Multi-modal proteomic characterization of lysosomal function and proteostasis in progranulin-deficient neurons.
Progranulin (PGRN) is a lysosomal glycoprotein implicated in various neurodegenerative diseases, including frontotemporal dementia and neuronal ceroid lipofuscinosis. Over 70 mutations discovered in the GRN gene all result in reduced expression of the PGRN protein. Genetic and functional studies point toward a regulatory role for PGRN in lysosome functions. However, the detailed molecular function of PGRN within lysosomes and the impact of PGRN deficiency on lysosomes remain unclear. We developed multifaceted proteomic techniques to characterize the dynamic lysosomal biology in living human neurons and fixed mouse brain tissues. Using lysosome proximity labeling and immuno-purification of intact lysosomes, we characterized lysosome compositions and interactome in both human induced pluripotent stem cell (iPSC)-derived glutamatergic neurons (i3Neurons) and mouse brains. Using dynamic stable isotope labeling by amino acids in cell culture (dSILAC) proteomics, we measured global protein half-lives in human i3Neurons for the first time. Leveraging the multi-modal proteomics and live-cell imaging techniques, we comprehensively characterized how PGRN deficiency changes the molecular and functional landscape of neuronal lysosomes. We found that PGRN loss impairs the lysosome's degradative capacity with increased levels of v-ATPase subunits on the lysosome membrane, increased hydrolases within the lysosome, altered protein regulations related to lysosomal transport, and elevated lysosomal pH. Consistent with impairments in lysosomal function, GRN-null i3Neurons and frontotemporal dementia patient-derived i3Neurons carrying GRN mutation showed pronounced alterations in protein turnover, such as cathepsins and proteins related to supramolecular polymerization and inherited neurodegenerative diseases. This study suggested PGRN as a critical regulator of lysosomal pH and degradative capacity, which influences global proteostasis in neurons. Beyond the study of progranulin deficiency, these newly developed proteomic methods in neurons and brain tissues provided useful tools and data resources for the field to study the highly dynamic neuronal lysosome biology.


MIG: Multi-Image Genome viewer.
Multi-Image Genome (MIG) viewer is a web-based application for visualizing, querying and filtering many thousands of genome browser regions as well as for exporting the data in a variety of formats. This methodology has been used successfully to analyze ChIP-Seq data and RNA-Seq data and to detect somatic mutations in genome resequencing projects. MIG is available at https://mig.molbiol.ox.ac.uk/mig/


Glucokinase activation repairs defective bioenergetics of islets of Langerhans isolated from type 2 diabetics.
It was reported previously that isolated human islets from individuals with type 2 diabetes mellitus (T2DM) show reduced glucose-stimulated insulin release. To assess the possibility that impaired bioenergetics may contribute to this defect, glucose-stimulated respiration (Vo(2)), glucose usage and oxidation, intracellular Ca(2+), and insulin secretion (IS) were measured in pancreatic islets isolated from three healthy and three type 2 diabetic organ donors. Isolated mouse and rat islets were studied for comparison. Islets were exposed to a "staircase" glucose stimulus, whereas IR and Vo(2) were measured. Vo(2) of human islets from normals and diabetics increased sigmoidally from equal baselines of 0.25 nmol/100 islets/min as a function of glucose concentration. Maximal Vo(2) of normal islets at 24 mM glucose was 0.40 ± 0.02 nmol·min(-1)·100 islets(-1), and the glucose S(0.5) was 4.39 ± 0.10 mM. The glucose stimulation of respiration of islets from diabetics was lower, V(max) of 0.32 ± 0.01 nmol·min(-1)·100 islets(-1), and the S(0.5) shifted to 5.43 ± 0.13 mM. Glucose-stimulated IS and the rise of intracellular Ca(2+) were also reduced in diabetic islets. A clinically effective glucokinase activator normalized the defective Vo(2), IR, and free calcium responses during glucose stimulation in islets from type 2 diabetics. The body of data shows that there is a clear relationship between the pancreatic islet energy (ATP) production rate and IS. This relationship was similar for normal human, mouse, and rat islets and the data for all species fitted a single sigmoidal curve. The shared threshold rate for IS was ∼13 pmol·min(-1)·islet(-1). Exendin-4, a GLP-1 analog, shifted the ATP production-IS curve to the left and greatly potentiated IS with an ATP production rate threshold of ∼10 pmol·min(-1)·islet(-1). Our data suggest that impaired β-cell bioenergetics resulting in greatly reduced ATP production is critical in the molecular pathogenesis of type 2 diabetes mellitus.


Outcomes of endoscopic treatment for malignant biliary obstruction in patients with surgically altered anatomy: analysis of risk factors for clinical failure.
To evaluate the outcomes of endoscopic retrograde cholangiopancreatography (ERCP) for malignant biliary obstruction (MBO) using short-type double-balloon enteroscope (sDBE) in patients with surgically altered anatomy. A total of 45 patients with surgically altered anatomy underwent ERCP using sDBE for the treatment of MBO between April 2011 and March 2019. We retrospectively evaluated the clinical and technical success (insertion and biliary intervention success), adverse events, and risk factors for clinical failure. The scope was successfully inserted in the target site in 82.2% of patients (37/45), and among them, biliary intervention success was achieved in 86.4% (32/37). The overall technical success rate was 71.1% (32/45) and clinical success rate was 68.9% (31/45), with an adverse event rate of 11.1%. In multivariate analysis, the presence of peritoneal dissemination (odds ratio, 7.3; 95% confidence interval, 1.5-43.5, p = 0.02) was as an independent risk factor for clinical failure. The clinical success rate was 38.5% in patients with peritoneal dissemination and 81.3% in those without peritoneal dissemination. Endoscopic treatment using sDBE in patients without peritoneal dissemination provided favorable outcomes, and it can be an initial treatment for MBO in patients with surgically altered anatomy.


Characterization of the magic angle effect in the equine deep digital flexor tendon using a low-field magnetic resonance system.
Three isolated equine limbs were imaged with a low-field magnetic resonance system with a vertical magnetic field. Each limb was scanned in multiple positions with mild variation of the angle between the magnetic field and the long axis of the limb. When the long axis of the limb was not perpendicular to the magnetic field, a linear hyperintense signal was present at the palmar aspect of one of the deep digital flexor tendon lobes, at the level of the navicular bone and collateral sesamoidean ligaments, in proton density and T1-weighted pulse sequences. With increased angulation of the limb, the palmar hyperintense signal extended farther distally and proximally and additional signal hyperintensity was present at the dorsal aspect of the distal part of the other lobe of the deep digital flexor tendon. Increased signal intensity was also present in the collateral ligament of the distal interphalangeal joint on the same side as the palmar hyperintense signal in the tendon. The changes in the deep digital flexor tendon are due to the specific orientation of fibers at the palmar and dorsal aspect of the tendon, which is responsible for focal manifestation of the magic angle effect. Careful positioning of the limb perpendicular to the magnetic field can prevent this phenomenon. The association of palmar increased signal intensity in the deep digital flexor tendon with increased signal in the collateral ligament of the distal interphalangeal joint on the same side should be recognized as manifestations of the magic angle effect.


Resistances of antibiotics and heavy metals in Enterobacteriaceae spp. isolated from gills and intestines of Achanthobrama marmid (Heckel,1843) from Sir Dam lake Turkey.
A total of 94 bacteria, associated with wild Achanthobrama marmid (Heckel, 1843) in Sir Dam lake of Turkey identified. Subsequently selected isolates were characterized and identified to the genus level The 94 members of Enterobacteriaceae were isolated in the gills and intestines, and among the isolates, E. coli were represented at a rate of 55%, Shigella spp. at a rate of 21%, Salmonella spp. at a rate of 9%, Citrobacter spp. at a rate of 9%, Klebsiella spp. at a rate of 3% and Proteus spp., at a rate of 3%. A total of 94 bacteria resistant to antibiotics and heavy metals were isolated from total 47 of A. marmid samples and were investigated. Viable counts of antibiotic resistant bacteria isolated from gill and intestinal content samples showed high frequencies of resistance to Penicilline-G (KP) (68%), CZ (54%), FOX (48%), while the proportion of CRO (39%) and CTX (36%) resistance was low. In this research, heavy metal contamination in Sir Dam lake water samples and resistance frequency against heavy metals in isolated bacteria from gill and intestinal contents in A. marmid were investigated. Heavy metal contamination such as nickel (Ni), cadmium (Cd), copper (Cu) and chromium (Cr) determined diverse rate (except Mn) in water samples. The resistance frequency of the isolates was revealed different rate for the following heavy metals: Ni, Cd, Cu and Cr When the concentration of heavy metals increased, the resistance against heavy metals in diverse genus of isolates in different rate decreased.


Lycopene attenuates oxidative stress induced experimental cataract development: an in vitro and in vivo study.
Lycopene, a nutritional antioxidant, was evaluated for its anticataract potential to further establish its role in cataract prevention. The ability of lycopene to modulate the biochemical parameters was investigated by in vitro studies. Enucleated rat lenses were maintained in organ culture containing Dulbecco's Modified Eagles Medium alone or in addition with 100 microM selenite and served as the normal and control groups, respectively. For the test group, the control medium was supplemented with 10 microM lycopene. The lenses were incubated for 24 h at 37 degrees C. At the end of the incubation period, the lenses were examined for morphologic variation, and biochemical parameters such as reduced glutathione, the lipid peroxidation product malondialdehyde, and the antioxidant enzymes glutathione peroxidase, glutathione S-transferase, superoxide dismutase, and catalase were estimated. In vivo selenite cataract was induced in 9-d-old rats by subcutaneous injection of sodium selenite (25 micromoles/kg of body weight). The rats in the test group were injected with lycopene (200 microg/kg body weight, intraperitoneally) 4 h before the selenite challenge. The incidence of cataract was observed when the rats first opened their eyes. Galactose cataract was induced in rats by feeding 30% galactose in the diet. Rats in the test group were fed orally with 200 microg/kg of lycopene daily, and rats in the control group received only vehicle. Cataract stages were graded at regular intervals. A fall (25%) in the glutathione level and a rise (32%) in the malondialdehyde content were observed in control as opposed to normal lenses. Lycopene supplementation in the medium significantly (P < 0.001) restored glutathione and malondialdehyde levels. A significant decrease in the activity of antioxidant enzymes also was observed in the control lenses. A significant restoration in the activities of superoxide dismutase (P < 0.05) and catalase and glutathione S-transferase (P < 0.01), with no effect on glutathione peroxidase, was observed in the lycopene-supplemented group. Lycopene also reduced the incidence of selenite cataract. Only 9% of the eyes in the test group developed dense nuclear opacity as opposed to 83% in the control group. A significant delay in the onset and progression of galactose cataract was observed with oral feeding of lycopene. Only 35% of the eyes developed mature cataract as opposed to 100% in the control group. Lycopene protects against experimental cataract development by virtue of its antioxidant properties, and it may be useful for prophylaxis or therapy against cataracts.


