Added prognostic value of myocardial blood flow quantitation in rubidium-82 positron emission tomography imaging.

AIMS: We studied the respective added value of the quantitative myocardial blood flow (MBF) and the myocardial flow reserve (MFR) as assessed with (82)Rb positron emission tomography (PET)/CT in predicting major adverse cardiovascular events (MACEs) in patients with suspected myocardial ischaemia. METHODS AND RESULTS: Myocardial perfusion images were analysed semi-quantitatively (SDS, summed difference score) and quantitatively (MBF, MFR) in 351 patients. Follow-up was completed in 335 patients and annualized MACE (cardiac death, myocardial infarction, revascularization, or hospitalization for congestive heart failure or de novo stable angor) rates were analysed with the Kaplan-Meier method in 318 patients after excluding 17 patients with early revascularizations (<60 days). Independent predictors of MACEs were identified by multivariate analysis. During a median follow-up of 624 days (inter-quartile range 540-697), 35 MACEs occurred. An annualized MACE rate was higher in patients with ischaemia (SDS >2) (n = 105) than those without [14% (95% CI = 9.1-22%) vs. 4.5% (2.7-7.4%), P < 0.0001]. The lowest MFR tertile group (MFR <1.8) had the highest MACE rate [16% (11-25%) vs. 2.9% (1.2-7.0%) and 4.3% (2.1-9.0%), P < 0.0001]. Similarly, the lowest stress MBF tertile group (MBF <1.8 mL/min/g) had the highest MACE rate [14% (9.2-22%) vs. 7.3% (4.2-13%) and 1.8% (0.6-5.5%), P = 0.0005]. Quantitation with stress MBF or MFR had a significant independent prognostic power in addition to semi-quantitative findings. The largest added value was conferred by combining stress MBF to SDS. This holds true even for patients without ischaemia. CONCLUSION: Perfusion findings in (82)Rb PET/CT are strong MACE outcome predictors. MBF quantification has an added value allowing further risk stratification in patients with normal and abnormal perfusion images.

Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype.

PURPOSE: To investigate the prognostic value of various cytogenetic components of a complex karyotype in acute myeloid leukemia (AML). PATIENTS AND METHODS: Cytogenetics and overall survival (OS) were analyzed in 1,975 AML patients age 15 to 60 years. RESULTS: Besides AML with normal cytogenetics (CN) and core binding factor (CBF) abnormalities, we distinguished 733 patients with cytogenetic abnormalities. Among the latter subgroup, loss of a single chromosome (n = 109) conferred negative prognostic impact (4-year OS, 12%; poor outcome). Loss of chromosome 7 was most common, but outcome of AML patients with single monosomy -7 (n = 63; 4-year OS, 13%) and other single autosomal monosomies (n = 46; 4-year OS, 12%) did not differ. Structural chromosomal abnormalities influenced prognosis only in association with a single autosomal monosomy (4-year OS, 4% for very poor v 24% for poor). We derived a monosomal karyotype (MK) as a predictor for very poor prognosis of AML that refers to two or more distinct autosomal chromosome monosomies (n = 116; 4-year OS, 3%) or one single autosomal monosomy in the presence of structural abnormalities (n = 68; 4-year OS, 4%). In direct comparisons, MK provides significantly better prognostic prediction than the traditionally defined complex karyotype, which considers any three or more or five or more clonal cytogenetic abnormalities, and also than various individual specific cytogenetic abnormalities (eg, del[5q], inv[3]/t[3;3]) associated with very poor outcome. CONCLUSION: MK enables (in addition to CN and CBF) the prognostic classification of two new aggregates of cytogenetically abnormal AML, the unfavorable risk MK-negative category (4-year OS, 26% +/- 2%) and the highly unfavorable risk MK-positive category (4-year OS, 4% +/- 1%).

Plac8 is an inducer of C/EBPβ required for brown fat differentiation, thermoregulation, and control of body weight.

Brown adipocytes oxidize fatty acids to produce heat in response to cold or to excessive energy intake; stimulation of brown fat development and function may thus counteract obesity. Brown adipogenesis requires activation of the transcription factor C/EBPβ and recruitment of the zinc finger protein Prdm16, but upstream inducers of these proteins are incompletely defined. Here, we show that genetic inactivation of Plac8, a gene encoding an evolutionarily conserved protein, induces cold intolerance, and late-onset obesity, as well as abnormal morphology and impaired function of brown adipocytes. Using brown preadipocyte lines we show that Plac8 is required for brown fat differentiation, that its overexpression induces C/EBPβ and Prdm16, and that upon induction of differentiation Plac8 associates with C/EBPβ and binds to the C/EBPβ promoter to induce its transcription. Thus, Plac8 is a critical upstream regulator of brown fat differentiation and function that acts, at least in part, by inducing C/EBPβ expression.

