Patient and graft survival after liver transplantation for hereditary hemochromatosis: Implications for pathogenesis

The clinical outcome of patients who have undergone liver transplantation for hereditary hemochromatosis (HH) or who have received iron-loaded donor grafts is unclear. We reviewed 3,600 adult primary orthotopic liver transplants and assessed the outcomes in 22 patients with HH. We also evaluated graft function and iron mobilization in 12 recipients of iron-loaded donor grafts. All 22 subjects who received liver transplants for HH were male; 13 had other risk factors for liver disease. HH patients had comparatively poor outcomes following transplantation: survival at 1, 3, and 5 years posttransplantation were 72%, 62%, and 55%, respectively. Recurrent hepatocellular cancer was the most common cause of death. There was no convincing evidence of reaccumulation of iron in the grafted liver in HH; however, 1 subject demonstrated increased serum ferritin concentration and grade 2 hepatic siderosis. Liver iron stores were slow to mobilize in 7 of the 12 recipients of iron-loaded grafts. These recipients had appropriate early graft function, but 2 patients with heavy iron loading and increased hepatic iron developed hepatic fibrosis. In conclusion. (1) HH is an uncommon indication for liver transplantation, and the majority of patients requiring transplantation had other risk factors for chronic liver disease; (2) reaccumulation of liver iron in HH patients is very unusual, but increased iron stores may be slow to mobilize in normal recipients of iron-loaded grafts, potentially compromising late graft function; (3) post-liver transplant survival is reduced in HH, and affected patients require careful clinical evaluation of perioperative and postoperative risk factors. Our data suggest that iron excess in HH does not wholly depend on intestinal iron absorption but is also influenced by liver factors that moderate iron metabolism.

Effects of early intensive postoperative physiotherapy on limb function after tibial plateau leveling osteotomy in dogs with deficiency of the cranial cruciate ligament

Objective-To determine effects of early intensive postoperative physiotherapy on limb function in dogs after tibial plateau leveling osteotomy (TPLO) for deficiency of the cranial cruciate ligament (CCL). Animals-8 adult dogs with CCL deficiency. Procedure-After TPLO, dogs underwent a physiotherapy program 3 times/wk (physiotherapy group; n = 4) or a walking program (home-exercise group; 4). All dogs were evaluated before surgery, 1 and 10 days after surgery, and 3 and 6 weeks after surgery. Thigh circumference (TC), stifle joint flexion and extension range of motion (ROM), lameness, and weight-bearing scores were recorded. Results-Before surgery, CCL-deficient limbs had significantly reduced TC and reduced flexion and extension ROMs, compared with values for the contralateral control limb. Six weeks after TPLO, the physiotherapy group had significantly larger TC than the home-exercise group, with the difference no longer evident between the affected and nonaffected limbs. Extension and flexion ROMs were significantly greater in the physiotherapy group, compared with values for the home-exercise group, 3 and 6 weeks after surgery. Six weeks after surgery, the difference in flexion and extension ROMs was no longer evident between the affected and nonaffected limbs in the physiotherapy group. Both groups had improvements for lameness and weight-bearing scores over time, but no difference was found between the 2 groups. Conclusions and Clinical Relevance-After TPLO in CCL-deficient dogs, early physiotherapy intervention should be considered as part of the postoperative management to prevent muscle atrophy, build muscle mass and strength, and increase stifle joint flexion and extension ROMs.

The use of a change in gentamicin clearance as an early predictor of gentamicin-induced nephrotoxicity

A retrospective review was undertaken in 744 patients who were dose-individualized with gentamicin once daily to evaluate a change in gentamicin clearance as a potential predictor of nephrotoxicity. The definition of nephrotoxicity was chosen to be a change in creatinine clearance greater than 20%. Similarly, a change in gentamicin clearance of greater than 20% was also considered a possible index of nephrotoxicity. Four criteria were developed to assess the usefulness of gentamicin clearance as a predictor of nephrotoxicity. Following the application of the inclusion/exclusion criteria, 132 patients were available for the analysis. The sensitivity, specificity, positive predictive value, and negative predictive value were assessed for each of the criteria. Receiver operating characteristic (ROC) curves were produced to determine if an optimum value in the change of gentamicin clearance could be found to maximize sensitivity and specificity. The overall incidence of nephrotoxicity based on a decrease in creatinine clearance by 20% or more was 3.8%. Women were overrepresented in the nephrotoxic group [71.4% versus 40.1% (P = 0.0025)]. Patients with nephrotoxicity had statistically longer treatment periods, increased cumulative dose, and more dosing predictions (P < 0.05 in each case). The sensitivity of the criteria ranged from 43 to 46%, and specificity ranged from 93 to 99%. The positive and negative predictive values ranged from 63 to 94% and 86 to 89%, respectively. In those patients in whom nephrotoxicity was predicted from a change in gentamicin clearance, this change occurred on average 3 days before the change in creatinine clearance (P < 0.05). A change in gentamicin clearance to predict nephrotoxicity may be a useful addition to current monitoring methods, although it is not the complete answer.