Depression in men in the postnatal period and later child psychopathology: a population cohort study.
Postnatal depression in women is associated with adverse effects on both maternal health and children's development. It is unclear whether depression in men at this time poses comparable risks. The present study set out to assess the association between depression in men in the postnatal period and later psychiatric disorders in their children and to investigate predisposing factors for depression in men following childbirth. A population-based cohort of 10,975 fathers and their children from the Avon Longitudinal Study of Parents and Children (ALSPAC) was recruited in the prenatal period and followed for 7 years. Paternal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale and later child psychiatric disorder (DSM-IV) with the Development and Well-Being Assessment. Depression in fathers in the postnatal period was significantly associated with psychiatric disorder in their children 7 years later (adjusted OR 1.72, 95% CI 1.07-2.77), most notably oppositional defiant/conduct disorders (adjusted OR 1.94, 95% CI 1.04-3.61), after adjusting for maternal depression and paternal educational level. A history of severe depression and high prenatal symptom scores for depression and anxiety were the strongest predictors of paternal depression in the postnatal period. Depression in fathers in the postnatal period is associated with later psychiatric disorders in their children, independently of maternal postnatal depression. Further research into the risks associated with paternal psychopathology is required because this could represent an important opportunity for public health intervention.


Asymptomatic giant congenital left atrial aneurysm.
Yakut K, Varan B, Erdoğan İ. Asymptomatic giant congenital left atrial aneurysm. Turk J Pediatr 2019; 61: 117-119. Congenital aneurysm of the left atrial appendage can be caused by congenital dysplasia of the pectinate muscles and may be accompanied by a congenital absence of the pericardium. Symptoms generally manifest after two decades and the most common symptom is atrial arrhythmia in the form of atrial fibrillation / flutter. A four year-old patient with no symptoms underwent an echocardiographic examination for the investigation of a heart murmur. Echocardiographic examination revealed a large cystic lesion occupying the left hemithorax and compressing the left ventricle. The patient was referred to our center. The lesion caused displacement of the heart rightward behind the sternum which made the examination difficult. We aimed to present this rare case of giant left atrial appendage aneurysm in the light of current literature.


Responses of distraction regenerate to high-frequency traction at a rapid rate.
Continuous traction is capable of creating an optimal biological environment for bone healing which may finally compensate for the rapid distraction rate in distraction osteogenesis. This study was designed to investigate the response of distraction callus to continuous distraction at a rapid rate using a rabbit model of mandibular lengthening. Thirty adult New Zealand white rabbits were randomly assigned to the intermittent (1 step/d) or continuous distraction (8 steps/s) group, with 15 in each. After osteotomy, manual-driven or autodriven distractor was adapted accordingly. The distraction was activated at a rate of 3.0 mm/d for 4 days. Five rabbits in each group were killed at week 2, week 4, and week 12 of consolidation, respectively. Plain radiography, microcomputed tomography, and histology examinations were used to evaluate the bone regeneration status. Plain radiographs and histologic studies demonstrated more advanced bone healing in continuous distraction group than that in intermittent distraction group at all the examined time points. Quantitative microcomputed tomography analysis showed significantly higher bone volume in continuous distraction group at week 2 (p < 0.01) and week 4 (p < 0.05) of consolidation. Continuous traction by autodriven distractor could be a promising clinical alternative to shorten the treatment course of distraction osteogenesis. Further studies to test its clinical potential using large animals that have similar metabolic rate and muscular resistance with human being are necessary.


Genomic variability in field populations of Schistosoma mansoni in Brazil as detected with a ribosomal gene probe.
A cloned fragment of the ribosomal gene of Schistosoma mansoni, pSM 389, which contains part of the small rRNA gene plus a portion of the nontranscribed intergenic spacer, was used in Southern hybridization analyses to investigate genomic variation in natural populations of S. mansoni in Brazil. Genomic DNAs were isolated from schistosomes from infected patients (some of whom did not respond to antischistosomal chemotherapy), and from snails from disparate geographic locations in Brazil. Restriction fragment length polymorphisms (RFLPs) were evident in Southern blot hybridizations of these schistosome DNAs, and the RFLPs indicated that the genomic profiles of a number of Brazilian strains were more similar to each other than they were to parasites from two laboratory reference strains of Puerto Rican origin. In addition, the Brazilian isolates could generally be separated from each other based on these RFLPs. Isolates from the southeastern state of Minas Gerais were more similar to each other than they were to parasites isolated in the northeastern states of Alagoas and Pernambuco. Variation was evident among individual worms from some of the isolates, and these individual variations contributed to the complex RFLP patterns that were characteristic for particular isolates. The variation within a natural population isolated directly from snails at Ressaca, Belo Horizonte, may be more marked than that exhibited by more established strains maintained in the laboratory for numerous generations.


Anatomic development of the oral and pharyngeal portions of the vocal tract: an imaging study.
The growth of the vocal tract (VT) is known to be non-uniform insofar as there are regional differences in anatomic maturation. This study presents quantitative anatomic data on the growth of the oral and pharyngeal portions of the VT from 605 imaging studies for individuals between birth and 19 years. The oral (horizontal) portion of the VT was segmented into lip-thickness, anterior-cavity-length, oropharyngeal-width, and VT-oral, and the pharyngeal (vertical) portion of the VT into posterior-cavity-length, and nasopharyngeal-length. The data were analyzed to determine growth trend, growth rate, and growth type (neural or somatic). Findings indicate differences in the growth trend of segments/variables analyzed, with significant sex differences for all variables except anterior-cavity-length. While the growth trend of some variables displays prepubertal sex differences at specific age ranges, the importance of such localized differences appears to be masked by overall growth rate differences between males and females. Finally, assessment of growth curve type indicates that most VT structures follow a combined/hybrid (somatic and neural) growth curve with structures in the vertical plane having a predominantly somatic growth pattern. These data on the non-uniform growth of the vocal tract reveal anatomic differences that contribute to documented acoustic differences in prepubertal speech production.


Gastrointestinal hypoalgesia in inflammatory bowel disease.
Pain perception is critical for detection of noxious bodily insults. Gastrointestinal hypoalgesia in inflammatory bowel disease (IBD) is a poorly understood phenomenon previously linked to poor patient outcomes. We aimed to evaluate the risk factors associated with this condition and to discern characteristics that might differentiate these patients from pain-free quiescent counterparts. We performed a retrospective analysis using an IBD natural history registry based in a single tertiary care referral center. We compared demographic and clinical features in 3 patient cohorts defined using data from simultaneous pain surveys and ileocolonoscopy: a) active IBD without pain (hypoalgesic IBD); b) active IBD with pain; and c) inactive IBD without pain. One hundred fifty-three IBD patients had active disease and 43 (28.1%) exhibited hypoalgesia. Hypoalgesic IBD patients were more likely to develop non-perianal fistulae (P=0.03). On logistic regression analysis, hypoalgesic IBD was independently associated with male sex, advancing age and mesalamine use, and inversely associated with anxious/depressed state and opiate use. Hypoalgesic IBD patients were demographically and clinically similar to the pain-free quiescent IBD cohort (n=59). Platelet count and C-reactive protein were more likely to be pathologically elevated in hypoalgesic IBD (P=0.03), though >25% did not exhibit elevated inflammatory markers. Hypoalgesia is common in IBD, particularly in male and older individuals, and is associated with an increased incidence of fistulae and corticosteroid use. Novel noninvasive diagnostic tools are needed to screen for this population, as inflammatory markers are not always elevated.


Neurobrucellosis: an evaluation of a rare presentation of brucellosis from a tertiary care centre in Central Anatolia, Turkey.
Nervous system involvement is a rare manifestation of brucellosis. We describe our experience of the diagnosis, treatment and final outcome of patients with neurobrucellosis at the Erciyes University Gevher Nesibe Hospital, a tertiary referral centre in Central Anatolia, Turkey. Thirty-six adult patients were diagnosed with neurobrucellosis from January 1997 to December 2006. Headache and fever were the most common symptoms. Neck stiffness was present in 25 patients. Brucella spp was isolated from the blood of nine patients and from the cerebrospinal fluid of 11. Doxycycline (by mouth) plus rifampin (by mouth) with ceftriaxone (intravenously) were the most common treatment choices. Three patients died as a result of problems other than neurobrucellosis and relapse occurred in one patient. Neurobrucellosis presents with hetoregenous clinical signs.


Dietary methionine restriction reduces hepatic steatosis and oxidative stress in high-fat-fed mice by promoting H2S production.
Methionine is an essential amino acid that plays important roles in mammalian metabolism. Interestingly, previous studies have consistently shown that a methionine-restricted diet (MRD) reduces hepatic lipid levels, reactive oxygen species production, and oxidative stress damage. However, the mechanisms responsible for these beneficial effects are unknown. Therefore, our study was aimed at investigating the hepatic systemic metabolic responses to MRD in high-fat-diet (HFD) mice and to clarify the possible mechanisms of such responses. C57BL/6J mice were fed a control diet (0.86% methionine + 4% fat), HFD (0.86% methionine + 20% fat), or MRD (0.17% methionine + 20% fat) for 22 consecutive weeks, and euthanized at week 11 or week 22. Our results showed that HFD inhibited hepatic energy expenditure, induced steatosis and oxidative stress, and decreased hydrogen sulfide (H2S) production in the mouse liver. MRD reduced the body weight, liver fat percentage, and plasma and hepatic lipid profiles. Moreover, MRD decreased lipid synthesis, increased energy metabolism (e.g. lipid catabolism and fatty acid oxidation, glycolysis and tricarboxylic acid cycle metabolism, and amino acid catabolism), enhanced the activity of antioxidant enzymes, and reduced the levels of oxidative damage products and purine metabolism in the liver. Furthermore, MRD up-regulated the hepatic gene and protein expression of cystathionine-γ-lyase (CSE), elevated the hepatic CSE activity, and promoted hepatic H2S production. These findings suggest that MRD can ameliorate the hepatic metabolic disorders induced by HFD and especially reduce hepatic steatosis and oxidative stress likely through increasing hepatic H2S production.


