Anterior chamber characteristics assessed by rotating Scheimpflug imaging in patients with retinitis pigmentosa.
The aim of this study was to evaluate anterior segment parameters and corneal aberrations in patients with retinitis pigmentosa using Scheimpflug imaging and to compare the findings with those for healthy controls. This single-center, case-control study included patients diagnosed with retinitis pigmentosa who were followed up at the Department of Ophthalmology of Kayseri Training and Research Hospital between February and June 2018. Age- and sex-matched healthy individuals with no known ophthalmologic disease formed the control group. Both patients with retinitis pigmentosa and controls underwent comprehensive ophthalmic assessments, including the measurement of the best-corrected visual acuity calculation of the spherical equivalent, slit-lamp examination, stereoscopic fundus examination, computerized visual field test, and electroretinography. Topographic and aberrometric values were measured using Scheimpflug-based tomography. This study was performed on 52 eyes of 26 patients with retinitis pigmentosa (14 men) and 52 eyes of 26 healthy controls (11 men). The average keratometry (K avg) values for the patient and control groups were similar (43.87 ± 2.23 versus 43.61 ± 1.68; p=0.546), but the maximum keratometry (K max) value was significantly higher in the patient group (45.85 ± 2.35 and 44.69 ± 1.86; p=0.015). Patients with retinitis pigmentosa had a significantly lower central corneal thickness (518.5 ± 42.3 versus 534.1 ± 24.5, respectively; p=0.042) and maximal corneal thickness (509.1 ± 50.5 versus 530.5 ± 24.1, respectively; p=0.015). Additionally, the iridocorneal angle for the patients was significantly lower (31.6 ± 9.2 versus 35.9 ± 7.7, p=0.025). The aberrometric findings indicated that patients with retinitis pigmentosa had significantly more higher-order aberrations than those in the healthy controls (0.794 ± 51 and 0.398 ± 08, respectively; p<0.001). The results of the present study demonstrated that patients with retinitis pigmentosa have different anterior segment parameters and corneal aberrations compared to healthy controls. These results should be supported by further studies.


Array-based resequencing for mutations causing familial hypercholesterolemia.
Familial hypercholesterolemia (FH) is a heterogeneous autosomal dominant disease with a prevalence of 1 in 500. To date, over 1200 unique pathogenic mutations have been identified in at least 3 genes. The large allelic and genetic heterogeneity of FH requires high-throughput, rapid, and affordable mutation detection technology to efficiently integrate molecular screening into clinical practice. We developed an array-based resequencing assay to facilitate genetic testing in FH patients. We designed a custom DNA resequencing array to detect mutations on all 3 FH-causing genes - LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 gene (PCSK9) - and 290 known insertion/deletion mutations on LDLR. We verified FH array performance by analyzing 35 previously sequenced subjects (21 with point mutations, 2 insertions, 7 deletions, and 5 healthy controls) and blindly screening 125 FH patients. The average microarray call rate was 98.45% and the agreement between microarray and capillary sequencing was 99.99%. The FH array detected mutations by using automated software analysis, followed by manual review in 28 of the 30 subjects (pickup rate, 93.3%). In the blinded study, the FH array detected at least 1 mutation in 77.5% of patients clinically diagnosed with definite FH according to Simon Broome FH criteria and in 52.9% with probable FH diagnosis. The high-throughput FH resequencing array detects LDLR, APOB, and PCSK9 with high efficiency and accuracy and identifies disease-causing mutations. Thus, it facilitates large-scale screening of the heterogeneous FH populations.


Heart failure in single right ventricle congenital heart disease: physiological and molecular considerations.
Because of remarkable surgical and medical advances over the past several decades, there are growing numbers of infants and children living with single ventricle congenital heart disease (SV), where there is only one functional cardiac pumping chamber. Nevertheless, cardiac dysfunction (and ultimately heart failure) is a common complication in the SV population, and pharmacological heart failure therapies have largely been ineffective in mitigating the need for heart transplantation. Given that there are several inherent risk factors for ventricular dysfunction in the setting of SV in addition to probable differences in molecular adaptations to heart failure between children and adults, it is perhaps not surprising that extrapolated adult heart failure medications have had limited benefit in children with SV heart failure. Further investigations into the molecular mechanisms involved in pediatric SV heart failure may assist with risk stratification as well as development of targeted, efficacious therapies specific to this patient population. In this review, we present a brief overview of SV anatomy and physiology, with a focus on patients with a single morphological right ventricle requiring staged surgical palliation. Additionally, we discuss outcomes in the current era, risk factors associated with the progression to heart failure, present state of knowledge regarding molecular alterations in end-stage SV heart failure, and current therapeutic interventions. Potential avenues for improving SV outcomes, including identification of biomarkers of heart failure progression, implications of personalized medicine and stem cell-derived therapies, and applications of novel models of SV disease, are proposed as future directions.


Trends in cardiac care: contractions, concentration, collaboration.
Cardiovascular services is entering an age of contraction and concentration. The number of programs and the growth in inpatient procedures have topped out and the presence of significant excess capacity has become apparent. During the next five years, there will be heightened pressures to simultaneously decrease the overall number of cardiac procedures performed and, on the part of individual providers, increase procedure volume in order to achieve economies of scale and high levels of quality. It is likely that the number of health care organizations with OHS programs and PTCA may be cut to 500 by the year 2000, significantly influencing the redistribution of cardiac services along regional lines. The public, government, and private payers have embarked on a quest for value; and in the future they will only purchase services from providers demonstrating high-quality outcomes and average, or below average, charges. HCFA's Cooperative Cardiovascular Project is typical of the direct continuous quality improvement and management initiatives that will be implemented to monitor appropriateness, outcome quality, and resource utilization through the application of clinical practice guidelines (CPGs) and data on the treatment of AMI, PTCA, and CABG surgery. A more indirect, managed care approach by purchasers to obtaining higher value can be seen in the Medicare Participating Heart Bypass Center Demonstration project, the federal government's first big step into selective specialty care contracting for clinical service on a package price basis. Several different types of private initiatives have been used to achieve wider distribution of service while maintaining high program volumes and high-quality care through collaboration and the formation of interhospital linkages. Although some of these have included collaborative programs to encourage voluntary community-based planning and discourage the duplication of services, the payers demand for value (cost/quality) and the organizational leverage of the regional health alliances will accelerate the process and spur the formation of a smaller number of high-volume invasive programs. Large invasive programs will continue to formalize interhospital linkages to provide an integrated set of services in a layered system of cardiac care.(ABSTRACT TRUNCATED AT 400 WORDS)


G-Quadruplexes and Their Ligands: Biophysical Methods to Unravel G-Quadruplex/Ligand Interactions.
Progress in the design of G-quadruplex (G4) binding ligands relies on the availability of approaches that assess the binding mode and nature of the interactions between G4 forming sequences and their putative ligands. The experimental approaches used to characterize G4/ligand interactions can be categorized into structure-based methods (circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography), affinity and apparent affinity-based methods (surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) and mass spectrometry (MS)), and high-throughput methods (fluorescence resonance energy transfer (FRET)-melting, G4-fluorescent intercalator displacement assay (G4-FID), affinity chromatography and microarrays. Each method has unique advantages and drawbacks, which makes it essential to select the ideal strategies for the biological question being addressed. The structural- and affinity and apparent affinity-based methods are in several cases complex and/or time-consuming and can be combined with fast and cheap high-throughput approaches to improve the design and development of new potential G4 ligands. In recent years, the joint use of these techniques permitted the discovery of a huge number of G4 ligands investigated for diagnostic and therapeutic purposes. Overall, this review article highlights in detail the most commonly used approaches to characterize the G4/ligand interactions, as well as the applications and types of information that can be obtained from the use of each technique.


Comparison of different adjuvant therapies for 9 resectable cancer types.
The objective of this study was to compare the clinical benefit across adjuvant therapies for cancer treatment, including adjuvant imatinib, and to quantify the results using the number-needed-to-treat (NNT) approach. We reviewed studies meeting the following criteria: 1) US and European randomized clinical trial populations consisting of patients with cancer who underwent surgical resection of the primary tumor and were considered cancer free; 2) comparators were either placebo or no treatment; and 3) recurrence-free survival (RFS) and overall survival (OS) rates were reported and showed benefit with the experimental treatment. The NNT was calculated as the inverse of the difference in event rate between the study groups in each trial. We identified 26 adjuvant treatment trials in 9 cancer types. With longer follow-up (3 years vs 1 year), 62.5% of treatments compared with placebo showed a decreased RFS NNT, including imatinib (7 vs 4). The largest relative decrease in RFS NNT over time was 91% (with trastuzumab or cyclophosphamide therapy). Approximately 25% of the treatments resulted in an increase in RFS NNT over time. The RFS NNT for imatinib was lower than that for all other treatments at 3 years of follow-up and lower than that for all but 2 treatments at 1 year. At both year 1 and year 3, the NNT for OS ranged from 6 to 100. Imatinib had an OS NNT of 31 at 3 years. With longer follow-up duration, most adjuvant cancer treatments showed a decreased NNT. Imatinib had one of the lowest NNTs among the adjuvant treatments at 1 and 3 years of follow-up using the RFS data.


Insulin suppression is associated with hypersomatostatinemia and hyperglucagonemia in glucose-injected rainbow trout.
Rainbow trout, Oncorhynchus mykiss, were used to evaluate the effects of carbohydrate loading on plasma levels of pancreatic hormones and associated changes in metabolic indexes in a carnivorous fish. Glucose (3,000 mg/dl, 10 microliters/g body wt) was injected intraperitoneally into fish (mean wt 54 +/- 5 g) that were killed 0.5-24 h after administration. Glucose injection resulted in hyperglycemia with maximum glucose levels of 306 +/- 13 mg/dl observed 60 min after injection. Glucose administration also resulted in hyperlipidemia. Plasma fatty acids increased twofold in glucose-injected animals. Alterations in plasma metabolites reflected changes in energy stores. Although total lipid concentration was unaffected by glucose injection, lipolytic enzyme activity in the liver was enhanced. Biosynthetic capacity, as indicated by NADPH production from glucose-6-phosphate dehydrogenase, was decreased by glucose injection. Liver glycogen content was reduced in glucose-injected animals 1 h after injection. Glucose injection was attended by increases in the plasma levels of gene II somatostatin-25 (predominant form of pancreatic somatostatin in salmonids) and of glucagon. Insulin levels were initially suppressed after glucose injection. These results indicate that metabolic adjustments caused by glucose administration can be related to the regulatory action of pancreatic hormones. Furthermore, these results suggest that the somatostatin-secreting cells of the trout are sensitive to glucose and that somatostatin-suppressed insulin secretion contributes to the glucose intolerance of trout.