Unilateral urinary flow impairment at the pelviureteral junction: outcome of renal function with respect to therapeutic strategy.

OBJECTIVES: To evaluate the renal function outcome in children with unilateral hydronephrosis and urinary flow impairment at the pelviureteral junction with respect to the therapeutic strategy. METHODS: We retrospectively selected 45 children with iodine-123-hippuran renography performed at diagnosis and after 3 or more years of follow-up. All children had bilateral nonobstructive pattern findings on diuretic renography at follow-up. Eleven children were treated conservatively, and 34 underwent unilateral pyeloplasty. Split and individual renal function, measured by an accumulation index, was computed from background-corrected renograms for the affected and contralateral kidneys at diagnosis and the follow-up examination. RESULTS: Of 11 children treated conservatively, 9 had normal bilateral function at diagnosis, all had reached normal function at follow-up. Of the 34 operated kidneys, 12 (38%) had initially normal function that remained normal at the follow-up examination, and 22 had impaired function that had normalized at the follow-up examination in 15 (68%). The function of the contralateral kidneys was increased in 5 of 8 children with persistently abnormal affected kidneys. Pyeloplasty was performed in 23 children (68%) and 11 children (32%) younger and older than 1 year, respectively. The function of the affected kidneys increased in both groups, but normalization occurred only in the younger children. CONCLUSIONS: Of the children selected for conservative treatment, 82% had normal bilateral renal function at diagnosis that was normal in all at the follow-up examination. Of the children treated surgically, 65% had initially impaired function of the affected kidney that improved in 87% after pyeloplasty. Normalization of function was observed only in children who were younger than 1 year old at surgery. Persistently low function of the affected kidney was compensated for by the contralateral one regardless of the age at surgery.

Asymmetric POSTS associated with unilateral EEG abnormalities.

OBJECTIVE: Positive occipital sharp transient of the sleep (POSTS) are considered a normal variant of non-REM sleep EEG. We describe a small series of patients with asymmetric POSTS and ipsilateral abnormal EEG findings. METHODS: Over a period of 30 weeks, we prospectively observed five consecutive subjects with strictly unilateral POSTS associated with ispilateral electrographic abnormalities. They represent 0.4% of all EEG performed over the same time lapse (5/1130), including inpatients, outpatients and long-term monitoring. RESULTS: Four women and one boy suffering from epileptic seizures (aged 7-76 years old) had unilateral POSTS, occurring only on the right side, during light sleep. They also presented ipsilateral epileptiform abnormalities. CONCLUSION: The fact that POSTS were asymmetric and found only on the same side as the abnormalities raises the question whether these transients should still be considered physiological or could be interpreted at times as markers of underlying electrical abnormalities, pointing to an increased cortical excitability on the more active side. Although larger samples are needed to confirm our preliminary results, this case study questions the interpretation of POSTS as a uniformly normal variant.

Epibulbar osseous choristoma: a clinicopathological case series and review of the literature [Epibulbäre knöcherne Choristome: eine klinisch-pathologische Fallserie und Überblick der Literatur]

BACKGROUND: Choristomas are benign, congenital tumours composed of normal tissue in an abnormal location. Osseous choristomas represent the rarest form of epibulbar choristomas, with now 65 cases reported in the literature. We did a retrospective clinicopathological study of all patients with epibulbar osseous choristoma observed at our institution since 1982 and updated the last review of the literature. HISTORY AND SIGNS: Three Caucasian male patients, aged between 3 months and 11 years, were identified. All osseous choristomas were located under the superotemporal bulbar conjunctiva of the right eye. THERAPY AND OUTCOME: All lesions were managed with surgical excision. Histopathology revealed the presence of lamellar bone in all cases, one of which was associated with a dermolipoma. CONCLUSIONS: We report a small rare case series of 3 epibulbar osseous choristomas and did a review of the literature. In one patient, the osteoma was associated with a dermolipoma, corresponding to the fourth reported complex choristoma of this type, in an otherwise normal eye, in the literature.

A Prognostic Score to Identify Low-risk Outpatients with Acute Deep Vein Thrombosis in the Lower Limbs.

