Book review: Humane medicine by Miles Little

No abstract

Immunohistochemical detection of polyductin and co-localization with liver progenitor cell markers during normal and abnormal development of the intrahepatic biliary system and in adult hepatobiliary carcinomas

The longest open reading frame of PKHD1 (polycystic kidney and hepatic disease 1), the autosomal recessive polycystic kidney disease (ARPKD) gene, encodes a single-pass, integral membrane protein named polyductin or fibrocystin. A fusion protein comprising its intracellular C-terminus, FP2, was previously used to raise a polyclonal antiserum shown to detect polyductin in several human tissues, including liver. In the current study, we aimed to investigate by immunohistochemistry the detailed polyductin localization pattern in normal (ductal plate [DP], remodelling ductal plate [RDP], remodelled bile ducts) and abnormal development of the primitive intrahepatic biliary system, known as ductal plate malformation (DPM). This work also included the characterization of polyductin expression profile in various histological forms of neonatal and infantile cholestasis, and in cholangiocellular carcinoma (CCC) and hepatocellular carcinoma (HCC). We detected polyductin expression in the intrahepatic biliary system during the DP and the RDP stages as well as in DPM. No specific staining was found at the stage of remodelled bile ducts. Polyductin was also detected in liver biopsies with neonatal cholestasis, including mainly biliary atresia and neonatal hepatitis with ductular reaction as well as congenital hepatic fibrosis. In addition, polyductin was present in CCC, whereas it was absent in HCC. Polyductin was also co-localized in some DP cells together with oval stem cell markers. These results represent the first systematic study of polyductin expression in human pathologies associated with abnormal development of intrahepatic biliary tree, and support the following conclusions: (i) polyductin expression mirrors developmental properties of the primitive intrahepatic biliary system; (ii) polyductin is re-expressed in pathological conditions associated with DPM and (iii) polyductin might be a potential marker to distinguish CCC from HCC.

Creatine in Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

GUALANO, B., V. DE. SALLES PAINNELI, H. ROSCHEL, G. G. ARTIOLI, M. NEVES JR, A. L. DE SA PINTO, M. E. DA SILVA, M. R. CUNHA, M. C. G. OTADUY, C. DA COSTA LEITE, J. C. FERREIRA, R. M. PEREIRA, P. C. BRUM, E. BONFA, and A. H. LANCHA JR. Creatine in Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial. Med. Sci. Sports Exerc., Vol. 43, No. 5, pp. 770-778, 2011. Creatine supplementation improves glucose tolerance in healthy subjects. Purposes: The aim was to investigate whether creatine supplementation has a beneficial effect on glycemic control of type 2 diabetic patients undergoing exercise training. Methods: A 12-wk randomized, double-blind, placebo-controlled trial was performed. The patients were allocated to receive either creatine (CR) (5 g.d(-1)) or placebo (PL) and were enrolled in an exercise training program. The primary outcome was glycosylated hemoglobin (Hb(A1c)). Secondary outcomes included the area under the curve of glucose, insulin, and C-peptide and insulin sensitivity indexes. Physical capacity, lipid profile, and GLUT-4 protein expression and translocation were also assessed. Results: Twenty-five subjects were analyzed (CR: n = 13; PL: n = 12). Hb(A1c) was significantly reduced in the creatine group when compared with the placebo group (CR: PRE = 7.4 +/- 0.7, POST = 6.4 +/- 0.4; PL: PRE = 7.5 +/- 0.6, POST = 7.6 +/- 0.7; P = 0.004; difference = -1.1%, 95% confidence interval = -1.9% to -0.4%). The delta area under the curve of glucose concentration was significantly lower in the CR group than in the PL group (CR = -7790 +/- 4600, PL = 2008 +/- 7614; P = 0.05). The CR group also presented decreased glycemia at times 0, 30, and 60 min during a meal tolerance test and increased GLUT-4 translocation. Insulin and C-peptide concentrations, surrogates of insulin sensitivity, physical capacity, lipid profile, and adverse effects were comparable between the groups. Conclusions: Creatine supplementation combined with an exercise program improves glycemic control in type 2 diabetic patients. The underlying mechanism seems to be related to an increase in GLUT-4 recruitment to the sarcolemma.

