Lower frequency of NPM1 and FLT3-ITD mutations in a South African adult de novo AML cohort.

INTRODUCTION: Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hemopoietic progenitor cells diagnosed in individuals of any age, but with a median age of 67 years at presentation in adults. Assessment of the mutation status of nucleophosmin protein-1 (NPM1) and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is essential for the prognosis, and treatment of AML. METHODS: A total of 160 de novo AML cases, both cytogenetically normal and abnormal, were analyzed for the presence of NPM1 and FLT3-ITD mutations, and the results assessed in conjunction with epidemiological, clinical, and laboratory findings. RESULTS: Nucleophosmin protein-1 mutations were found in 7.5%, while FLT3-ITD was present in 12% of these cases. Both of these were lower than expected. The median age at diagnosis of AML was 41 years, and for the FLT3-ITD only cases, median age was 33 years; these ages were younger than expected. CONCLUSION: The lower reported frequencies and younger median age at diagnosis of AML and these specific mutations may be contributed to by a number of factors including effects of race on age of presentation, inclusion of patients diagnosed with de novo AML only, and a generally younger median age of the South African population.

Asymmetrical attenuation of vibration sensation in unilateral diabetic Charcot foot neuroarthropathy.

AIMS: To further characterize the distal sensory neuropathy in subjects with unilateral diabetic Charcot foot neuroarthropathy. METHODS: A retrospective cohort study to assess the level to which the sensory modalities of pinprick, light touch, vibration, joint position and temperature were attenuated in the affected and unaffected limbs in subjects with unilateral Charcot. The level to which the sensory modality was attenuated in each limb was assigned a score. The Wilcoxon signed rank test was used to compare the scores in the affected and unaffected limbs and also to compare the scores of the different sensory modalities in the affected and unaffected limbs. RESULTS: Fifty subjects with unilateral Charcot foot neuroarthropathy were assessed. Mean age was 45 ± SD 6 years for the 17 subjects with Type 1 diabetes and 62 ± 10 years for the 33 subjects with Type 2 diabetes. Duration of diabetes was 21 ± 13 years, HbA(1c) was 70 ± 19 mmol/mol [8.6 ± 1.8 %] and 15 subjects (30%) required renal replacement therapy. The level of attenuation of vibration sensation was more proximal in the affected compared with the unaffected limbs (P = 0.002). Pinprick, light touch, joint position and temperature sensations were not different. Joint position sensation was less attenuated bilaterally than the other sensory modalities. CONCLUSIONS: Asymmetrical attenuation of vibration sensation may predict the side that will develop a Charcot joint and may suggest a more important role for vibration sense loss than loss of other sensory modalities in the pathophysiology of Charcot.

Performance of subjects with and without severe mental illness on a clinical test of problem solving.

Severe mental illness is associated with impairments in executive functions, such as conceptual reasoning, planning, and strategic thinking all of which impact problem solving. The present study examined the utility of a novel assessment tool for problem solving, the Rapid Assessment of Problem Solving Test (RAPS) in persons with severe mental illness. Subjects were 47 outpatients with severe mental illness and an equal number healthy controls matched for age and gender. Results confirmed all hypotheses with respect to how subjects with severe mental illness would perform on the RAPS. Specifically, the severely mentally ill subjects (1) solved fewer problems on the RAPS, (2) when they did solve problems on the test, they did so far less efficiently than their healthy counterparts, and (3) the two groups differed markedly in the types of questions asked on the RAPS. The healthy control subjects tended to take a systematic, organized, but not always optimal approach to solving problems on the RAPS. The subjects with severe mental illness used some of the problem solving strategies of the healthy controls, but their performance was less consistent and tended to deteriorate when the complexity of the problem solving task increased. This was reflected by a high degree of guessing in lieu of asking constraint questions, particularly if a category-limited question was insufficient to continue the problem solving effort.

Planar imaging versus gated blood-pool SPECT for the assessment of ventricular performance: a multicenter study.

