A toolbox for tuberculosis (TB) diagnosis: an Indian multicentric study (2006-2008). Evaluation of QuantiFERON-TB gold in tube for TB diagnosis.
The aim of this multicentric prospective study in India was to assess the performance of the QuantiFERON TB-Gold in tube (QFT-GIT), Tuberculin Skin Test (TST) and microbiological results as additional tools for diagnosing active tuberculosis (TB) and latent infection (LTBI) according to Human Immunodeficiency Virus (HIV) status. Individuals with and without active TB and HIV infection were enrolled between 2006-2008. QFT-GIT and TST results were analyzed per se and in combination with microbiological data. Among the 276 individuals (96 active pulmonary TB and 180 no active TB) tested by QFT-GIT, 18 indeterminate results (6.5%) were found, more significantly numerous in the HIV-infected (15/92; 16.3%) than the HIV-uninfected (3/184; 1.6%)(p<0.0001). QFT-GIT sensitivity for active TB was 82.3% and 92.9% respectively after including or excluding indeterminate results. Clinical sensitivity was significantly lower in the HIV-infected (68.4%) than the HIV-uninfected (91.4%) patients (p = 0.0059). LTBI was detected in 49.3% of subjects without active TB but varied according to TB exposure. When the TST and QFT-GIT were concomitantly performed, the respective sensitivity for active TB diagnosis was 95.0% and 85.0% in the HIV-uninfected (p = 0.60), and 66.7% and 51.5% in the HIV-infected patients (p = 0.32). QFT-GIT and TST respective specificity for active TB in the HIV-uninfected was 25.0% and 57.1% (p = 0.028), and 64.8% and 83.3% in the HIV-infected (p = 0.047). In those with active TB, QFT-GIT results were not associated with microbiological parameters (smear grade, liquid culture status, time-to-positivity of culture) or clinical suspicion of active TB score (provided by the clinicians at enrollment). Combining microbiological tests with both immunological tests significantly increased sensitivity for active TB diagnosis (p = 0.0002), especially in the HIV-infected individuals (p = 0.0016). QFT-GIT and TST have similar diagnostic value for active TB diagnosis. In HIV-infected patients, combining microbiological tests with both immunological tests significantly increases the sensitivity for active TB diagnosis.


Long-term clinical outcomes of war-related hip disarticulation and transpelvic amputation.
The Iran-Iraq war (1980 to 1988) was one of the longest wars of the twentieth century. Few studies are available in the current literature evaluating the long-term results of proximal lower-extremity war-related amputations. The purpose of the present cross-sectional study was to evaluate the current health-related quality of life and clinical musculoskeletal function of Iranian veterans with hip or hemipelvic amputation. Seventy-six patients from a cohort of eighty-four veterans with hip disarticulation and transpelvic amputation participated in this study. A Persian version of Medical Outcomes Study Short Form-36 (SF-36) was completed for all of the veterans. The average duration of follow-up was 26.6 ± 3.7 years. The average age (and standard deviation) of the veterans was 44.1 ± 7.0 years. The average scores for the physical and mental health dimensions of the SF-36 were 45.85 ± 21.56 and 57.98 ± 25.19, respectively. These data indicate that the amputees were doing better in the mental domain than in the physical domain. Forty-five patients with a primary amputation (97.8%) and ten with a secondary amputation (33.3%) complained of pain in the amputation stump. Veterans with proximal lower-extremity amputation will need life-long care. Supervision starts with stump management and the application of appropriate surgical techniques at the time of the injury and continues with periodic examination throughout life.


Development of locally relevant clinical guidelines for procedure-related neonatal analgesic practice in Kenya: a systematic review and meta-analysis.
Background Increasing numbers of neonates are undergoing painful procedures in low-income and middle-income countries, with adequate analgesia seldom used. In collaboration with a multi-disciplinary team in Kenya, we aimed to establish the first evidence-based guidelines for the management of routine procedure-related neonatal pain that consider low-resource hospital settings. We did a systematic review by searching MEDLINE, Embase, CINAHL, and CENTRAL databases for studies published from Jan 1, 1953, to March 31, 2019. We included data from randomised controlled trials using heart rate, oxygen saturation (SpO2), premature infant pain profile (PIPP) score, neonatal infant pain scale (NIPS) score, neonatal facial coding system score, and douleur aiguë du nouveau-né scale score as pain outcome measures. We excluded studies in which neonates were undergoing circumcision or were intubated, studies from which data were unextractable, or when pain was scored by non-trained individuals. We did a narrative synthesis of all studies, and meta-analysis when data were available from multiple studies comparing the same analgesics and controls and using the same outcome measures. 17 Kenyan health-care professionals formed our clinical guideline development panel, and we used the Grading of Recommendations, Assessment, Development and Evaluation framework and the panel's knowledge of the local health-care context to guide the guideline development process. This study is registered with PROSPERO, CRD42019126620. Of 2782 studies assessed for eligibility, data from 149 (5%) were analysed, with 80 (3%) of these further contributing to our meta-analysis. We found a high level of certainty for the superiority of breastfeeding over placebo or no intervention (standardised mean differences [SMDs] were -1·40 [95% CI -1·96 to -0·84] in PIPP score and -2·20 [-2·91 to -1·48] in NIPS score), and the superiority of oral sugar solutions over placebo or no intervention (SMDs were -0·38 [-0·61 to -0·16] in heart rate and 0·23 [0·04 to 0·42] in SpO2). We found a moderate level of certainty for the superiority for expressed breastmilk over placebo or no intervention (SMDs were -0·46 [95% CI -0·87 to -0·05] in heart rate and 0·48 [0·20 to 0·75] in SpO2). Therefore, the panel recommended that breastfeeding should be given as first-line analgesic treatment, initiated at least 2 min pre-procedure. Given contextual factors, for neonates who are unable to breastfeed, 1-2 mL of expressed breastmilk should be given as first-line analgesic, or 1-2 mL of oral sugar (≥10% concentration) as second-line analgesic. The panel also recommended parental presence during procedures with adjunctive provision of skin-to-skin care, or non-nutritive sucking when possible. We have generated Kenya's first neonatal analgesic guidelines for routine procedures, which have been adopted by the Kenyan Ministry of Health, and have shown a framework for clinical guideline development that is applicable to other low-income and middle-income health-care settings. Wellcome Trust Research Programme, and the Africa-Oxford Initiative.


Venous and arterial thromboembolism in severe sepsis.
The burden of thromboembolism (TE) in severe sepsis is largely unknown. We assessed the prevalence of venous and arterial TE in patients with severe sepsis over a four-week period. We performed a retrospective analysis of a pooled database of three randomized, placebo-controlled trials of two novel pharmacological agents for the treatment of severe sepsis, drotrecogin alfa (activated) (DrotAA) and secretory phospholipase A2 inhibitor (sPLA(2)I). The study was conducted at intensive care units of the participating institutions. A total of 2,649 patients with known or suspected infection and sepsis-associated acute organ dysfunction were enrolled in the three trials and were assigned to treatment groups (DrotAA=850; sPLA2I=578; placebo=1221). The database was queried for venous and arterial TE, using investigator reports of serious adverse events. Eighty-four of 2,649 patients (3.2%; 95% confidence interval, 2.5% to 3.9%) developed at least one thromboembolic event over 28 days. Nearly three-quarters of episodes were atheroembolic (n=62); 25% involved the deep venous system (n=25). Ischemic stroke (n=30) and venous thromboembolism (n=25) each occurred in about 1% of patients. Ischemic stroke and acute coronary syndrome had a higher peak incidence during the first five days compared to venous TE onset, which was more constant over the 28-day period. Subgroup analysis by pooled treatment groups yielded TE rates of 2.0% (DrotAA), 3.5% (placebo), and 4.0% (sPLA2I), respectively. Clinically manifest TE occurred in about 3% of severe sepsis patients treated in the intensive care unit over a 28-day period. Arterial TE may be more common than previously recognized. More accurate estimates of TE prevalence and relationship to sepsis await future studies.