Beneficial Effect of Creatine Supplementation in Knee Osteoarthritis

NEVES JR., M., B. GUALANO, H. ROSCHEL, R. FULLER, F. B. BENATTI, A. L. DE SA PINTO, F. R. LIMA, R. M. PEREIRA, A. H. LANCHA JR., E. BONFA. Beneficial Effect of Creatine Supplementation in Knee Osteoarthritis. Med. Sci. Sports Exerc., Vol. 43, No. 8, pp. 1538-1543, 2011. Introduction: The aim of this study was to investigate the efficacy of creatine (CR) supplementation combined with strengthening exercises in knee osteoarthritis (OA). Methods: A randomized, double-blind, placebo-controlled trial was performed. Postmenopausal women with knee OA were allocated to receive either CR (20 g.d(-1) for 1 wk and 5 g.d(-1) thereafter) or placebo (PL) and were enrolled in a lower limb resistance training program. They were assessed at baseline (PRE) and after 12 wk (POST). The primary outcome was the physical function as measured by the timed-stands test. Secondary outcomes included lean mass, quality of life, pain, stiffness, and muscle strength. Results: Physical function was significantly improved only in the CR group (P = 0.006). In addition, a significant between-group difference was observed (CR: PRE = 15.7 +/- 1.4, POST = 18.1 +/- 1.8; PL: PRE = 15.0 +/- 1.8, POST = 15.2 +/- 1.2; P = 0.004). The CR group also presented improvements in physical function and stiffness subscales as evaluated by the Western Ontario and McMaster Universities Osteoarthritis Index (P = 0.005 and P = 0.024, respectively), whereas the PL group did not show any significant changes in these parameters (P > 0.05). In addition, only the CR group presented a significant improvement in lower limb lean mass (P = 0.04) as well as in quality of life (P = 0.01). Both CR and PL groups demonstrated significant reductions in pain (P G 0.05). Similarly, a main effect for time revealed an increase in leg-press one-repetition maximum (P = 0.005) with no significant differences between groups (P = 0.81). Conclusions: CR supplementation improves physical function, lower limb lean mass, and quality of life in postmenopausal women with knee OA undergoing strengthening exercises.

Ten-Year Follow-Up Survival of the Medicine, Angioplasty, or Surgery Study (MASS II) A Randomized Controlled Clinical Trial of 3 Therapeutic Strategies for Multivessel Coronary Artery Disease

Background-This study compared the 10-year follow-up of percutaneous coronary intervention (PCI), coronary artery surgery (CABG), and medical treatment (MT) in patients with multivessel coronary artery disease, stable angina, and preserved ventricular function. Methods and Results-The primary end points were overall mortality, Q-wave myocardial infarction, or refractory angina that required revascularization. All data were analyzed according to the intention-to-treat principle. At a single institution, 611 patients were randomly assigned to CABG (n = 203), PCI (n = 205), or MT (n = 203). The 10-year survival rates were 74.9% with CABG, 75.1% with PCI, and 69% with MT (P = 0.089). The 10-year rates of myocardial infarction were 10.3% with CABG, 13.3% with PCI, and 20.7% with MT (P < 0.010). The 10-year rates of additional revascularizations were 7.4% with CABG, 41.9% with PCI, and 39.4% with MT (P < 0.001). Relative to the composite end point, Cox regression analysis showed a higher incidence of primary events in MT than in CABG (hazard ratio 2.35, 95% confidence interval 1.78 to 3.11) and in PCI than in CABG (hazard ratio 1.85, 95% confidence interval 1.39 to 2.47). Furthermore, 10-year rates of freedom from angina were 64% with CABG, 59% with PCI, and 43% with MT (P < 0.001). Conclusions-Compared with CABG, MT was associated with a significantly higher incidence of subsequent myocardial infarction, a higher rate of additional revascularization, a higher incidence of cardiac death, and consequently a 2.29-fold increased risk of combined events. PCI was associated with an increased need for further revascularization, a higher incidence of myocardial infarction, and a 1.46-fold increased risk of combined events compared with CABG. Additionally, CABG was better than MT at eliminating anginal symptoms.