UNLABELLED: Gated blood-pool SPECT (GBPS), inherently 3-dimensional (3D), has the potential to replace planar equilibrium radionuclide angiography (ERNA) for computation of left ventricular ejection fraction (LVEF), analysis of regional wall motion (RWM), and analysis of right heart function. The purpose of this study was to compare GBPS and ERNA for the assessment of ventricular function in a large, multicenter cohort of patients. METHODS: One hundred seventy-eight patients referred in the usual manner for nuclear medicine studies underwent ERNA followed by GBPS. Each clinical site followed a GBPS acquisition protocol that included 180 degrees rotation, a 64 by 64 matrix, and 64 or 32 views using single- or double-head cameras. Transverse GBPS images were reconstructed with a Butterworth filter (cutoff frequency, 0.45-0.55 Nyquist; order, 7), and short-axis images were created. All GBPS studies were processed with a new GBPS program, and LVEF was computed from the isolated left ventricular chamber and compared with standard ERNA LVEF. Reproducibility of GBPS LVEF was evaluated, and right ventricular ejection fraction (RVEF) was computed in a subset of patients (n = 33). Using GBPS, RWM and image quality from 3D surface-shaded and volume-rendered cine displays were evaluated qualitatively in a subset of patients (n = 30). RESULTS: The correlation between GBPS LVEF and planar LVEF was excellent (r = 0.92). Mean LVEF was 62.2% for GBPS and 54.1% for ERNA. The line of linear regression was GBPS LVEF = (1.04 x ERNA LVEF) + 6.1. Bland-Altman plotting revealed an increasing bias in GBPS LVEF with increasing LVEF (Y = 0.13x + 0.61; r = 0.30; mean difference = 8.1% +/- 7.0%). Interoperator reproducibility of GBPS LVEF was good (r = 0.92). RVEF values averaged 59.8%. RWM assessment using 3D cine display was enhanced in 27% of the studies, equivalent in 67%, and inferior in 7%. CONCLUSION: GBPS LVEF was reproducible and correlated well with planar ERNA. GBPS LVEF values were somewhat higher than planar ERNA, likely because of the exclusion of the left atrium.

Kinetic analysis of 125I-iodorotenone as a deposited myocardial flow tracer: comparison with 99mTc-sestamibi.

UNLABELLED: The goal of this investigation was to assess the accuracy of 7'-Z-[125I]iodorotenone (125I-iodorotenone) as a new deposited myocardial flow tracer and compare the results with those for 99mTc-sestamibi. METHODS: The kinetics of these two flow tracers were evaluated in 25 isolated, erythrocyte- and albumin-perfused rabbit hearts over a flow range relevant to patients. The two flow tracers and a vascular reference tracer (131I-albumin) were introduced simultaneously as a compact bolus through a port just above the aortic cannula in the absence of tracer recirculation. Myocardial extraction, retention, washout, and uptake parameters were computed from the venous outflow curves using the multiple-indicator dilution technique and spectral analysis. RESULTS: The extraction of 125I-iodorotenone was much higher than the extraction of 99mTc-sestamibi (0.84 +/- 0.05 vs. 0.48 +/- 0.10, respectively, P < 0.001). 125I-iodorotenone extraction was also less affected by flow than was 99mTc-sestamibi (P < 0.001). Net retention of 125I-iodorotenone was significantly greater than 99mTc-sestamibi net retention at 1 min (0.77 +/- 0.08 vs. 0.41 +/- 0.11, respectively, P < 0.001) and 26 min (0.46 +/- 0.13 vs. 0.27 +/- 0.11, respectively, P < 0.001) after tracer injection. Flow had less effect on 125I-iodorotenone net retention than on 99mTc-sestamibi net retention 1 min after tracer injection (P < 0.04). However, at 26 min, flow had an equivalent effect on the retention of both flow tracers (P < 0.4). The relationship between 125I-iodorotenone and 99mTc-sestamibi washout was complex and depended on elapsed time after isotope introduction and perfusion rate. Reflecting the favorable extraction and retention characteristics of 125I-iodorotenone, both its maximum myocardial uptake and its 26-min uptake were more closely related to flow than were those of 99mTc-sestamibi (P < 0.001 for both comparisons). CONCLUSION: The extraction and retention of 125I-iodorotenone were greater than those of 99mTc-sestamibi, making 125I-iodorotenone the superior flow tracer in the isolated rabbit heart.

