Adaptive working memory strategy training in early Alzheimer's disease: randomised controlled trial.

BACKGROUND: Interventions that improve cognitive function in Alzheimer's disease are urgently required. AIMS: To assess whether a novel cognitive training paradigm based on 'chunking' improves working memory and general cognitive function, and is associated with reorganisation of functional activity in prefrontal and parietal cortices (trial registration: ISRCTN43007027). METHOD: Thirty patients with mild Alzheimer's disease were randomly allocated to receive 18 sessions of 30 min of either adaptive chunking training or an active control intervention over approximately 8 weeks. Pre- and post-intervention functional magnetic resonance imaging (fMRI) scans were also conducted. RESULTS: Adaptive chunking training led to significant improvements in verbal working memory and untrained clinical measures of general cognitive function. Further, fMRI revealed a bilateral reduction in task-related lateral prefrontal and parietal cortex activation in the training group compared with controls. CONCLUSIONS: Chunking-based cognitive training is a simple and potentially scalable intervention to improve cognitive function in early Alzheimer's disease.

Association of genes with physiological functions by comparative analysis of pooled expression microarray data.

The physiological functions of a tissue in the body are carried out by its complement of expressed genes. Genes that execute a particular function should be more specifically expressed in tissues that perform the function. Given this premise, we mined public microarray expression data to build a database of genes ranked by their specificity of expression in multiple organs. The database permitted the accurate identification of genes and functions known to be specific to individual organs. Next, we used the database to predict transcriptional regulators of brown adipose tissue (BAT) and validated two candidate genes. Based upon hypotheses regarding pathways shared between combinations of BAT or white adipose tissue (WAT) and other organs, we identified genes that met threshold criteria for specific or counterspecific expression in each tissue. By contrasting WAT to the heart and BAT, the two most mitochondria-rich tissues in the body, we discovered a novel function for the transcription factor ESRRG in the induction of BAT genes in white adipocytes. Because the heart and other estrogen-related receptor gamma (ESRRG)-rich tissues do not express BAT markers, we hypothesized that an adipocyte co-regulator acts with ESRRG. By comparing WAT and BAT to the heart, brain, kidney and skeletal muscle, we discovered that an isoform of the transcription factor sterol regulatory element binding transcription factor 1 (SREBF1) induces BAT markers in C2C12 myocytes in the presence of ESRRG. The results demonstrate a straightforward bioinformatic strategy to associate genes with functions. The database upon which the strategy is based is provided so that investigators can perform their own screens.

A neural basis for general intelligence.

Universal positive correlations between different cognitive tests motivate the concept of "general intelligence" or Spearman's g. Here the neural basis for g is investigated by means of positron emission tomography. Spatial, verbal, and perceptuo-motor tasks with high-g involvement are compared with matched low-g control tasks. In contrast to the common view that g reflects a broad sample of major cognitive functions, high-g tasks do not show diffuse recruitment of multiple brain regions. Instead they are associated with selective recruitment of lateral frontal cortex in one or both hemispheres. Despite very different task content in the three high-g-low-g contrasts, lateral frontal recruitment is markedly similar in each case. Many previous experiments have shown these same frontal regions to be recruited by a broad range of different cognitive demands. The results suggest that "general intelligence" derives from a specific frontal system important in the control of diverse forms of behavior.

Assessment of radiation doses to cardiologists during interventional examinations.