BACKGROUND: No prior studies have identified which patients with deep vein thrombosis in the lower limbs are at a low risk for adverse events within the first week of therapy. METHODS: We used data from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) to identify patients at low risk for the composite outcome of pulmonary embolism, major bleeding, or death within the first week. We built a prognostic score and compared it with the decision to treat patients at home. RESULTS: As of December 2013, 15,280 outpatients with deep vein thrombosis had been enrolled. Overall, 5164 patients (34%) were treated at home. Of these, 12 (0.23%) had pulmonary embolism, 8 (0.15%) bled, and 4 (0.08%) died. On multivariable analysis, chronic heart failure, recent immobility, recent bleeding, cancer, renal insufficiency, and abnormal platelet count independently predicted the risk for the composite outcome. Among 11,430 patients (75%) considered to be at low risk, 15 (0.13%) suffered pulmonary embolism, 22 (0.19%) bled, and 8 (0.07%) died. The C-statistic was 0.61 (95% confidence interval [CI], 0.57-0.65) for the decision to treat patients at home and 0.76 (95% CI, 0.72-0.79) for the score (P = .003). Net reclassification improvement was 41% (P < .001). Integrated discrimination improvement was 0.034 for the score and 0.015 for the clinical decision (P < .001). CONCLUSIONS: Using 6 easily available variables, we identified outpatients with deep vein thrombosis at low risk for adverse events within the first week. These data may help to safely treat more patients at home. This score, however, should be validated.

Le point sur l'ergométrie en 2012 dans le diagnostic de la maladie coronarienne.

Background In patients presenting with acute cardiac symptoms, abnormal ECG and raised troponin, myocarditis may be suspected after normal angiography. Aims To analyse cardiac magnetic resonance (CMR) findings in patients with a provisional diagnosis of acute coronary syndrome (ACS) in whom acute myocarditis was subsequently considered more likely. Methods and results 79 patients referred for CMR following an admission with presumed ACS and raised serum troponin in whom no culprit lesion was detected were studied. 13% had unrecognised myocardial infarction and 6% takotsubo cardiomyopathy. The remainder (81%) were diagnosed with myocarditis. Mean age was 45615 years and 70% were male. Left ventricular ejection fraction (EF) was 58610%; myocardial oedema was detected in 58%. A myocarditic pattern of late gadolinium enhancement (LGE) was detected in 92%. Abnormalities were detected more frequently in scans performed within 2 weeks of symptom onset: oedema in 81% vs 11% (p<0.0005), and LGE in 100% vs 76% (p<0.005). In 20 patients with both an acute (<2 weeks) and convalescent scan (>3 weeks), oedema decreased from 84% to 39% (p<0.01) and LGE from 5.6 to 3.0 segments (p¼0.005). Three patients presented with sustained ventricular tachycardia, another died suddenly 4 days after admission and one resuscitated 7 weeks following presentation. All 5 patients had preserved EF. Conclusions Our study emphasises the importance of access to CMR for heart attack centres. If myocarditis is suspected, CMR scanning should be performed within 14 days. Myocarditis should not be regarded as benign, even when EF is preserved.

Testosterone and doping control.

BACKGROUND AND OBJECTIVES: Anabolic steroids are synthetic derivatives of testosterone, modified to enhance its anabolic actions (promotion of protein synthesis and muscle growth). They have numerous side effects, and are on the International Olympic Committee's list of banned substances. Gas chromatography-mass spectrometry allows identification and characterisation of steroids and their metabolites in the urine but may not distinguish between pharmaceutical and natural testosterone. Indirect methods to detect doping include determination of the testosterone/epitestosterone glucuronide ratio with suitable cut-off values. Direct evidence may be obtained with a method based on the determination of the carbon isotope ratio of the urinary steroids. This paper aims to give an overview of the use of anabolic-androgenic steroids in sport and methods used in anti-doping laboratories for their detection in urine, with special emphasis on doping with testosterone. METHODS: Review of the recent literature of anabolic steroid testing, athletic use, and adverse effects of anabolic-androgenic steroids. RESULTS: Procedures used for detection of doping with endogenous steroids are outlined. The World Anti-Doping Agency provided a guide in August 2004 to ensure that laboratories can report, in a uniform way, the presence of abnormal profiles of urinary steroids resulting from the administration of testosterone or its precursors, androstenediol, androstenedione, dehydroepiandrosterone or a testosterone metabolite, dihydrotestosterone, or a masking agent, epitestosterone. CONCLUSIONS: Technology developed for detection of testosterone in urine samples appears suitable when the substance has been administered intramuscularly. Oral administration leads to rapid pharmacokinetics, so urine samples need to be collected in the initial hours after intake. Thus there is a need to find specific biomarkers in urine or plasma to enable detection of long term oral administration of testosterone.