Removal of fluoride ions from aqueous solution at low pH using schwertmannite.
Wastewater containing fluoride requires polishing after precipitation/coagulation treatment in order to meet stringent environmental legislation. Accordingly, adsorption characteristics of fluoride onto schwertmannite adsorbent were studied in a batch system with respect to changes in initial concentration of fluoride, equilibrium pH of sample solution, adsorbent dosage and co-existing ions. Equilibrium adsorption data were obtained at 295.6, 303 and 313 K, and are interpreted in terms of two-site Langmuir, Freundlich, Langmuir-Freundlich, Redlich-Peterson, Tóth and Dubinin-Radushkevitch isotherm models. The experimental and equilibrium modeling results revealed that the capacity of schwertmannite for fluoride is high but insensitive to changes in solution temperature. An increase in equilibrium pH of sample solution reduced significantly the fluoride removal efficiency. In binary component systems, inner-sphere complex forming species had negative effects on fluoride adsorption while outer-sphere complex forming species improved slightly the fluoride removal efficiency. The schwertmannite adsorbent was regenerable and had the ability to lower the fluoride concentration to acceptable levels.


Evolthon: A community endeavor to evolve lab evolution.
In experimental evolution, scientists evolve organisms in the lab, typically by challenging them to new environmental conditions. How best to evolve a desired trait? Should the challenge be applied abruptly, gradually, periodically, sporadically? Should one apply chemical mutagenesis, and do strains with high innate mutation rate evolve faster? What are ideal population sizes of evolving populations? There are endless strategies, beyond those that can be exposed by individual labs. We therefore arranged a community challenge, Evolthon, in which students and scientists from different labs were asked to evolve Escherichia coli or Saccharomyces cerevisiae for an abiotic stress-low temperature. About 30 participants from around the world explored diverse environmental and genetic regimes of evolution. After a period of evolution in each lab, all strains of each species were competed with one another. In yeast, the most successful strategies were those that used mating, underscoring the importance of sex in evolution. In bacteria, the fittest strain used a strategy based on exploration of different mutation rates. Different strategies displayed variable levels of performance and stability across additional challenges and conditions. This study therefore uncovers principles of effective experimental evolutionary regimens and might prove useful also for biotechnological developments of new strains and for understanding natural strategies in evolutionary arms races between species. Evolthon constitutes a model for community-based scientific exploration that encourages creativity and cooperation.


The SIESTA Trial: A Randomized Study Investigating the Efficacy, Safety, and Tolerability of Acupressure versus Sham Therapy for Improving Sleep Quality in Patients with End-Stage Kidney Disease on Hemodialysis.
Objectives. To compare the effectiveness of real acupressure versus sham acupressure therapy in improving sleep quality in patients receiving hemodialysis (HD) or hemodiafiltration (HDF). Methods. A multicenter, single-blind, randomized controlled trial was conducted in two Australian dialysis units located in Princess Alexandra Hospital and Logan Hospital, respectively. Forty-two subjects with self-reported poor sleep quality were randomly assigned to real (n = 21) or sham (n = 21) acupressure therapy delivered thrice weekly for four consecutive weeks during routine dialysis sessions. The primary outcome was the Pittsburgh Sleep Quality Index (PSQI) score measured at week four adjusted for baseline PSQI measurements. Secondary outcomes were quality of life (QOL) (SF-8), adverse events, and patient acceptability (treatment acceptability questionnaire, TAQ). Results. The two groups were comparable on global PSQI scores (difference 0.19, 95% confidence interval [CI] -1.32 to 1.70) and on the subscale scores. Similar results were observed for QOL both in the mental (difference -3.88, 95% CI -8.63 to 0.87) and the physical scores (difference 2.45, 95% CI -1.69 to 6.58). There were no treatment-related adverse events and acupressure was perceived favorably by participants. Conclusion. Acupressure is a safe, well-tolerated, and highly acceptable therapy in adult hemodialysis patients in a Western healthcare setting with uncertain implications for therapeutic efficacy.


Six-year follow-up of the clinical significance of karyotype in acute lymphoblastic leukemia.
To evaluate the importance of pretreatment karyotype in predicting long-term outcome in acute lymphoblastic leukemia (ALL), we performed a follow-up study of the 329 patients from the Third International Workshop on Chromosomes in Leukemia. Living patients have now been followed a minimum of 6 years. Patients were divided into ten groups according to pretreatment karyotype: no abnormalities, one of the following structural abnormalities [the Philadelphia chromosome, rearrangements involving 8q24, t(4;11), 14q+, 6q-] or, in the remaining cases, modal number (less than 46, 46, 47-50, greater than 50). As previously reported for achievement and duration of complete remission, and overall survival, disease-free survival differed significantly (p less than 0.001) among chromosome groups for both adults and children. Among children, karyotype was an independent prognostic factor for predicting disease-free survival. Because of the long follow-up, we now have been able to utilize statistical models to estimate the percentage of patients cured, according to karyotype alone and combined with other risk factors. Adults with the highest likelihood of cure (21-33%) were those patients with FAB-L1, a leukocyte count of 50,000/microliters or less, and one of the following chromosome groups: greater than 50, 47-50, 6q-, or normal. In children these same characteristics were associated with the highest percentage of cure (58-71% cured). In addition, we identified several groups of children with less than 15% chance of cure who clearly need to be treated as high-risk patients at diagnosis. Future studies of patients who have received risk-adapted therapy based on these chromosome data are needed to determine if more intensive treatment will improve the outlook of patients with cytogenetically unfavorable types of ALL.


Positional Role Differences in the Aerobic and Anaerobic Power of Elite Basketball Players.
The aim of the present study was to compare the aerobic and anaerobic power and capacity of elite male basketball players who played multiple positions. Fifty-five healthy players were divided into the following three different subsamples according to their positional role: guards (n = 22), forwards (n = 19) and centers (n = 14). The following three tests were applied to estimate their aerobic and anaerobic power and capacities: the countermovement jump (CMJ), a multistage shuttle run test and the Running-based Anaerobic Sprint Test (RAST). The obtained data were used to calculate the players' aerobic and anaerobic power and capacities. To determine the possible differences between the subjects considering their different positions on the court, one-way analysis of variance (ANOVA) with the Bonferroni post-hoc test for multiple comparisons was used. The results showed that there was a significant difference between the different groups of players in eleven out of sixteen measured variables. Guards and forwards exhibited greater aerobic and relative values of anaerobic power, allowing shorter recovery times and the ability to repeat high intensity, basketball-specific activities. Centers presented greater values of absolute anaerobic power and capacities, permitting greater force production during discrete tasks. Coaches can use these data to create more individualized strength and conditioning programs for different positional roles.


Predictors of perceived social effectiveness of individuals with serious mental illness.
Social effectiveness continues to play a critical role in recovery of people with serious mental illness (SMI), with greater social effectiveness predicting many positive life outcomes. Despite the abundance of literature supporting the relationship between perceptions and behavior, little is known about predictors of perceived social effectiveness of individuals with SMI. The purpose of this study is to examine the predictors of perceived social effectiveness of individuals with SMI. Cross-sectional data of 192 participants with SMI recruited from four psychiatric rehabilitation clubhouses in 2 states in the South and Midwest regions of the United States were used for this study. Self-report data on category of psychiatric disabilities, psychiatric symptoms, cognition, insight, educational attainment, empathy, interpersonal interactions and relationships, self-stigma, disability acceptance, and perceived social effectiveness were collected and analyzed using multiple regression analysis (MRA). MRA yielded a regression model that accounted for 56% of the variance in perceived social effectiveness, which is considered a large effect size. Controlling for all other factors, mood disorder, educational attainment, empathy, interpersonal interactions and relationships, and disability acceptance were found to be significant predictors of perceived social effectiveness of persons with SMI. Practitioners should consider determining points of intervention and targeting specific elements that enhance perceived social effectiveness. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Examining the association between adiposity and biochemical recurrence after radical prostatectomy.
Herein, we examined the association between adiposity, as measured by computed tomography (CT), and biochemical recurrence (BCR) after radical prostatectomy (RP). Using axial CT images, preoperative fat mass index (FMI) was calculated for 698 men who underwent RP from 2007-2010 by using measurements of total surface area of adipose tissue at the L3 level. Obesity was classified according to National Health and Nutrition Examination Survey (NHANES) standards for obesity (FMI >9 kg/m2). The associations between obesity and the distribution of adiposity (visceral vs. subcutaneous) with BCR were examined using the Kaplan-Meier method and Cox proportional hazards regression analyses. Obese men were older than non-obese men (63.0 vs. 60.7 years; p<0.001), but were similar with regards to all other clinical and pathological characteristics. With a median followup of six years, 152 patients were diagnosed with BCR. Five-year BCR-free survival was similar between obese and non-obese patients (80.6% vs. 82.1%; p=0.27). Furthermore, in multivariable analyses, obesity was not independently associated with the risk of BCR (hazard ratio [HR] 1.02; 95% confidence interval [CI] 0.73-1.43). Similar results were obtained when analyzing FMI as a continuous variable (HR 1.02; 95% CI 0.94-1.09 for each 1 kg/m2 increase in FMI). Additionally, neither visceral adiposity, subcutaneous adiposity, or visceral-to-subcutaneous adiposity ratio were associated with BCR (all p>0.05) in multivariable analyses. Neither total abdominal adiposity nor the distribution of adiposity were independently associated with BCR after RP in this study. As such, the presence of obesity may not be a marker of increased oncological risk after RP.


