely interferes with daily activities.

Adult↗
PubMed2005

A prospective study of reversible dementias: frequency, causes, clinical profile and results of treatment.

BACKGROUND: Dementia due to potentially reversible etiologies is an important group of dementias to be identified not only because of the number of such Patients encountered but also due to the potential for substantial improvement with treatment. AIMS: To prospectively investigate the frequency and causes of dementias with potentially reversible etiologies; to examine the clinical features of this subgroup with a view to identifying a signature profile and to determine if this potential reversibility translates into actual reversibility with appropriate treatment. SETTING AND DESIGN: A prospective longitudinal study of patients with dementia presenting to the outpatient services of a tertiary referral hospital. METHODS: All Patients above 40 years referred for evaluation of cognitive complaints were serially enrolled and underwent clinical examination, various laboratory tests and neuroimaging. Patients were followed-up for one year. STATISTICAL ANALYSIS: One way analysis of variance for continuous variables followed by post hoc comparisons using Scheffe's procedure. RESULTS: A total of 129 patients met Diagnostic and Statistical Manual of Mental Disorders edition 4 (DSM IV) criteria for dementia and qualified for inclusion into the study. Twenty-four patients (18%), all with moderately severe cognitive [mean mini mental state examination (MMSE) score +/- SD = 17.9 +/- 4.8] and neuropsychiatric [mean neuropsychiatric inventory (NPI) score +/- SD = 30.7 +/- 8.7] dysfunction were diagnosed to have reversible causes - neuroinfections in 11 patients, normal pressure hydrocephalus in 8 patients and vitamin B12 deficiency in 5 patients. The majority of these patients had gait and urinary dysfunction reminiscent of subcortical dementias. These reversible causes were clinically suspected in only 58% of patients. In 20/24 patients in whom follow up was possible mean MMSE score had improved to 22.2 and mean NPI score had improved to 8.0, following 6 months of treatment. CONCLUSIONS: Reversible causes, especially neuroinfections and vitamin B12 deficiency accounted for 18% all dementias in this study. The majority of these conditions was not clinically suspected though resulting in moderate to severe cognitive and psychiatric dysfunction. Most of these patients had a subcortical pattern of dementia and showed substantial improvement with treatment.

Adult↗
PubMed2001

Changes in bone and calcium metabolism following hip fracture in elderly patients.

Although hip fracture is one of the most common causes of acute immobilization in elderly patients, little is known about the influence of immobilization on changes in bone and calcium metabolism following this event. We therefore compared serum biochemical indices of bone and calcium metabolism in 20 elderly subjects with hip fracture with those measured in 20 healthy age-matched controls. Rankin scores, a measure of functional dependence with 0 representing independence and 5 representing total dependence, were assigned. We also examined serial changes in these biochemical indices from shortly following the fracture to the early recovery period. Ionized calcium, intact parathyroid hormone (PTH), intact bone Gla protein (BGP), pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), 25-hydroxyvitamin D (25-OHD), and 1,25-dihydroxyvitamin D (1,25-[OH]2D) were measured. One week after the fracture, mean serum concentrations of calcium and ICTP were elevated in correspondence to degree of immobilization (mean Rankin score; 4.4), while serum concentrations of BGP, PTH, 25-OHD, and 1,25-[OH]2D were depressed. Rankin score (mean: 4.4) correlated positively with ICTP and negatively with BGP at this time. At 2 months, calcium and ICTP elevation decreased and BGP, PTH and 1,25-[OH]2D were less depressed, coinciding with a decline in Rankin score from 4.2 to 2.2. Indices were further improved at 3 months (mean Rankin score, 1.3), with calcium and BGP returning to normal. We concluded that increased bone resorption, and decreased bone formation, and hypercalcemia are present by 1 week following the hip fracture, and some resorption increase persists for at least 3 months. These changes could explain in part the high risk of another hip fracture.

Activities of Daily Living↗
PubMedDate not supplied

Thallium pulmonary scintigraphy. Relationship to pulmonary fluid volumes during left atrial hypertension and the acute release of pressure.

To evaluate the relationship between thallium-201 lung activity and pulmonary fluid volumes, we compared thallium pulmonary scintigrams with measures of intravascular (PBV), extravascular (EVLW) and total lung water (TLW) during gradual left atrial (LA) hypertension and then serially after the acute release of pressure. The study group was composed of nine mongrel dogs who were each studied at seven levels of elevated LA pressure, and then every 15 minutes for 2 hours after the acute release of pressure. During LA pressure (congestion phase) elevation, lung counts (normalized for myocardial activity), correlated best with TLW (r = .91), rather than PBV (r = .84) or EVLW (r = .81). After the release of pressure (recovery phase), lung counts correlated well with EVLW (r = .92) and TLW (r = .82), but not with PBV (r = .28). Postmortem lung counts from 197 separate lung sections correlated well with the corresponding wet weight/dry weight ratio from that section (r = .81). Thus, we conclude that changes in pulmonary thallium emissions during cardiogenic pulmonary edema relate to corresponding changes in pulmonary fluid volumes. During congestion, the confounding effects of nonlinear increases in EVLW and PBV make thallium emissions more a marker of TLW than either the intravascular or extravascular pulmonary fluid compartment. After pressure release, PBV immediately returns to normal, at which time EVLW and pulmonary emissions correlate closely. These latter data, more applicable to postexercise stress thallium data, lend support to the hypothesis that elevated pulmonary emissions during postexercise thallium scintigrams reflect elevations in EVLW that develop during exercise.