Hepatic haemangiomata: diagnosis and management.
Five cases of hepatic haemangioma are described, and a sixth (previously reported) is reviewed. Clinical features, investigation, and management are described to show the great variability of the complications and prognosis. Five children presented in the first 10 weeks of life with hepatomegaly; 4 developed congestive cardiac failure; 3 had cutaneous haemangiomata. One child presented at age 4 years with hepatomegaly and anaemia, and on investigation had features of chronic disseminated intravascular coagulation. Focal decrease or patchiness in hepatic uptake of technetium-99m colloid, and abnormal intrahepatic circulation was shown in all cases. In 3 children liver biopsy was performed to exclude malignant disease. In one patient there was spontaneous regression of the tumour by age 3 years. In 3 cases hepatic artery ligation was necessary to control congestive cardiac failure which had persisted despite treatment with digoxin, diuretics, and oral corticosteroids, a procedure which was without complications after up to 8 years. One infant with intractable portal hypertension, hepatic vein obstruction, and severe cholestasis died with persisting alimentary haemorrhage and intra-abdominal sepsis. One child aged 4 years showed no immediate response to hepatic artery ligation but the size of her tumour got smaller and the clinical features diminished after irradiation. These tumours cause considerable morbidity and have a high reported mortality. If congestive cardiac failure is not rapidly controlled, hepatic artery ligation should be performed.


The alpha and eta isoforms of protein kinase C stimulate transcription of human involucrin gene.
Involucrin is one of the precursor proteins of the cornified cell envelope that is formed beneath the cell membrane during terminal differentiation of keratinocytes. 12-O-tetradecanoylphorbol-13-acetate (TPA), which is a potent protein kinase C (PKC) activator, induces terminal differentiation of keratinocytes. We previously demonstrated that involucrin promoter activity is stimulated by TPA in cultured fetal rat skin keratinocytes. PKC is a large family of proteins and keratinocytes containing five PKC isozymes: alpha, delta, epsilon, eta, and zeta. In order to determine the role of the PKC isozyme(s) on involucrin gene expression, we constructed the chloramphenicol acetyl transferase (CAT)-involucrin promoter expression vector by connecting the 5'-upstream region of the human involucrin gene containing the untranslated first exon to the CAT reporter gene. The CAT-involucrin promoter expression vector was transfected with various PKC isozyme expression vectors into SV40-transformed human keratinocytes (SVHK cells). Transfection of the CAT-involucrin promoter expression vector with PKC-alpha or PKC-eta expression vectors resulted in a significant increase in the TPA-dependent involucrin promoter activity. The PKC inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine dihydrochloride, inhibited the promoter activity stimulated by TPA. Transfection of PKC-delta, -epsilon, and -zeta had no effect on the involucrin-promoter activity. Although the promoter activity was stimulated by transfection of PKC-gamma, TPA did not enhance the promoter activity in the PKC-gamma-transfected SVHK cells. Previously we showed three AP-1 binding sites (AP1-1, -2, and -3) on the involucrin promoter region. Both the basal and the TPA-stimulated involucrin promoter activities were suppressed by deleting the AP1-1 site (-119 to -113) that is the most proximal to the transcription start site. The deletion of AP1-2 (-297 to -303) or AP1-3 (-447 to -453) did not affect the involucrin promoter activity. Gel retardation analyses disclosed that TPA stimulated the specific DNA binding of the nuclear protein(s) of control, PKC-alpha, or PKC-eta-transfected SVHK cells, but not of PKC-gamma-transfected cells. Addition of anti-c-Jun and anti-c-Fos antibodies decreased the specific protein-DNA complex band with a concomitant appearance of supershifted bands. These results indicate that PKC, specifically PKC-alpha and PKC-eta, mediates the TPA-dependent activation of involucrin gene expression of SVHK cells. PKC-gamma, which is not present in keratinocytes, also induces involucrin gene expression in a TPA-independent manner, when introduced into SVHK cells.


Synaptic excitation may activate a calcium-dependent potassium conductance in hippocampal pyramidal cells.
In hippocampal CAl pyramidal cells, orthodromic synaptic excitation is followed by an early hyperpolarization mediated by gamma-aminobutyric acid (GABA) and a late non-GABA-mediated hyperpolarization that has properties consistent with an increase in potassium conductance. Depolarizations produced by iontophoretically applied glutamate are followed by hyperpolarizations that have features in accordance with an increase in potassium conductance. The hyperpolarizations are independent of chloride and resistant to tetradotoxin but are blocked by a low-calcium, high-cobalt medium. Voltage clamping the glutamate depolarization does not reduce the subsequent hyperpolarization, indicating that the hyperpolarization results from a direct increase in calcium conductance produced by glutamate, rather than from activation of voltage-sensitive calcium channels. A single transmitter, possibly acting on one type of receptor and channel, may initiate both excitation and inhibition in the same postsynaptic cell.


Ca(V)1.2 channel N-terminal splice variants modulate functional surface expression in resistance size artery smooth muscle cells.
Voltage-dependent Ca(2+) (Ca(V)1.2) channels are the primary Ca(2+) influx pathway in arterial smooth muscle cells and are essential for contractility regulation by a variety of stimuli, including intravascular pressure. Arterial smooth muscle cell Ca(V)1.2 mRNA is alternatively spliced at exon 1 (e1), generating e1b or e1c variants, with e1c exhibiting relatively smooth muscle-specific expression in the cardiovascular system. Here, we examined physiological functions of Ca(V)1.2e1 variants and tested the hypothesis that targeting Ca(V)1.2e1 modulates resistance size cerebral artery contractility. Custom antibodies that selectively recognize Ca(V)1.2 channel proteins containing sequences encoded by either e1b (Ca(V)1.2e1b) or e1c (Ca(V)1.2e1c) both detected Ca(V)1.2 in rat and human cerebral arteries. shRNA targeting e1b or e1c reduced expression of that Ca(V)1.2 variant, induced compensatory up-regulation of the other variant, decreased total Ca(V)1.2, and reduced intravascular pressure- and depolarization-induced vasoconstriction. Ca(V)1.2e1b and Ca(V)1.2e1c knockdown reduced whole cell Ca(V)1.2 currents, with Ca(V)1.2e1c knockdown most effectively reducing total Ca(V)1.2 and inducing the largest vasodilation. Knockdown of α(2)δ-1, a Ca(V)1.2 auxiliary subunit, reduced surface expression of both Ca(V)1.2e1 variants, inhibiting Ca(V)1.2e1c more than Ca(V)1.2e1b. e1b or e1c overexpression reduced Ca(V)1.2 surface expression and whole cell currents, leading to vasodilation, with e1c overexpression inducing the largest effect. In summary, data indicate that arterial smooth muscle cells express Ca(V)1.2 channels containing e1b or e1c-encoded N termini that contribute to Ca(V)1.2 surface expression, α(2)δ-1 preferentially traffics the Ca(V)1.2e1c variant to the plasma membrane, and targeting of Ca(V)1.2e1 message or the Ca(V)1.2 channel proximal N terminus induces vasodilation.


How Much Attention Do We Pay to Attention Deficits in Poststroke Aphasia?
Although language deficits are the primary area of weakness, people with poststroke aphasia often experience challenges with nonlinguistic cognitive skills, including attention processing. The purpose of this review is to synthesize the evidence for the relationship between attention deficits and language deficits in people with poststroke aphasia. Three different types of studies are reviewed: (1) studies exploring whether people with poststroke aphasia exhibit concomitant attention and language deficits, (2) studies explicitly exploring the relationship between attention and language deficits in people with poststroke aphasia, and (3) either language or attention (or both) treatment studies exploring whether treatment gains in one domain generalize to the other. In the last section, we briefly review research evidence for the neural basis of the attention-language relationship in aphasia.


Retinal Manifestations in High Altitude.
Dangi, Meenu, Arnab Sadhukhan, Poninder Kumar, S. Bandopadhayay, Vijay K. Sharma, V.K. Patra, Manu Chaudhary, and Vipin Rana. Retinal manifestations in high altitude. High Alt Med Biol. 00:000-000, 2023. Aim: To study the high altitude (HA)-related retinal manifestations among security personnel and thus to provide new insights into the characteristics and mechanisms of retinopathy. Materials and Methods: This was a multicentric, nonrandomized prospective observational and descriptive study. We studied 54 security personnel over 1 year, who were referred from HA areas of northern India and north-eastern India for ocular problems. Complete coagulation profile was performed among patients with vascular occlusion. Results: There were total of 54 patients with ages ranging from 22 to 55 years. HA retinopathy was noticed in 28 patients: central retinal vein occlusion (6 patients), branch retinal vein occlusion (4 patients), branch retinal artery occlusion (1 patient), central retinal artery occlusion (4 patients), ocular ischemic syndrome (1 patient), central serous chorioretinopathy (7 patients), acetazolamide-induced maculopathy (1 patient), and solar retinopathy (2 patients). Along with an increased hematocrit, serum homocysteine was raised in the majority of vascular occlusions. The mean age was 38.16 years, the mean altitude was 14,716 ft, and the mean duration of stay was 11.2 weeks. Conclusion: Hypobaric hypoxia due to HA is a potential risk for HA retinopathy and associated vascular occlusions. Aside from increased hematocrit, hyperhomocysteinemia is a potential cause of vascular occlusions.