Non-Publication Is Common among Phase 1, Single-Center, Not Prospectively Registered, or Early Terminated Clinical Drug Trials.
The objective of this study was to investigate the occurrence and determinants of non-publication of clinical drug trials in the Netherlands.All clinical drug trials reviewed by the 28 Institutional Review Boards (IRBs) in the Netherlands in 2007 were followed-up from approval to publication. Candidate determinants were the sponsor, phase, applicant, centers, therapeutic effect expected, type of trial, approval status of the drug(s), drug type, participant category, oncology or other disease area, prospective registration, and early termination. The main outcome was publication as peer reviewed article. The percentage of trials that were published, crude and adjusted odds ratio (OR), and 95% confidence interval (CI) were used to quantify the associations between determinants and publication. In 2007, 622 clinical drug trials were reviewed by IRBs in the Netherlands. By the end of follow-up, 19 of these were rejected by the IRB, another 19 never started inclusion, and 10 were still running. Of the 574 trials remaining in the analysis, 334 (58%) were published as peer-reviewed article. The multivariable logistic regression model identified the following determinants with a robust, statistically significant association with publication: phase 2 (60% published; adjusted OR 2.6, 95% CI 1.1-5.9), phase 3 (73% published; adjusted OR 4.1, 95% CI 1.7-10.0), and trials not belonging to phase 1-4 (60% published; adjusted OR 3.2, 95% CI 1.5 to 6.5) compared to phase 1 trials (35% published); trials with a company or investigator as applicant (63% published) compared to trials with a Contract Research Organization (CRO) as applicant (50% published; adjusted OR 1.7; 95% CI 1.1-2.8); and multicenter trials also conducted in other EU countries (68% published; adjusted OR 2.2, 95% CI 1.1-4.4) or also outside the European Union (72% published; adjusted OR 2.0, 95% CI 1.0-4.0) compared to single-center trials (45% published). Trials that were not prospectively registered (48% published) had a lower likelihood of publication compared to prospectively registered trials (75% published; adjusted OR 0.5, 95% CI 0.3-0.8), as well as trials that were terminated early (33% published) compared to trials that were completed as planned (64% published; adjusted OR 0.2, 95% CI 0.1-0.3). The non-publication rate of clinical trials seems to have improved compared to previous inception cohorts, but is still far from optimal, in particular among phase 1, single-center, not prospectively registered, and early terminated trials.


Early administration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and meta-analysis.
To determine whether early administration of aspirin prevents severe and mild preeclampsia. A systematic review and meta-analysis of randomized controlled trials were performed. Studies in which women were randomized at or before 16 weeks' gestation to low-dose aspirin versus placebo or no treatment were included. The outcomes of interest were severe preeclampsia and mild preeclampsia. Pooled relative risks with their 95% confidence intervals (CIs) were calculated. Among 7941 citations retrieved, 352 were completely reviewed and four studies (392 women) fulfilled the inclusion criteria and were analyzed. When compared with controls, aspirin started at ≤16 weeks was associated with a significant reduction in severe (relative risk: 0.22, 95% CI: 0.08 to 0.57) but not mild (relative risk: 0.81, 95% CI: 0.33 to 1.96) preeclampsia. Low-dose aspirin initiated at or before 16 weeks reduces the risk of severe preeclampsia, but not mild preeclampsia.


Laparoscopic robotic-assisted pancreaticoduodenectomy: a case-matched comparison with open resection.
Minimally invasive procedures have expanded recently to include pancreaticoduodenectomy (PD), but the efficacy of a laparoscopic robotic-assisted approach has not been demonstrated. A case-matched comparison was undertaken to study outcomes between laparoscopic robotic approach (LRPD) and the conventional open counterpart (OPD). From March 2009 through December 2010, 30 LRPD were performed by two pancreaticobiliary surgeons at the Cleveland Clinic. Thirty OPD patients operated by four pancreaticobiliary surgeons during this same period were matched by demographics, and postoperative outcomes were compared from review of a prospectively collected database. Mean age was 62 years for LRPD versus 61 years for OPD (p = 0.43). Mean body mass index was 24.8 versus 25.6 kg/m(2) (p = 0.49). Surgical indications included adenocarcinoma in 14 patients from each group (46%), intraductal papillary mucinous neoplasm in 4 (14%), and other in 12 (40%). There was one preoperative death in the LRPD group and none following OPD. Morbidity occurred in nine patients (30%) following LRPD versus 13 (44%) in the OPD group (p = 0.14). Intraoperative factors assessed included blood loss (485.8 vs 775 ml, p = 0.13) and operative time (476.2 vs 366.4 min, p = 0.0005). Conversion from LRPD to open occurred in three patients (12%) due to bleeding. Reoperation was performed in two patients (6%) following LRPD versus seven (24%) following OPD (p = 0.17). Length of hospital stay was 9.79 days for LRPD versus 13.26 days in the OPD group (p = 0.043). This is the first comparison of a novel laparoscopic robotic-assisted PD with the open PD in a case-matched fashion. Our data demonstrate a significant increase in operative time but decreased length of stay for LRPD. The favorable morbidity following LRPD makes it a reasonable surgical approach for selected patients requiring PD.


Phosphorylated immunoreceptor signaling motifs (ITAMs) exhibit unique abilities to bind and activate Lyn and Syk tyrosine kinases.
Signal transduction by T and B cell Ag receptors and certain receptors for Ig Fc regions (Fc gamma RI, hFc gamma RIIA, Fc gamma RIII, Fc alpha R, and Fc epsilon RI) involves a conserved sequence motif, termed an immunoreceptor tyrosine-based activation motif (ITAM) and found in multiple receptor chains. Phosphorylation of the two ITAM tyrosines is a critical event in signal transduction. To address the function of this phosphorylation, we assessed the ability of nonphosphorylated and biphosphorylated ((p)2ITAM) ITAM peptides to bind and modify the activity of src and syk family kinases in vivo and in vitro. All (p)2ITAMs, but not their nonphosphorylated counterparts, induced extensive protein tyrosine phosphorylation in permeabilized cells. However, the patterns of proteins phosphorylated differed among (p)2ITAMs. This phosphorylation was found to reflect activation of the src family kinase Lyn, but not Syk. In vitro studies using purified Lyn showed that src family kinase activation resulted from a direct interaction with (p)2ITAM. Binding studies demonstrated clear differences in binding specificity of (p)2ITAMs. Most strikingly, Ig alpha (p)2ITAM and TCR-zeta c and CD3 epsilon (p)2ITAMs exhibit inverse binding preferences for src and syk family kinases. Taken together, these findings demonstrate a novel mechanism by which src family tyrosine kinases are activated, and are consistent with the possibility that different ITAMs may preferentially activate distinct signaling pathways as a consequence of distinct effector Src homology 2 domain (SH2) binding preference.


Acute Liver Failure.
Acute liver failure, also known as fulminant hepatic failure, is a rare life-threatening disease that has a high mortality rate and affects many organ systems. Causes of acute liver failure vary-it can be attributed to drugs, viruses, and other uncommon sources. Complications of liver failure can include encephalopathy, cerebral edema, sepsis, renal failure, gastrointestinal bleeding, and respiratory failure. Fortunately, with advances in critical care medicine and emergent liver transplant, mortality rates have decreased in the past decade. This article reviews acute liver failure, its manifestations in different organ systems, and its treatment.


Colonoscopic versus nasogastric fecal transplantation for the treatment of Clostridium difficile infection: a review and pooled analysis.
Fecal microbiota transplantation (FMT) has been demonstrated to be highly effective for the treatment of recurrent Clostridium difficile infection (CDI). However, the best route of administration has not been established. We present a pooled analysis of the reported cases of CDI treated with FMT via colonoscopy or nasogastric tube (NGT) to evaluate treatment efficacy. PubMed was searched for English-written articles published up to December 2011. Studies that reported cases of FMT for recurrent CDI using either colonoscopy or NGT-guided fecal infusion were reviewed. A total of 182 patients from 12 published studies were identified; 148 patients received FMT via colonoscopy (colonoscopy group) and 34 patients received FMT via NGT (NGT group). The median age in the colonoscopy group as compared with the NGT group was 72 and 82 years, respectively. There were differences regarding pre-FMT treatment for CDI; 134 patients (90.5 %, 134/148) received lavage with/without antibiotic in the colonoscopy group and 34 patients (100.0 %, 34/34) received antibiotic without lavage in the NGT group, P < 0.001. A higher stool volume was used for FMT in the colonoscopy group (121 patients, 81.8 %, used 100-400 ml) than in the NGT group (33 patients, 97.0 %, used <100 ml), P < 0.001. The treatment efficacy did not differ significantly; 93.2 % (138/148) success for the colonoscopy group as compared to 85.3 % success (29/34) for the NGT group, P = 0.162. Recurrence of CDI after FMT was also similar in both the colonoscopy group (8/148 5.4 %) versus the NGT group (2/34, 5.9 %), P = 1.000. Despite procedural differences, FMT via colonoscopy or NGT appears to be highly effective and safe for the management of recurrent CDI.


Gold-containing indoles as anticancer agents that potentiate the cytotoxic effects of ionizing radiation.
This report describes the design and application of several distinct gold-containing indoles as anticancer agents. When used individually, all gold-bearing compounds display cytostatic effects against leukemia and adherent cancer cell lines. However, two gold-bearing indoles show unique behavior by increasing the cytotoxic effects of clinically relevant levels of ionizing radiation. Quantifying the amount of DNA damage demonstrates that each gold-indole enhances apoptosis by inhibiting DNA repair. Both Au(I)-indoles were tested for inhibitory effects against various cellular targets including thioredoxin reductase, a known target of several gold compounds, and various ATP-dependent kinases. While neither compound significantly inhibits the activity of thioreoxin reductase, both showed inhibitory effects against several kinases associated with cancer initiation and progression. The inhibition of these kinases provides a possible mechanism for the ability of these Au(I)-indoles to potentiate the cytotoxic effects of ionizing radiation. Clinical applications of combining Au(I)-indoles with ionizing radiation are discussed as a new strategy to achieve chemosensitization of cancer cells.


Psychiatric outpatients report their experiences as participants in a randomized clinical trial.
We conducted exit interviews with 45 outpatients with severe and persistent mental illness (SPMI) who had participated in a randomized clinical trial. The interviews followed a semistructured format and were audiotaped for later transcription and rating by two independent raters. Content analyses of the interviews revealed that most participants evaluated their experiences quite favorably. For example, most noted that the assessment process was thought-provoking and motivational and that the intervention groups led to increased self-confidence and new friendships. Although a few participants noted that the assessment contained sensitive material, all appreciated the frequent reminders that information disclosed was strictly confidential. These results indicate that persons living with a SPMI often enjoy participating in behavioral research, which can yield immediate benefits to patient-participants. Exit interview research such as this can help investigators to understand reasons for consent and participation, to identify needs for protocol modifications, and to facilitate the integration of evidence-based interventions into the mental health care systems.