Animals↗
PubMed2003

Safety of intravitreal voriconazole: electroretinographic and histopathologic studies.

PURPOSE: Voriconazole, a novel triazole antifungal agent, presents potent activity against a broad spectrum of yeast and molds. To determine whether it could be safely used as an intravitreal agent in the treatment of fungal endophthalmitis, retinal toxicity of voriconazole was examined in a rodent animal model. METHODS: Voriconazole solutions were serially diluted and injected intravitreally into eyes of normal adult Sprague-Dawley rats so that the final intravitreal concentrations were 5 microg, 10 microg, 25 microg, 50 microg, and 500 microg/mL (N = 3 for each concentration group). Saline was injected into the fellow eyes of each animal as controls. Three weeks after injections, electroretinograms (ERGs) were measured, and eyes were subsequently enucleated for histologic examination. RESULTS: In ERG studies, maximum scotopic b-wave, bmax intensity needed for half saturation, I0.5, and saturated a-wave amplitude were measured. There was no statistically significant difference in these parameters recorded between control eyes and voriconazole-injected eyes in any concentration groups. Histologic examination with light microscopy did not reveal any retinal abnormality in the eyes with 5 to 25 microg/mL intravitreal voriconazole. In the eyes with 50 microg/mL and 500 microg/mL voriconazole, small foci of retinal necrosis were occasionally observed in the outer retina, especially in the eyes with 500 mg/mL voriconazole. CONCLUSION: Our results demonstrate that intravitreal voriconazole of up to 25 mg/mL causes no ERG change or histologic abnormality in rat retina. This indicates that voriconazole is a safe antifungal agent that may be employed by intravitreal injection in the treatment of fungal endophthalmitis.

Animals↗
PubMed2001

Changes of haemostasis in patients undergoing major abdominal surgery--is there a difference between elderly and younger patients?

Many physiological functions are altered in the elderly. It is not clear whether this applies to haemostatic mechanisms in patients undergoing major surgery. Twenty-five consecutive patients <60 yr and 25 consecutive patients >70 yr scheduled for abdominal surgery for malignancies were included in our study. Various standard coagulation variables and specific markers of coagulation were serially measured before surgery (baseline), at arrival on the intensive care unit (ICU), 4 h after arrival on ICU, and on the morning of the first postoperative day. Platelet function was assessed using the Platelet Function Analyser PFA-100 with adenosine diphosphate (ADP) as an inductor. Anaesthesia and surgery were similar between the elderly (76(3) years) and younger (53(5) years) groups. Baseline plasma levels of prothrombin fragments F1+2, thrombin-antithrombin III (TAT) complex, and D-dimers were significantly different between the two groups, indicating thrombin activation and fibrin formation in the elderly. Postoperatively, only F1+2 plasma levels were significantly higher in the elderly (4.0(0.8) nmol/l) than in the younger patients (2.2(0.9) nmol/l), whereas the course of D-dimer and TAT did not differ significantly between the two groups. Endothelial-derived markers of coagulation (von Willebrand factor, collagen-binding activity of von Willebrand factor) were not different between the groups throughout the study period. Platelet function was impaired in the elderly compared with the younger patients. It is concluded that elderly patients showed more prothrombin activation/thrombin generation and increased fibrinolytic activity prior to surgery than younger patients. However, perioperative changes of coagulation in the elderly were similar to those seen in younger patients.

Abdominal Neoplasms↗
PubMed2004

Intravitreal voriconazole: an electroretinographic and histopathologic study.