A look ahead: PET/MR versus PET/CT.
Integration of positron emission tomography (PET) and magnetic resonance (MR) has become a topic of increasing interest to the imaging community over the past two years. In this text, the authors attempt to distinguish facts from fiction concerning such integrated systems. Analysis of existing information of combined imaging on existing brain PET/MR systems and imaging experience with PET-computed tomography (CT) is reviewed. Various types of system integration of PET and MR are discussed with completely independent systems on one hand and completely integrated systems with the possibility of simultaneous data acquisition on the other hand. Furthermore, it is discussed, what simultaneous data acquisition with nuclear imaging systems combined with MR or CT really means, as technical simultaneity may not be relevant in light of the pharmacokinetics of the nuclear tracers used. The authors conclude that combining PET/MR is an interesting research endeavor with uncertain outcome. They argue that, while completely simultaneous brain applications are of research interest immediately, clinical applications do not currently warrant the construction of fully integrated systems. Systems adjacent to each other, where imaging tables are linked with a patient "shuttle" thereby requiring only patient translation but no repositioning, may be a good start to assess the value of integrated PET/MR.


Psychosocial characteristics differentiate non-distressing and distressing voices in 10,346 adolescents.
Adolescents hearing non-existent voices may be at risk for psychosis, but the prevalence of voice-hearing (VH) in the general population complicates clinical interpretations. Differentiating between VH with and without distress may aid treatment decisions in psychosis services, but understanding the differences between these two phenomena as they present in the normal adolescent population is necessary to validate this differentiation. The present study compared VH with and without distress in 10,346 adolescents in relation to clinical characteristics, known risk factors, predictors and psychosocial moderators of psychosis. A population-based cohort of Norwegian 16-19 years old adolescents completed a comprehensive web-based questionnaire, including two questions from the extended Launay-Slade Hallucinations Scale: (1) I often hear a voice speaking my thoughts aloud and (2) I have been troubled by hearing voices in my head. Adolescents reporting no VH, non-distressing VH or distressing VH were compared on 14 psychosocial and clinical variables. A multinomial regression model showed that non-disturbing voices were predicted by better school grades, social dysfunction, distractibility, affective symptoms and experience of trauma, while the disturbing voices were predicted by the experience of bullying and trauma, perceived negative self-worth and self-efficacy, less family support, dysregulation of activation, distractibility, self-harm and anxiety. Hearing voices without distress versus being distressed by the voices is related to different constellations of psychosocial variables, suggesting that they represent two separate groups of adolescents. The findings validate the emphasis on distress in clinical practice.


Different selective pressures shape the molecular evolution of color vision in chimpanzee and human populations.
A population genetic analysis of the long-wavelength opsin (OPN1LW, "red") color vision gene in a global sample of 236 human nucleotide sequences had previously discovered nine amino acid replacement single nucleotide polymorphisms, which were found at high frequencies in both African and non-African populations and associated with an unusual haplotype diversity. Although this pattern of nucleotide diversity is consistent with balancing selection, it has been argued that a recombination "hot spot" or gene conversion within and between X-linked color vision genes alone may explain these patterns. The current analysis investigates a closely related primate with trichromatism to determine whether color vision gene amino acid polymorphism and signatures of adaptive evolution are characteristic of humans alone. Our population sample of 56 chimpanzee (Pan troglodytes) OPN1LW sequences shows three singleton amino acid polymorphisms and no unusual recombination or linkage disequilibrium patterns across the approximately 5.5-kb region analyzed. Our comparative population genetic approach shows that the patterns of OPN1LW variation in humans and chimpanzees are consistent with positive and purifying selection within the two lineages, respectively. Although the complex role of color vision has been greatly documented in primate evolution in general, it is surprising that trichromatism has followed very different selective trajectories even between humans and our closest relatives.


Living on a trophic subsidy: Algal quality drives an upper-shore herbivore's consumption, preference and absorption but not growth rates.
The transfer of seaweeds from subtidal bottoms to nearby intertidal rocky shores is a common but often overlooked phenomenon. Freshly detached seaweeds often represent critical trophic subsidies for herbivores living in upper-shore rocky intertidal areas, such as the marine snail Diloma nigerrima. This species relies on three species of seaweeds for food and displays feeding strategies to deal with a resource that is scarce and at times unpredictable. This study focused on the nutritional quality of freshly detached algae (Durvillaea antarctica, Lessonia spicata and Lessonia trabeculata) and measured Diloma nigerrima's algal consumption rates in trials with and without choice. Absorption efficiency and growth of individual snails fed on each alga were also measured. Durvillaea antarctica had the highest nutritional quality and was the most consumed algae in both single and multiple-choice trials. Absorption efficiency was also highest for D. antarctica but growth rates of snails fed with this species were similar to those fed with the other algae. Combined, these results suggest that D. nigerrima has the ability to discriminate among seaweeds based on their nutritional quality. A potential increase in oxygen uptake when D. nigerrima is consuming the preferred food item is also proposed as a plausible hypothesis to explain the mismatch between snails' preference and growth rate. These results aim to guide further studies on trophic subsidies and their role in coastal systems.


Excision of 8-oxoguanine within clustered damage by the yeast OGG1 protein.
Clustered damages are formed in DNA by ionising radiation and radiomimetic anticancer agents and are thought to be biologically severe. 7,8-dihydro-8-oxoguanine (8-oxoG), a major DNA damage resulting from oxidative attack, is highly mutagenic leading to a high level of G.C-->T.A transversions if not previously excised by OGG1 DNA glycosylase/AP lyase proteins in eukaryotes. However, 8-oxoG within clustered DNA damage may present a challenge to the repair machinery of the cell. The ability of yeast OGG1 to excise 8-oxoG was determined when another type of damage [dihydrothymine, uracil, 8-oxoG, abasic (AP) site or various types of single-strand breaks (SSBs)] is present on the complementary strand 1, 3 or 5 bases 5' or 3' opposite to 8-oxoG. Base damages have little or no influence on the excision of 8-oxoG by yeast OGG1 (yOGG1) whereas an AP site has a strong inhibitory effect. Various types of SSBs, obtained using either oligonucleotides with 3'- and 5'-phosphate termini around a gap or through conversion of an AP site with either endonuclease III or human AP endonuclease 1, strongly inhibit excision of 8-oxoG by yOGG1. Therefore, this large inhibitory effect of an AP site or a SSB may minimise the probability of formation of a double-strand break in the processing of 8-oxoG within clustered damages.


Comparison of Healthy and Dandruff Scalp Microbiome Reveals the Role of Commensals in Scalp Health.
Several scalp microbiome studies from different populations have revealed the association of dandruff with bacterial and fungal dysbiosis. However, the functional role of scalp microbiota in scalp disorders and health remains scarcely explored. Here, we examined the bacterial and fungal diversity of the scalp microbiome and their potential functional role in the healthy and dandruff scalp of 140 Indian women. Propionibacterium acnes and Staphylococcus epidermidis emerged as the core bacterial species, where the former was associated with a healthy scalp and the latter with dandruff scalp. Along with the commonly occurring Malassezia species (M. restricta and M. globosa) on the scalp, a strikingly high association of dandruff with yet uncharacterized Malassezia species was observed in the core mycobiome. Functional analysis showed that the fungal microbiome was enriched in pathways majorly implicated in cell-host adhesion in the dandruff scalp, while the bacterial microbiome showed a conspicuous enrichment of pathways related to the synthesis and metabolism of amino acids, biotin, and other B-vitamins, which are reported as essential nutrients for hair growth. A systematic measurement of scalp clinical and physiological parameters was also carried out, which showed significant correlations with the microbiome and their associated functional pathways. The results point toward a new potential role of bacterial commensals in maintaining the scalp nutrient homoeostasis and highlights an important and yet unknown role of the scalp microbiome, similar to the gut microbiome. This study, therefore, provides new perspectives on the better understanding of the pathophysiology of dandruff.