The cause of infant and toddler subdural hemorrhage: a prospective study.
To determine the frequency of child abuse and unintentional injury as a cause of infant and toddler subdural hemorrhage (SDH). A prospective case series of a level I regional trauma center, regional children's hospital, and county medical examiner's office assessed consecutive children who were </=36 months old and had SDH. Children who had previously known hemorrhagic disease, previous neurosurgical procedure, previously recognized perinatal brain injury, meningitis, renal dialysis, and severe dehydration were excluded. Concurrent medical, retinal, skeletal, and social work abuse evaluation were measured. Etiologic assessment using predetermined criteria was conducted. From March 1995 through December 1998, 66 children were admitted with SDH. Abuse was confirmed in 39 (59%), unintentional injury in 15 (23%), and indeterminate cause in 12 (18%). The mean age of abused children was 8.7 +/- 8.1 months and of children with unintentional injuries was 19.1 +/- 10.0 months. The predominant presenting histories for abusive injury were a minor fall or no mechanism for 33 (84%) of 39 patients. All unintentional injuries resulted from a motor vehicle accident or other documented major trauma. Chronic or mixed acute and chronic SDH were found only in abused children (17 [44%] of 39) and in children whose injuries were indeterminate (8 [67%] of 12), not in children who were unintentionally injured (0 [0%] of 15). Long bone and/or rib fractures were found in 20 (51%) of 39 abused children but in only 1 unintentionally injured child. Retinal bleeding was present in 28 (72%) of 39 of the abused children. Only 1 of the 3 unintentionally injured children who had a retinal examination had bleeding, which was of the type associated with acute increased intracranial pressure. Nearly one fifth of infant and toddler SDH resulted from unintentional trauma. Of those without obvious unintentional trauma, 76% were corroborated to have been abused. Abused children were younger, more likely to have chronic SDH, and more likely to have multiple associated injuries. Their injury history usually was minor or absent.


Evaluation of a patient navigation program.
This study examined the value and effectiveness of a patient navigation program in terms of timeliness of access to cancer care, resolution of barriers, and satisfaction in 55 patients over a six-month period. Although not statistically significant, the time interval between diagnostic biopsy to first consultation with a cancer specialist after program implementation was reduced from an average of 14.6 days to 12.8 days. The time interval between diagnostic biopsy to initiation of cancer treatment also was reduced from 30 days to 26.2 days (not statistically significant). In addition, 71% of patient barriers were resolved by the time treatment was initiated. Overall, patients were highly satisfied with their navigated care experience. Consistent evaluation and monitoring of quality-of-care indicators are critical to further develop the program and to direct resource allocation. Oncology nurses participating in patient navigation programs should be encouraged to evaluate their importance and impact in this developing concept. Nurses should seek roles that allow them to optimize the effective use of their specialized knowledge and skills to the benefit of patients along the cancer care continuum.


Strengthening vaccination policies in Latin America: an evidence-based approach.
Despite many successes in the region, Latin American vaccination policies have significant shortcomings, and further work is needed to maintain progress and prepare for the introduction of newly available vaccines. In order to address the challenges facing Latin America, the Commission for the Future of Vaccines in Latin America (COFVAL) has made recommendations for strengthening evidence-based policy-making and reducing regional inequalities in immunisation. We have conducted a comprehensive literature review to assess the feasibility of these recommendations. Standardisation of performance indicators for disease burden, vaccine coverage, epidemiological surveillance and national health resourcing can ensure comparability of the data used to assess vaccination programmes, allowing deeper analysis of how best to provide services. Regional vaccination reference schemes, as used in Europe, can be used to develop best practice models for vaccine introduction and scheduling. Successful models exist for the continuous training of vaccination providers and decision-makers, with a new Latin American diploma aiming to contribute to the successful implementation of vaccination programmes. Permanent, independent vaccine advisory committees, based on the US Advisory Committee on Immunization Practices (ACIP), could facilitate the uptake of new vaccines and support evidence-based decision-making in the administration of national immunisation programmes. Innovative financing mechanisms for the purchase of new vaccines, such as advance market commitments and cost front-loading, have shown potential for improving vaccine coverage. A common regulatory framework for vaccine approval is needed to accelerate delivery and pool human, technological and scientific resources in the region. Finally, public-private partnerships between industry, government, academia and non-profit sectors could provide new investment to stimulate vaccine development in the region, reducing prices in the long term. These reforms are now crucial, particularly as vaccines for previously neglected, developing-world diseases become available. In summary, a regionally-coordinated health policy will reduce vaccination inequality in Latin America.


The lipidome of an omnivorous insect responds to diet composition and social environment.
Lipids are biomolecules with essential roles in metabolic processes, signaling, and cellular architecture. In this study, we investigated changes in the lipidome of the house cricket Acheta domesticus subjected to diets of different nutritional composition (i.e., protein to carbohydrate ratio) and two distinct social environments (i.e., solitary or in groups). We measured relative abundances of 811 lipid species in whole-body cricket samples using flow injection analysis coupled to tandem mass spectrometry. We assessed differences in the relative abundances of lipid species induced by diet composition and social environment in female and male A. domesticus. Additionally, we performed a functional analysis of the lipids with significant differences using a recently developed database. We found that most differences in the relative abundances of lipid species were explained by sex alone. Furthermore, the lipidome of female A. domesticus was responsive to diet composition. Females fed with the balanced diet had an even higher abundance of lipids involved in lipid storage than their counterparts fed with a protein-rich diet. Interestingly, the male cricket lipidome was not responsive to diet composition. In addition, the social environment did not induce significant changes in the lipid profile neither in female nor in male crickets.


Association of single nucleotide polymorphisms of MD-1 gene with pediatric and adult asthma in the Taiwanese population.
MD-1 (myeloid differentiation 1; also known as Ly86, lymphocyte antigen 86), interacting with radioprotective 105, plays an important role in the Toll-like receptor 4 signaling pathway. It has been suggested that MD-1 is involved in the development of inflammation and atopic diseases. The purpose of this study was to investigate the genetic association of single nucleotide polymorphisms (SNPs) of MD-1 and asthma in the Taiwanese population. Genotyping 34 SNPs in the MD-1 gene region was performed in a case-control study involving 281 children with asthma and 237 controls. A further 309 children and adults were genotyped for the SNP rs7740529 only, for validation of an identified association. In intron 1, we identified an SNP, rs7740529, which is associated with asthma in Taiwanese children (p=0.0358). Inclusion of a further 309 subjects increased the significance of the association (p=0.0093), and also demonstrated that rs7740529 is associated with adult asthma. The TT genotype confers risk of both pediatric and adult asthma. These results suggest that MD-1 could be a susceptible gene for asthma in the Taiwanese population.


The Bacillus subtilis conjugative transposon ICEBs1 mobilizes plasmids lacking dedicated mobilization functions.
Integrative and conjugative elements (ICEs, also known as conjugative transposons) are mobile elements that are found integrated in a host genome and can excise and transfer to recipient cells via conjugation. ICEs and conjugative plasmids are found in many bacteria and are important agents of horizontal gene transfer and microbial evolution. Conjugative elements are capable of self-transfer and also capable of mobilizing other DNA elements that are not able to self-transfer. Plasmids that can be mobilized by conjugative elements are generally thought to contain an origin of transfer (oriT), from which mobilization initiates, and to encode a mobilization protein (Mob, a relaxase) that nicks a site in oriT and covalently attaches to the DNA to be transferred. Plasmids that do not have both an oriT and a cognate mob are thought to be nonmobilizable. We found that Bacillus subtilis carrying the integrative and conjugative element ICEBs1 can transfer three different plasmids to recipient bacteria at high frequencies. Strikingly, these plasmids do not have dedicated mobilization-oriT functions. Plasmid mobilization required conjugation proteins of ICEBs1, including the putative coupling protein. In contrast, plasmid mobilization did not require the ICEBs1 conjugative relaxase or cotransfer of ICEBs1, indicating that the putative coupling protein likely interacts with the plasmid replicative relaxase and directly targets the plasmid DNA to the ICEBs1 conjugation apparatus. These results blur the current categorization of mobilizable and nonmobilizable plasmids and indicate that conjugative elements play a role in horizontal gene transfer even more significant than previously recognized.


Necessary and Sufficient Conditions for an Extended Noncontextuality in a Broad Class of Quantum Mechanical Systems.
The notion of (non)contextuality pertains to sets of properties measured one subset (context) at a time. We extend this notion to include so-called inconsistently connected systems, in which the measurements of a given property in different contexts may have different distributions, due to contextual biases in experimental design or physical interactions (signaling): a system of measurements has a maximally noncontextual description if they can be imposed a joint distribution on in which the measurements of any one property in different contexts are equal to each other with the maximal probability allowed by their different distributions. We derive necessary and sufficient conditions for the existence of such a description in a broad class of systems including Klyachko-Can-Binicioğlu-Shumvosky-type (KCBS), EPR-Bell-type, and Leggett-Garg-type systems. Because these conditions allow for inconsistent connectedness, they are applicable to real experiments. We illustrate this by analyzing an experiment by Lapkiewicz and colleagues aimed at testing contextuality in a KCBS-type system.


Long-term effectiveness of projection control suture in rhinoplasty.
The aim of this study is to report the long-term effectiveness of septocolumellar projection control suture (PCS). Fourteen cases underwent rhinoplasty including projection control suture have been included into the study. The long-term effectiveness of PCS is investigated on patients' early and late postoperative photographs. Mean durations between operation and early and late postoperative photographic documentations were 1.28 +/- 06 (range 1-3) and 23.27 +/-7.84 (range 12-48) months, respectively. The measurement of the nasal tip projection by using Goode and Byrd-Hobar techniques were accomplished on the lateral view photographs. The Scion Image software program was utilized for numerical analysis. There was no statistically significant change in nasal tip projection on early and late postoperative periods. The Goode and Byrd-Hobar ratios were measured as 0.584 and 0.572 in preoperative photographs. There were statistical significant differences between the preoperative and postoperative results (p = 0.001 for Goode and p = 0.0001 for Byrd-Hobar). The mean Goode's ratio was 0.614 +/- 0.035 in the early postoperative period, and 0.616 +/- 0.035 in the late postoperative period. The mean Byrd-Hobar's ratio was 0.673 +/- 0.037 in the early postoperative period, and 0,668 +/- 0,039 in the late postoperative period (p = 0.336 for Goode, p = 0.374 for Byrd-Hobar). There was no projection loss in any of our cases after a two years follow-up period. According to these preliminary results on a limited number of patients, PCS seems to be a reliable and effective surgical method to create the desired nasal tip projection for a long time.