The accuracy of two on line dosimetric techniques was investigated for the estimation of cardiologist doses. The first technique involves the establishment of a database relating the cardiologist extremity doses to patient DAP values. Doses of nine cardiologists were measured together with patient doses during the interventional cardiac examinations of 166 patients for this purpose. Data were collected from five cardiology departments. The mean of the eye, thyroid, waist, right-left wrist, and right-left leg doses per procedure were measured as 72.4 (31.6-107.1), 68.5 (13.3-174.6), 11.2 (0.9-28.4), 67.8 (21.9-120.3) to 216 (52.7-425.4), and 137 (51.4-386.2) to 384 (135-1168.3) microGy/procedure. The effective doses were calculated according to the use of protection tools and a mean value of 12.14 (1.2-30.2) microSv/procedure was found. The ratios of staff dose to patient DAP were found to be within the range of 0.14-3.75 for each procedure. In the second method, cardiologist doses were calculated and compared with the measured values. Scatter doses were measured at the positions of cardiologists from Rando phantom exposures using similar conditions with patient procedures for this purpose. The parameters obtained from these exposures and patient examinations were used to calculate the doses to cardiologists.

Reference levels at European level for cardiac interventional procedures.

In interventional cardiology, a wide variation in patient dose for the same type of procedure has been recognised by different studies. Variation is almost due to procedure complexity, equipment performance, procedure protocol and operator skill. The SENTINEL consortium has performed a survey in nine european centres collecting information on near 2000 procedures, and a new set of reference levels (RLs) for coronary angiography and angioplasty and diagnostic electrophysiology has been assessed for air kerma-area product: 45, 85 and 35 Gy cm2, effective dose: 8, 15 and 6 mSv, cumulative dose at interventional reference point: 650 and 1500 mGy, fluoroscopy time: 6.5, 15.5 and 21 min and cine frames: 700 and 1000 images, respectively. Because equipment performance and set-up are the factors contributing to patient dose variability, entrance surface air kerma for fluoroscopy, 13 mGy min(-1), and image acquisition, 0.10 mGy per frame, have also been proposed in the set of RLs.

Simultaneous determination of equivalent dose to organs and tissues of the patient and of the physician in interventional radiology using the Monte Carlo method.

This study presents the results of computations of organ equivalent doses and effective doses for the patient and the primary physician during an interventional cardiological examination. The simulations were carried out for seven x-ray spectra (between 60 kVp and 120 kVp) using the Monte Carlo code MCNP. The voxel-based whole-body model VIP-Man was employed to represent both the patient and the physician, the former lying on the operation table while the latter standing 15 cm from the patient at about waist level behind a lead apron. The x-rays, which were generated by a point source positioned around the table and were directed with a conical distribution, irradiated the patient's heart under five major projections used in a coronary angiography examination. The mean effective doses under LAO45, PA, RAO30, LAO45/CAUD30 and LLAT irradiation conditions were calculated as 0.092, 0.163, 0.161, 0.133 and 0.118 mSv/(Gy cm2) for the patient and 1.153, 0.159, 0.145, 0.164 and 0.027 microSv/(Gy cm2) for the shielded physician. The effective doses for the patient determined in this study were usually lower than the literature data obtained through measurements and/or calculations and the discrepancies could be attributed to the fact that this study computes the effective doses specific to the VIP-Man body model, which lacks an ovarian contribution to the gonadal equivalent dose. The effective doses for the physician agreed reasonably well with the literature data.

Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart.

The muscular ventricular septum separates the flow of oxygenated and de-oxygenated blood in air-breathing vertebrates. Defects within it, termed muscular ventricular septal defects (VSDs), are common, yet less is known about how they arise than rarer heart defects. Mutations of the cardiac transcription factor NKX2-5 cause cardiac malformations, including muscular VSDs. We describe here a genetic interaction between Nkx2-5 and Sarcospan (Sspn) that affects the risk of muscular VSD in mice. Sspn encodes a protein in the dystrophin-glycoprotein complex. Sspn knockout (SspnKO) mice do not have heart defects, but Nkx2-5+/-/SspnKO mutants have a higher incidence of muscular VSD than Nkx2-5+/- mice. Myofibers in the ventricular septum follow a stereotypical pattern that is disrupted around a muscular VSD. Subendocardial myofibers normally run in parallel along the left ventricular outflow tract, but in the Nkx2-5+/-/SspnKO mutant they commonly deviate into the septum even in the absence of a muscular VSD. Thus, Nkx2-5 and Sspn act in a pathway that affects the alignment of myofibers during the development of the ventricular septum. The malalignment may be a consequence of a defect in the coalescence of trabeculae into the developing ventricular septum, which has been hypothesized to be the mechanistic basis of muscular VSDs.