Technical competency in flexible sigmoidoscopy.

BACKGROUND: Family practice residencies offer training in flexible sigmoidoscopy; however, there are no objective recommendations for determining competency in learners. We describe a longitudinal study designed to determine the mean procedure time and depth of insertion for family practice residents. METHODS: During a 21-month period, data were collected for 421 patients undergoing flexible sigmoidoscopy. Second- or third-year family medicine residents supervised by family medicine faculty did all procedures. The data were analyzed with simple descriptive statistics, t test, and linear and logistic regression. RESULTS: The mean procedure time was 18+/-9.3 minutes (17.2 - 19.6, 95% confidence interval [CI]). The mean insertion depth was 51.4+/-12.4 cm (50.4 - 52.6 cm, 95% CI). Performing a biopsy was associated with an increase in procedure time (17.0 vs 27.3 minutes, P < .0001). Women with a history of pelvic surgery had less depth of insertion than did those who had no history of pelvic surgery (47 vs 53 cm, P = .002, t test). CONCLUSION: Procedural competency consists of knowledge, technical skills, and attitudes. Knowledge and attitudes can be assessed with other items, such as examinations and observation. Primary care faculty can now use these standards of insertion depth and procedure time when determining technical skill proficiency for their residents in flexible sigmoidoscopy.

Quantitative gated blood pool SPECT for the assessment of coronary artery disease at rest.

BACKGROUND: Planar gated blood pool imaging (GBPI) has long proven to be useful for the noninvasive assessment of ventricular function. From a practical viewpoint, gated blood pool single photon emission computed tomography (GBPS) acquisition can be accomplished in the same time as a three-view planar series, with the benefit of a tomographic perspective that avoids chamber overlap. METHODS AND RESULTS: Quantitative gated blood pool SPECT was applied to 10 patients who underwent coronary arteriography, contrast ventriculography, and planar gated blood pool imaging. For each patient, the mid-short axis oblique slice was divided into 4 discrete segments using 4 different reference models and 2 forms of segmentation. A center of mass (counts) fixed in the end-diastolic frame and segmentation that bisected the ventricular septum proved to have the highest sensitivity and specificity for determining regional wall motion abnormalities at rest in myocardium supplied by severely diseased coronary arteries (>75 %). GBPS correctly identified 19 of 21 abnormal segments (90%), with good specificity (95%), whereas ventriculography identified 12 (57%) and planar GBPI identified 9 (43%) of the segments supplied by diseased coronaries. CONCLUSION: Quantitative GBPS appears to be a sensitive method for assessing coronary artery disease at rest in myocardium perfused by severely diseased coronary arteries.

Estimating glucose metabolism using glucose analogs and two tracer kinetic models in isolated rabbit heart.

The purpose of this investigation was to 1) evaluate the relative accuracy of the Sokoloff and Patlak tracer kinetic models in estimating glucose metabolic rate (GMR) in the presence and absence of insulin; 2) evaluate the effect of nutritional state on the lumped constant (LC); and 3) compare the kinetics of 2-fluoro-2-deoxy-D-[14C]glucose (FDG) and 2-deoxy-D-[3H]glucose (DG) membrane transport and phosphorylation. The experimental preparation was the isolated, red blood cell-albumin-perfused rabbit heart. Our results showed that both tracer kinetic models provided GMR estimates that correlated well with the Fick method (for FDG, R = 0. 84 and 0.91 for the Sokoloff and Patlak models, respectively); nutritional state did not affect the LC; and FDG and DG have different transport and/or phosphorylation parameters. We also observed that 1) the addition of a fourth compartment to the Sokoloff model reduced the mean squared error between measured and modeled data by a factor of 7.4; 2) a longer time (21.8 min) was required to obtain a linear phase of the Patlak plot than is allowed in clinical studies; and 3) accurate GMR estimates were obtained only by using different LCs reflecting insulin's presence or absence. Our results indicate potential sources of error in the use of FDG and positron emission tomography to quantify GMR in patients.

Kinetic analysis of rubidium and thallium as deposited myocardial blood flow tracers in isolated rabbit heart.