Clinical decision support for colon and rectal surgery: an overview.
Clinical decision support (CDS) has been shown to improve clinical processes, promote patient safety, and reduce costs in healthcare settings, and it is now a requirement for clinicians as part of the Meaningful Use Regulation. However, most evidence for CDS has been evaluated primarily in internal medicine care settings, and colon and rectal surgery (CRS) has unique needs with CDS that are not frequently described in the literature. The authors reviewed published literature in informatics and medical journals, combined with expert opinion to define CDS, describe the evidence for CDS, outline the implementation process for CDS, and present applications of CDS in CRS.CDS functionalities such as order sets, documentation templates, and order facilitation aids are most often described in the literature and most likely to be beneficial in CRS. Further research is necessary to identify and better evaluate additional CDS systems in the setting of CRS.


The validity of a portable clinical force plate in assessment of static postural control: concurrent validity study.
The broad use of force plates in clinical settings for postural control assessment suggests the need for instruments that are easy to use, affordable and readily available. In addition, these instruments of measurement should be reliable and valid as adequate reliability and validity are prerequisites to making correct inferences. The aim of this study was to examine the concurrent validity of postural control measures obtained with a clinical force plate. Thirty-one healthy adults were recruited. Participants completed 1 set of 5 trials on each force plate. Postural control measures (centre of pressure [COP] average velocity and sway area) were collected and compared using the Midot Posture Scale Analyzer (clinical force plate) and the Accugait force plate (criterion measure). Intra class correlation coefficient (ICC), standard error of measurement , and paired t-tests were calculated and Bland-Altman plots were constructed to compare the force plates and assess consistency of measurement and agreement between them. The ICC values (ICC = 0.14-0.60) between the two force plates were lower than the acceptable value for both COP average velocity and sway area. There was significant difference (p > 0.05) in COP average velocity and sway area between the force plates. Examination of the plots revealed that there is less difference between the force plates in lower magnitudes of COP for average velocity and sway area however, the greater the average velocity and sway area, the greater the difference between the measures obtained from the two force plates. Findings of this study showed poor concurrent validity of the clinical force plate. This clinical force plate cannot be a replacement for known reliable and valid force plates and consequently measures obtained from this force plate should be treated with caution especially in a clinical population.


Seed maturation: developing an intrusive phase to accomplish a quiescent state.
Plants, as sessile life forms, have evolved diverse mechanisms to circumvent unfavourable growth conditions, among them interruption of the life cycle is one of the most successful strategies. During seed formation, embryo development can proceed through a maturation phase that allows the entry into a quiescent state and represents an evolutionary advantage, since it facilitates dispersal and resuming of growth under optimal environmental conditions. In the maturation phase different gene expression programmes devoted to the accumulation of storage compounds, acquisition of desiccation tolerance and entry into quiescence occur, which are highly coordinated and under fine regulatory control. This paper is focused on recent findings related to central transcription factors which regulate gene expression during maturation. The structure of established regulatory networks is presented based on extensive gene promoter analyses and the characterisation of mutants affecting seed development and maturation. Different aspects of gene regulation both in the embryo and endosperm are covered and comparisons between monocot and dicot species on the basis of current knowledge of the system are also presented.


GABA-mediated presynaptic inhibition is required for precision of long-term memory.
Though much attention has been given to the neural structures that underlie the long-term consolidation of contextual memories, little is known about the mechanisms responsible for the maintenance of memory precision. Here, we demonstrate a rapid time-dependent decline in memory precision in GABAB(1a) receptor knockout mice. First, we show that GABAB(1a) receptors are required for the maintenance, but not encoding, of a precise fear memory. We then demonstrate that GABAB(1a) receptors are required for the maintenance, but not encoding, of spatial memories. Our findings suggest that GABA-mediated presynaptic inhibition regulates the maintenance of memory precision as a function of memory age.


Development of perceived prenatal maternal stress scale.
Pregnancy is a state, which is often associated with extreme joy and happiness. Women undergo a number of physiological and psychological changes during pregnancy, which are often stressful if aligned with other adverse life events, compromising their health and well-being. However, there exists no comprehensive psychological instruments for measuring this stress. The study was conducted to develop a multidimensional scale to assess prenatal maternal stress (PNMS) comprehensively. The initial phase of the study focuses on developing items and assessing the content validity of these items. The second phase focuses on pilot-testing and field-testing the newly developed perceived PNMS scale (PPNMSS) among 356 pregnant women belonging to different parity and trimester from November 2015 to October 2016. The underlying factor structure of the 28-item PPNMSS had explored using exploratory factor analysis. The final scale is retained with 15 items having considerable item loading under four major factors as follows: perceived social support, pregnancy-specific concerns, intimate partner relations, and financial concerns. Reliability of each of these dimensions was assessed using Cronbach's alpha. Convergent and divergent validity of the scale was assessed by correlating the scores with perceived stress scale and the World Health Organization (five) well-being index (1998 version). As a comprehensive scale, PPNMSS is efficient to measure PNMS, which facilitates an early detection of stress and depression among pregnant women and timely intervention by health care professionals.


Activation adverse events induced by the selective serotonin reuptake inhibitor fluvoxamine in children and adolescents.
The aim of this study was to examine the prevalence of activation cluster adverse events (AC-AEs) in youths treated with the selective serotonin reuptake inhibitor (SSRI) fluvoxamine for anxiety and the relationship of AC-AEs to SSRI blood levels. Data from the Research Units on Pediatric Psychopharmacology (RUPP) Anxiety Study were examined for 45 youths (22 active fluvoxamine, 23 placebo) treated for Diagnostic and Statistical Manual for Mental Disorders, 4(th) edition (DSM-IV) anxiety disorders at the Johns Hopkins University site with an 8-week forced-flexible titration schedule. As part of the double-blind placebo-controlled trial, AC-AEs were recorded by clinicians at weekly patient visits. AC-AEs were defined as hyperactivity, activation, and disinhibition. Demographic characteristics, daily doses, and week-8 blood levels were examined in relation to the presence of AC-AEs. The prevalence of AC-AE and time to first event were established for those who experienced this side effect. AC-AEs were found in 10 of 22 participants (45%) receiving fluvoxamine and only 1 of 23 in the placebo group (4%). The onset of AC-AEs occurred from week 1 to week 8, with the majority occurring at or before week 4. The mean fluvoxamine blood level at week 8 in subjects with AC-AEs was higher than in subjects without AC-AEs (n = 16, t = -2.61, p = 0.04). Neither the age of the participants nor family history of bipolar or anxiety disorder differed between those who did and did not develop an AC-AE. AC-AEs were common side effects of fluvoxamine, often appeared during the first 8 weeks of treatment, and were associated with higher fluvoxamine blood levels. Close monitoring for AC-AEs, not only when initiating SSRI treatment but also throughout dose titration, is recommended for early identification of activation.


The role of PCNA as a scaffold protein in cellular signaling is functionally conserved between yeast and humans.
Proliferating cell nuclear antigen (PCNA), a member of the highly conserved DNA sliding clamp family, is an essential protein for cellular processes including DNA replication and repair. A large number of proteins from higher eukaryotes contain one of two PCNA-interacting motifs: PCNA-interacting protein box (PIP box) and AlkB homologue 2 PCNA-interacting motif (APIM). APIM has been shown to be especially important during cellular stress. PIP box is known to be functionally conserved in yeast, and here, we show that this is also the case for APIM. Several of the 84 APIM-containing yeast proteins are associated with cellular signaling as hub proteins, which are able to interact with a large number of other proteins. Cellular signaling is highly conserved throughout evolution, and we recently suggested a novel role for PCNA as a scaffold protein in cellular signaling in human cells. A cell-penetrating peptide containing the APIM sequence increases the sensitivity toward the chemotherapeutic agent cisplatin in both yeast and human cells, and both yeast and human cells become hypersensitive when the Hog1/p38 MAPK pathway is blocked. These results suggest that the interactions between APIM-containing signaling proteins and PCNA during the DNA damage response is evolutionary conserved between yeast and mammals and that PCNA has a role in cellular signaling also in yeast.


[Cognitive, linguistic, motoric, and social deficits in schoolstarters with behavioral disorders].
Studies show that ADHD, conduct disorders, and anxiety disorders are clinical disorders mostly diagnosed in schoolstarters. The preschool medical examination in Bremen was therefore extended by behavioral screenings. Based on their screening results from the SEU (health examination for school entry) 2011 in Bremen, 67 preschoolers were tested for behavioral disorders. Subsequently, children with behavioral or emotional symptoms (N = 56) were compared to symptomfree controls (N = 52) for their cognitive, motoric, linguistic, and social-emotional development. Psychosocial health was obtained through external assessment by the parents and kindergarten teachers. Results of the WPPSI-III, M-ABC-2, and ET 6-6 were included in the analysis. 32 children met the criteria for behavioral disorders. Children with behavioral or emotional symptoms showed significant lower scores on tests measuring cognitive, motoric, linguistic and emotional development compared to controls. Results suggest that there is necessity to screen all preschoolers for behavioral disorders before entering school. Because children with clinical or subclinical behavioral disorders showed major developmental deficits compared to children without behavioral symptoms, it is essential to conduct a multiple assessment on children with suspected behavioral disorders to ensure early developmental support and adequate interventional programs.