Patient and staff doses in interventional neuroradiology.

Radiation doses for interventional examinations are generally high and therefore necessitate dose monitoring for patients and staff. Relating the staff dose to a patient dose index, such as dose-area product (DAP), could be quite useful for dose comparisons. In this study, DAP and skin doses of 57 patients, who underwent neurointerventional examinations, were measured simultaneously with staff doses. Although skin doses were comparable with the literature data, higher DAP values of 215 and 188.6 Gy cm2 were measured for the therapeutical cerebral and carotid examinations, respectively, owing to the use of biplane system and complexity of the procedure. Mean staff doses for eye, finger and thyroid were measured as 80.6, 77.6 and 28.8 microGy per procedure. The mean effective dose per procedure for the radiologists was 32 microSv. In order to allow better comparisons to be made, DAP normalised doses were also presented.

Endocarditis prophylaxis for patients with mitral valve prolapse. A quantitative analysis.

Antimicrobial prophylaxis of bacterial endocarditis is widely recommended for patients with mitral valve prolapse who undergo procedures that may cause bacteremia. The benefits and risks of this practice have been analyzed on the basis of published data and response to a questionnaire survey of leading authorities on bacterial endocarditis. Among 10 million patients with mitral valve prolapse undergoing a dental procedure, an estimated 47 nonfatal cases and two fatal cases of bacterial endocarditis would occur if no prophylaxis were given, five cases of bacterial endocarditis and 175 deaths due to drug reactions would occur if all patients were given prophylaxis with a penicillin, and 12 nonfatal cases and one fatal case of bacterial endocarditis would be expected if a policy of prophylaxis with erythromycin were adopted. Even using assumptions most favorable to the penicillin regimen, this analysis predicts that no prophylaxis and penicillin prophylaxis would result in a similar number of deaths. No prophylaxis or prophylaxis with erythromycin appears preferable to prophylaxis with a penicillin.

Cardiopulmonary function following post-cardiac surgical mediastinitis.

Eleven survivors of bacterial mediastinitis, which followed cardiac surgery through a median sternotomy approach, underwent noninvasive cardiopulmonary evaluation to determine whether clinically apparent mediastinal fibrosis had developed. Compared to preoperative values, forced vital capacity was reduced by 9.75 percent of predicted; the greatest reduction occurred in those patients with Gram-negative mediastinitis. In one patient, an abnormal jugular venous wave form and apex cardiogram were consistent with constrictive cardiac physiology, but this was not associated with an abnormal echocardiogram or impaired functional status. In this small series, no serious abnormalities in cardiopulmonary function were detected which could be attributed to prior mediastinal infection.

A council of elders: creating a multi-voiced dialogue in a community of care.

In an era of 'medical care delivery systems', there is an increasing need for the patient's voice to be heard, for it to be invited, listened to, and taken seriously. This challenge is particularly evident in geriatrics education, a domain of clinical training in which educators and clinicians alike must struggle to overcome adverse attitudes towards the elderly ('ageism'). In this paper we introduce a 'Council of Elders' as an educational innovation in which we invited community elders to function as our 'Senior Faculty', to whom medical residents present their challenging and heartfelt dilemmas in caring for elder patients. In the conversations that ensue, the elders come to function not simply as teachers, but collaborators in a process in which doctors, researchers, and elders together create a community of resources, capable of identifying novel ways to overcome health-related difficulties which might not have been apparent to either group separately. Using the first meeting of the Council as an exemplar, we describe and discuss the special nature of such meetings and also the special preparations required to build a dialogic relationship between participants from very different worlds--different generations, different cultures (including the professional culture and the world of lived experience). Meetings with the council have become a required part of the primary care residency program--a very different kind of 'challenging case conference' in which moral dilemmas can be presented, discussed and reflected upon. It is not so much that elders give good advice in their responses--although they often do--as that they provide life world and value orientation as young residents gain a better sense of the elder's experience and what matters most to them. This project has been particularly worthwhile in addressing the problem of ageism--a way to render visible stereotypes and adverse physician values, with implications for decision-making with the patient, not for the patient.