Cardiac function in fetuses of poorly-controlled pre-gestational diabetic pregnancies - a pilot study

Objective: Cardiac impairment is frequently found in babies of diabetic mothers. It is still controversial whether this is due to poor glucose control. The aim of this study is to compare the cardiac function in fetuses of well- and poorly-controlled pre-gestational diabetic pregnancy in third trimester. Methods:Women with type 1 pre-gestational diabetes were enrolled at 30-32 weeks. Cardiac size and interventricular septal wall thickness were measured by M-mode at end-diastolic phase. The right and left ventricular ejection fractions were calculated. At the mitral and tricuspid valves inflow, the ratio between early ventricular filling and active atrial filling (E/A) at both atrioventricular valves were measured by Doppler echocardiography. Peak velocities of ascending aorta and pulmonary artery were assessed. The angle of isonation was kept at 6.5%) were compared with those with satisfactorily controlled diabetes (HbA1c less than or equal to 6.5%). Results: A total of 21 women with pre-gestational diabetes were recruited for this study. Eight women with well-controlled diabetes were compared with 9 women who had poorly-controlled diabetes. HbA1c in the poorly-controlled group was 7.3% and in the well-controlled group it was 5.4% (p < 0.001). There was no difference between the two groups in cardiac size, interventricular septal wall thickness, ejection fraction, aorta and pulmonary artery peak flow velocities. The right atrioventricular E/A ratio was significantly lower among the poorly-controlled diabetic pregnancies (0.71 vs. 0.54; p < 0.05). Conclusion: Fetuses of poorly-controlled diabetic mothers had a lower right atrioventricular E/A ratio. This may be due to metabolic acidosis, non-hypertrophic cardiac dysfunction or fetal polycythemia. Copyright (C) 2003 S. Karger AG, Basel.

Renal function and cardiovascular risk markers in a remote Australian Aboriginal community

Background. Australian Aborigines living in remote areas have exceedingly high rates of renal failure together with increased cardiovascular morbidity and mortality. To examine the basis of this association, we studied markers of renal function and cardiovascular (CV) risk in a coastal Aboriginal community in a remote area of the Northern Territory of Australia. End-stage renal disease (ESRD) incidence rates in that community are 15 times the national non-Aboriginal rate and CV mortality rates in the region are increased 5-fold. Methods. A cross-sectional community survey was conducted. Markers of early renal disease examined included urine albumin/creatinine ratio (ACR), serum creatinine concentration and calculated glomerular filtration rate (GFR). CV risk markers included blood pressure as well as measures of glycaemia, diabetes and serum lipids. Results. The study group included 237 people, 58% of the adult population of the community. The crude prevalence of microalbuminuria (urine ACR: 3.4-33.9 g/mol, 30-299 mg/g) was 31% and of overt albuminuria (urine ACR: greater than or equal to34 g/mol, greater than or equal to300 mg/g), 13%. The prevalence of overt albuminuria increased with age, but the prevalence of microalbuminuria was greatest in the 45-54 year age group. Microalbuminuria was associated with increasing body mass index, whereas overt albuminuria was associated with increasing glycated haemoglobin (HbA1c) and systolic blood pressure and a history of diabetes. The prevalence of elevated serum creatinine concentration (greater than or equal to120 mumol/l) was 10%. GFR (calculated using the MDRD equation) was <60 ml/min/1.73m(2) in 12% and 60-79 ml/min/1.73 m(2) in a further 36% of the study population. Although many people with albuminuria had well preserved GFRs, mean GFR was lower in people with higher levels of albuminuria. Conclusions. The high prevalence of markers of renal disease in this community was consistent with their high rates of ESRD. The distribution of microalbuminuria suggested a 'cohort effect', representing a group who will progress to overt albuminuria. The powerful association of renal disease markers with CV risk factors confirms a strong link between renal and CV disease in the early, asymptomatic stages of each. Thus, pathologic albuminuria, in part, might be a manifestation of the metabolic/haemodynamic syndrome and both conditions might arise out of a common menu of risk factors. Hence, a single agenda of primary and secondary intervention may benefit both.