Oxyphor 2P: A High-Performance Probe for Deep-Tissue Longitudinal Oxygen Imaging.
Quantitative imaging of oxygen distributions in tissue can provide invaluable information about metabolism in normal and diseased states. Two-photon phosphorescence lifetime microscopy (2PLM) has been developed to perform measurements of oxygen in vivo with micron-scale resolution in 3D; however, the method's potential has not yet been fully realized due to the limitations of current phosphorescent probe technology. Here, we report a new sensor, Oxyphor 2P, that enables oxygen microscopy twice as deep (up to 600 μm below the tissue surface) and with ∼60 times higher speed than previously possible. Oxyphor 2P allows longitudinal oxygen measurements without having to inject the probe directly into the imaged region. As proof of principle, we monitored oxygen dynamics for days following micro-stroke induced by occlusion of a single capillary in the mouse brain. Oxyphor 2P opens up new possibilities for studies of tissue metabolic states using 2PLM in a wide range of biomedical research areas.


[Research articles].
Since 1973, Revista Médica de Chile has classified biomedical and clinical prospective research papers in a Section named "Research Articles", while purely clinical and retrospective studies were classified into another Section, named "Clinical Experiences". This distinction seems no longer necessary, because both types of manuscripts are subjected to a uniform external peer-review system and their intrinsic quality is not a distinctive feature. Furthermore, the name of Sections where similar papers are classified by the major general clinical medicine journals is clearly non-uniform. Therefore, "Research Articles" and "Clinical Experiences" will from now on be included into a single Section: "Research Articles".


c-erbB-2 oncoprotein in screen-detected breast carcinoma: an immunohistological study.
This study was aimed at comparing screen-detected and symptomatic breast carcinomas with regard to the prevalence of positive immunostaining for c-erb-B-2 oncoprotein. Paraffin sections of 81 breast carcinomas detected through the National Screening Programme were examined for the over-expression of c-erbB-2 oncoprotein using the avidin-biotin immunoperoxidase technique and 2 different specific antibodies: 21N and 4D5. Twenty-one other carcinomas detected in symptomatic patients were similarly examined for comparison. The screen-detected lesions were of 2 types: palpable and impalpable which required needle localization prior to surgical removal. Of the 81 screen-detected tumours, only 8 were c-erbB-2 positive, compared with 5 out of 21 non-screen-detected tumours. When only invasive carcinomas were considered, 5 out of 63 screen-detected cases were positive, compared with 5 out of 15 symptomatic cases. Four out of the 5 screen-detected positive invasive carcinomas were clinically palpable. Our results show an obvious trend towards a lower prevalence of c-erbB-2 oncoprotein over-expression in screen-detected carcinomas. As this over-expression is thought to be associated with increased tumour aggressiveness, the findings suggest a low prevalence of aggressive tumours in screen-detected lesions, particularly impalpable invasive carcinomas, identified so far.


Protein interactions during coronavirus assembly.
Coronaviruses assemble and obtain their envelope at membranes of the intermediate compartment between the endoplasmic reticulum and Golgi complex. Like other enveloped viruses, coronavirus assembly is presumably dependent on protein localization and protein-protein as well as protein-RNA interactions. We have used the bovine coronavirus (BCV) as a model to study interactions between the viral proteins in virus-infected cells that are important for coronavirus assembly. BCV is a prototype for the coronaviruses that express an additional major structural protein, the hemagglutinin esterase (HE), in addition to the spike (S) glycoprotein, membrane (M) glycoprotein, and nucleocapsid (N) protein. Complexes consisting of the M, S, and HE proteins were detected in virus-infected cells by coimmunoprecipitations. Kinetic analyses demonstrated that S protein and HE each quickly formed a complex with M protein after synthesis, whereas heterocomplexes consisting of all three proteins formed more slowly. The kinetics of HE biosynthesis revealed that the half-life of oligomerization was approximately 30 min, which correlated with the appearance of complexes consisting of M, HE, and S proteins, suggesting that oligomerization and/or conformational changes may be important for the S-M-HE protein complexes to form. Only HE dimers were found associated with the heterocomplexes consisting of all three proteins. S-M-HE protein complexes were detected prior to processing of the oligosaccharide chains on HE, indicating that these protein complexes formed in a premedial Golgi compartment before trimming of sugar chains. Transient coexpressions and double-labeling immunofluorescence demonstrated that HE and S proteins colocalized with M protein. This was further supported by coimmunoprecipitation of specific HE-M and S-M protein complexes from transfected cells, indicating that these proteins can form complexes in the absence of other viral proteins.


Bottom-up guidance to grouped items in conjunction search: evidence for color grouping.
Previous studies have demonstrated that observers can search through a subset of items carrying a minority feature to find a conjunction target (Sobel & Cave, 2002). We examined whether subset search takes place when participants have less specific foreknowledge of the target (when the target is one of two possible items), measuring eye movements as well as reaction times. When there were unequal ratios of distractors, fixations were initially directed to the small subset. These initial eye movements were often directed between items with the same feature, suggesting guidance from pooled feature values. There was stronger guidance within color- than orientation-defined groups, although the features were balanced for salience. The results suggest that grouping of items by color operates more globally than grouping in orientation.


Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress.
The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.


Transcriptome difference and potential crosstalk between liver and mammary tissue in mid-lactation primiparous dairy cows.
Liver and mammary gland are among the most important organs during lactation in dairy cows. With the purpose of understanding both the different and the complementary roles and the crosstalk of those two organs during lactation, a transcriptome analysis was performed on liver and mammary tissues of 10 primiparous dairy cows in mid-lactation. The analysis was performed using a 4×44K Bovine Agilent microarray chip. The transcriptome difference between the two tissues was analyzed using SAS JMP Genomics using ANOVA with a false discovery rate correction (FDR). The analysis uncovered >9,000 genes differentially expressed (DEG) between the two tissues with a FDR<0.001. The functional analysis of the DEG uncovered a larger metabolic (especially related to lipid) and inflammatory response capacity in liver compared with mammary tissue while the mammary tissue had a larger protein synthesis and secretion, proliferation/differentiation, signaling, and innate immune system capacity compared with the liver. A plethora of endogenous compounds, cytokines, and transcription factors were estimated to control the DEG between the two tissues. Compared with mammary tissue, the liver transcriptome appeared to be under control of a large array of ligand-dependent nuclear receptors and, among endogenous chemical, fatty acids and bacteria-derived compounds. Compared with liver, the transcriptome of the mammary tissue was potentially under control of a large number of growth factors and miRNA. The in silico crosstalk analysis between the two tissues revealed an overall large communication with a reciprocal control of lipid metabolism, innate immune system adaptation, and proliferation/differentiation. In summary the transcriptome analysis confirmed prior known differences between liver and mammary tissue, especially considering the indication of a larger metabolic activity in liver compared with the mammary tissue and the larger protein synthesis, communication, and proliferative capacity in mammary tissue compared with the liver. Relatively novel is the indication by the data that the transcriptome of the liver is highly regulated by dietary and bacteria-related compounds while the mammary transcriptome is more under control of hormones, growth factors, and miRNA. A large crosstalk between the two tissues with a reciprocal control of metabolism and innate immune-adaptation was indicated by the network analysis that allowed uncovering previously unknown crosstalk between liver and mammary tissue for several signaling molecules.