Washington State's Lystedt law in concussion documentation in Seattle public high schools.
The Lystedt law requires high school athletes who have sustained a concussion to be removed from practice and play and not to be allowed to return until cleared by a medical professional. To determine the effect of the Lystedt law on injury and concussion documentation in the Seattle public high schools. Cross-sectional study. Seattle public high schools. The numbers of students, aged 13 to 19 years in the 2008-2009, 2009-2010, and 2010-2011 school years, were 4348, 4925, and 4806, respectively. All injuries documented in SportsWare by athletic trainers in Seattle public high schools. We evaluated all injuries, including concussions recorded during the 2008-2009 school year, before the Lystedt law, and during the 2 school years after the law took effect (2009-2010 and 2010-2011). Incidence rates before and after the law were estimated and compared. The concussion rate was -1.09% in 2008-2009, 2.26% in 2009-2010, and 2.26% in 2010-2011. A comparison of relative risks showed that the incidence rates of concussions were different before and 1 year after the Lystedt law (relative risk = 2.10; 95% confidence interval [CI] = 1.50, 2.93) and 2 years after the law (relative risk = 2.10; 95% CI = 1.49, 2.93). Overall, the mean number of days out of play after 2008-2009 was almost 7 days greater after the law took effect (difference = 6.9 days; 95% CI = 0.70, 13.1). For females, the mean number of days out of play after 2008-2009 was more than 17 days in 2009-2010 (difference = 17.2 days; 95% CI = 4.81, 29.5) and was more than 6 days in 2010-2011 (difference = 6.3 days; 95% CI = 1.62, 11.0). The number of documented concussions more than doubled after the institution of the Lystedt law, which may be attributed to heightened awareness and closer monitoring.


Atlas-based segmentation of developing tissues in the human brain with quantitative validation in young fetuses.
Imaging of the human fetus using magnetic resonance (MR) is an essential tool for quantitative studies of normal as well as abnormal brain development in utero. However, because of fundamental differences in tissue types, tissue properties and tissue distribution between the fetal and adult brain, automated tissue segmentation techniques developed for adult brain anatomy are unsuitable for this data. In this paper, we describe methodology for automatic atlas-based segmentation of individual tissue types in motion-corrected 3D volumes reconstructed from clinical MR scans of the fetal brain. To generate anatomically correct automatic segmentations, we create a set of accurate manual delineations and build an in utero 3D statistical atlas of tissue distribution incorporating developing gray and white matter as well as transient tissue types such as the germinal matrix. The probabilistic atlas is associated with an unbiased average shape and intensity template for registration of new subject images to the space of the atlas. Quantitative whole brain 3D validation of tissue labeling performed on a set of 14 fetal MR scans (20.57-22.86 weeks gestational age) demonstrates that this atlas-based EM segmentation approach achieves consistently high DSC performance for the main tissue types in the fetal brain. This work indicates that reliable measures of brain development can be automatically derived from clinical MR imaging and opens up possibility of further 3D volumetric and morphometric studies with multiple fetal subjects.


G-actin regulates rapid induction of actin nucleation by mDia1 to restore cellular actin polymers.
mDia1 belongs to the formin family of proteins that share FH1 and FH2 domains. Although formins play a critical role in the formation of many actin-based cellular structures, the physiological regulation of formin-mediated actin assembly within the cell is still unknown. Here we show that cells possess an acute actin polymer restoration mechanism involving mDia1. By using single-molecule live-cell imaging, we found that several treatments including low-dose G-actin-sequestering drugs and unpolymerizable actin mutants activate mDia1 to initiate fast directional movement. The FH2 region, the core domain for actin nucleation, is sufficient to respond to latrunculin B (LatB) to increase its actin nucleation frequency. Simulation analysis revealed an unexpected paradoxical effect of LatB that leads to a several fold increase in free G-actin along with an increase in total G-actin. These results indicate that in cells, the actin nucleation frequency of mDia1 is enhanced not only by Rho, but also strongly through increased catalytic efficiency of the FH2 domain. Consistently, frequent actin nucleation by mDia1 was found around sites of vigorous actin disassembly. Another major actin nucleator, the Arp2/3 complex, was not affected by the G-actin increase induced by LatB. Taken together, we propose that transient accumulation of G-actin works as a cue to promote mDia1-catalyzed actin nucleation to execute rapid reassembly of actin filaments.


[Age and sex features of antioxidation protection and free-radical processes in white rats brain].
With the years, the activity of antioxidation enzymes and speeds of its free-radical oxidation in different molecules changes. These changes depend also on an animal sex. The brain tissue is especially subjects to oxidising destruction and has the features of antioxidation protection. Level of free-radical processes and activity of basic components of antioxidation link in the different parts of the central nervous system has been investigated. The young animals demonstrated most sex differences in big hemispheres and in intermediate brain, and in a less degree in the middle brain, cerebellum and oblong brain. Sex differences in spinal cord of young animals were not revealed. In aging of animals of different sex, the level of free-radical processes and activity of enzymatic antioxidants changes with unequal speed, and these changes often have an opposite orientation.


Fetal hemoglobin levels and beta (s) globin haplotypes in an Indian populations with sickle cell disease.
To further explore the cause for variation in hemoglobin F (Hb F) levels in sickle cell disease, the beta globin restriction-fragment length polymorphism haplotypes were determined in a total of 303 (126 SS, 141 AS, 17 S beta(0), 7 A beta, (0) and 12 AA) Indians from the state of Orissa. The beta(s) globin gene was found to be linked almost exclusively to a beta(S) haplotype ( -++-), which is also common in Saudi Arabian patients from the Eastern Province (referred to as the Asian beta(s) haplotype). By contrast, the majority of beta A and beta(0) thalassemia globin genes are linked to haplotypes common in all European and Asian populations (+-----[+/-]; --++-++). Family studies showed that there is a genetic factor elevating Hb F levels dominantly in homozygotes (SS). This factor appears to be related to the Asian beta(s) globin haplotype, and a mechanism for its action is discussed. There is also a high prevalence of an independent Swiss type hereditary persistence of fetal hemoglobin (HPFH) determinant active in both the sickle cell trait and in sickle cell disease.


Predicting course of illness in patients with severe obsessive-compulsive disorder.
Few data are available to inform clinical expectations about course and prognosis of severe obsessive-compulsive disorder (OCD). Such information is necessary to guide clinicians and to inform criteria for invasive interventions for severe and intractable OCD. This study sought to examine course and prospective predictors of a chronic course in patients with severe OCD over 5 years. A selected subset of adults in the Brown Longitudinal Obsessive-Compulsive Study (BLOCS) was included. Adult BLOCS participants were enrolled between 2001 and 2006. All participants in the current study (N = 113) had DSM-IV OCD diagnosis, severe OCD symptoms at baseline, and at least 1 year of follow-up data. Cox proportional hazard models were used to examine the general pattern of course in the severe OCD sample based on Longitudinal Interval Follow-Up Evaluation (LIFE) psychiatric status ratings, as well as test predictors of chronically severe course. Results indicated that approximately half of patients with severe OCD at baseline had illness drop to a moderate or lower range of severity during 5 years of follow-up (50.4%) and that marked improvement was rare after 3 years of severe illness. The only unique predictor of a more chronically severe course was patient report of ever having been housebound for a week or more due to OCD symptoms (P < .05). Findings of this study were 3-fold: (1) half of participants with severe OCD have symptom improvement over 5 years of follow-up, (2) the majority of participants that drop out of the severe range of symptom severity do so within the first 3 years of follow-up, and (3) patient-reported history of being housebound for 1 week or more due to OCD is a significant predictor of OCD's remaining severe over the 5-year follow-up.


Working memory costs of task switching.
Although many accounts of task switching emphasize the importance of working memory as a substantial source of the switch cost, there is a lack of evidence demonstrating that task switching actually places additional demands on working memory. The present study addressed this issue by implementing task switching in continuous complex span tasks with strictly controlled time parameters. A series of 4 experiments demonstrate that recall performance decreased as a function of the number of task switches and that the concurrent load of item maintenance had no influence on task switching. These results indicate that task switching induces a cost on working memory functioning. Implications for theories of task switching, working memory, and resource sharing are addressed.


Expression of antioxidant protective proteins in the rat retina during prenatal and postnatal development.
In retinopathy of prematurity, capillary growth in the retina is attenuated. Subsequent cyclic elevation of oxygen levels leads to renewed capillary growth that may eventually result in retinal detachment. It is hypothesized that the sensitivity of the premature retina to oxidative shock results from the absence of antioxidant protective proteins. The expression of heme oxygenase-1, metallothionein, superoxide dismutase, and catalase mRNAs was measured in retinas of rats from 6 days before birth to 4 days after birth using in situ hybridization and semiquantitative reverse transcription-polymerase chain reaction with Southern blot analysis. Superoxide dismutase mRNA was expressed to a similar extent at all time points. Metallothionein mRNA expression, which was high at embryonic days (E) 16 and 18, decreased to low levels by the time of birth and remained low at least until 4 days after birth. Catalase mRNA expression was low until birth and increased until at least postnatal day 4. Heme oxygenase-1 mRNA showed low expression at E16 and E18, increased before birth, and then diminished. Four antioxidant protein mRNAs showed very different patterns of expression in the rat retina. Two of these proteins, heme oxygenase-1 and catalase, were expressed at relatively low levels until approximately the time of birth. The former is important in protection against heme-mediated generation of reactive oxygen species, whereas the latter protects against hydrogen peroxide-generated damage. As a result of the low expression of these mRNAs, and presumably the proteins encoded by them, the premature rat (and probably the premature human) is likely to be born without a full complement of antioxidant defenses.


Cognitive Impairment and Delirium in Older Patients Undergoing Major Head and Neck Surgery.
The study objective was to measure the prevalence and predictors of cognitive impairment (CI) and delirium. Adults undergoing major head and neck cancer surgery completed the Clock Draw Test to screen for CI, defined as a score of 0 or 1. Postoperative delirium was recorded. Predictors of delirium and length of stay were assessed by univariate logistic regression and the latter with multivariate linear regression. Overall 274 patients were included, of which 47% had a Clock Draw Test score of 0 or 1. Post-operative delirium occurred in 17 (6%). CI was a predictor of postoperative delirium (odds ratio, 3.9; 95% CI, 1.2-12; P = .02). Postoperative delirium was a predictor of increased length of stay (adjusted odds ratio, 1.30; 95% CI, 1.07-1.57; P = .0073) on multivariate regression while baseline Clock Draw Test result was not a predictor on univariate regression (P = .98). Screening for CI can help predict delirium and facilitate targeted interventions in the postoperative period.