Assessing the Glaucoma Quality of Life-15 (GCL-15) Questionnaire, Goldmann Tonometry and Moorfields Motion Displacement Test in Glaucoma Case Finding

Purpose: To compare the performance Glaucoma Quality of Life-15 (GQL-15) Questionnaire, intraocular pressure measurement (IOP Goldmann tonometry) and a measure of visual field loss using Moorfields Motion Displacement Test (MDT) in detecting glaucomatous eyes from a self referred population. Methods: The GQL-15 has been suggested to correlate with visual disability and psychophysical measures of visual function in glaucoma patients. The Moorfields MDT is a multi location perimetry test with 32 white line stimuli presented on a grey background on a standard laptop computer. Each stimulus is displaced between computer frames to give the illusion of "apparent motion". Participants (N=312, 90% older than 45 years; 20.5% family history of glaucoma) self referred to an advertised World Glaucoma Day (March 2009) Jules Gonin Eye Hospital, Lausanne Switzerland. Participants underwent a clinical exam (IOP, slit lamp, angle and disc examination by a general ophthalmologist), 90% completed a GQL-15 questionnaire and over 50% completed a MDT test in both eyes. Those who were classified as abnormal on one or more of the following (IOP >21 mmHg/ GQL-15 score >20/ MDT score >2/ clinical exam) underwent a follow up clinical examination by a glaucoma specialist including imaging and threshold perimetry. After the second examination subjects were classified as "healthy"(H), "glaucoma suspect" (GS) (ocular hypertension and/or suspicious disc, angle closure with SD) or "glaucomatous" (G). Results: One hundred and ten subjects completed all 4 initial examinations; of these 69 were referred to complete the 2nd examination and were classified as; 8 G, 24 GS, and 37 H. MDT detected 7/8 G, and 7/24 GS, with false referral rate of 3.8%. IOP detected 2/8 G and 8/24 GS, with false referral rate of 8.9%. GQL-15 detected 4/8 G, 16/24 GS with a false referral rate of 42%. Conclusions: In this sample of participants attending a self referral glaucoma detection event, the MDT performed significantly better than the GQL-15 and IOP in discriminating glaucomatous patients from healthy subjects. Further studies are required to assess the potential of the MDT as a glaucoma screening tool.

Does this child have a foreign body aspiration?

Context: Foreign body aspiration (FbA) is a serious problem in children. Accurate clinical and radiographic diagnosis is important because missed or delayed diagnosis can result in respiratory difficulties ranging from life-treatening airway obstruction to chronic wheezing or recurrent pneumonia. Bronchoscopy also has risks and accurate clinical and radiographc diagnosis can support the decision of bronchoscopy. Objective: To rewiev the diagnostic accuracy of clinical presentation (CP) and pulmonary radiograph (PR) for the diagnosis of FbA. There is no previous rewievMethods: A search of Medline is conducted for articles containing data regarding CP and PR signes of FbA. Calculation of likelihood ratios (LR) and pre and post test probability using Bayes theorem were performed for all signs of CP and PR. Inclusion criteria: Articles containing prospective data regarding CP and PR of FbA. Exclusion criteria: Retrospectives studies. Articles containing incomplete data for calculation of LR. Results: Five prospectives studies are included with a total of 585 patients. Prevalence of FbA is 63% in children suspected of FbA. If CP is normal, probability of FbA is 25% and if PR is normal, probability is 14%. If CP is pathologic, probability of FbA is 69-76% with presence of cough (LR = 1.32) or dyspnea (LR = 1.84) or localized crackles (LR = 1.5). Probability is 81-88% if cyanosis (LR = 4.8) or decreased breaths sounds (LR = 4.3) or asymetric auscultation (LR = 2.9) or localized wheezing (LR = 2.5) are present. When CP is anormal and PR show mediatinal shift (LR = 100), pneumomediatin (LR = 100), radio opaque foreign body (LR = 100), lobar distention (LR = 4), atelectasis (LR = 2.5), inspiratory/expiratory abnormal (LR = 7), the probability of FbA is 96-100%. If CP is normal and PR is abnormal the probability is 40-100%. If CP is abnormal and PR is normal the probability is 55-75%. Conclusions: This rewiev of prospective studies demonstrates the importance of CP and PR and an algorithm can be proposed. When CP is abnormal with or without PR pathologic, the probability of FbA is high and bronchoscopy is indicated. When CP and PR are normal the probability of FbA is low and bronchoscopy is not necessary immediatly, observation should be proposed. This approach should be validated with prospective study.