Loss compensation in metamaterials through embedding of active transistor based negative differential resistance circuits.
Dielectric and ohmic losses in metamaterials are known to limit their practical use. In this paper, an all-electronic approach for loss compensation in metamaterials is presented. Each unit cell of the meta-material is embedded with a cross-coupled transistor pair based negative differential resistance circuit to cancel these losses. Design, simulation and experimental results for Split Ring Resonator (SRR) metamaterials with and without loss compensation are presented. Results indicate that the quality factor (Q) of the SRR improves by over 400% at 1.6 GHz, showing the effectiveness of the approach. The proposed technique is scalable over a broad frequency range and is limited only by the maximum operating frequency of transistors, which is reaching terahertz in today's semiconductor technologies.


Large cities are less green.
We study how urban quality evolves as a result of carbon dioxide emissions as urban agglomerations grow. We employ a bottom-up approach combining two unprecedented microscopic data on population and carbon dioxide emissions in the continental US. We first aggregate settlements that are close to each other into cities using the City Clustering Algorithm (CCA) defining cities beyond the administrative boundaries. Then, we use data on CO2 emissions at a fine geographic scale to determine the total emissions of each city. We find a superlinear scaling behavior, expressed by a power-law, between CO2 emissions and city population with average allometric exponent β = 1.46 across all cities in the US. This result suggests that the high productivity of large cities is done at the expense of a proportionally larger amount of emissions compared to small cities. Furthermore, our results are substantially different from those obtained by the standard administrative definition of cities, i.e. Metropolitan Statistical Area (MSA). Specifically, MSAs display isometric scaling emissions and we argue that this discrepancy is due to the overestimation of MSA areas. The results suggest that allometric studies based on administrative boundaries to define cities may suffer from endogeneity bias.


Limitations in Prehospital Communication Between Trauma Helicopter, Ambulance Services, and Dispatch Centers.
Prehospital communication with Emergency Medical Services (EMS) is carried out in hectic situations. Proper communication among all medical personal is required to enhance collaboration, to provide the best care and enable shared situational awareness. The objective of this article was to give insight into current Dutch prehospital emergency care communication among all EMS and evaluate the usage of a new physician staffed helicopter EMS (P-HEMS) cancellation model. Trauma-related P-HEMS dispatches between November 1, 2014 and May 31, 2015 for the Lifeliner 1 were included; a random sample of 100 dispatches was generated. Tape recordings on all verbal prehospital communication between the dispatch center, EMS, and P-HEMS were transcribed and analyzed. Qualitative content analysis was performed, using open coding to code key messages. Ninety-two tape recordings were analyzed. The most frequent reason for P-HEMS dispatch was suspicion of brain injury (24%). The cancellation model was followed in 66%, overruled in 9%, and not applicable in 25%. The main reason for not adhering to the model was hemodynamic stability. In 5% of P-HEMS dispatches, a complete ABCD (airway, breathing, circulation, disability) methodology was used for handover, in 9% a complete Situation-Background-Assessment-Recommendation technique, in 2% a complete Mechanism-Injuries-Signs-Treatment method was used. The other handovers were incomplete. Prehospital handover between EMS on-scene and P-HEMS often entails insufficient information. The cancellation model for P-HEMS is frequently used and promotes adequate information transfer. To increase joined decision-making, more patient and situational information needs to be handed over. Standardization of prehospital trauma handovers will facilitate this and improve trauma patient's outcome.


Addressing the Symptom Management Gap in Patients With Cancer and Heart Failure Using the Interactive Voice Response System: A Pilot Study.
Patients with cancer and concurrent heart failure (HF) have severe symptoms that may adversely affect patients' quality of life in addition to limiting effective anticancer therapy. A system of frequent monitoring could alert clinicians, providing the opportunity for timely intervention before patients become severely ill and require hospitalization. The purpose of this pilot study was to evaluate if the MD Anderson Symptom Inventory-Heart Failure (MDASI-HF) instrument preprogrammed via the interactive voice response system (IVRS) can be used to collect symptom data that will generate symptom alerts to providers based on preset severity levels. Twenty-six patients were enrolled in the study. Symptoms were monitored using the MDASI-HF delivered via IVRS on a weekly basis for 3 months. When a participant's reported symptom(s) reached critical predetermined threshold levels, an alert prompted the nurse to triage the patient's response and initiate interventions per protocol. Descriptive statistics were used to describe the ratings of symptom severity and symptom interference with daily function. Demographic and disease characteristics were summarized using means, standard deviations, ranges, count, and proportions. Paired t-tests were used to examine symptom reduction from baseline to the end of 3 months. Fourteen (54%) participants completed the study with average IVRS usage rates of 84% at 1 month and 82% at 3 months. Over the course of the IVRS monitoring, 152 IVRS calls were completed and 107 critical threshold alerts were generated, prompting physician notification, medication titration, and non-routine clinic visits. Most of these alerts were managed by telephone, particularly those related to diuretic titration, and prevented hospital readmission. Symptom monitoring via the IVRS can potentially bridge the gap in symptom management to improve clinical outcomes in patients with cancer and HF. The IVRS can be of benefit in the symptom management of patients, especially those constrained by geographic location. This can potentially improve the quality of care, patient satisfaction, and quality of life of these patients.


The extent of lymphadenectomy in esophageal resection for cancer should be standardized.
The incidence of esophageal cancer increases, with approximately 482,000 patients diagnosed with esophageal cancer each year. Despite the growing incidence of esophageal carcinoma, the extent of the lymphadenectomy is still under discussion. Lymph node status is an important prognostic parameter in esophageal cancer and an independent predictor of survival. Surgical strategy depends on the distribution pattern of nodal metastases but consensus on the extent of lymphadenectomy differs worldwide. For squamous cell cancer, Japanese surgeons have standardized the 2- or 3-field lymphadenectomy according to the location of the tumor. For adenocarcinoma, in the Western World accounting for 85% of all esophageal cancers, the type of lymphadenectomy to perform is not clear. Moreover, the use of neoadjuvant therapy may influence the mediastinal lymph nodes and the significance of the lymphadenectomy for survival. These aspects have challenged the traditional policy concerning lymphadenectomy, at least in the Western World. Furthermore, an extensive lymphadenectomy may improve survival but, on the other hand, may cause significant more morbidity. An overview of the literature on the extent of lymphadenectomy for esophageal cancer with respect to the supposed lymph node distribution patterns for squamous cell carcinoma and adenocarcinoma, the different lymph node classification systems, the commonly used surgical techniques and outcomes, and the proposal of observational cohort study to standardize the type of lymphadenectomy according to the type of tumor, location and use of neoadjuvant therapy will be provided.


Effect of the new pyridoindole antioxidant SMe1EC2 on functional deficits and oedema formation in rat hippocampus exposed to ischaemia in vitro.
The idea of neuroprotective therapy for ischaemic stroke is based on results from studies on experimental animal models of brain ischaemia demonstrating efficacy of many natural and synthetic agents. Contrary to positive conclusions with antioxidants from animal models, clinical experience failed to find neuroprotectants so efficient in human stroke, infarction, brain trauma, tissue preservation, etc. Thus new highly effective neuroprotective agents need to be discovered. Effects of 10-day oral treatment with the new pyridoindole derivative, code SMe1EC2, was analysed in the model of ischaemia in vitro measured five days after oral treatment, with focus on neuronal function recovery. The responses were determined by extracellular recording from rat hippocampal slices. Further, effect of SMe1EC2, applied into the incubation medium before and during ischaemia in vitro, was studied on the oedema extent in neurons of the CA1 area. Ten-day oral treatment of rats with SMe1EC2 at the doses 50 or 250 mg/kg resulted in improved resistance of hippocampal neurons to 6.5-min hypoxia/hypoglycaemia in vitro measured during reoxygenation, compared to untreated rats. Application of the drug tested into the incubation medium 30 min before and during 6-min hypoxia/hypoglycaemia resulted in reduction of oedema formation in the CA1 area compared to untreated slices exposed to ischaemia in vitro. The current study confirmed the neuroprotective effect of the pyridoindole antioxidant SMe1EC2 on the level of recovery of neuronal function as well as on affection of morphological changes expressed by reduced oedema extent in the rat hippocampus under ischemic conditions in vitro.