Data integration with high dimensionality.
We consider situations where the data consist of a number of responses for each individual, which may include a mix of discrete and continuous variables. The data also include a class of predictors, where the same predictor may have different physical measurements across different experiments depending on how the predictor is measured. The goal is to select which predictors affect any of the responses, where the number of such informative predictors tends to infinity as the sample size increases. There are marginal likelihoods for each experiment; we specify a pseudolikelihood combining the marginal likelihoods, and propose a pseudolikelihood information criterion. Under regularity conditions, we establish selection consistency for this criterion with unbounded true model size. The proposed method includes a Bayesian information criterion with appropriate penalty term as a special case. Simulations indicate that data integration can dramatically improve upon using only one data source.


The use of wavelet transforms in low-resolution phase extension.
A method to extend low-resolution phases has been developed using histogram matching not only of the electron density itself but also of histograms obtained from the different levels of detail provided by the wavelet transform of the electron density. It is shown that the method can extend phases from 10 A to around 6-7 A on a wide range of trial structures differing in size, space group and solvent content. This level of phase extension can improve the electron-density map from little more than a molecular envelope to one in which secondary structure can often be identified.


Vascular risk factors: a ticking time bomb to Alzheimer's disease.
Evidence is growing that vascular risk factors (VRFs) for Alzheimer's disease (AD) affect cerebral hemodynamics to launch a cascade of cellular and molecular changes that initiate cognitive deficits and eventual progression of AD. Neuroimaging studies have reported VRFs for AD to be accurate predictors of cognitive decline and dementia. In regions that participate in higher cognitive function, middle temporal, posterior cingulate, inferior parietal and precuneus regions, and neuroimaging studies indicate an association involving VRFs, cerebral hypoperfusion, and cognitive decline in elderly individuals who develop AD. The VRF can be present in cognitively intact individuals for decades before mild cognitive deficits or neuropathological signs are manifested. In that sense, they may be "ticking time bombs" before cognitive function is demolished. Preventive intervention of modifiable VRF may delay or block progression of AD. Intervention could target cerebral blood flow (CBF), since most VRFs act to lower CBF in aging individuals by promoting cerebrovascular dysfunction.


Transformation of sporozoites into early exoerythrocytic malaria parasites does not require host cells.
Malaria parasite species that infect mammals, including humans, must first take up residence in hepatic host cells as exoerythrocytic forms (EEF) before initiating infection of red blood cells that leads to malaria disease. Despite the importance of hepatic stages for immunity against malaria, little is known about their biology and antigenic composition. Here, we show that sporozoites, the parasites' transmission stage that resides in the mosquito vector salivary glands, can transform into early EEF without intracellular residence in host hepatocytes. The morphological sequence of transformation and the expression of proteins in the EEF appear indistinguishable from parasites that develop within host cells. Transformation depends on temperature elevation to 37 degrees C and serum. Our findings demonstrate that residence in a host hepatocyte or specific host cell-derived factors are not necessary to bring about the profound morphological and biochemical changes of the parasite that occur after its transmission from vector to mammalian host.


Automatic liver segmentation using a statistical shape model with optimal surface detection.
In this letter, we present an approach for automatic liver segmentation from computed tomography (CT) scans that is based on a statistical shape model (SSM) integrated with an optimal-surface-detection strategy. The proposed method is a hybrid method that combines three steps. First, we use localization of the average liver shape model in a test CT volume via 3-D generalized Hough transform. Second, we use subspace initialization of the SSM through intensity and gradient profile. Third, we deform the shape model to adapt to liver contour through an optimal-surface-detection approach based on graph theory. The proposed method is evaluated on MICCAI 2007 liver-segmentation challenge datasets. The experiment results demonstrate availability of the proposed method.


[Effect of ATP on the sensitivity of the from heart to adrenaline].
Adenosinthreephosphoric acid (ATP) in concentration 1-10(-6)--1-10(-5) g/ml decreases sensitivity of the frog heart muscle to adrenaline by half. It is suggested that ATP present in the specific granules of adrenals, c. n. s. and adrenergic axons together with catecholamines and excreted with the mediator during excitation of adrenergic nerve, alters the sensitivity of postsynaptic membrane to adrenaline.


The Effect of Comedication With a Conventional Synthetic Disease-Modifying Antirheumatic Drug on Drug Retention and Clinical Effectiveness of Anti-Tumor Necrosis Factor Therapy in Patients With Axial Spondyloarthritis.
To explore the effect of comedication with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) on drug retention and clinical effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (SpA). The study included all patients starting treatment with a TNFi in a large prospective cohort of axial SpA patients (Swiss Clinical Quality Management in axial SpA). Crude drug retention was analyzed using the Kaplan-Meier method, and in adjusted analyses, Cox proportional hazards regression was used to model TNFi discontinuation. We evaluated multiple disease activity measures and validated clinical response criteria over time. A total of 2,765 TNFi treatment courses were included from 1,914 patients with axial SpA, 20.4% in combination with a conventional synthetic DMARD. In unadjusted analyses, the monotherapy group had significantly shorter median TNFi retention time (32.7 months) compared to the cotherapy group (39.1 months) (P = 0.04). In multivariate adjusted analyses, the monotherapy group had significantly lower TNFi retention, with a hazard ratio (HR) of 1.17 (95% confidence interval [95% CI] 1.01-1.35). This effect was even larger when only infliximab-treated patients were considered, with an HR for monotherapy of 1.36 (95% CI 1.06-1.74). Clinical response rates were almost identical at 1 year, with a change in the Bath Ankylosing Spondylitis Disease Activity Index of -2.02 and -2.00 (P = 0.83) and a change in the Ankylosing Spondylitis Disease Activity Score using C-reactive protein of -1.14 and -1.12 (P = 0.45) in the monotherapy and cotherapy groups, respectively. We demonstrate an association between the combination of a TNFi with conventional synthetic DMARDs and improved drug retention in patients with axial SpA, particularly in the subgroup of patients with infliximab.


Putting poly (ADP-ribose) polymerase and other DNA repair inhibitors into clinical practice.
Poly (ADP-ribose) polymerase (PARP) and other DNA repair inhibitors are currently tested in numerous clinical trials, with variable success. Inhibitors are used in monotherapy, for example, PARP inhibitors in BRCA mutated cancers, or more widely in combination treatments. DNA repair inhibitors have, as chemotherapy, great potential for long-term disease control, or potentially even cures. However, the design of clinical trials using DNA repair inhibitors is intricate, as these inhibitors may also potentiate normal tissue toxicity without improving overall disease control. Recent findings of mechanism of action of PARP inhibitors and other DNA repair inhibitors are presented, and how the underlying genetic background and interplay between DNA repair pathways influence the choice of tumour location and combination strategies. The hallmark of individualized cancer therapy is to be able to genetically distinguish the responding subclass of cancer patients, and it is widely used when targeting oncogenes. The PARP inhibitors in BRCA mutated cancers also demonstrate that this approach is possible in a synthetic lethal context. There is strong proof-of-concept for DNA repair inhibitors being a useful anticancer strategy in well designed clinical trials.


Reproductive system, social organization, human disturbance and ecological dominance in native populations of the little fire ant, Wasmannia auropunctata.
The invasive ant species Wasmannia auropunctata displays both ecologically dominant and non-dominant populations within its native range. Three factors could theoretically explain the ecological dominance of some native populations of W. auropunctata: (i) its clonal reproductive system, through demographic and/or adaptive advantages; (ii) its unicolonial social organization, through lower intraspecific and efficient interspecific competition; (iii) the human disturbance of its native range, through the modification of biotic and abiotic environmental conditions. We used microsatellite markers and behavioural tests to uncover the reproductive modes and social organization of dominant and non-dominant native populations in natural and human-modified habitats. Microsatellite and mtDNA data indicated that dominant and non-dominant native populations (supercolonies as determined by aggression tests) of W. auropunctata did not belong to different evolutionary units. We found that the reproductive system and the social organization are neither necessary nor sufficient to explain W. auropunctata ecological dominance. Dominance rather seems to be set off by unknown ecological factors altered by human activities, as all dominant populations were recorded in human-modified habitats. The clonal reproductive system found in some populations of W. auropunctata may however indirectly contribute to its ecological dominance by allowing the species to expand its environmental niche, through the fixation over time of specific combinations of divergent male and female genotypes. Unicoloniality may rather promote the range expansion of already dominant populations than actually trigger ecological dominance. The W. auropunctata model illustrates the strong impact of human disturbance on species' ecological features and the adaptive potential of clonal reproductive systems.


Targeting PLD2 in adipocytes augments adaptive thermogenesis by improving mitochondrial quality and quantity in mice.
Phospholipase D (PLD)2 via its enzymatic activity regulates cell proliferation and migration and thus is implicated in cancer. However, the role of PLD2 in obesity and type 2 diabetes has not previously been investigated. Here, we show that during diet-induced thermogenesis and obesity, levels of PLD2 but not PLD1 in adipose tissue are inversely related with uncoupling protein 1, a key thermogenic protein. We demonstrate that the thermogenic program in adipose tissue is significantly augmented in mice with adipocyte-specific Pld2 deletion or treated with a PLD2-specific inhibitor and that these mice are resistant to high fat diet-induced obesity, glucose intolerance, and insulin resistance. Mechanistically, we show that Pld2 deletion in adipose tissue or PLD2 pharmacoinhibition acts via p62 to improve mitochondrial quality and quantity in adipocytes. Thus, PLD2 inhibition is an attractive therapeutic approach for obesity and type 2 diabetes by resolving defects in diet-induced thermogenesis.


Segmental arterial mediolysis in splanchnic arteries: an uncommon cause of abdominal pain.
Segmental arterial mediolysis is an uncommon arterial disease that primarily involves splanchnic arteries; abdominal pain is the most common clinical manifestation. We report the case of a 53-year-old male with postprandial diffuse abdominal pain of one month's standing. Physical examination was uneventful, and laboratory tests revealed no abnormal findings. Abdominopelvic CT/Angio-CT showed an increased caliber of the superior mesenteric artery resulting from eccentric circumferential wall thickening. The patent lumen had a segment with fusiform aneurysmal dilatation, 7 x 26 mm long. These vascular changes extended along a number of distal jejunal branches, which also presented complete lumen obliteration. Abdominal arteries were free from signs of arteriosclerotic disease. Findings were consistent with segmental arterial mediolysis.