Microvascular hematocrit and red cell flow in resting and contracting striated muscle.
Microvascular hematocrit and its possible relation to oxygen supply were systematically examined. We studied the red cell volume fraction (hematocrit) in arterial blood and in capillaries under a variety of circumstances. Control capillary hematocrit averaged 10.4 +/- 2.0% (SE) and arteriolar (14.2 micrometer ID) hematocrit averaged 13.9 +/- 1.2% in cremaster muscles of pentobarbital-anesthetized hamsters. Carotid artery hematocrit was 53.2 +/- 0.6%. The low microvessel hematocrit could not be entirely explained by a high red cell flux through arteriovenous channels other than capillaries (shunting). Hematocrit was not only low at rest, but varied with physiological stimuli. A 1-Hz muscle contraction increased capillary hematocrit to 18.5 +/- 2.4%, and maximal vasodilation induced a rise to 39.3 +/- 9.5%. The quantitative relations between capillary red cell flux, arterial hematocrit, and total blood flow could be explained by a two-element model of microvascular blood flow that incorporated a relatively slow-moving plasma layer (1.2 micrometer). Such a model would generate a low microvessel hematocrit and might reduce the diffusion capacity of individual capillaries, but would not reduce time-averaged red cell flux or alter steady-state vascular oxygen supply.


Detection of complement factor B in the cerebrospinal fluid of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease using two-dimensional gel electrophoresis and mass spectrometry.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary condition with onset in mid-adulthood and is associated with mutations in the Notch-3 gene. (Joutel, A., Corepechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenda, V., Cecilion, M., Marechal, J., Vayssiere, C., Cruaud, C., Cabanis, E.A., Ruchoux, M.M. , Weissenvach, J., Bach, J.F., Bousser, M.G. and Tournier-Lasserve, E., Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature, 383 (1996) 707-710) Ultrastructural examination of the pathology of the cerebral infarcts reveals deposits in the vascular smooth muscle cells of the small arteries of the brain, but there is no obvious indication how the Notch-3 mutations give rise the observed pathology, nor is there any information on the exact nature of the deposits. We have investigated cerebrospinal fluid (CSF) from three CADASIL cases with known mutations in Notch-3 using two-dimensional gel electrophoresis. CSF from these patients was compared to that of six controls. We detected a single spot in the protein maps of patients which was absent from all the controls. In-gel tryptic digestion of this protein followed by mass spectrometric analysis of the tryptic fragments and a database search identified the spot as human complement factor B. These preliminary findings suggest that the alternative complement pathway may play a role in the pathogenesis of CADASIL.


SOURCE: a unified genomic resource of functional annotations, ontologies, and gene expression data.
The explosion in the number of functional genomic datasets generated with tools such as DNA microarrays has created a critical need for resources that facilitate the interpretation of large-scale biological data. SOURCE is a web-based database that brings together information from a broad range of resources, and provides it in manner particularly useful for genome-scale analyses. SOURCE's GeneReports include aliases, chromosomal location, functional descriptions, GeneOntology annotations, gene expression data, and links to external databases. We curate published microarray gene expression datasets and allow users to rapidly identify sets of co-regulated genes across a variety of tissues and a large number of conditions using a simple and intuitive interface. SOURCE provides content both in gene and cDNA clone-centric pages, and thus simplifies analysis of datasets generated using cDNA microarrays. SOURCE is continuously updated and contains the most recent and accurate information available for human, mouse, and rat genes. By allowing dynamic linking to individual gene or clone reports, SOURCE facilitates browsing of large genomic datasets. Finally, SOURCEs batch interface allows rapid extraction of data for thousands of genes or clones at once and thus facilitates statistical analyses such as assessing the enrichment of functional attributes within clusters of genes. SOURCE is available at http://source.stanford.edu.


Influence of specimen designs on the microtensile bond strength to dentin.
The purpose of this study was to examine the sensitivity of the microtensile bond strength (muTBS) to changes in the specimen design using three different dentin bonding systems, utilizing both experimental and finite element analysis (FEA). Freshly extracted bovine central incisors were randomly divided into 9 experimental groups. Flat dentin surfaces were exposed and polished with 600-grit SiC papers. The dentin bonding agents (DBA) Adper Prompt L-Pop, Adper Scotchbond 1XT, and Adper Scotchbond Multi-Purpose Plus were bonded to the dentin surface. A 5- to 6-mm-thick layer of resin composite Filtek Supreme was built up incrementally. For each DBA, after 24 h in water, the bonded specimens were sectioned vertically into slabs of stick-, dumbbell- and hourglass-shaped specimens (n = 30). The muTBS test was performed at a crosshead speed of 0.5 mm/min and the fracture surfaces were examined under optical microscopy and SEM. FEA models of the three designs were developed using the TOMECH program and viewed using FEMSYS visualization software. One-way ANOVA, Tukey's and Kaplan-Meier tests revealed no significant differences between the bond strengths for the three designs for the same dentin bonding agent (p > 0.05). However, there were significant differences between the three adhesive systems when using one specimen design. FEA results showed no major differences between the three designs in the maximum stress within the adhesive layer, although the stress distributions for the hourglass shape followed a different pattern. The three different specimen designs had no influence on the bond strength to dentin within one adhesive system. FEA predictions are consistent with the results of the experiments.


Influenza and Pneumococcal Vaccination Uptake in Patients with Rheumatoid Arthritis Treated with Immunosuppressive Therapy in the UK: A Retrospective Cohort Study Using Data from the Clinical Practice Research Datalink.
Guidelines for the management of rheumatoid arthritis (RA) recommend using influenza and pneumococcal vaccinations to mitigate infection risk. The level of adherence to these guidelines is not well known in the UK. The aims of this study were to describe the uptake of influenza and pneumococcal vaccinations in patients with RA in the UK, to compare the characteristics of those vaccinated to those not vaccinated and to compare vaccination rates across regions of the UK. A retrospective cohort study of adults diagnosed with incident RA and treated with non-biologic immunosuppressive therapy, using data from a large primary care database. For the influenza vaccination, patients were considered unvaccinated on 1st September each year and upon vaccination their status changed to vaccinated. For pneumococcal vaccination, patients were considered vaccinated after their first vaccination until the end of follow-up. Patients were stratified by age 65 at the start of follow-up, given differences in vaccination guidelines for the general population. Overall (N=15,724), 80% patients received at least one influenza vaccination, and 50% patients received a pneumococcal vaccination, during follow-up (mean 5.3 years). Of those aged below 65 years (N=9,969), 73% patients had received at least one influenza vaccination, and 43% patients received at least one pneumococcal vaccination. Of those aged over 65 years (N=5,755), 91% patients received at least one influenza vaccination, and 61% patients had received at least one pneumococcal vaccination. Those vaccinated were older, had more comorbidity and visited the GP more often. Regional differences in vaccination rates were seen with the highest rates in Northern Ireland, and the lowest rates in London. One in five patients received no influenza vaccinations and one in two patients received no pneumonia vaccine over five years of follow-up. There remains significant scope to improve uptake of vaccinations in patients with RA.


Predicting Refractive Outcome of Small Incision Lenticule Extraction for Myopia Using Corneal Properties.
To investigate whether preoperative corneal topographic and biomechanical parameters (CTBPs) predict postoperative residual refractive error (RRE). We retrospectively included 151 eyes from 151 patients of small-incision lenticule extraction (SMILE) with target RRE of plano and 3-month measurements of refractive error from Tianjin Eye Hospital. Multivariate linear/logistic regressions were performed to associate age, gender, preoperative refractive error, lenticule thickness, and CTBPs with postoperative RRE/the occurrence of myopic RRE ≤ -0.25 diopter (D). Stepwise regression was used for feature selection. Leave-one-cross-validation was used for model evaluation by the area under the receiver operating characteristic curve (AUC). From linear regression, more myopic RRE was associated with higher preoperative myopia, intraocular pressure (IOP), flattest curvature of anterior cornea (AC), and highest concavity deformation (HCD), and was associated with lower anterior elevation, anterior asphericity, steepest curvature of AC, and second applanation velocity. The occurrence of ≤ -0.25 D RRE was associated with higher myopia, IOP, posterior elevation and asphericity, flattest curvature of AC, first applanation velocity and HCD, and was associated with lower first applanation stiffness parameter, central corneal thickness, anterior elevation and asphericity, steepest curvature of AC, and second applanation velocity as well as thinner lenticule thickness. Compared to the baseline model using age, gender, and preoperative refractive error, adding CTBPs significantly (P < 0.001) improved the AUC performance to 0.771 from 0.615. Postoperative outcomes of SMILE can be predicted by individual CTBPs. Our findings could be used to customize a refractive nomogram based on individual corneal properties improving outcomes and patient satisfaction.


Canine leishmaniasis caused by Leishmania leishmania infantum in two Labrador retrievers.
Canine leishmaniasis, a generally fatal parasitic disease, was diagnosed in 2 dogs with a medical history of foreign travel, lymphadenopathy, emaciation, anorexia, intermittent fever, and cutaneous lesions. Clinically, hyperproteinemia, proteinuria, azotemia, and glomerulopathy were evident. Isolation of Leishmania species was done using Schneider's Drosophila medium. Syrian hamsters were used for infectivity studies. Clear taxonomic identification was done biochemically by isoenzyme analysis and comparison of zymogram banding patterns with 6 World Health Organization reference strains. Based on the geographic origin of affected dogs, clinicopathologic presentation, visceralization with hepatosplenomegaly in hamsters, and isoenzyme analysis, a diagnosis of Leishmania leishmania infantum was made. This study, representing the first taxonomic identification of an isolate from canine leishmaniasis, demonstrates the zoonotic and epidemiologic implications of this disease.


Fumagillin treatment of hepatocellular carcinoma in rats: an in vivo study of antiangiogenesis.
To investigate the effect and possible mechanisms of antiangiogenesis therapy for HCC in rats. Adult male LEW/SsN rats were divided into 3 groups, 25 animals each. Group A was the control group. Groups B and C were given diethylnitrosamine, 5 mg/kg/d. In addition, group C rats received an intraperitoneal injection of fumagillin, 30 mg/(kg x d). Five animals in each group were killed at 6th, 12th, 18th, 20th and 24th wk to evaluate the development of HCC and metastasis. Weight of the rats, liver tumors, and number of organs involved by HCC were measured at each stage. We compared methionine aminopeptidase-2 (MetAP-2) mRNA, Bcl-2 mRNA, telomerase mRNA, and telomerase activity at 24th wk in the liver tissue of group A rats and tumor tissue of HCC from group B and C rats. No HCC developed in group A, but tumors were present in group B and C rats by the 18th wk. At wk 20 and 24, the median liver weight in group B was 0.64 g (range: 0.58-0.70 g) and 0.79 g (range: 0.70-0.90 g) (P = 0.04), and that in group C was 0.37 g (range: 0.35-0.42 g) and 0.39 g (range: 0.35-0.47 g) (P = 0.67). The liver weight in group C rats was significantly lower than that in group B rats (P = 0.009). At the same time, the median metastasis score (number of organ systems involved) was 3 (range2-3) in group B, and 1 (range 1-2) in group C, a significant difference between the groups (P = 0.007, 0.004). The levels of MetAP-2 mRNA were significantly higher in groups B and C than in group A (P = 0.025), and significantly higher in group C than in group B (P = 0.047). The level of Bcl-2 mRNA was significantly higher in group B than in group A (P = 0.024), but lower in group C than in group B, although not significantly (P = 0.072). Telomerase mRNA was significantly higher in group B than in group A (P = 0.025), but significantly lower in group C than in group B (P = 0.016). The same inter-group relationship was also true for telomerase activity (P = 0.025 and 0.046). Fumagillin effectively inhibits both liver tumor growth and metastasis in rats in vivo. A possible mechanism is fumagillin-induced inhibition of MetAP-2, which plays an essential role in endothelial cell proliferation. Inhibition of MetAP-2 also results in inhibition of Bcl-2 and telomerase activity.