The LINC-anchored actin cap connects the extracellular milieu to the nucleus for ultrafast mechanotransduction.
Cells continuously sense and respond to external mechanical forces through their cytoskeleton. Here we show that only a small subset of actin fibers, those forming the perinuclear actin cap that wraps around the nucleus, form in response to low physiological mechanical stresses in adherent fibroblasts. While conventional basal stress fibers form only past a threshold shear stress of 0.5 dyn/cm(2), actin-cap fibers are formed at shear stresses 50 times lower and orders-of-magnitude faster than biochemical stimulation. This fast differential response is uniquely mediated by focal adhesion protein zyxin at low shear stress and actomyosin fibers of the actin cap. We identify additional roles for lamin A/C of the nuclear lamina and linkers of nucleus to cytoskeleton (LINC) molecules nesprin2giant and nesprin3, which anchor actin cap fibers to the nucleus. These results suggest an interconnected physical pathway for mechanotransduction, from the extracellular milieu to the nucleus.


Autonomic nervous system markers of psychopathology in childhood-onset schizophrenia.
Consistent abnormalities in peripheral indicators of autonomic activity, ie, skin conductance (SC) and heart rate (HR), have been reported in adult-onset schizophrenia. Herein, we use these markers to test the hypothesis of continuity between childhood-onset schizophrenia and adult-onset schizophrenia. Skin conductance and HR were recorded from 21 severely ill children and adolescents (mean age, 14.1 years) with childhood-onset (< or = 12 years) schizophrenia (patient group) and from 54 age-matched controls (control group) during a rest period, a series of innocuous tones, reaction time instructions, and a simple warned reaction time task. During rest, patients had higher rates of spontaneous SC responses (SCRs) and HRs than controls, but their SC level was marginally lower and declined more slowly over time. Half of the patients, compared with 4% of the controls, failed to give SC-orienting responses to the first 2 tones. Patients who responded had impaired SCR magnitudes, and their habituation was more erratic than that of controls. The increase in SC level and SCR frequency at the onset of the task period was greatly attenuated in the patients, so that both variables were higher in controls. Patients had smaller SCRs and anticipatory HR responses to the reaction time stimuli. Skin conductance nonresponding was associated with negative and total symptoms, and spontaneous SCR frequency was associated with positive symptoms. The findings show similar abnormalities in autonomic nervous system activity in childhood-onset schizophrenia to those found in adult chronic schizophrenia, thus supporting the hypothesis of continuity of the childhood and adult forms of the illness. Comparisons with data from other childhood disorders suggest that the combination of low-elicited SC activity with high levels of spontaneous SC activity may be specific to schizophrenia.


Assembling the marine metagenome, one cell at a time.
The difficulty associated with the cultivation of most microorganisms and the complexity of natural microbial assemblages, such as marine plankton or human microbiome, hinder genome reconstruction of representative taxa using cultivation or metagenomic approaches. Here we used an alternative, single cell sequencing approach to obtain high-quality genome assemblies of two uncultured, numerically significant marine microorganisms. We employed fluorescence-activated cell sorting and multiple displacement amplification to obtain hundreds of micrograms of genomic DNA from individual, uncultured cells of two marine flavobacteria from the Gulf of Maine that were phylogenetically distant from existing cultured strains. Shotgun sequencing and genome finishing yielded 1.9 Mbp in 17 contigs and 1.5 Mbp in 21 contigs for the two flavobacteria, with estimated genome recoveries of about 91% and 78%, respectively. Only 0.24% of the assembling sequences were contaminants and were removed from further analysis using rigorous quality control. In contrast to all cultured strains of marine flavobacteria, the two single cell genomes were excellent Global Ocean Sampling (GOS) metagenome fragment recruiters, demonstrating their numerical significance in the ocean. The geographic distribution of GOS recruits along the Northwest Atlantic coast coincided with ocean surface currents. Metabolic reconstruction indicated diverse potential energy sources, including biopolymer degradation, proteorhodopsin photometabolism, and hydrogen oxidation. Compared to cultured relatives, the two uncultured flavobacteria have small genome sizes, few non-coding nucleotides, and few paralogous genes, suggesting adaptations to narrow ecological niches. These features may have contributed to the abundance of the two taxa in specific regions of the ocean, and may have hindered their cultivation. We demonstrate the power of single cell DNA sequencing to generate reference genomes of uncultured taxa from a complex microbial community of marine bacterioplankton. A combination of single cell genomics and metagenomics enabled us to analyze the genome content, metabolic adaptations, and biogeography of these taxa.


Emotional face processing in women with high and low levels of eating disorder related symptoms.
Emotional processing has rarely been investigated in those "at risk" of developing an eating disorder. This study investigated the processing of six basic emotions depicted on faces in an "at risk" group, compared to a control group. Participants were women with high (N=29) and low (N=23) levels of eating disorder symptoms who were not taking psychotropic medication. A well characterised computerised task (Facial Expression Emotion Task) was administered to all participants. Women with high levels of eating disorder symptoms, compared to those with low levels, were less accurate at recognising happy and neutral faces, but showed no differences in their accuracy at recognising other emotions. They also showed a trend to be less good at discriminating anger, but better at discriminating surprise from other emotions. Depressive and anxious symptoms did not provide a complete explanation for the findings. The findings support the inclusion of emotional processing in models of eating disorders, and suggest that it may have a role in their development. Emotional processing warrants further investigation particularly in those "at risk" but also in those with eating disorders.


Long-term hearing outcome in patients receiving intratympanic gentamicin for Ménière's disease.
To determine the long-term hearing outcome in patients with intractable vertigo caused by unilateral Ménière's disease who were treated with intratympanic injection of gentamicin. The study was a longitudinal analysis of hearing and control of vertigo in patients with unilateral Ménière's disease who received intratympanic gentamicin. Pure-tone thresholds and speech discrimination scores on audiometry were analyzed, along with the control of vertigo. Criteria described in 1995 by the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) were used. Patients treated with intratympanic gentamicin had "definite" Ménière's disease and had intractable vertigo despite optimal medical therapy, no symptoms suggestive of Ménière's disease in the contralateral ear, and serviceable hearing in the contralateral ear. The study analyzed the outcomes of 34 patients for whom follow-up data were available for periods greater than 24 months after intratympanic gentamicin. Complete control of vertigo (AAOHNS Class A) was obtained in 90% of the patients. Profound sensorineural hearing loss occurred as a result of gentamicin injection in 1 of the 34 patients (3%). When data from all patients were grouped together, hearing was improved in 5 (15%), unchanged in 23 (68%), and worse in 6 (17%) patients. This distribution of hearing outcome is similar to that in patients whose symptoms of Ménière's disease were managed with medical measures. Recurrent vertigo developed in 10 patients (29%) at an interval of 4 to 15 months after initially complete control. Treatment with additional intratympanic injection(s) of gentamicin did not result in a change in hearing. The risk of hearing loss in patients treated with infrequent intratympanic injection(s) of gentamicin is low.


Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance.
BDNF plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val66met) has been associated with abnormal intracellular trafficking and regulated secretion of BDNF in cultured hippocampal neurons transfected with the met allele. In addition, the met allele has been associated with abnormal hippocampal neuronal function as well as impaired episodic memory in human subjects, but a direct effect of BDNF alleles on hippocampal processing of memory has not been demonstrated. We studied the relationship of the BDNF val66met genotype and hippocampal activity during episodic memory processing using blood oxygenation level-dependent functional magnetic resonance imaging and a declarative memory task in healthy individuals. Met carriers exhibited relatively diminished hippocampal engagement in comparison with val homozygotes during both encoding and retrieval processes. Remarkably, the interaction between the BDNF val66met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance. These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory and suggest that the basic effects of BDNF signaling on hippocampal function in experimental animals are important in humans.


Thermal tachypnea in avian embryos.
Many adult mammals and birds respond to high surrounding temperatures with thermal tachypnea - an increase in breathing frequency accompanied by shallow tidal volume, with minimal increase in oxygen consumption (V̇O2 ). This pattern favors heat dissipation by evaporative water loss (EWL) through the respiratory tract. We asked to what extent this response was apparent at the earliest stages of development, when pulmonary ventilation initiates. Measurements of pulmonary ventilation (V̇E; barometric technique), V̇O2 (open-flow methodology) and EWL (water scrubbers) were performed on chicken embryos at the earliest appearance of pulmonary ventilation, during the internal pipping stage. Data were collected, first, at the normal incubation temperature (37.5°C); then, ambient and egg temperatures were increased to approximately 44°C over a 2 h period. Other embryos of the same developmental stage (controls) were maintained in normothermia for the whole duration of the experiment. During heat exposure, the embryo's V̇O2 and carbon dioxide production increased little. In contrast, V̇E more than doubled (∼128% increase), entirely because of the large rise in breathing frequency (∼132% increase), with no change in tidal volume. EWL did not change significantly, probably because, within the egg, the thermal and water vapor gradients are almost nonexistent. We conclude that chicken embryos respond to a major heat load with tachypnea, like many adult mammals and birds do. Its appearance so early in development, although ineffective for heat loss, signifies that thermal tachypnea represents an important breathing response necessary to be functional from hatching.


The 58-kilodalton inhibitor of the interferon-induced double-stranded RNA-activated protein kinase is a tetratricopeptide repeat protein with oncogenic properties.
The interferon-induced RNA-dependent protein kinase (PKR) is considered to play an important role in the cellular defense against viral infection and, in addition, has been suggested to be a tumor suppressor gene because of its growth-suppressive properties. Activation of PKR by double-stranded RNAs leads to the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha) and a resultant block to protein synthesis initiation. To avoid the consequences of kinase activation, many viruses have developed strategies to down-regulate PKR. Recently, we reported on the purification and characterization of a cellular inhibitor of PKR (referred to as p58), which is activated during influenza virus infection. Subsequent cloning and sequencing has revealed that p58 is a member of the tetratricopeptide repeat (TPR) family of proteins. To further examine the physiological role of this PKR inhibitor, we stably transfected NIH 3T3 cells with a eukaryotic expression plasmid containing p58 cDNA under control of the cytomegalovirus early promoter. By taking advantage of a recently characterized p58 species-specific monoclonal antibody, we isolated cell lines that overexpressed p58. These cells exhibited a transformed phenotype, growing at faster rates and higher saturation densities and exhibiting anchorage-independent growth. Most importantly, inoculation of nude mice with p58-overexpressing cells gave rise to the production of tumors. Finally, murine PKR activity and endogenous levels of eIF-2 alpha phosphorylation were reduced in the p58-expressing cell lines compared with control cells. These data, taken together, suggest that p58 functions as an oncogene and that one mechanism by which the protein induces malignant transformation is through the down-regulation of PKR and subsequent deregulation of protein synthesis.


Extent of Elder Abuse Training in Dental Hygiene Curricula and Program Directors' Perceptions of Importance of and Barriers to Implementation.
Research published in 2002 reported limited elder abuse training in U.S. dental hygiene curricula although its importance has increased with an aging population. The aims of this study were to determine the current extent of elder abuse training in U.S. dental hygiene curricula and to explore dental hygiene program directors' perspectives on the topic. A 25-item online survey was distributed to all 361 program directors, coordinators, and/or department chairs of Commission on Dental Accreditation (CODA)-accredited dental hygiene programs via email in August 2017. A response rate of 27.2% (n=98) was achieved. A large percentage of the respondents (83.3%) included elder abuse training in their program curricula; for most (58.7%), one to three curriculum hours were spent on the topic. A large percentage (89%) agreed the topic was at least somewhat important to include, and 29.5% said a personal or professional elder abuse experience influenced the depth of instruction at their program. Various barriers to inclusion were identified. At least 40% of these educators perceived their graduates to be appropriately competent in their ability to recognize elders' oral neglect (63.5%) and general neglect (48.7%) and to document potential signs of elder abuse (43.8%). Lower percentages perceived that their graduates were competent in the areas of communication regarding elder abuse (21.9%) and reporting suspected abuse (32.4%). Despite rising awareness about elder abuse among dental hygienists and widespread incorporation of the subject in dental hygiene curricula, these results suggest that there are still deficiencies in training. To prepare dental hygiene graduates to confidently recognize and respond to elder abuse, educators should seek to overcome barriers by modifying instruction and embracing interprofessional collaboration.


Effects of ion etching on the properties of GaAs.
Effects of ion etching on the optical properties and lattice disorder of GaAs were studied by means of photoluminescence, He backscattering, and enhanced chemical etching. The photoluminescence intensity excited by a He-Cd laser (3250 A), which penetrates a distance of approximately 150 A into GaAs, is decreased to less than 20% of the initial value after ion etching by 100-eV Ar and recovered almost completely by 450 degrees C annealing. Helium backscattering and electron diffraction pattern indicate the existence of an amorphous layer, the thickness of which is 20% larger than the value estimated by LSS theory. Photoluminescence measurement shows that beyond this amorphous region there are distributed a lot of nonradiative recombination centers as well as radiative recombination centers which diffuse into the bulk. The depth of this distribution is larger than that of the amorphous region by 1 order of magnitude.


Systems biology of complex symptom profiles: capturing interactivity across behavior, brain and immune regulation.
As our thinking about the basic principles of biology and medicine continue to evolve, the importance of context and regulatory interaction is becoming increasingly obvious. Biochemical and physiological components do not exist in isolation but instead are part of a tightly integrated network of interacting elements that ensure robustness and support the emergence of complex behavior. This integration permeates all levels of biology from gene regulation, to immune cell signaling, to coordinated patterns of neuronal activity and the resulting psychosocial interaction. Systems biology is an emerging branch of science that sits as a translational catalyst at the interface of the life and computational sciences. While there is no universally accepted definition of systems biology, we attempt to provide an overview of some the basic unifying concepts and current efforts in the field as they apply to illnesses where brain and subsequent behavior are a chief component, for example autism, schizophrenia, depression, and others. Methods in this field currently constitute a broad mosaic that stretches across multiple scales of biology and physiological compartments. While this work by no means constitutes an exhaustive list of all these methods, this work highlights the principal sub-disciplines presently driving the field as well as future directions of progress.


Diversity of containers and buildings infested with Aedes aegypti in Puerto Iguazú, Argentina.
Aedes aegypti is the main domestic vector of the dengue virus. Control measures to prevent dengue transmission focus on the treatment and elimination of this vector's oviposition sites. There is limited biological information on Ae. aegypti in Argentina. The aim of this study was to characterize Ae. aegypti oviposition sites in the city of Puerto Iguazú, Argentina. We surveyed an area covering nine neighborhoods in 2005. We identified 191 premises as positive for Ae. aegypti, giving a general house index of 9.6%. Premises classified as residential and vacant lots presented the highest number of infested premises, with 9% and 22% respectively. The total number of surveyed containers was 29,600. The overall container index (CI) was 1.1. The most frequently infested containers were water tanks (CI = 37). These preliminary results suggest that vacant lots and water tanks provide suitable breeding areas and environmental conditions, improving the chances of Ae. aegypti survival in Puerto Iguazú.