Evaluation of myocardial perfusion with tracers such as thallium and rubidium is based on the assumption that tissue tracer content is proportional to flow. The purpose of this study was to evaluate the relationship between flow and tissue tracer content of 201Tl and 83Rb in the isolated perfused rabbit heart. 83Rb (86-day half-life), an isotope that is not used clinically, was used as a subsitute for 82Rb (76-s half-life) to improve the accuracy and precision of data acquisition. The multiple indicator-dilution technique was employed with two independent computational approaches. The first approach explicitly deconvolved 201Tl and 83Rb venous concentration curves by the intravascular reference tracer curve. The second approach used a conventional analysis. Both approaches showed that there was more early washout of 83Rb than 201Tl and that the heart retained 201Tl better than 83Rb within 2 min after isotope introduction. These data indicate that 201Tl is a better perfusion tracer than 83Rb in the isolated rabbit heart.

Retrieval of famous names on a Rebus Riddle task by middle-aged and older subjects.

This study compared the performances of 20 middle-aged and 20 older subjects on a Rebus Riddle task that required they retrieve the names of famous persons. Older subjects solved significantly more riddles and responded to prompts designed to aid riddle-solving efforts with significantly greater success than middle-aged subjects. Older subjects also had nonsignificantly faster riddle-solving times than middle-aged subjects. Similar riddles were difficult or easy for both groups. Superior performance of the older group appeared to be related to the age of the subject at the time the persons in the riddles had become famous.

Comparison of personalized cueing and provided cueing on the facilitation of verbal labeling by aphasic subjects.

This study investigated the effects of two associative learning tasks on aphasic subjects' labeling of novel symbols. It was designed to determine if aphasic subjects need to develop their own associations for word-symbols pairs (personalized cueing) to obtain the long-term labeling benefits observed in prior research or if comparable results are obtained when "ready-made" associations are used during training (provided cueing). The results showed that the two cueing techniques were equal in their ability to elicit correct responses from the subjects. The results also demonstrated the long-term effectiveness of both cueing procedures on the subjects' labeling accuracy up to 30 days after training was discontinued.

Morphological and biochemical characteristics of trichothiodystrophy-variant hair are maintained after grafting of scalp specimens on to nude mice.

Trichothiodystrophy (TTD) is a hair defect associated with abnormal composition of the high-sulphur proteins (HSP). HSP can be modified quantitatively (reduced amount of qualitatively normal HSP: TTD-variant) and qualitatively (TTD). In this study we show that the amino acid composition of hairs collected from the scalp of a patient with TTD-variant (donor) was preserved in hairs produced by donor scalp follicles maintained up to 6 months as grafts on to nude mice. It is the first time that an exceptionally rare, clinically and biochemically well-characterized hair dysplasia has been maintained under laboratory conditions for a long period of time. The linear growth rate of TTD-variant hairs was similar to that of control hairs grown under comparable conditions. The persistence of disease-specific abnormalities in the hair shaft indicates that the TTD-variant mutation is expressed without significant quantitative modifications, and appears independent of systemic host-related factors. This model may serve as a clinically relevant working platform for evaluating regulation of abnormal gene expression in the hair follicle under well-controlled experimental conditions.

The effect of flow on technetium-99m-teboroxime (SQ30217) and thallium-201 extraction and retention in rabbit heart.

In order to evaluate the accuracy of blood flow measurement, the single-pass extraction, retention/wash-out and relative net uptake of 99mTc-teboroxime (SQ30217) and 201Tl were evaluated and compared in 20 isolated blood-perfused rabbit hearts at coronary flow rates ranging from 0.49 to 2.85 ml/g wet wt min-1. The average peak extraction of 201Tl (+/- s.d.) (0.67 +/- 0.11) marginally exceeded that of SQ30217 (0.62 +/- 0.12) (p = 0.06). Flow significantly affected the maximum net extraction of 201Tl and the 40-min net extractions of both 201Tl and SQ30217. Unexpectedly, the rate of 201Tl myocardial washout was significantly faster (p less than 0.05) than SQ30217 washout at all flow rates evaluated. Increasing coronary blood flow rate was associated with a more rapid clearance of both tracers from the myocardium (p less than 0.05 for both comparisons). The slope of the linear correlations between relative net SQ30217 uptake versus flow and relative net 201Tl uptake versus flow were found to be similar for up to 10 min after isotope injection. These data were interpreted to indicate that: 1. Thallium-201 might be slightly better extracted than SQ30217. 2. SQ30217 is cleared more slowly from the myocardium. 3. Thallium-201 and SQ30217 appear to be comparable tracers of myocardial perfusion for up to 10 min after injection under the single-pass conditions currently employed. 4. Additional studies are needed to clarify myocardial SQ30217 kinetics.