Effects of Exercise Training in Patients with Chronic Heart Failure and Sleep Apnea

Study Objectives: To test the effects of exercise training on sleep and neurovascular control in patients with systolic heart failure with and without sleep disordered breathing. Design: Prospective interventional study. Setting: Cardiac rehabilitation and exercise physiology unit and sleep laboratory. Patients: Twenty-five patients with heart failure, aged 42 to 70 years, and New York Heart Association Functional Class I-III were divided into 1 of 3 groups: obstructive sleep apnea (n = 8), central sleep apnea (n 9) and no sleep apnea (n = 7). Interventions: Four months of no-training (control) followed by 4 months of an exercise training program (three 60-minute, supervised, exercise sessions per week). Measures and Results: Sleep (polysomnography), microneurography, forearm blood flow (plethysmography), peak VO(2). and quality of life were evaluated at baseline and at the end of the control and trained periods. No significant changes occurred in the control period. Exercise training reduced muscle sympathetic nerve activity (P < 0.001) and increased forearm blood flow (P < 0.01), peak VO(2) (P < 0.01), and quality of life (P < 0.01) in all groups, independent of the presence of sleep apnea. Exercise training improved the apnea-hypopnea index, minimum O(2) saturation, and amount stage 3-4 sleep (P < 0.05) in patients with obstructive sleep apnea but had no significant effects in patients with central sleep apnea. Conclusions. The beneficial effects of exercise training on neurovascular function, functional capacity, and quality of life in patients with systolic dysfunction and heart failure occurs independently of sleep disordered breathing. Exercise training lessens the severity of obstructive sleep apnea but does not affect central sleep apnea in patients with heart failure and sleep disordered breathing.

Physicians` attitudes and adherence to use of risk scores for primary prevention of cardiovascular disease: cross-sectional survey in three world regions

Objective: To evaluate physicians` attitudes and adherence to the use of risk scores in the primary prevention of cardiovascular disease (CVD). Design and methods: A cross-sectional survey of 2056 physicians involved in the primary prevention of CVD. Participants included cardiologists (47%), general practitioners (42%), and endocrinologists (11%) from several geographical regions: Brazil (n=968), USA (n=381), Greece (n=275), Chile (n=157), Venezuela (n=128), Portugal (n=42), The Netherlands (n=41), and Central America (Costa Rica, Panama, El Salvador and Guatemala; n=64). Results: The main outcome measure was the percentage of responses on a multiple-choice questionnaire describing a hypothetical asymptomatic patient at intermediate risk for CVD according to the Framingham Risk Score. Only 48% of respondents reported regular use of CVD risk scores to tailor preventive treatment in the case scenario. Of non-users, nearly three-quarters indicated that `It takes up too much of my time` (52%) or `I don`t believe they add value to the clinical evaluation` (21%). Only 56% of respondents indicated that they would prescribe lipid-lowering therapy for the hypothetical intermediate-risk patient. A significantly greater proportion of regular users than non-users of CVD risk scores identified the need for lipid-lowering therapy in the hypothetical patient (59 vs. 41%; p<0.0001).

Cardiovascular prevention in HIV patients: Results from a successful intervention program

Objectives: To analyze the effect of a prevention program oil the estimated cardiovascular risk calculated by three risk scores. Methods: We prospectively evaluated 87 HIV+ patients with elevated cardiovascular risk estimation. Framirigham (FIRS), PROCAM and National Cholesterol Education Program (ATP-III) were applied. Cardiovascular risk was defined as elevated if >10%. All patients received non-pharmacological (diet, exercise, smoking cessation) and, when appropriate, pharmacological therapy. Results: Mean age was 52 years, 92% were male, 39.1% were smokers, 70.1% had hypertension, 18.4% had diabetes. All patients were under HAART, 56.3% were receiving protease inhibitors (131). After 6 months, intervention was associated to significant changes oil triglycerides (298 242 and 206 +/- 135 mg/dL, p<0.05), total-cholesterol (224 +/- 47 and 189 +/- 38 mg/dL, p<0.001). LDL-cholesterol (129 +/- 44 and 109 +/- 30 mg/dL,p<0.001). Frequencies of patients with elevated cardiac risk before and 6 months after intervention were 92% x 27.6% (p < 0.0001), 80.5% x 50.6% (p < 0.0002), and 25.3% x 14.9% (p = 0.12), for FIRS, ATP III and PROCAM, respectively. Conclusions: An intervention Program focused on reduction of traditional risk factors was able to decrease the frequency of patients with HIV infection and elevated cardiovascular risk estimation. FIRS showed greater sensitivity than the other scores. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Outpatient Radioiodine Therapy for Thyroid Cancer A Safe Nuclear Medicine Procedure