Comparison of effective doses obtained from dose-area product and air kerma measurements in interventional radiology.

In this study, measurements of dose-area product (DAP) and entrance dose were carried out simultaneously in a sample of 162 adult patients who underwent different interventional examinations. Effective doses for each measurement technique were estimated using the conversion factors that have been determined for specific X-ray views in a mathematical phantom. Exposure conditions used in clinical practice never match these theoretical models exactly, and deviations from the assumed standard conditions cause uncertainties in effective dose estimations. Higher effective dose values are found if the air kerma results are used rather than DAP readings, both for patient and Rando phantom studies. Comparison of DAP, fluoroscopy times and skin doses were made with published data. DAP measurement for the effective dose calculation and thermoluminescent dosimeter for the skin dose estimates are found to be the most reliable methods for patient dosimetry.

Will cost effectiveness analysis worsen the cost effectiveness of health care?

Cost effectiveness analysis is increasingly advocated as a basis for health policy. Analysts often compare expensive interventions with highly cost-effective programs such as hypertension screening, implying that if the former were curtailed resources would be reallocated to the latter and the efficiency of health care would improve. However, in practice, savings are unlikely to be targeted in this way. We present refined policy models that take into account actual patterns of resource allocation in the United States, and provide more realistic estimates of the likely uses of savings. We illustrate the implications of these models in an analysis of the effects of diverting funds from an expensive but effective practice. Eliminating such a practice would actually worsen the overall cost-effectiveness of U.S. health care unless there are radical changes in health policy. Cost effectiveness analysis incorrectly predicts health and cost outcomes of policy initiatives because it ignores the political constraints to health care decision-making.

Trends in health insurance coverage, 1989-1997.

The authors analyze trends in health insurance coverage in the United States from 1989 through 1997, using cross-sectional surveys by the U.S. Census Bureau (Current Population Survey) of 160,000 persons representative of the non-institutionalized population. Between 1989 and 1997, the number of people without health insurance increased by 10.1 million to 43.4 million. From 1989 to 1993, the proportion covered by Medicaid increased by 3.6 percentage points while the proportion covered by private insurance declined by 4.2 percentage points. Since then, private coverage rates have stabilized and Medicaid coverage has decreased. Consequently, the number and percent uninsured continues to rise. Young adults age 18-39 had the largest increase in the proportion uninsured, and rates among children have also risen steeply since 1992. While blacks had the largest increase in the percent uninsured, Hispanics accounted for 35.6 percent of the increase in the number uninsured. Low-income families constituted over half of the increase in the number uninsured, but since 1993 the middle income group had the largest increase in the percent uninsured. Northeastern states had the largest increase in the percent uninsured. Thus, despite economic prosperity, the numbers and rates of the uninsured continue to rise. Principally affected are children and young adults, poor and middle-income families, blacks, and Hispanics.

Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation.