Echocardiographic detection of early diabetic myocardial disease

OBJECTIVES We sought to determine whether disturbances of myocardial contractility and reflectivity could be detected in diabetic patients without overt heart disease and whether these changes were independent and incremental to left ventricular hypertrophy (LVH). BACKGROUND Left ventricular (LV) dysfunction is associated with diabetes mellitus, but LVH is common in this population and the relationship between diabetic LV dysfunction and LVH is unclear. METHODS We studied 186 patients with normal ejection fraction and no evidence of CAD: 48 with diabetes mellitus only (DM group), 45 with LVH only (LVH group), 45 with both diabetes and LVH (DH group), and 48 normal controls. Peak strain and strain rate of six walls in apical four-chamber, long-axis, and two-chamber views were evaluated and averaged for each patient. Calibrated integrated backscatter (113) was assessed by comparison of the septal or posterior wall with pericardial IB intensity. RESULTS All patient groups (DM, DH, LVH) showed reduced systolic function compared with controls, evidenced by lower peak strain (p < 0.001) and strain rate (p = 0.005). Calibrated 113, signifying myocardial reflectivity, was greater in each patient group than in controls (p < 0.05). Peak strain and strain rate were significantly lower in the DH group than in those in the DM alone (p < 0.03) or LVH alone (p = 0.01) groups. CONCLUSIONS Diabetic patients without overt heart disease demonstrate evidence of systolic dysfunction and increased myocardial reflectivity. Although these changes are similar to those caused by LVH, they are independent and incremental to the effects of LVH. (C) 2003 by the American College of Cardiology Foundation.

Patients with a hypertensive response to exercise have impaired systolic function without diastolic dysfunction or left ventricular hypertrophy

OBJECTIVES We sought to determine if a hypertensive response to exercise (HRE) is associated with myocardial changes consistent with early hypertensive heart disease. BACKGROUND An HRE predicts the development of chronic hypertension (HT) and may reflect a preclinical stage of HT. METHODS Patients with a normal left ventricular (LV) ejection fraction and a negative stress test were recruited into three matched groups: 41 patients (age 56 +/- 10 years) with HRE (210/105 mm Hg in men; > 190/105 in women), comprising 22 patients with (HT+) and 19 without resting hypertension (HT-); and 17 matched control subjects without HRE. Long-axis function was determined by measurement of the strain rate (SR), peak systolic strain, and cyclic variation (CV) of integrated backscatter in three apical views. RESULTS An HRE was not associated with significant differences in LV mass index. Exercise performance and diastolic function were reduced in HRE(HT+) patients, but similar in HRE(HT-) patients and controls. Systolic dysfunction (peak systolic strain, SR, and CV) was significantly reduced in HRE patients (p < 0.001 for all). These reductions were equally apparent in patients with and without a history of resting HT (p = NS) and were independent of LV mass index and blood pressure (p < 0.01). CONCLUSIONS An HRE is associated with subtle systolic dysfunction, even in the absence of resting HT. These changes occur before the development of LV hypertrophy or detectable diastolic dysfunction and likely represent early hypertensive heart disease. (C) 2004 by the American College of Cardiology Foundation.