Purposes: To evaluate the dosimetric effect of outpatient radioiodine therapy for thyroid cancer in members of a patient`s family and their living environment, when using iodine-131 doses reaching 7.4 GBq. The following parameters were thus defined: (a) whole-body radiation doses to caregivers, (b) the production of contaminated solid waste, and (c) radiation potential and surface contamination within patients` living quarters. Methods: In total, 100 patients were treated on an outpatient basis, taking into consideration their acceptable living conditions, interests, and willingness to comply with medical and radiation safety guidelines. Both the caregivers and the radiation dose potentiality inside patients` residences were monitored by using thermoluminescent dosimeters. Surface contamination and contaminated solid wastes were identified and measured with a Geiger-Muller detector. Results: A total of 90 monitored individuals received a mean dose of 0.27 (+/- 0.28) mSv, and the maximum dose registered was 1.6 mSv. The mean value for the potential dose within all living quarters was 0.31(+/- 0.34) mSv, and the mean value per monitored surface was 5.58 Bq/cm(2) for all the 1659 points measured. The overall production of contaminated solid wastes was at a low level, being about 3 times less than the exemption level indicated by the International Atomic Energy Agency. Conclusions: This study indicates that the treatment of thyroid cancer by applying radioiodine activities up to 7.4 GBq, on an outpatient basis, is a safe procedure, especially when supervised by qualified professionals. This alternative therapy should be a topic for careful discussion considering the high potential for reducing costs in healthcare and improving patient acceptance.

Issues in geriatric medicine

In Australia there has been rapid growth in the number of geriatricians and the provision of aged care services. This has been accompanied by increasing sophistication in the assessment and management of the common syndromes of old age: impaired cognition, incontinence, impaired mobility, impaired homeostasis and iatrogenic disease. Innovative systems of service delivery have been developed in diverse fields including dementia services and orthogeriatrics. Adequate planning and funding strategies are required to ensure that older people continue to have appropriate access to high quality services and that there is provision for education and research in ageing.

Supporting contexts in program refinement

A program can be refined either by transforming the whole program or by refining one of its components. The refinement of a component is, for the main part, independent of the remainder of the program. However, refinement of a component can depend on the context of the component for information about the variables that are in scope and what their types are. The refinement can also take advantage of additional information, such as any precondition the component can assume. The aim of this paper is to introduce a technique, which we call program window inference, to handle such contextual information during derivations in the refinement calculus. The idea is borrowed from a technique, called window inference, for handling context in theorem proving. Window inference is the primary proof paradigm of the Ergo proof editor. This tool has been extended to mechanize refinement using program window inference. (C) 1997 Elsevier Science B.V.

Effect of aquatic respiratory exercise-based program in patients with fibromyalgia

Objective: This study assessed the effects of an aquatic respiratory exercise-based program in patients with fibromyalgia (FMS). Methods: Forty women, aged between 20 and 60 years, were randomly assigned into two groups of 20 patients: the aquatic respiratory exercise-based program (ARG) and the control group (CTL). The ARG group performed the exercise program for 1 h, four times a week, for 4 weeks which included: (i) warming-Lip; (ii) respiratory exercises, consisting of five different breathing patterns, along With upper, lower limbs and trunk movements (45 min); and (iii) relaxation exercises. Both groups were included in supervised recreational activities of 1 h, once a week, for 4 weeks. Questionnaires were applied before and after intervention to assess quality of life and functional capacity (SF-36, Fibromyalgia Impact Questionnaire [FIQ]), anxiety (Hamilton Anxiety Scale [HAS]), and quality of sleep (Pittsburg Sleep Quality Index [PSQI]). Number of tender points and pain (Visual Analogue Scale [VAS]) were also evaluated. Results: At baseline there was no difference between the two groups, including number of tender points and questionnaire responses. After intervention, the ARG group, compared with the CTL group, showed improvement in SF-36 scores (physical functioning P = 0.001, bodily pain 1) = 0.001, vitality P = 0.009, social functioning P = 0.001, emotional role P = 0.001), in FIQ (total score P = 0.049, work missed P = 0.036, fatigue P = 0.013, morning tiredness P = 0.007) plus in VAS-pain (P = 0.029), VAS-dyspnea (P = 0.04), anxiety (HAS P = 0.005) and quality of sleep (PSQI P = 0.004). Conclusions: The short-term aquatic respiratory exercise-based program improved pain, quality of life, functional capacity, anxiety and quality of sleep in patients with FMS and may be a relevant addition to the treatment of these patients.