Porous bioprinted constructs in BMP-2 non-viral gene therapy for bone tissue engineering.
A well-known osteogenic agent in the field of regenerative medicine is bone morphogenetic protein-2 (BMP-2). Non-viral delivery of a plasmid containing the gene encoding BMP-2 has shown to induce bone formation in vivo. In order to develop gene activated matrices into larger constructs, we created porosity in a hydrogel using bioprinting technology, thereby allowing better diffusion and blood vessel ingrowth. We were able to produce 3D constructs that were accurate and reproducible in size, shape and pore geometry. Constructs consisting of alginate supplemented with multipotent stromal cells (MSCs) and calcium phosphate particles were printed either in a porous or a non-porous/solid fashion. The plasmid DNA encoding BMP-2 was included in the constructs. Porous constructs were reproducibly bioprinted and remained intact for at least 14 days in culture. Cells were efficiently transfected by the plasmid DNA, and differentiated towards the osteogenic lineage as shown by elevated BMP-2 and ALP production. Porous constructs performed in the first week were better in producing BMP-2 than solid constructs. However, after implantation for six weeks subcutaneously in nude mice, no bone formation was seen, which calls for optimization of the biomaterials used. In conclusion, we show for the first time a model in which 3D printing and non-viral gene therapy can be combined.


Lichen myxoedematosus associated with human immunodeficiency virus infection--report of two cases and review of the literature.
Lichen myxoedematosus (LM), or papular mucinosis, is an uncommon papular eruption caused by the dermal deposition of mucin. Three clinical forms can be distinguished, namely localised, disseminated (involving more than one site), and generalised LM, the last is called scleromyxoedema, and demonstrates erythema and skin sclerosis. Paraproteinaemia, often consisting of an abnormal IgG with lambda light chains, is usually present in patients with LM. Visceral involvement has also been documented. An association between LM and human immunodeficiency virus (HIV) infection has been reported recently. We now describe two further HIV-positive patients with LM and present a review of the literature regarding this association.


Application of the resource-based relative value scale system to pediatrics.
The majority of public and private payers in the United States currently use the Medicare Resource-Based Relative Value Scale as the basis for physician payment. Many large group and academic practices have adopted this objective system of physician work to benchmark physician productivity, including using it, wholly or in part, to determine compensation. The Resource-Based Relative Value Scale survey instrument, used to value physician services, was designed primarily for procedural services, leading to current concerns that American Medical Association/Specialty Society Relative Value Scale Update Committee (RUC) surveys may undervalue nonprocedural evaluation and management services. The American Academy of Pediatrics is represented on the RUC, the committee charged with maintaining accurate physician work values across specialties and age groups. The Academy, working closely with other primary care and subspecialty societies, actively pursues a balanced RUC membership and a survey instrument that will ensure appropriate work relative value unit assignments, thereby allowing pediatricians to receive appropriate payment for their services relative to other services.


C-terminal invariable domain of VlsE is immunodominant but its antigenicity is scarcely conserved among strains of Lyme disease spirochetes.
VlsE, the variable surface antigen of Borrelia burgdorferi, contains two invariable domains located at the amino and carboxyl terminal ends, respectively, and a central variable domain. In this study, both immunogenicity and antigenic conservation of the C-terminal invariable domain were assessed. Mouse antiserum to a 51-mer synthetic peptide (Ct) which reproduced the entire sequence of the C-terminal invariable domain of VlsE from B. burgdorferi strain B31 was reacted on immunoblots with whole-cell lysates extracted from spirochetes of 12 strains from the B. burgdorferi sensu lato species complex. The antiserum recognized only VlsE from strain B31, indicating that epitopes of this domain differed among these strains. When Ct was used as enzyme-linked immunosorbent assay (ELISA) antigen, all of the seven monkeys and six mice that were infected with B31 spirochetes produced a strong antibody response to this peptide, indicating that the C-terminal invariable domain is immunodominant. None of 12 monkeys and only 11 of 26 mice that were infected with strains other than B31 produced a detectable anti-Ct response, indicating a limited antigenic conservation of this domain among these strains. Twenty-six of 33 dogs that were experimentally infected by tick inoculation were positive by the Ct ELISA, while only 5 of 18 serum samples from dogs clinically diagnosed with Lyme disease contained detectable anti-Ct antibody. Fifty-seven of 64 serum specimens that were collected from American patients with Lyme disease were positive by the Ct ELISA, while only 12 of 21 European samples contained detectable anti-Ct antibody. In contrast, antibody to the more conserved invariable region IR(6) of VlsE was present in all of these dog and human serum samples.


Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand?
Chronic lymphocytic leukemia (CLL) is a clinically and biologically heterogeneous disease where the majority of patients have an indolent disease course, while others may experience a far more aggressive disease, treatment failure and poor overall survival. During the last two decades, there has been an intense search to find novel biomarkers that can predict prognosis as well as guide treatment decisions. Two of the most reliable molecular prognostic markers, both of which are offered in routine diagnostics, are the immunoglobulin heavy chain variable (IGHV) gene mutational status and fluorescence in situ hybridization (FISH) detection of prognostically relevant genomic aberrations (e.g. 11q-, 13q-, +12 and 17p-). In addition to these markers, a myriad of additional biomarkers have been postulated as potential prognosticators in CLL, on the protein (e.g. CD38, ZAP70, TCL1), the RNA (e.g. LPL, CLLU1, micro-RNAs) and the genomic (e.g. TP53, NOTCH1, SF3B1 and BIRC3 mutations) level. Efforts are now being made to test these novel markers in larger patient cohorts as well as in prospective trials, with the ultimate goal to combine the "best" markers in a "CLL prognostic index" applicable for the individual patient. Although it is clear that these studies have significantly improved our knowledge regarding both prognostication and the biology of the disease, there is still an immediate need for recognizing biomarkers that can predict therapy response, and efforts should now focus on addressing this pertinent issue. In the present article, we review the extensive literature in the field of prognostic markers in CLL, focus on the most clinically relevant markers and discuss future directions regarding biomarkers in CLL.


Quantitative monitoring of the PRAME gene for the detection of minimal residual disease in leukaemia.
PRAME (Preferentially expressed antigen of melanoma) has been previously identified as a melanoma antigen recognized by cytotoxic T cells (CTLs) and found to be expressed in a variety of cancer cells including leukaemic cells. We have screened 98 Japanese patients with leukaemia and lymphoma for expression of the PRAME gene using semiquantitative reverse transcription polymerase chain reaction (RT-PCR). Forty-one patients (42%) showed high levels of PRAME expression. Eight of these patients were then monitored using real-time PCR for a period of 10-37 months. Significant reductions in the PRAME expression were observed in all patients after chemotherapy. An increased expression was detected in the two patients who relapsed, one of which was before cytological diagnosis. These changes were correlated with those of other known genetic markers, such as the bcr-abl gene. Therefore, quantitative monitoring of the PRAME gene using real-time PCR method may be useful for detecting minimal residual disease and to predict subsequent relapse, especially in patients without known genetic markers. In addition, a PRAME-positive leukaemia cell line and fresh leukaemic cells were found to be susceptible to lysis by PRAME-specific CTLs established from a patient with melanoma, suggesting that the PRAME peptide can also be a target leukaemia antigen for T cells.


Interventional radiology education: Patient experience with an educational website.
The aim of this study was to examine the impact of an educational website on patient understanding of Interventional Radiology (IR). An informational website with descriptions and images of 12 common IR procedures was developed with the aim of educating patients. One hundred patients referred to a large, academic institution were randomly selected to participate. Anonymous 11-question, 5-point Likert-scale assessments were administered before and after engaging with the educational website. The survey evaluated patients' understanding of IR procedures and satisfaction with the website as an educational tool. One hundred patients completed the pre-/post-implementation evaluations. Among matched questions, there was an increase in patient understanding of IR with mean score improvement from 2.10 to 4.57 (p < 0.001), their knowledge of common procedures from 1.74 to 4.66 (p < 0.001), and their consideration for their next procedure to be with IR from 2.24 to 4.62 (p < 0.001). Additionally, patients had an overall positive impression of the website (mean 4.80). Over 75% of patients found the descriptions and images "very helpful". This study demonstrated that website use for patient education has the potential to be effective in increasing overall patient understanding of IR and familiarity with common interventional procedures.


Relevance, quick hits, and vibe: Features of meaningful teaching and learning during trainee consult interactions.
Consults are increasingly frequent in inpatient pediatric services. Consult interactions between trainees provide a rich opportunity for teaching and learning. What constitutes meaningful teaching interactions with trainees has not been described. Explore how consulting fellows and residents define "meaningful teaching interactions" associated with inpatient consult interactions. Four focus groups were conducted with 21 pediatric trainees (11 subspecialty fellows and 10 residents) at one institution. Transcriptions were analyzed using thematic analysis to inductively create categories and themes. Five factors define meaningful teaching interactions: (1) Relevance; (2) Quick Hits; (3) Vibe; (4) Face-to-face Interactions; and (5) Timing and Busyness. Meaningful content was described as relevant to current or future patient care. Residents valued content that would enable them to explain the reasoning behind recommendations and think through the next steps. Trainees highlighted brief clinical pearls as superior to longer teaching sessions. The "vibe" between resident and fellow was described as a prerequisite to meaningful teaching and included aspects of interest, receptivity, tone, and attitude. Face-to-face interactions were preferred by many trainees, from initial consults to seeing patients or co-rounding. Timing and workload reflected discordant schedules, including time of day and week, but setting a planned time for teaching was beneficial. Relevant, bite-sized educational content combined with a good vibe and optimal timing creates a context in which consult fellows can foster meaningful teaching opportunities for residents.


The role of ex-POWs' PTSD symptoms and trajectories in wives' secondary traumatization.
Secondary traumatization describes the phenomenon whereby those in proximity to trauma survivors develop psychological symptoms similar to those experienced by the direct survivor. The current study examined secondary trauma (ST) and generalized distress symptoms (general psychiatric symptomatology, functional disability, and self-rated health) in wives of former prisoners of war (ex-POWs). The study compared wives of Israeli ex-POWs from the 1973 Yom Kippur War with wives of a matched control group of non-POW Yom Kippur War combat veterans (CVs). The wives also were divided into groups based on their husbands' current posttraumatic stress disorder (PTSD) status and PTSD trajectory (i.e., chronic, delayed), and their outcomes were compared with resilient CVs. We found that wives of ex-POWs with PTSD reported higher ST and generalized distress than wives of ex-POWs and non-POW CVs without PTSD. Wives of ex-POWs with chronic PTSD reported the highest levels of functional disability. We also found that the relationships between husbands' prior captivity, and wives' ST and general psychiatric symptomatology were fully mediated by the husbands' PTSD symptoms. These findings indicate that it is exposure to a partner with PTSD that leads to overall ST and other distress symptoms, and not simply to a trauma survivor. Furthermore, the more severe their husbands' PTSD, the more wives are at risk for ST and general psychiatric symptomatology. Wives of partners with PTSD should therefore be considered high-risk groups for ST and distress that may require targeted interventions.