Measurement of total vitamin B12 and holotranscobalamin, singly and in combination, in screening for metabolic vitamin B12 deficiency.
The standard screening test for vitamin B12 deficiency, measurement of total plasma vitamin B12, has limitations of sensitivity and specificity. Plasma vitamin B12 bound to transcobalamin (holoTC) is the fraction of total vitamin B12 available for tissue uptake and therefore has been proposed as a potentially useful alternative indicator of vitamin B12 status. We compared the diagnostic accuracy of total vitamin B12, holoTC, and a combination of both measures to screen for metabolic vitamin B12 deficiency in an elderly cohort (age > or = 60 years). Plasma methylmalonic acid and homocysteine were used as indicators of vitamin B12 deficiency. Low total vitamin B12 (< 148 pmol/L) and low holoTC (< 35 pmol/L) were observed in 6.5% and 8.0%, and increased methylmalonic acid (> 350 nmol/L) and homocysteine (> 13 micromol/L) were observed in 12.1% and 17.0% of the study participants. In multiple regression models, holoTC explained 5%-6% more of the observed variance in methylmalonic acid and homocysteine than did total vitamin B12 (P < or = 0.004). ROC curve analysis indicated that total vitamin B12 and holoTC were essentially equivalent in their ability to discriminate persons with and without vitamin B12 deficiency. Individuals with low concentrations of both total vitamin B12 and holoTC had significantly higher concentrations of methylmalonic acid and homocysteine than did individuals with total vitamin B12 and/or holoTC within the reference intervals (P < 0.001). HoloTC and total vitamin B12 have equal diagnostic accuracy in screening for metabolic vitamin B12 deficiency. Measurement of both holoTC and total vitamin B12 provides a better screen for vitamin B12 deficiency than either assay alone.


Efficacy of a Forearm Rotation Orthosis for People With a Hemiparetic Arm.
Insufficient voluntary forearm movements are associated with ineffective and inefficient functional performance among people poststroke. Although evidence supports the application of the occupational therapy task-oriented (OTTO) approach for this population, the training protocol does not explicitly address the role of forearm rotation movements. In addition, a need exists for theoretical support for orthotic interventions for people poststroke. Objective: To examine the efficacy of (1) a forearm rotation orthosis, (2) the OTTO approach, and (3) the combination of the two with people poststroke with a hemiparetic arm. Stratified, randomized, two-group, single-blinded, repeated-measures design. Rehabilitation clinic. Participants (N = 14) with a diagnosis of stroke and at least 10° of voluntary shoulder and elbow movement. Participants were stratified into three groups by motor function (mild, moderate, severe) and randomly assigned either to 6 wk of no treatment followed by 6 wk of OTTO or to 6 wk of orthotic intervention followed by 6 wk of orthosis plus OTTO. Outcomes and Measures: Primary outcome measures were the Canadian Occupational Performance Measure (COPM), Wolf Motor Function Test (WMFT), and Motor Activity Log (MAL), administered at baseline (Week 1), at the end of Phase 1 (Week 7), and at the end of Phase 2 (Week 15) by blinded evaluators. Both groups showed clinically important improvements on the COPM. No significant differences were found on the WMFT or MAL. The OTTO intervention provides clinically important benefits in self-perceived functional performance to people poststroke. What This Article Adds: The OTTO approach is an occupation-focused intervention that aims at functional performance and emphasizes clients' active engagement throughout the process. The findings suggest that the protocol of the OTTO intervention and its efficacy are appropriate for clinical practice.


Validation of reference genes for quantitative expression analysis by real-time RT-PCR in Saccharomyces cerevisiae.
Real-time RT-PCR is the recommended method for quantitative gene expression analysis. A compulsory step is the selection of good reference genes for normalization. A few genes often referred to as HouseKeeping Genes (HSK), such as ACT1, RDN18 or PDA1 are among the most commonly used, as their expression is assumed to remain unchanged over a wide range of conditions. Since this assumption is very unlikely, a geometric averaging of multiple, carefully selected internal control genes is now strongly recommended for normalization to avoid this problem of expression variation of single reference genes. The aim of this work was to search for a set of reference genes for reliable gene expression analysis in Saccharomyces cerevisiae. From public microarray datasets, we selected potential reference genes whose expression remained apparently invariable during long-term growth on glucose. Using the algorithm geNorm, ALG9, TAF10, TFC1 and UBC6 turned out to be genes whose expression remained stable, independent of the growth conditions and the strain backgrounds tested in this study. We then showed that the geometric averaging of any subset of three genes among the six most stable genes resulted in very similar normalized data, which contrasted with inconsistent results among various biological samples when the normalization was performed with ACT1. Normalization with multiple selected genes was therefore applied to transcriptional analysis of genes involved in glycogen metabolism. We determined an induction ratio of 100-fold for GPH1 and 20-fold for GSY2 between the exponential phase and the diauxic shift on glucose. There was no induction of these two genes at this transition phase on galactose, although in both cases, the kinetics of glycogen accumulation was similar. In contrast, SGA1 expression was independent of the carbon source and increased by 3-fold in stationary phase. In this work, we provided a set of genes that are suitable reference genes for quantitative gene expression analysis by real-time RT-PCR in yeast biological samples covering a large panel of physiological states. In contrast, we invalidated and discourage the use of ACT1 as well as other commonly used reference genes (PDA1, TDH3, RDN18, etc) as internal controls for quantitative gene expression analysis in yeast.


Effects of surrounding tissue on the sound spectrum of arterial bruits in vivo.
Turbulent flow distal to arterial stenoses producers bruits with a characteristic sound spectrum, analysis of which has permitted accurate non-invasive assessment of the residual lumen diameter of the stenosis in the case of the human carotid artery. In contrast, investigators working with in vitro elastic models of arteries or with excised vessels have reported finding mainly resonant spectra of bruits recorded distal to stenoses. We have studied the effects of turbulent flow on the sound spectrum produced at the arterial wall and the influence of surrounding tissue on this spectrum. Aortic, carotid, and femoral stenoses were produced in dogs by external banding of the arteries with 5mm wide Teflon bands. Recordings of bruits made directly on the vessel wall had a sound spectrum made up of 2 components, one due to turbulent flow, and the second to a superimposed resonant spectrum from arterial wall vibration. This was true of 3 kinds of vessels studied. The effects of surrounding tissue on the sound spectrum of arterial bruits was shown by comparing the spectra o bruits recorded directly on the vessel wall, on the freshly closed wound and on the healed wound. The sound properties of the artery in situ are very different from those of exposed or excised vessels or elastic tubes. Although intravascular turbulence may be accurately appreciated at the skin surface, arterial wall resonance in the intact animal is extensively damped by the normal coupling of the artery to its surrounding tissue.


The work of commissioning: a multisite case study of healthcare commissioning in England's NHS.
To examine the work of commissioning care for people with long-term conditions and the factors inhibiting or facilitating commissioners making service change. Multisite mixed methods case study research, combining qualitative analysis of interviews, documents and observation of meetings. Primary care trust managers and clinicians, general practice-based commissioners, National Health Service trust and foundation trust senior managers and clinicians, voluntary sector and local government representatives. Three 'commissioning communities' (areas covered by a primary care trust) in England, 2010-2012. Commissioning services for people with long-term conditions was a long drawn-out process involving a range of activities and partners. Only some of the activities undertaken by commissioners, such as assessment of local health needs, coordination of healthcare planning and service specification, appeared in the official 'commissioning cycle' promoted by the Department of Health. Commissioners undertook a significant range of additional activities focused on reviewing and redesigning services and providing support for implementation of new services. These activities often involved partnership working with providers and other stakeholders and appeared to be largely divorced from contracting and financial negotiations. At least for long-term condition services, the time and effort involved in such work appeared to be disproportionate to the anticipated or likely service gains. Commissioners adopting an incremental approach to service change in defined and manageable areas of work appeared to be more successful in terms of delivering planned changes in service delivery than those attempting to bring about wide-scale change across complex systems. Commissioning for long-term condition services challenges the conventional distinction between commissioners and providers with a significant amount of work focused on redesigning services in partnership with providers. Such work is labour-intensive and potentially unsustainable at a time of reduced finances. New clinical commissioning groups will need to determine how best to balance the relational and transactional elements of commissioning.