The use of the local flora in Switzerland: a comparison of past and recent medicinal plant knowledge.
This analysis of documented medicinal plants of the Swiss Flora over the last two millennia provides a rich source of knowledge on earlier uses of plants and use patterns of the local flora. We ask which local plant species were used during different time periods of the last 2000 years and how the numbers of species and the use intensity of specific plant families, growth forms and habitats changed over time. Totally 25 herbals from the antiquity, monastic medicine, Renaissance, early modern era and the contemporary time as well as five recent ethnobotanical studies were considered. Use patterns were analysed with the Bayesian approach. A total of 768 species, i.e. 32% of the vascular plants of the Swiss Flora have been documented as medicinal plants. Numbers increase until the monastic period (366 spp.) and the Renaissance (476) and remain relatively stable since then (modern and contemporary era: 477). But, 465 formerly documented species do not occur in the ethnobotanical studies and thus seem not to be used any more. Overall, 104 species are documented through all time periods. Archeophytes, trees and forest plants are generally overrepresented in herbals from all time periods while plants from above the timberline are generally underrepresented. Most widely used are the Lamiaceae and Apiaceae. A constant body of medicinal plant knowledge in Switzerland exists since ancient time. This knowledge was always influenced by knowledge from neighboring countries and no "typical Swiss specialties" seem to exist. Medicinal plants are not randomly chosen from the available flora. Certain species are deliberately introduced others are neglected. This process, which is still ongoing, can be traced back with the help of herbals to the antiquity.


Growth and patterning in the limb: signaling gradients make the decision.
The vertebrate limb bud provides a unique system to investigate the coordinated regulation of growth and patterning, two key processes that govern the formation of a complex multicellular organism from a fertilized egg. Two studies have advanced our understanding of limb development by elucidating that signaling gradients from the limb ectoderm, including the apical ectoderm ridge (AER), act in concert to establish a basic pattern of tissue layers by coordinating cell proliferation and cell fate determination. These studies reveal that cell proliferation and fate determination in development can be two faces of the same coin in that they are regulated by the same signaling pathways. Alterations in the duration and range of the signaling gradients may underlie many of the morphological differences in the evolution of vertebrate limbs.


Selective vs routine use of intraoperative cholangiography. An argument.
We reviewed the course of 314 patients who underwent cholecystectomy at a University Hospital in 1985. Two hundred eighty-five patients underwent cholecystectomy for cholelithiasis. Preoperatively elevated liver function test results, history of jaundice or pancreatitis, or operative findings of palpable common bile duct stone or dilated extrahepatic ducts were criteria for indicated cholangiography. Of 142 patients who had cholangiography with negative results, only 31 were indicated by these criteria. In 93 patients not having cholangiography performed, the criteria were met in only 8 patients. Of 38 patients who underwent common bile duct exploration, only 29 had stones. As operative time, morbidity, and cost were demonstrably increased in patients undergoing cholangiography, a selective approach is advocated. The number of unnecessary common bile duct explorations might be cut by almost half, while the incidence of finding clinically unsuspected yet significant common bile duct stones is negligible.


Cancer/testis antigens are novel targets of immunotherapy for adult T-cell leukemia/lymphoma.
Adult T-cell leukemia/lymphoma (ATLL) is an intractable hematologic malignancy caused by human T-lymphotropic virus type 1 (HTLV-1), which infects approximately 20 million people worldwide. Here, we have explored the possible expression of cancer/testis (CT) antigens by ATLL cells, as CT antigens are widely recognized as ideal targets of cancer immunotherapy against solid tumors. A high percentage (87.7%) of ATLL cases (n = 57) expressed CT antigens at the mRNA level: NY-ESO-1 (61.4%), MAGE-A3 (31.6%), and MAGE-A4 (61.4%). CT antigen expression was confirmed by immunohistochemistry. This contrasts with other types of lymphoma or leukemia, which scarcely express these CT antigens. Humoral immune responses, particularly against NY-ESO-1, were detected in 11.6% (5 of 43) and NY-ESO-1-specific CD8(+) T-cell responses were observed in 55.6% (5 of 9) of ATLL patients. NY-ESO-1-specific CD8(+) T cells recognized autologous ATLL cells and produced effector cytokines. Thus, ATLL cells characteristically express CT antigens and therefore vaccination with CT antigens can be an effective immunotherapy of ATLL.


Expensive care? Resource-based thresholds for potentially inappropriate treatment in intensive care.
In intensive care, disputes sometimes arise when patients or surrogates strongly desire treatment, yet health professionals regard it as potentially inappropriate. While professional guidelines confirm that physicians are not always obliged to provide requested treatment, determining when treatment would be inappropriate is extremely challenging. One potential reason for refusing to provide a desired and potentially beneficial treatment is because (within the setting of limited resources) this would harm other patients. Elsewhere in public health systems, cost effectiveness analysis is sometimes used to decide between different priorities for funding. In this paper, we explore whether cost-effectiveness could be used to determine the appropriateness of providing intensive care. We explore a set of treatment thresholds: the probability threshold (a minimum probability of survival for providing treatment), the cost threshold (a maximum cost of treatment), the duration threshold (the maximum duration of intensive care), and the quality threshold (a minimum quality of life). One common objection to cost-effectiveness analysis is that it might lead to rationing of life-saving treatment. The analysis in this paper might be used to inform debate about the implications of applying cost-effectiveness thresholds to clinical decisions around potentially inappropriate treatment.


Practice-based randomized controlled-comparison clinical trial of chiropractic adjustments and brief massage treatment at sites of subluxation in subjects with essential hypertension: pilot study.
To determine the feasibility of conducting a randomized clinical trial in the private practice setting examining short- and long-term effects of chiropractic adjustments for subjects with essential hypertension compared with a brief soft tissue massage, as well as a nontreatment control group. Randomized controlled-comparison trial with 3 parallel groups. Private practice outpatient chiropractic clinic. Twenty-three subjects, aged 24 to 50 years with systolic or diastolic essential hypertension. Two months of full-spine chiropractic care (ie, Gonstead) consisting primarily of specific-contact, short-lever-arm adjustments delivered at motion segments exhibiting signs of subluxation. The massage group had a brief effleurage procedure delivered at localized regions of the spine believed to be exhibiting signs of subluxation. The nontreatment control group rested alone for a period of approximately 5 minutes in an adjustment room. Cost per enrolled subject, as well as systolic and diastolic blood pressure (BP) measured with a random-0 sphygmomanometer and patient reported health status (SF-36). Pilot study outcome measures also included an assessment of cooperation of subjects to randomization procedures and drop-out rates, recruitment effectiveness, analysis of temporal stability of BPs at the beginning of care, and the effects of inclusion/exclusion criteria on the subject pool. Thirty subjects enrolled, yielding a cost of $161 per enrolled subject. One subject was later determined to be ineligible, and 6 others dropped out. In both the chiropractic and massage therapy groups, all subjects were classified as either overweight or obese; in the control group there were only 2 classified as such. SF-36 profiles for the groups were similar to that of a normal population. The mean change in diastolic BP was -4 (95% confidence interval [CI]: -8.6, 0.5) in the chiropractic care group, 0.5 (95% CI: -3.5, 4.5) in the brief massage treatment group, and -4.9 (95% CI: -9.7, -0.1) in the no treatment control group. At the end of the study period, this change was -6.3 (95% CI: 13.1, 0.4), -1.0 (95% CI: -7.5, 15.6), -7.2 (95% CI: -13.3, -1.1) in the 3 study groups. The mean improvements in the chiropractic care and no treatment control groups remained consistent over the follow-up period. This pilot study elucidated several procedural issues that should be addressed before undertaking a full-scale clinical trial on the effects of chiropractic adjustments in patients with essential hypertension. A multidisciplinary approach to recruitment may need to be used in any future efforts because of the limited subject pool of patients who have hypertensive disease but are not taking medications for its control. Measures need to be used to assure comparable groups regarding prognostic variables such as weight. Studies such as these demonstrate the feasibility of conducting a full-scale 3-group randomized clinical trial in the private practice setting.


Bone architectural and structural properties after 56Fe26+ radiation-induced changes in body mass.
High-energy, high-charge (HZE) radiation, including iron ions ((56)Fe(26+)), is a component of the space environment. We recently observed a profound loss of trabecular bone in mice after whole-body HZE irradiation. The goal of this study was to examine morphology in bones that were excluded from a (56)Fe(26+) beam used to irradiate the body. Using 10-week-old male Sprague-Dawley rats and excluding the hind limbs and pelvis, we irradiated animals with 0, 1, 2 and 4 Gy (56)Fe(26+) ions and killed them humanely after 9 months. Animals grew throughout the experiment. Trabecular bone volume, connectivity and thickness within the proximal tibiae were significantly lower than control in a dose-dependent manner. Irradiated animals generally had less body mass than controls, which largely accounted for the variability in bone parameters as determined by ANCOVA. Likewise, lower cortical parameters were associated with reduced mass. However, lesser trabecular thickness in the 4-Gy group could not be attributed to body mass alone. Indicators of bone metabolism were generally unchanged, suggesting stabilized turnover. Exposure to (56)Fe(26+) ions can alter trabecular microarchitecture in shielded bones. Reduced body mass seems to be correlated with these deficits of trabecular and cortical bone.