Enhancing effects of gamma interferon on phagocytic cell association with and killing of Trypanosoma cruzi.
The effects of gamma interferon (IFN-gamma) on P388D1 cell or mouse resident peritoneal macrophage association (i.e., binding and internalization) with the protozoan Trypanosoma cruzi were studied, as well as the effects of this lymphokine on intracellular parasite killing. Incubation of either type of cell with a conditioned medium containing IFN-gamma and traces of interleukin 2 markedly increased the capacities of the cells to associate with virulent blood forms of T. cruzi, as evidenced by significant increases in both the proportion of parasite-associated cells and the number of parasites associated with the cells. Three lines of evidence pointed to IFN-gamma, and not interleukin 2, as the lymphokine responsible for the noted effect. First, a conditioned medium containing interleukin 2 but not IFN-gamma failed to enhance P338D1 cell-parasite association. Second, treatment of the IFN-gamma preparation at pH 2 to selectively inactivate IFN-gamma reduced its enhancing effect. Third, recombinant IFN-gamma, devoid of other lymphokines, also enhanced parasite association with P388D1 cells. Incubation of P388D1 cells with IFN-gamma for 24, 48, or 72 h increased cell association with T. cruzi, whereas a 12-h incubation period was insufficient, suggesting that IFN-gamma triggered time-dependent cellular events leading to the enhancement. Treatment of mouse resident peritoneal macrophages with the IFN-gamma-containing conditioned medium also increased the capacity of these cells to kill internalized trypanosomes. P388D1 cells, which showed minimal or no cytotoxicity after mock treatment with medium, displayed cytotoxicity after incubation with the IFN-gamma-containing conditioned medium; similar results were obtained with recombinant IFN-gamma. Catalase prevented parasite killing by P388D1 cells, indicating that H2O2 mediated the cytotoxicity. These results, underscoring the regulatory effects of IFN-gamma on macrophage-parasite interactions, suggest a possible role for this lymphokine in the mechanisms of host defense active against T. cruzi infection.


Mechanism of enzyme inhibition by phosphate esters.
A theory for the rapid specific reaction of certain phosphorous-containing esters with many proteolytic enzymes based on the ability of phosphorous to form one additional bond relative to carbon is presented. A stable tetrahedral phosphate ester is compared with a labile tetrahedral orthocarbonyl ester and a relatively stable pentagonal enzyme-phosphate ester complex is compared with a pentagonal enzyme-carbonyl substrate complex. The latter complex is assumed to be the transition state in the enzyme-catalyzed reaction. If the theory is correct, it opens up the possibility of studying intermediates and transition states from the known structures of chemical inhibitors.


Apoptosis and DNA damage in type 2 alveolar epithelial cells cultured from hyperoxic rats.
Apoptosis is a genetically controlled cellular response to developmental stimuli and environmental insult that culminates in cell death. Sublethal hyperoxic injury in rodents is characterized by a complex but reproducible pattern of lung injury and repair during which the alveolar surface is damaged, denuded, and finally repopulated by type 2 alveolar epithelial cells (AEC2). Postulating that apoptosis might occur in AEC2 after hyperoxic injury, we looked for the hallmarks of apoptosis in AEC2 from hyperoxic rats. A pattern of increased DNA end labeling, DNA laddering, and induction of p53, p21, and Bax proteins, strongly suggestive of apoptosis, was seen in AEC2 cultured from hyperoxic rats when compared with control AEC2. In contrast, significant apoptosis was not detected in freshly isolated AEC2 from oxygen-treated rats. Thus the basal culture conditions appeared to be insufficient to ensure the ex vivo survival of AEC2 damaged in vivo. The oxygen-induced DNA strand breaks were blocked by the addition of 20 ng/ml of keratinocyte growth factor (KGF) to the culture medium from the time of plating and were partly inhibited by Matrigel or a soluble extract of Matrigel. KGF treatment resulted in a partial reduction in the expression of the p21, p53, and Bax proteins but had no effect on DNA laddering. We conclude that sublethal doses of oxygen in vivo cause damage to AEC2, resulting in apoptosis in ex vivo culture, and that KGF can reduce the oxygen-induced DNA damage. We speculate that KGF plays a role as a survival factor in AEC2 by limiting apoptosis in the lung after acute hyperoxic injury.


The predictive value of lncRNA MIR31HG expression on clinical outcomes in patients with solid malignant tumors.
Emerging studies have explored the prognostic value of MIR31HG in cancers, but its role remains elusive. Herein, we aimed to summarize the prognostic potential of MIR31HG in this study. Several databases were searched for literature retrieval on Dec 5, 2019. Overall and subgroup analyses were conducted to measure the relationship between MIR31HG expression and clinical outcomes. Moreover, GEPIA was applied for validation of prognostic value of MIR31HG in tumor patients in TCGA dataset. Overall, seventeen studies with 2573 patients were enrolled. Compared to counterparts, those patients with high MIR31HG expression tended to have shorter RFS. Notably, MIR31HG overexpression predicted unfavorable OS in lung cancer. By contrast, gastrointestinal cancer patients with elevated MIR31HG expression predicted better OS and disease-free survival. Additionally, MIR31HG overexpression was significantly associated with worse clinicopathological features including advanced tumor stage and LNM in lung cancer, but favorable clinical characteristics in gastrointestinal cancer. Moreover, the positive association between MIR31HG and OS in lung cancer was further confirmed in TCGA dataset. Overexpression of MIR31HG suggested remarkable association with poor prognosis in terms of OS, tumor stage, and LNM in lung cancer, but favorable prognosis in gastrointestinal cancer. Therefore, MIR31HG may serve as a promising prognostic biomarker in multiple cancers.


Instrumental variable-based assessment of the effect of psychotherapy on suicide attempts, health, and economic outcomes in schizophrenia.
The literature on the effect of psychotherapy for schizophrenia is limited and characterized by small samples and possible bias from risk selection. We examined the effects of psychotherapy on suicide attempts and health and economic outcomes using an instrumental variable (IV) approach that exploits the variation in the propensities of hospital departments to prescribe psychotherapy. This was supplemented with naïve probit models as exogeneity could not be ruled out for all of the outcomes. The validity of the instrument was examined by distributional plots and various tests. The assumed randomness in referring patients to providers with high versus low propensities to psychotherapy appeared to be a critical aspect. Splitting the sample into homogeneous provider types did not substantially alter the results. Based on the IV results, we found no support for the effect of psychotherapy on suicide attempt, psychiatric readmission, assisted living, or labor market attachment. However, we cannot rule out smaller effects due to confidence intervals including the probit estimates. The main contribution of this study is new evidence on a broad range of outcomes and a large and representative population.


Nitrate Loss in Subsurface Drainage from a Corn-Soybean Rotation as Affected by Nitrogen Rate and Nitrapyrin.
Successful N management practices for the US Midwest must optimize crop production and minimize NO-N losses from subsurface tile drainage. The objective of this study was to measure the effects of N rate, N application timing, and nitrapyrin [2-chloro-6-(trichlormethyl) pyridine] on corn ( L.) production and NO-N in tile drainage water in a corn-soybean [ (L.) Merr.] rotation in Minnesota. Anhydrous ammonia was applied at 90 and 179 kg ha with nitrapyrin in the fall and at 134 kg ha with and without nitrapyrin in fall and spring. However, drainage water monitoring was only conducted on fall treatments. Over a 5-yr period, 71% of drainage occurred in April through June and <1% occurred from November through March due to frozen soil. Averaged across N treatments and crops, annual drainage ranged from 69 to 380 mm among years. From 2001 through 2003, NO-N concentrations averaged 13.8, 15.6, and 20.0 mg L in corn and 7.3, 8.2, and 12.6 mg L in soybean when 90, 134, and 179 kg N ha was fall applied with nitrapyrin to corn, respectively. Corn grain yields were greater with spring-applied N at 134 kg ha (11.3 Mg ha) than with fall-applied N at 134 and 179 kg ha with nitrapyrin (10.5 and 10.8 Mg ha, respectively), and nitrapyrin did not affect corn production or water quality. Fall application of N is common on cold soils in Minnesota. These data showed that fall application required a greater rate of N to optimize yield than spring and that greater fall rate often increased NO-N concentration and load in tile drainage water.


Combat-related flashbacks in posttraumatic stress disorder: phenomenology and similarity to panic attacks.
Combat veterans (N = 25) with posttraumatic stress disorder had flashbacks related to their combat stressors, which included major losses and exposure to danger. Certain affects, loud noises, fatigue, and personal stress tended to precipitate flashback episodes. Flashbacks began a year or more after exposure to combat in 50% of patients; 56% of patients experienced daily flashbacks. Flashback phenomenology met DSM-III criteria for panic attacks. The similarity of flashbacks to panic attacks suggests treatment trials with monoamine oxidase inhibitors or imipramine for these selected symptoms.