BACKGROUND: The occurrence of a congenital heart defect has long been thought to have a multifactorial basis, but the evidence is indirect. Complex trait analysis could provide a more nuanced understanding of congenital heart disease. METHODS AND RESULTS: We assessed the role of genetic and environmental factors on the incidence of ventricular septal defects (VSDs) caused by a heterozygous Nkx2-5 knockout mutation. We phenotyped >3100 hearts from a second-generation intercross of the inbred mouse strains C57BL/6 and FVB/N. Genetic linkage analysis mapped loci with lod scores of 5 to 7 on chromosomes 6, 8, and 10 that influence the susceptibility to membranous VSDs in Nkx2-5(+/-) animals. The chromosome 6 locus overlaps one for muscular VSD susceptibility. Multiple logistic regression analysis for environmental variables revealed that maternal age is correlated with the risk of membranous and muscular VSD in Nkx2-5(+/-) but not wild-type animals. The maternal age effect is unrelated to aneuploidy or a genetic polymorphism in the affected individuals. The risk of a VSD is not only complex but dynamic. Whereas the effect of genetic modifiers on risk remains constant, the effect of maternal aging increases over time. CONCLUSIONS: Enumerable factors contribute to the presentation of a congenital heart defect. The factors that modify rather than cause congenital heart disease substantially affect risk in predisposed individuals. Their characterization in a mouse model offers the potential to narrow the search space in human studies and to develop alternative strategies for prevention.

Correction methodology for the spectral interfering γ-rays overlapping to the analytical peaks used in the analysis of 232Th.

In the γ-ray spectrometric analysis of the radionuclides, a correction factor is generally required for the spectral interfering γ-rays in determining the net areas of the analytical peaks because some interfering γ-rays often might contribute to the analytical peaks of interest. In present study, a correction methodology for the spectral interfering γ-rays (CSI) is described. In particular, in the analysis of (232)Th contained in samples, the interfering γ-rays due to (226)Ra, (235)U, (238)U and their decay products often overlap to the peaks of interest from (232)Th decay products, and vise versa. For the validation of the proposed CSI method, several certified reference materials (CRM) containing U and Th were measured by using a 76.5% efficient n-type Ge detector. The required correction factors were quantified for spectral interference, self-absorption and true coincidence summing (TCS) effects for the relevant γ-rays. The measured results indicate that if one ignores the contributions of the interfering γ-rays to the analytical peaks at 583.2 keV of (208)Tl and 727.3 keV of (212)Bi, this leads to a significantly systematic influence on the resulted activities of (232)Th. The correction factors required for spectral interference and TCS effects are estimated to be ∼13.6% and ∼15.4% for 583.2 keV peak. For the 727.3 keV peak, the correction factor is estimated to be ∼15% for spectral interference, and ∼5% for the TCS effects at the presently used detection geometry. On the other hand, the measured results also indicate that ignoring the contribution of the interfering γ-rays to the areas of the analytical peaks at 860.6 keV of (208)Tl, 338.3 and 911.2 keV of (228)Ac does not lead to any significant systematic influence on the (232)Th analysis. Because these factors are remained generally less than ∼5%, i.e., within overall uncertainty limits. The present study also showed that in view of both the spectral interference and TCS effects, the "cleaner" analytical peaks are seen at 338.3 keV (11.25%) and 911.2 keV (26.13%) of (228)Ac when high resolution γ-rays spectrometry was used in the (232)Th activity measurements. Therefore, they can be adopted as the "reference" peaks in the (232)Th analysis.

Methods for spectral interference corrections for direct measurements of 234U and 230Th in materials by gamma-ray spectrometry.