Response of B-type natriuretic pepticle to exercise in hypertensive patients with suspected diastolic heart failure: Correlation with cardiac function, hemodynamics, and workload

Background Diastolic heart failure (DHF) is characterized by dyspnea due to increased left ventricular (LV) filling pressures during stress. We sought the relationship of exercise-induced increases in B-type natriuretic peptide (BNP) to LV filling pressures and parameters of cardiovascular performance in suspected DHF. Methods Twenty-six treated hypertensive patients with suspected DHF (exertional dyspnea, LV ejection fraction >50%, and diastolic dysfunction) underwent maximal exercise echocardiography using the Bruce protocol. BNP, transmitral Doppler, and tissue Doppler for systolic (So) and early (Ea) and late (Aa) diastolic mitral annular velocities were obtained at rest and peak stress. LV filling pressures were estimated with E/Ea ratios. Results Resting BNP correlated with resting pulse pressure (r=0.45, P=0.02). Maximal exercise performance (4.6 +/- 2.5min) was limited by dyspnea. Blood pressure increased with exercise (from 143 +/- 19/88 +/- 8 to 191 +/- 22/90 +/- 10 mm Hg); 13 patients (50%) had a hypertensive response. Peak exercise BNP correlated with peak transmitral E velocity (r = 0.41, P <.05) and peak heart rate (r = -0.40, P <.05). BNP increased with exercise (from 48 57 to 74 97 pg/mL, P =.007), and the increment of BNP with exercise was associated with maximal workload and peak exercise So, Ea, and Aa (P <.01 for all). Filling pressures, approximated by lateral E/Ea ratio, increased with exercise (7.7 +/- 2.0 to 10.0 +/- 4.8, P <.01). BNP was higher in patients with possibly elevated filling pressures at peak exercise (E/Ea >10) compared to those with normal pressures (123 +/- 124 vs 45 +/- 71 pg/mL, P =.027). Conclusions Augmentation of BNP with exercise in hypertensive patients with suspected DHF is associated with better exercise capacity, LV systolic and diastolic function, and left atrial function. Peak exercise BNP levels may identify exercise-induced elevation of filling pressures in DHF.

The 2dF-SDSS LRG and QSO (2SLAQ) survey: the z < 2.1 quasar luminosity function from 5645 quasars to g=21.85

We have used the Two-Degree Field (2dF) instrument on the Anglo-Australian Telescope (AAT) to obtain redshifts of a sample of z < 3 and 18.0 < g < 21.85 quasars selected from Sloan Digital Sky Survey (SDSS) imaging. These data are part of a larger joint programme between the SDSS and 2dF communities to obtain spectra of faint quasars and luminous red galaxies, namely the 2dF-SDSS LRG and QSO (2SLAQ) Survey. We describe the quasar selection algorithm and present the resulting number counts and luminosity function of 5645 quasars in 105.7 deg(2). The bright-end number counts and luminosity functions agree well with determinations from the 2dF QSO Redshift Survey (2QZ) data to g similar to 20.2. However, at the faint end, the 2SLAQ number counts and luminosity functions are steeper (i.e. require more faint quasars) than the final 2QZ results from Croom et al., but are consistent with the preliminary 2QZ results from Boyle et al. Using the functional form adopted for the 2QZ analysis ( a double power law with pure luminosity evolution characterized by a second-order polynomial in redshift), we find a faint-end slope of beta =-1.78 +/- 0.03 if we allow all of the parameters to vary, and beta =-1.45 +/- 0.03 if we allow only the faint-end slope and normalization to vary (holding all other parameters equal to the final 2QZ values). Over the magnitude range covered by the 2SLAQ survey, our maximum-likelihood fit to the data yields 32 per cent more quasars than the final 2QZ parametrization, but is not inconsistent with other g > 21 deep surveys for quasars. The 2SLAQ data exhibit no well-defined 'break' in the number counts or luminosity function, but do clearly flatten with increasing magnitude. Finally, we find that the shape of the quasar luminosity function derived from 2SLAQ is in good agreement with that derived from Type I quasars found in hard X-ray surveys.

How can experience in clinical and community settings contribute to early medical education? A BEME systematic review