BACKGROUND: Voriconazole, a novel triazole antifungal agent, presents potent activity against a broad spectrum of yeast and molds. OBJECTIVE: To determine whether voriconazole could be safely used as an intravitreal agent in the treatment of fungal endophthalmitis. METHODS: Retinal toxicity of voriconazole was examined in a rodent animal model. Voriconazole solutions were serially diluted and injected intravitreally into the eyes of normal adult Sprague-Dawley rats so that the final intravitreal concentrations were 5 microg/mL, 10 microg/mL, 25 microg/mL, 50 microg/mL, and 500 microg/mL (n = 3 for each concentration group). Saline was injected into the fellow eyes of all animals as controls. Three weeks after injections, electroretinograms were measured, and eyes were subsequently enucleated for histologic examination. RESULTS: In electroretinographic studies, maximum scotopic b-wave, intensity needed for half saturation, and saturated a-wave amplitude were measured. There was no statistically significant difference in these parameters recorded between control eyes and voriconazole-injected eyes in any concentration groups. Histologic examination with light microscopy did not reveal any retinal abnormality in the eyes with 5 to 25 microg/mL of intravitreal voriconazole. In the eyes with 50 microg/mL and 500 microg/mL of voriconazole, small foci of retinal necrosis were occasionally observed in the outer retina, especially in the eyes with 500 microg/mL of voriconazole. CONCLUSIONS: Our results demonstrate that intravitreal voriconazole of up to 25 microg/mL [corrected] causes no electroretinographic change or histologic abnormality in rat retinas. This indicates that voriconazole is a safe antifungal agent for intravitreal injection in rodents and may be used in the treatment of human fungal endophthalmitis following further study.

Animals↗
PubMed1981

Recovery from prolonged abnormalities of canine myocardium salvaged from ischemic necrosis by coronary reperfusion.

The purpose of this study was to determine whether or not the biochemical, functional, and ultrastructural abnormalities produced by brief temporary coronary occlusions (unassociated with necrosis) ever resolve and, if so, when they do. Anesthetized open-chest dogs were subjected to 15 min of coronary artery occlusion followed by 72 hr, 7 days, or 14 days of reperfusion. Serial in vivo myocardial biopsies were performed for measurement of ATP and for ultrastructural analysis. Regional function was evaluated by sonomicrometry. Mean (+/- SEM) myocardial ATP concentration was 36.6 +/- 1.2 nmol/mg of cardiac protein in nonischemic subendocardium and 18.9 +/- 1.5 in ischemic subendocardium after 15 min of ischemia. ATP remainede performed for measurement of ATP and for ultrastructural analysis. Regional function was evaluated by sonomicrometry. Mean (+/- SEM) myocardial ATP concentration was 36.6 +/- 1.2 nmol/mg of cardiac protein in nonischemic subendocardium and 18.9 +/- 1.5 in ischemic subendocardium after 15 min of ischemia. ATP remainede performed for measurement of ATP and for ultrastructural analysis. Regional function was evaluated by sonomicrometry. Mean (+/- SEM) myocardial ATP concentration was 36.6 +/- 1.2 nmol/mg of cardiac protein in nonischemic subendocardium and 18.9 +/- 1.5 in ischemic subendocardium after 15 min of ischemia. ATP remained depressed in the reperfused previously ischemic subendocardium at both 90 min (68% of nonischemic value) and 72 hr (78% of nonischemic value) but returned to normal at 7 days. Regional systolic function and cardiac ultrastructural abnormalities required 7 days for full recovery. Histologic and histochemical analysis did not reveal necrosis at any time. Therefore, biochemical, functional, and ultrastructural abnormalities induced by brief periods of transient coronary occlusion not associated with necrosis do resolve completely but the recovery period is prolonged.

Adenosine Triphosphate↗
PubMed2005

An autoregulatory loop controlling orphan nuclear receptor DAX-1 gene expression by orphan nuclear receptor ERRgamma.

The estrogen receptor-related receptor gamma (ERRgamma/ERR3/NR3B3) is a member of the nuclear receptor superfamily that activates transcription in the absence of ligand. However, the detailed mechanism of gene regulation by ERRgamma is not fully understood. In this study we have found that the orphan nuclear receptor ERRgamma activates the DAX-1 promoter, which, in turn, represses transactivation by ERRgamma. Serial deletions of mouse DAX-1 (mDAX-1) gene promoter have revealed that the region responding to ERRgamma is located between -129 and -121 bp and -334 and -326 bp. Gel shift assays and chromatin immunoprecipitation (ChIP) assays demonstrated that ERRgamma binds directly to the mDAX-1 promoter. Site-directed mutagenesis results demonstrated that ERRE1 (-129 to -121 bp) is more important than ERRE2 (-334 to -326 bp) which is not conserved in the human DAX-1 promoter. In addition, adenovirus-mediated overexpression of ERRgamma induced DAX-1 gene expression in MCF-7 breast cancer cells that co-expressed ERRgamma and DAX-1. Moreover, yeast two-hybrid and glutathione S-transferase (GST)-pull down assays demonstrated that DAX-1 physically interacted with ERRgamma and inhibited ERRgamma transactivation, and that this interaction was dependent on the AF-2 domain of ERRgamma. In addition, in vitro competition assays showed that DAX-1 inhibited PGC-1alpha mediated ERRgamma transactivation, via competition between these two factors for the AF-2 binding domain. We thus propose a novel autoregulatory loop that controls DAX-1 gene expression by ERRgamma.

Animals↗