Structure and biochemistry of mammalian hard keratin.

In this review, the structure and biological formation of hard alpha-keratin are drawn together. The hard keratins comprising wool, hairs, quills, hooves, horns, nails and baleen contain partly alpha-helical polypeptides which show homology with epidermal polypeptides only in the helical regions. These polypeptides (about 32 chains) are organized into intermediate filaments (IFs) of 7.5 nm diameter which are embedded in variable amounts of a matrix of non-helical cystine-rich proteins and glycine-tyrosine-rich proteins. The total number of proteins may exceed 100. In addition keratins contain a variety of lipid components. Wool and hair are produced in follicles in a multistep procedure. In the lower levels of the follicle, IFs without associated matrix are found. Subsequently matrix proteins are laid down between the IFs and further synthesis takes place concurrently. Finally the proteins are insolubilized by the oxidative formation of disulphide bonds. Keratinized fibres shows considerable complexity and diversity in the structural arrangement of IFs and matrix within cortical cells. Typically the IFs show hexagonal packing or give a whorl-like appearance in cross-section.

Korean hemorrhagic fever: environmental health and medical surveillance measures.

Throughout history, battles, campaigns, and wars have often been decided by diseases, rather than bullets and tacticians. During the Korean War, Korean hemorrhagic fever (KHF) afflicted several thousand allied soldiers and an unknown number of Communist soldiers. This disease, and other members of a closely related group, the hemorrhagic fevers with renal syndrome, represent a continuing worldwide military and civilian threat. Through inexpensive and flexible environmental health measures, and readily available medical surveillance and testing, it is now possible to reduce the risk from this disease. In this paper, we will outline various environmental health measures developed to reduce the risk of contracting KHF and the justification for their use. We will also discuss a medical surveillance and testing program designed to get at-risk and symptomatic individuals to definitive care quickly in order to reduce overall morbidity and mortality.

Technetium-99m hexakis 2-methoxy-2-isobutyl isonitrile and thallium-201 extraction, washout, and retention at varying coronary flow rates in rabbit heart.

Technetium-99m hexakis 2-methoxy-2-isobutyl isonitrile (Tc-MIBI) and thallium-201 extraction, washout, and retention were investigated and compared in 20 isolated, isovolumic, retrograde blood-perfused rabbit hearts at flow rates ranging from 0.5 to 3.5 ml/g wet wt min-1 in the absence of tracer recirculation. Mean Tc-MIBI peak instantaneous extraction was lower (0.55 +/- 0.10, p less than 0.001) and more affected by flow rate (p less than 0.05) than 201Tl peak instantaneous extraction (0.83 +/- 0.06). In contrast, the rate of 201Tl washout was significantly faster (p less than 0.05) and initially more dependent on perfusion rate (p less than 0.05) than Tc-MIBI washout. Reflecting its higher peak instantaneous extraction, 201Tl retention was 55-79% higher immediately after isotope injection (p less than 0.001) than Tc-MIBI retention, and relative changes in maximal 201Tl net uptake correlated better (p less than 0.05) with relative flow changes than maximal Tc-MIBI net uptake. However, due to its faster washout rate, the superiority of thallium over Tc-MIBI as a perfusion indicator was lost within 10 minutes of tracer injection under the present single-pass experimental conditions. These data were interpreted to indicate that 1) Tc-MIBI is not as well extracted and has a slower washout rate than 201Tl; 2) varying the coronary flow rate has significant but divergent effects on the extraction, washout, and retention of Tc-MIBI and 201Tl; and 3) the present results support continued evaluation of Tc-MIBI as a possible perfusion indicator.