Loss of serum response factor in keratinocytes results in hyperproliferative skin disease in mice.

The transcription factor serum response factor (SRF) plays a crucial role in the development of several organs. However, its role in the skin has not been explored. Here, we show that keratinocytes in normal human and mouse skin expressed high levels of SRF but that SRF expression was strongly downregulated in the hyperproliferative epidermis of wounded and psoriatic skin. Keratinocyte-specific deletion within the mouse SRF locus during embryonic development caused edema and skin blistering, and all animals died in utero. Postnatal loss of mouse SRF in keratinocytes resulted in the development of psoriasis-like skin lesions. These lesions were characterized by inflammation, hyperproliferation, and abnormal differentiation of keratinocytes as well as by disruption of the actin cytoskeleton. Ultrastructural analysis revealed markedly reduced cell-cell and cell-matrix contacts and loss of cell compaction in all epidermal layers. siRNA-mediated knockdown of SRF in primary human keratinocytes revealed that the cytoskeletal abnormalities and adhesion defects were a direct consequence of the loss of SRF. In contrast, the hyperproliferation observed in vivo was an indirect effect that was most likely a consequence of the inflammation. These results reveal that loss of SRF disrupts epidermal homeostasis and strongly suggest its involvement in the pathogenesis of hyperproliferative skin diseases, including psoriasis.

Rapid cohort generation and analysis of disease spectrum of large animal model of cone dystrophy.

Large animal models are an important resource for the understanding of human disease and for evaluating the applicability of new therapies to human patients. For many diseases, such as cone dystrophy, research effort is hampered by the lack of such models. Lentiviral transgenesis is a methodology broadly applicable to animals from many different species. When conjugated to the expression of a dominant mutant protein, this technology offers an attractive approach to generate new large animal models in a heterogeneous background. We adopted this strategy to mimic the phenotype diversity encounter in humans and generate a cohort of pigs for cone dystrophy by expressing a dominant mutant allele of the guanylate cyclase 2D (GUCY2D) gene. Sixty percent of the piglets were transgenic, with mutant GUCY2D mRNA detected in the retina of all animals tested. Functional impairment of vision was observed among the transgenic pigs at 3 months of age, with a follow-up at 1 year indicating a subsequent slower progression of phenotype. Abnormal retina morphology, notably among the cone photoreceptor cell population, was observed exclusively amongst the transgenic animals. Of particular note, these transgenic animals were characterized by a range in the severity of the phenotype, reflecting the human clinical situation. We demonstrate that a transgenic approach using lentiviral vectors offers a powerful tool for large animal model development. Not only is the efficiency of transgenesis higher than conventional transgenic methodology but this technique also produces a heterogeneous cohort of transgenic animals that mimics the genetic variation encountered in human patients.

Altered brain mechanisms of emotion processing in pre-manifest Huntington's disease.

Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntington's disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntington's disease may precede the development of overt clinical symptoms and detectable cerebral atrophy.

Feasibility Study of Strengthening Existing Single Span Steel Beam Concrete Deck Bridges, June 1961

Iowa has the same problem that confronts most states in the United States: many bridges constructed more than 20 years ago either have deteriorated to the point that they are inadequate for original design loads or have been rendered inadequate by changes in design/maintenance standards or design loads. Inadequate bridges require either strengthening or posting for reduced loads. A sizeable number of single span, composite concrete deck - steel I beam bridges in Iowa currently cannot be rated to carry today's design loads. Various methods for strengthening the unsafe bridges have been proposed and some methods have been tried. No method appears to be as economical and promising as strengthening by post-tensioning of the steel beams. At the time this research study was begun, the feasibility of posttensioning existing composite bridges was unknown. As one would expect, the design of a bridge-strengthening scheme utilizing post-tensioning is quite complex. The design involves composite construction stressed in an abnormal manner (possible tension in the deck slab), consideration of different sizes of exterior and interior beams, cover-plated beams already designed for maximum moment at midspan and at plate cut-off points, complex live load distribution, and distribution of post-tensioningforces and moments among the bridge beams. Although information is available on many of these topics, there is miminal information on several of them and no information available on the total design problem. This study, therefore, is an effort to gather some of the missing information, primarily through testing a half-size bridge model and thus determining the feasibility of strengthening composite bridges by post-tensioning. Based on the results of this study, the authors anticipate that a second phase of the study will be undertaken and directed toward strengthening of one or more prototype bridges in Iowa.