Effects of Aerobic Training on Airway Inflammation in Asthmatic Patients

MENDES, F. A. R., F. M. ALMEIDA, A. CUKIER, R. STELMACH, W. JACOB-FILHO, M. A. MARTINS, and C. R. F. CARVALHO. Effects of Aerobic Training on Airway Inflammation in Asthmatic Patients. Med. Sci. Sports Exerc., Vol. 43, No. 2, pp. 197-203, 2011. Purpose: There is evidence suggesting that physical activity has anti-inflammatory effects in many chronic diseases; however, the role of exercise in airway inflammation in asthma is poorly understood. We aimed to evaluate the effects of an aerobic training program on eosinophil inflammation (primary aim) and nitric oxide (secondary aim) in patients with moderate or severe persistent asthma. Methods: Sixty-eight patients randomly assigned to either control (CG) or aerobic training (TG) groups were studied during the period between medical consultations. Patients in the CG (educational program + breathing exercises; N = 34) and TG (educational program + breathing exercises + aerobic training; N = 34) were examined twice a week during a 3-month period. Before and after the intervention, patients underwent induced sputum, fractional exhaled nitric oxide (FeNO), pulmonary function, and cardiopulmonary exercise testing. Asthma symptom-free days were quantified monthly, and asthma exacerbation was monitored during 3 months of intervention. Results: At 3 months, decreases in the total and eosinophil cell counts in induced sputum (P = 0.004) and in the levels of FeNO (P = 0.009) were observed after intervention only in the TG. The number of asthma symptom-free days and (V) over dotO(2max) also significantly improved (P < 0.001), and lower asthma exacerbation occurred in the TG (P < 0.01). In addition, the TG presented a strong positive relationship between baseline FeNO and eosinophil counts as well as their improvement after training (r = 0.77 and r = 0.9, respectively). Conclusions: Aerobic training reduces sputum eosinophil and FeNO in patients with moderate or severe asthma, and these benefits were more significant in subjects with higher levels of inflammation. These results suggest that aerobic training might be useful as an adjuvant therapy in asthmatic patients under optimized medical treatment.

FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC(3) program

Background & Aims: EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon-alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. Methods: Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. Results: Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2 = 0.80 (p<0.00001). Five baseline factors were associated (p<0.001) with SVR in UV and MV analyses (odds ratio: UV/MV): fibrosis stage estimated using FT (4.5/5.9) or biopsy (1.5/1.6), genotype 2/3 (4.5/5.1), BVL (1.5/1.3), prior relapse (1.6/1.6), previous treatment with non-PEG-IFN (2.6/2.0). These same factors were associated (p <= 0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis (p <= 0.001): genotype 2/3 (odds ratio = 2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). Conclusions: FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12 weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Surgical Outcomes after Preceptored Laparoscopic Colorectal Surgery: Results of a Brazilian Preceptorship Program

Background/Aims: Safety of laparoscopic colectomy education methods remains unknown. This study aimed at comparing the outcomes of patients undergoing preceptored laparoscopic colectomy with patients operated on by the same preceptor. Methodology: A prospective analysis of 30 preceptored operations performed by nine surgeons (PD group) between 2006 and 2008 was conducted. Data of 30 operations matched for diagnosis and surgery type conducted by the same preceptor (P group) were evaluated. Results: Median age was 56.2 (26-80) and 55.2 (22-81) respectively in P and PD group (p=0.804). Eleven (36.7%) were male in P group, 16 (53.3%) in PD group (p=0.194). Preceptored operations were not significantly longer than operations performed by the preceptor (198 vs. 156 min) - p=0.072. Length of hospital stay did not differ [4 days (3-12) in P group, and 5 (3-15) in PD group, p=0.296]. Conversion occurred in 4 cases in PD and in 2 in P group (p=0.389). Morbidity was similar (23.3% in P and 26.7% in PD group). One patient from P and two from PD group needed re-operation. No deaths occurred. Conclusions: Laparoscopic colorectal surgery preceptorship programs in surgeon learner`s place are safe. Surgeons` introduction through basic and hands-on courses is required for skills acquisition needed to minimize adverse outcomes.