Review date: Review period January 1992-December 2001. Final analysis July 2004-January 2005. Background and review context: There has been no rigorous systematic review of the outcomes of early exposure to clinical and community settings in medical education. Objectives of review: (1) Identify published empirical evidence of the effects of early experience in medical education, analyse it, and synthesize conclusions from it. (2) Identify the strengths and limitations of the research effort to date, and identify objectives for future research. Search strategy: Ovid search of. BEI, ERIC, Medline, CIATAHL and EMBASE Additional electronic searches of: Psychinfo, Timelit, EBM reviews, SIGLE, and the Cochrane databases. Hand-searches of: Medical Education, Medical Teacher, Academic Medicine, Teaching and Learning in Medicine, Advances in Health Sciences Education, Journal of Educational Psychology. Criteria: Definitions: Experience: Authentic (real as opposed to simulated) human contact in a social or clinical context that enhances learning of health, illness and/or disease, and the role of the health professional. Early: What would traditionally have been regarded as the preclinical phase, usually the first 2 years. Inclusions: All empirical studies (verifiable, observational data) of early experience in the basic education of health professionals, whatever their design or methodology, including papers not in English. Evidence from other health care professions that could be applied to medicine was included. Exclusions: Not empirical; not early; post-basic; simulated rather than 'authentic' experience. Data collection: Careful validation of selection processes. Coding by two reviewers onto an extensively modified version of the standard BEME coding sheet. Accumulation into an Access database. Secondary coding and synthesis of an interpretation. Headline results: A total of 73 studies met the selection criteria and yielded 277 educational outcomes; 116 of those outcomes (from 38 studies) were rated strong and important enough to include in a narrative synthesis of results; 76% of those outcomes were from descriptive studies and 24% from comparative studies. Early experience motivated and satisfied students of the health professions and helped them acclimatize to clinical environments, develop professionally, interact with patients with more confidence and less stress, develop self-reflection and appraisal skill, and develop a professional identity. It strengthened their learning and made it more real and relevant to clinical practice. It helped students learn about the structure and function of the healthcare system, and about preventive care and the role of health professionals. It supported the learning of both biomedical and behavioural/social sciences and helped students acquire communication and basic clinical skills. There were outcomes for beneficiaries other than students, including teachers, patients, populations, organizations and specialties. Early experience increased recruitment to primary care/rural medical practice, though mainly in US studies which introduced it for that specific purpose as part of a complex intervention. Conclusions: Early experience helps medical students socialize to their chosen profession. It. helps them acquire a range of subject matter and makes their learning more real and relevant. It has potential benefits for other stakeholders, notably teachers and patients. It can influence career choices.

Low dietary protein during early pregnancy alters bovine placental development

To determine if low dietary protein concentration in the first two trimesters of pregnancy alters placental development, genetically similar heifers from closed herd were fed diets containing different levels of protein in the first and second trimesters of gestation. There were four animals per treatment group, the groups being: L/L = fed a diet containing 7% crude protein (CP) (low protein) in the first and second trimesters; H/H = fed a diet containing 14% (P thigh protein) in the first and second trimesters; L/H = fed low protein in the first trimester and high in the second trimester and vice versa for the H/L group. Low protein diets in the first trimester increased dry cotyledon weight at term. Trophectoderm volume density increased in the H/L and L/H group compared to the L/L and H/H groups. Blood vessel volume and volume density in foetal villi decreased in the H/L and L/H groups compared with the H/H and L/L groups. There was no effect of diet treatment on cotyledon number, diameter or wet weight and no effect on the volume density of connective tissue or fibroblasts in the foetal villi. These results show that a low dietary protein concentration in the first trimester of pregnancy followed by increased protein in the second trimester enhanced placental development. Further, trophectoderm volume was highly correlated with birth weight. Early protein restriction in the pregnant cow may enhance foetal growth in part by stimulating placental growth and function. (C) 1999 Published by Elsevier Science B.V. All rights reserved.

A misspelt youth: Spelling and orthographic learning in university students as a function of spelling-sound consistency

Pseudowords with inconsistent vs. consistent spellings (e.g., nurch, with rhyme neighbours search, lurch & perch, vs. mish, with neighbours dish, wish) were presented with definitions for naming either twice or 6 times. In an oral spelling test, there were main and interactive effects of consistency and the number of training trials on accuracy and main effects only on response latency, with the improvement in accuracy from 2 to 6 training trials greater for the more poorly learned inconsistent items. Of most interest, the smaller effect of training on accuracy in the consistent condition was reliable; contrary to the most obvious prediction of dual route spelling models that the sublexical procedure should produce correct spellings for consistent items early in training. In a second task students wrote spellings of multisyllabic words containing unstressed indeterminate (schwa) vowels. In their errors on the schwa vowel, students showed sensitivity to the most common spelling overall but also they were influenced by differences in schwa spellings in English words as a function of the number of syllables and schwa position. These results indicate that dual route models of spelling will need to accommodate the consistency of spellings within categories defined by lexical structure variables.