Blame, coping, and psychosocial outcomes in caregivers of individuals with brain injury.
Acquired brain injury (ABI) is associated with many physical and psychiatric conditions. Oftentimes, the individual's family members are responsible for providing long-term care, leaving caregivers vulnerable to negative effects of caregiving including stress, depression, and decreased quality of life. Attribution theory suggests that caregivers may blame the individual with the ABI for their injury as a way to understand their own circumstances. The objective of this study was to investigate caregiver coping strategies as possible mediators between caregiver family member blame and caregiver psychosocial outcomes among caregivers of individuals with ABI. Caregivers of individuals with ABI (n = 94) completed an online survey of self-report measures regarding coping (emotion-focused, problem-focused, and dysfunctional strategies), blame (direct, indirect, and preoccupation with blame), depressive symptoms, and quality of life (QOL). Bootstrapping mediation analyses were conducted to investigate the mediating role of caregiver coping strategies between blame attributions, and either depressive symptoms or QOL. Results demonstrated that the use of more dysfunctional coping strategies significantly mediated the relationship between indirect blame, and depressive symptoms and QOL. Furthermore, using more dysfunctional coping strategies also significantly mediated the relationship between preoccupation with blame and depressive symptoms. Results of this study point to the important role blame attributions play in the use of coping strategies and subsequent psychosocial outcomes. By understanding the relationships between blame attributions, coping behavior, and psychosocial outcomes, clinicians may better tailor treatments to optimize QOL and promote the psychological well being of caregivers and care recipients. (PsycINFO Database Record


Changes in basal metabolic rate during pregnancy in relation to changes in body weight and composition, cardiac output, insulin-like growth factor I, and thyroid hormones and in relation to fetal growth.
The total energy cost of pregnancy is largely due to an elevated basal metabolic rate (BMR). Large variations in the BMR response to pregnancy have been reported, but the factors associated with this variability are incompletely known. The objective was to identify factors associated with variability in the BMR response to pregnancy. In 22 healthy women, BMR, body weight (BW), total body fat (TBF), fat-free mass (FFM), circulatory variables, serum concentrations of insulin-like growth factor I (IGF-I), and thyroid hormones were measured before pregnancy and in gestational weeks 14 and 32. BMR and BW were also measured in gestational weeks 8, 20, and 35. Fetal weight was estimated in gestational week 31. In gestational week 14, the increase in BMR correlated significantly with the corresponding increase in BW and with the prepregnancy percentage of TBF. Together these variables explained approximately 40% of the variability in the BMR response. In gestational week 32, the increase in BMR correlated significantly with the corresponding changes in BW, TBF, FFM, IGF-I, cardiac output, and free triiodothyronine. The increase in BW in combination with fetal weight or with the elevated concentration of IGF-I in serum explained approximately 60% of the variability in the increase in BMR. Weight gain and the prepregnancy percentage of TBF-ie, factors related to the maternal nutritional situation-are important factors with regard to the variability in the BMR response to pregnancy. Thus, it is important to consider the nutritional situation before and during gestation when assessing pregnancy energy requirements.


Cushing syndrome: current concepts of diagnosis and therapy.
A variety of diagnostic advances including radioimmunoassay of adrenocorticotropic hormone (ACTH) have increased the number of methods for laboratory investigation of Cushing syndrome.* However, experience with these procedures has led to a recognition of their limitations. We have developed an algorithm which incorporates these newer techniques and minimizes the number of procedures required to diagnose the various causes of Cushing syndrome. At present, we recommend pituitary surgical operations for pituitary-dependent Cushing syndrome because we believe this disease is caused by the development of a pituitary ACTH-secreting tumor.


Cidofovir for BK virus-associated hemorrhagic cystitis: a retrospective study.
BK virus-associated hemorrhagic cystitis (BKV-HC) is a severe complication after allogeneic hematopoietic stem cell transplantation (HSCT), but antiviral treatment for this condition has not been evaluated. We conducted a retrospective survey on the safety and outcome of cidofovir treatment for patients with BKV-HC in centers affiliated with the European Group for Blood and Marrow Transplantation. From 1 April 2004 to 31 December 2007, 62 patients received a diagnosis of BKV-HC after a median interval of 35 days after HSCT (range, 3-577 days). Fifty-seven patients (92%) received intravenous cidofovir, whereas 5 patients received cidofovir intravesically. Complete response (CR) was recorded in 38 (67%) of 57 patients with HC treated with intravenous cidofovir, whereas partial response (PR) was documented in 7 patients (12%). CR was documented in 3 patients and PR in 1 patient with HC treated with intravesical cidofovir. A reduction of 1-3 logs in BKV load was documented in 8 of the 10 patients achieving CR. Mild-to-moderate toxic effects were recorded in 18 of 57 patients who received intravenous cidofovir administration. In a multivariate analysis, the factors significantly associated with response to cidofovir were the stem cell source (P = .01) and the use of total body irradiation (P = .03). After a median follow-up of 287 days, overall survival and total treatment-related mortality rates were 63% and 40% for patients achieving CR, compared with 14% and 72% for patients with PR or no response to cidofovir, respectively (P = .001 and P = .001, respectively). Cidofovir may be a potentially effective therapy for BKV-HC, but evidence supporting its use requires randomized controlled trials.


Chronic pain and mental health problems among Syrian refugees: associations, predictors and use of medication over time: a prospective cohort study.
This study aims to examine associations, predictors and pharmacological treatment of chronic pain and mental health problems among Syrian refugees in a longitudinal perspective. Prospective cohort study. We collected survey data among Syrian refugees in Lebanon granted resettlement to Norway (self-administered questionnaires) and at follow-up 1 year after arrival in Norway (structured telephone interviews). Adult Syrian refugees attending mandatory pretravel courses in Lebanon in 2017-2018 were invited to participate. In total, 353 individuals participated at both time points. We examined the cross-sectional associations between pain, mental health and migration-related exposures at baseline and follow-up and assessed whether associations changed significantly with time. Furthermore, we investigated the longitudinal association between mental health at baseline and pain at follow-up. We also evaluated temporal changes in use of analgesics and psychotropic drugs. While most refugees reported improved health from the transit phase in Lebanon to the early resettlement phase in Norway, a few had persisting and intertwined health problems. Most migration-related stressors were more closely associated with chronic pain and mental health problems after resettlement as compared with the transit phase. In parallel, poor mental health was associated with chronic pain in the follow-up (adjusted risk ratio (ARR) 1.5 (1.0, 2.2)), but not at baseline (ARR 1.1 (0.8, 1.5)). Poor mental health at baseline was a statistically significant predictor of chronic pain at follow-up among those not reporting chronic pain at baseline. At both timepoints, one in four of those with chronic pain used analgesics regularly. None with mental health problems used antidepressants daily. Providers of healthcare services to refugees should be attentive to the adverse effect of postmigration stressors and acknowledge the interrelations between pain and mental health. Possible gaps in pharmacological treatment of pain and mental health problems need further clarification.


Dual role of inorganic polyphosphate in cardiac myocytes: The importance of polyP chain length for energy metabolism and mPTP activation.
We have previously demonstrated that inorganic polyphosphate (polyP) is a potent activator of the mitochondrial permeability transition pore (mPTP) in cardiac myocytes. PolyP depletion protected against Ca2+-induced mPTP opening, however it did not prevent and even exacerbated cell death during ischemia-reperfusion (I/R). The central goal of this study was to investigate potential molecular mechanisms underlying these dichotomous effects of polyP on mitochondrial function. We utilized a Langendorff-perfused heart model of I/R to monitor changes in polyP size and chain length at baseline, 20 min no-flow ischemia, and 15 min reperfusion. Freshly isolated cardiac myocytes and mitochondria from C57BL/6J (WT) and cyclophilin D knock-out (CypD KO) mice were used to measure polyP uptake, mPTP activity, mitochondrial membrane potential, respiration and ATP generation. We found that I/R induced a significant decrease in polyP chain length. We, therefore, tested, the ability of synthetic polyPs with different chain length to accumulate in mitochondria and induce mPTP. Both short and long chain polyPs accumulated in mitochondria in oligomycin-sensitive manner implicating potential involvement of mitochondrial ATP synthase in polyP transport. Notably, only short-chain polyP activated mPTP in WT myocytes, and this effect was prevented by mPTP inhibitor cyclosprorin A and absent in CypD KO myocytes. To the contrary, long-chain polyP suppressed mPTP activation, and enhanced ADP-linked respiration and ATP production. Our data indicate that 1) effect of polyP on cardiac function strongly depends on polymer chain length; and 2) short-chain polyPs (as increased in ischemia-reperfusion) induce mPTP and mitochondrial uncoupling, while long-chain polyPs contribute to energy generation and cell metabolism.


School injuries. Epidemiology and clinical features of 307 cases registered at hospital during one school year.
Injuries at school were studied for one school year in 57 primary and three secondary schools (13,733 students, aged 7-19 years) at Umeå in northern Sweden. The injury rate was 22/1000 student years. There was a wide variation in injury rate between different schools. The boy/girl ratio was 1.1/1. Physical education was the dominating activity at the time of injury for the older students and play in the school yard for the younger. The majority of the students had a minor injury, but 17% had a fracture. The injured students did not seem to have more somatic, psychological or social problems than students in general. Fewer competitive sports and ball games and more adult supervision and organized activities during breaks are suggestions to reduce injuries at school. A hospital-based injury registration system is well fitted for serving as a base for analysing school injuries.


Dynamic response and transfer characteristics of joint neurons in somatosensory thalamus of the cat.
1. The dynamic response of neurons sensitive to knee joint rotation in the cat somatosensory thalamus was studied during sinusoidal variation of joint angle. The input sine waves were applied with a precise voltage-controlled, electromechanical actuator. The average rate of discharge of a single cell was considered as the output parameter. Describing functions of the sensory system were extracted by correlation and spectral analysis techniques. The effects of anesthetic, bias angle, and excursion angle were investigated. Discrete and swept sinusoidal waveforms between 0.1 and 7.0 Hz were used as inputs.2. The majority of joint cells in the thalamus were rapidly adapting and had frequency-response curves that were characterized as highpass filters. Although the major features of the response curves for individual cells were very similar, they could not all be fit with a single transfer function. The describing function of all the rapidly adapting cells averaged together was well fit by a transfer function that could be termed velocity sensitive in the bandwidth between 0.1 and 6.5 Hz. Most of these phasic cells showed a phase-locking tendency, particularly at high frequencies.3. The dynamics of the response for the rapidly adapting cells was relatively independent of anesthetic, bias angle, and excursion angle. Threshold and saturation effects were exhibited by some cells for very small (less than 1 degree) and large (greater than 10 degrees) input amplitudes, respectively. In addition a few (17%) showed a bidirectional response, i.e., responded at both flexion and extension of the limb. The anesthetic had a strong effect in depressing the spontaneous discharge of the cells and seemed to change the character of the tonic response by introducing a bursting component.4. The transfer characteristic of the thalamic cells was found to be a single-pole low-pass filter plus a time delay. The optimized value for the filter was found to have a corner frequency of 6.0 Hz with a time delay of 6 ms.5. Of the knee joint sensitive cells, 17% were slowly adapting or tonic, and more tonic cells were found in the unanesthetized animals. Only one tonic cell was studied in detail, and its dynamic characteristics were similar to that of the slowly adapting joint receptors at low frequencies. In this respect the rapidly adapting and slowly adapting joint cells in the thalamus have strikingly different frequency-response curves, the former curves have a much steeper slope in the magnitude.6. The functional implications of these results and of other recent findings in relation to the probable role of joint receptors in mediating proprioception are discussed.