When the high-resolution gamma-ray spectrometry was used in the analysis of (234)U and (230)Th in samples, there is a much more need to correct for the measured activity results of (234)U and (230)Th mainly due to self-absorption effects and the interfering lines from (226)Ra, (235)U, (238)U and their decay products that often might be present in the samples. Therefore, in the present study, the methods for the spectral interference corrections for the analytical peaks of (234)U and (230)Th are suggested to take into account the contributions of the overlapping gamma rays to these peaks. For the method validation, direct gamma-ray spectrometric measurements were carried out using certified reference materials (CRM) by use of a 76.5 % n-type Ge detector. The activities measured for the CRM samples were corrected for spectral interferences, self-absorption and true coincidence-summing (TCS) effects. The obtained results indicate that ignoring of the contribution of the interference gamma rays to the main analytical peak at 53.2 keV of (234)U leads to a lager systematic error of 87.3-90.4 % for the measured activities of (234)U, and similarly if one ignores the contributions of the interference gamma rays to the main analytical peak at 67.7 keV of (230)Th, this leads to a much smaller systematic error of 2.1-2.7 % for the activities of (230)Th. Therefore, the required correction factors for spectral interferences to the analytical peaks of (234)U and (230)Th are not negligible and thus they should also be considered besides necessary self-absorption factors to determine more accurate activities in the samples. On the other hand, it is estimated that although the TCS effects on the main analytical peaks of both (234)U and (230)Th are negligibly small, those TCS correction factors for their interference gamma rays to these peaks should be taken into account when direct measurements are performed in a close-counting geometry condition. Otherwise, the resulted activities can have serious erroneous results for both (234)U and (230)Th while using gamma-ray spectrometry, thereby leading to inaccuracies in their derived quantities, for instance, the corresponding age determinations of the samples.

True coincidence-summing corrections for the coincident gamma-rays measured with coplanar grid CdZnTe detectors.

In this study, true coincidence-summing (TCS) correction factors have been measured for the sources (22)Na, (60)Co, (133)Ba and (152)Eu by use of three large volume coplanar grid CdZnTe (acronym: CZT) detectors. In case of a close-in detection geometry, two different TCS calculation algorithms were used to compute the required TCS correction factors. Both of the algorithms are based on the measured total-to-peak (TTP) ratio and full-energy peak (FEP) efficiency values that were obtained using almost "single" energy and coincidence-free nuclides. The results for TCS correction factors obtained by two different algorithms were agreeable to each other. The obtained TCS factors were ranged from about 7% to 30.5% in a 2250 mm(3) CZT detector when a close counting geometry was used. For other two detectors with a volume of 1000 and 1687.5mm(3), the resulted TCS correction factors were relatively smaller and varied between about 0.1% and 20% at the close counting geometry condition. Therefore, the results indicate that there is a need for the estimation of TCS corrections in CZT detectors, especially when their crystal volumes are greater than 1cm(3) and these detectors are used in the case of a close-in detection geometry.

Patient and staff doses for some complex x-ray examinations.

The aim of this study was to measure patient and staff doses simultaneously for some complex x-ray examinations. Measurements of dose-area product (DAP) and entrance skin dose (ESD) were carried out in a sample of 107 adult patients who underwent different x-ray examinations such as double contrast barium enema (DCBE), single contrast barium enema (SCBE), barium swallow, endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC), and various orthopaedic surgical procedures. Dose measurements were made separately for each projection, and DAP, thermoluminescent dosimetry (TLD), film dosimetry and tube output measurement techniques were used. Staff doses were measured simultaneously with patient doses for these examinations, with the exception of barium procedures. The measured mean DAP values were found to be 8.33, 90.24, 79.96 Gy cm(2) for barium swallow, SCBE and DCBE procedures with the fluoroscopy times of 3.1, 4.43 and 5.86 min, respectively. The calculated mean DAP was 26.33 Gy cm(2) for diagnostic and 89.76 Gy cm(2) therapeutic ERCP examinations with the average fluoroscopy times of 1.9 and 5.06 min respectively. Similarly, the calculated mean DAP was 97.53 Gy cm(2) with a corresponding fluoroscopy time of 6.1 min for PTC studies. The calculated mean entrance skin dose (ESD) was 172 mGy for the orthopaedic surgical studies. Maximum skin doses were measured as 324, 891, 1218, 750, 819 and 1397 mGy for barium swallow, SCBE, DCBE, ERCP, PTC and orthopaedic surgical procedures, respectively. The high number of radiographs taken during barium enema examinations, and the high x-ray outputs of the fluoroscopic units used in ERCP, were the main reasons for high doses, and some corrective actions were immediately taken.