Effect of kinins on the central action of serotonin.
Kinins, the biologically active peptides, potentiate the central stimulatory effects of NA and depressant action of acetylcholine as have been shown by the authors previously. The aim of the work has been to study the effects of these peptides on the central action of 5-HT. For experiments female Wistar rats were used. 5-HT given ivc to the animals and 5-HTP applied ip resulted in an increase of the pain threshold to the electrical stimuli and in a worse motor coordination. Bradykinin injected ivc or kallikrein ip to some extent abolished these effects. The biochemical tests revealed that bradykinin ivc lead to a significant decrease in 5-HT content in the midbrain. In experiments in vitro this peptide increased markedly the release of the platelets 5-HT and inhibited the uptake of this mediator to platelets. The results have shown that kinins can attenuate the central action of 5-HT. This effect can be ascribed, at least in part to a kinin-induced changes of 5-HT concentration in some structures of the central nervous system.


E-Cadherin/β-Catenin Complex: A Target for Anticancer and Antimetastasis Plants/Plant-derived Compounds.
Plants reputed to have cancer-inhibiting potential and putative active components derived from those plants have emerged as an exciting new field in cancer study. Some of these compounds have cancer-inhibiting potential in different clinical staging levels, especially metastasis. A few of them which stabilize cell-cell adhesions are controversial topics. This review article introduces some effective herbal compounds that target E-cadherin/β-catenin protein complex. In this article, at first, we briefly review the structure and function of E-cadherin and β-catenin proteins, Wnt signaling pathway, and its target genes. Then, effective compounds of the Teucrium persicum, Teucrium polium, Allium sativum (garlic), Glycine max (soy), and Brassica oleracea (broccoli) plants, which influence stability and cellular localization of E-cadherin/β-catenin complex, were studied. Based on literature review, there are some compounds in these plants, including genistein of soy, sulforaphane of broccoli, organosulfur compounds of garlic, and the total extract of Teucrium genus that change the expression of variety of Wnt target genes such as MMPs, E-cadherin, p21, p53, c-myc, and cyclin D1. So they may induce cell-cycle arrest, apoptosis and/or inhibition of Epithelial-Mesenchymal Transition (EMT) and metastasis.


Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015.
There has been limited surveillance for acute flaccid paralysis in North America since the regional eradication of poliovirus. In 2012, the California Department of Public Health received several reports of acute flaccid paralysis cases of unknown etiology. To quantify disease incidence and identify potential etiologies of acute flaccid paralysis cases with evidence of spinal motor neuron injury. Case series of acute flaccid paralysis in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the California Department of Public Health with symptom onset between June 2012 and July 2015. Patients meeting diagnostic criteria for other acute flaccid paralysis etiologies were excluded. Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing. Case incidence and infectious agent association. Fifty-nine cases were identified. Median age was 9 years (interquartile range [IQR], 4-14 years; 50 of the cases were younger than 21 years). Symptoms that preceded or were concurrent included respiratory or gastrointestinal illness (n = 54), fever (n = 47), and limb myalgia (n = 41). Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging and 43 patients had cerebrospinal fluid pleocytosis. During the course of the initial hospitalization, 42 patients received intravenous steroids; 43, intravenous immunoglobulin; and 13, plasma exchange; or a combination of these treatments. Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months (IQR, 3-12 months). Two patients, both immunocompromised adults, died within 60 days of symptom onset. Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested). No pathogens were isolated from the cerebrospinal fluid. The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 (0.16 cases per 100,000 person-years) compared with other monitoring periods (0.028 cases per 100,000 person-years; P <.001). In this series of patients identified in California from June 2012 through July 2015, clinical manifestations indicated a rare but distinct syndrome of acute flaccid paralysis with evidence of spinal motor neuron involvement. The etiology remains undetermined, most patients were children and young adults, and motor weakness was prolonged.


Technique and timing in the women's reverse two and one half somersault tuck (305C) and the men's reverse two and one half somersault pike (305B) 3m springboard dives.
The purpose of this study was to compare the reverse two and one half somersault dive in a tuck position (305C) performed by females (n = 24), and the reverse two and one half somersault dive in a pike position (305B) performed by males (n = 21), to determine changes required by females to successfully perform 305B. Key performance variables in reverse dives were also compared to those of forward dives. Video data of the dives performed at the 1999 FINA World Diving Cup were captured and digitised to obtain times and postures of the divers at specific events including hurdle landing, takeoff, and entry. Estimates of hurdle flight height and mass-normalised work done on the springboard were obtained from hurdle and flight times. The males did more work on the springboard to achieve greater height and rotation than females. Females performing 305C had less hip and knee flexion at hurdle landing than males performing 305B and took longer to achieve maximum hip flexion after takeoff from the springboard. To progress from 305C to 305B females need to adjust their techniques to put more energy into the system. Desirable changes include increased height in the hurdle and increased hip and knee flexion prior to hurdle landing. Comparison of results for reverse dives with data previously presented for forward dives indicated that divers are more limited in the number of somersaults and dive position in reverse dives than forward dives despite equivalent or better height in reverse dives than forward dives.


Marriage abdominoplasty expands the mini-abdominoplasty concept.
The marriage of aggressive superwet liposculpture of the abdomen and adjacent anatomic regions with a modification of well-established open surgical techniques to address skin excess and perform muscle plication was used to treat 29 patients presenting for aesthetic abdominal contouring over the past 3 1/2 years. The charts of 57 patients who had aesthetic contouring procedures on the abdomen performed from December of 1994 to July of 1998 were retrospectively reviewed. Fifteen patients underwent suction lipectomy alone, 13 patients were treated with conventional abdominoplasty, and 29 underwent "marriage abdominoplasty." The 29 patients who underwent marriage abdominoplasty presented with deformities marked by excess lower abdominal skin and adipose tissue, with or without muscle laxity (Psillakis types II, III, and IV). Seventeen procedures were performed under local anesthesia with deep conscious sedation on an outpatient surgical basis. In 12 patients, the operation accompanied a hysterectomy, urologic procedure, or additional aesthetic surgical procedure(s) and was done under general anesthesia. Suction aspirates ranged between 540 and 2600 cc (mean, 1160 cc) and were accompanied by lower abdominal skin excision in every case, which was performed predominantly through short and medium-length incisions (mean, 15 cm). Rectus abdominis muscle plication was performed where necessary, using vertical plication of the infraumbilical rectus muscles in 27 patients (93 percent) and full-length plication in two patients (7 percent). All patients demonstrated significantly improved contours and have seemed to manifest less pain when compared with patients treated by full traditional abdominoplasty. Postoperative complications have included upper abdominal skin waviness (2), annoying paresthesias and discomfort persisting for 6 months (1), seroma (1), and marginal skin necrosis with an open wound (1). The latter problem occurred in the only patient who was treated with a revision procedure. Thus, the complication rate was 17 percent (5 of 29 patients). The marriage of aggressive superwet liposculpture of the entire abdomen with standard open surgical techniques used to treat skin excesses and allow abdominal muscle plication where necessary offers the advantage of reduced surgery when compared with full abdominoplasty, while consistently achieving significant contour improvement. This concept is applicable to the majority of patients presenting for the treatment of abdominal deformities and has markedly expanded the application of the mini-abdominoplasty concept.


High-dose-rate brachytherapy combined with hypofractionated external beam radiotherapy for men with intermediate or high risk prostate cancer: analysis of short- and medium-term urinary toxicity and biochemical control.
The best management of localized and locally advanced prostate cancer remains controversial, but there are clinical evidences that for patients considered of unfavorable outcome that dose escalation radiotherapy has a significantly better outcome. Between 2005-2009 a total of 39 unfavorable patients were treated in a phase I-II trial for dose escalation with high-dose rate (HDR)- 30 Gy given by 4 fractions BID, in two separated implants and hypofractionated conformal/tri-dimensional radiotherapy (hEBRT) - 45 Gy (3 Gy per fraction in 3 weeks), at Hospital AC Camargo, Sao Paulo, Brazil. Median age of patients was 69 (range, 58-80) years old. With a median follow up of 42.5 months the highest RTOG acute severe genitourinary toxicity (GU-TX) was grade 3 in two (5.1%) patients. Late severe GU-TX was observed in one (2.6%) patient. On univariate analysis the prostate volume > 45cc (p=0.024), <11 needles per implant (p=0.038) and urethral dose >130% of prescribed dose (p<0,001) were statistical significant predictive factors. Multivariate analysis showed urethral dose >130% as the only predictive factor for late severe GU-TX, p=0.017 (95%CI-1.39-29.49), HR-6.4. The actuarial overall survival, biochemical control and disease specific survival rates for the entire group at 3.5-years were 92.0%, 87.6% and 96.9%, respectively. HDR combined to hEBRT is well tolerated in the short and medium term. Acute toxicity was minimal and improved outcomes in terms of reduced late toxicity can be achieved using at least 11 needles and prostate with no more than 45cc to be implanted. The maximum urethral dose should be kept bellow 130% of prescribed dose.


Immunodetection of human double homeobox 4.
Double homeobox 4 (DUX4) is a candidate disease gene for facioscapulohumeral dystrophy (FSHD), one of the most common muscular dystrophies characterized by progressive skeletal muscle degeneration. Despite great strides in understanding precise genetics of FSHD, the molecular pathophysiology of the disease remains unclear. One of the major limitations has been the availability of appropriate molecular tools to study DUX4 protein. In the present study, we report the development of five new monoclonal antibodies targeted against the N- and C-termini of human DUX4, and characterize their reactivity using Western blot and immunofluorescence staining. Additionally, we show that expression of the canonical full coding DUX4 induces cell death in human primary muscle cells, whereas the expression of a shorter splice form of DUX4 results in no such toxicity. Immunostaining with these new antibodies reveals a differential effect of two DUX4 isoforms on human muscle cells. These antibodies will provide an excellent tool for investigating the role of DUX4 in FSHD pathogenesis.