Life satisfaction among informal caregivers in comparison with non-caregivers.
Being a caregiver with responsibility for someone with reduced health compared with not being a caregiver may mean different views of life satisfaction. Knowledge of what leads to reduced life satisfaction in caregivers may be helpful in interventions. Informal caregivers gainfully employed or not, aged 50-89 years, were studied with regard to life satisfaction depending on the extent of caregiving to identify types of social support of value for caregivers. A cross-sectional study was conducted including a sample of 151 informal caregivers with a high caregiving extent, 392 caregivers with a lower caregiving extent and 1258 non-caregivers. The sample was randomly selected to correspond with older Swedes as a whole aged 50-89 years. A questionnaire containing a modified form of Older Americans' Resources Schedule (OARS) and Life Satisfaction Index Z (LSIZ) was used; 19.6% helped someone with activities of daily living and of these 27% stated that they did so frequently. Frequent caregiving implied significantly higher age, being more often married and retired, than less frequent caregivers and non-caregivers. Frequent caregivers also performed personal activities of daily living (PADL) to a higher extent than less frequent caregivers and had significantly lower LSIZ (mean 14.8) than less frequent caregivers (mean 17.6) and non-caregivers (mean 17.7). No significant differences were found between less frequent caregivers and non-caregivers in LSIZ. One-fourth had support from others, the commonest type being able to converse with a next of kin, and help and advice from professionals. Lower life satisfaction was associated with not being employed, low social resources, not refreshed after a night's sleep, overall poor health and frequent caregiving in the entire sample. High caregiving extent was associated with lower life satisfaction. The most important factors explaining lower life satisfaction among frequent caregivers were having low social resources and having poor health. Economic compensation or payment was the support most desired.


Morphologically cryptic biological species within the liverwort Frullania asagrayana.
The Frullania tamarisci complex includes eight Holarctic liverwort species. One of these, F. asagrayana, is distributed broadly throughout eastern North America from Canada to the Gulf Coast. Preliminary genetic data suggested that the species includes two groups of populations. This study was designed to test whether the two groups are reproductively isolated biological species. • Eighty-eight samples from across the range of F. asagrayana, plus 73 samples from one population, were genotyped for 13 microsatellite loci. Sequences for two plastid loci and nrITS were obtained from 13 accessions. Genetic data were analyzed using coalescent models and Bayesian inference. • Frullania asagrayana is sequence-invariant at the two plastid loci and ITS2, but two clear groups were resolved by microsatellites. The two groups are largely reproductively isolated, but there is a low level of gene flow from the southern to the northern group. No gene flow was detected in the other direction. A local population was heterogeneous but displayed strong genetic structure. • The genetic structure of F. asagrayana in eastern North America reflects morphologically cryptic differentiation between reproductively isolated groups of populations, near-panmixis within groups, and clonal propagation at local scales. Reproductive isolation between groups that are invariant at the level of nucleotide sequences shows that caution must be exercised in making taxonomic and evolutionary inferences from reciprocal monophyly (or lack thereof) between putative species.


A pivotal role for cADPR-mediated Ca2+ signaling: regulation of endothelin-induced contraction in peritubular smooth muscle cells.
cADPR, a potent calcium-mobilizing intracellular messenger synthesized by ADP-ribosyl cyclases regulates openings of ryanodine receptors (RyR). Here we report that in the rat testis, a functional cADPR Ca2+ release system is essential for the contractile response of peritubular smooth muscle cells (PSMC) to endothelin (ET). We previously showed that this potent smooth muscle agonist elicits intracellular Ca2+ release in PSMC and seminiferous tubule contraction via activation of ETA and ETB receptors. ETB-R induces the mobilization of a thapsigargin-sensitive but IP3-independent intracellular Ca2+ pool. Stimulation of permeabilized PSMC with cADPR was found to elicit large Ca2+ releases blocked by either a selective antagonist of cADPR or a RyR blocker, but not by heparin. Western blotting and confocal fluorescence microscopy indicated the specific expression of type 2 RyR in perinuclear localization. ET was found to stimulate the activity of ADP-ribosyl cyclase. Microinjection of the selective cADPR antagonist 8NH2-cADPR completely abolished subsequent stimulation of Ca2+ signaling via ETA and ETB receptors. cADPR therefore appears to have an obligatory role for ETA-R and ETB-R-mediated calcium signaling in PSMC. However, ETB-R seem to be coupled exclusively to cADPR whereas ETA-R activation may be linked to IP3 and cADPR signaling pathways.


Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival.
Purpose: Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome.Experimental Design: Patient-resected GBM, The Cancer Genome Atlas, human T-cell:GBM cocultures, as well as nu/nu, NOD-scid, and humanized (NSG-SGM3-BLT) mice-engrafted human GBM form the basis of our investigation.Results:In situ hybridization for IDO1 revealed transcript expression throughout patient-resected GBM, whereas immunohistochemical IDO1 positivity was highly variable. Multivariate statistical analysis revealed that higher levels of IDO1 transcript predict a poor patient prognosis (P = 0.0076). GBM IDO1 mRNA levels positively correlated with increased gene expression for markers of cytolytic and regulatory T cells, in addition to decreased patient survival. Humanized mice intracranially engrafted human GBM revealed an IFNγ-associated T-cell-mediated increase of intratumoral IDO1Conclusions: Our data demonstrate that high intratumoral IDO1 mRNA levels correlate with a poor GBM patient prognosis. It also confirms the positive correlation between increased GBM IDO1 levels and human-infiltrating T cells. Collectively, this study suggests that future efforts aimed at increasing T-cell-mediated effects against GBM should consider combinatorial approaches that coinhibit potential T-cell-mediated IDO1 enhancement during therapy. Clin Cancer Res; 23(21); 6650-60. ©2017 AACR.


Febrile infection-related epilepsy syndrome (FIRES): prevalence, impact and management strategies.
Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy with a yet undefined etiology, affecting healthy children. It is characterized by acute manifestation of recurrent seizures or refractory status epilepticus preceded by febrile illness, but without evidence of infectious encephalitis. To date, the absence of specific biomarkers poses a significant diagnostic challenge; nonetheless, early diagnosis is very important for optimal management. FIRES is mostly irreversible and its sequelae include drug-resistant epilepsy and neuropsychological impairments. The treatment of FIRES represents a significant challenge for clinicians and is associated with low success rates. Early introduction of ketogenic diet seems to represent the most effective and promising treatment. This review aims to highlight the most recent insights on clinical features, terminology, epidemiology, pathogenesis, diagnostic challenges and therapeutic options.


Fatal pericardial tamponade after Wallstent implantation for malignant superior vena cava syndrome.
To report a rare, fatal complication of superior vena cava Wallstent implantation. A 59-year-old man presenting with superior vena cava syndrome caused by small-cell lung cancer underwent stent implantation of 2 kissing Wallstents >1.5 cm above the right atrium. Despite correct stent deployment, vessel perforation occurred in a section not encased by tumor, which led to fatal pericardial tamponade shortly after the procedure. Autopsy revealed perforation of a stent strut through the caval wall into the pericardial space. Anatomical and methodological reasons are discussed. The interventionist should be aware of this rare complication. Alternative stent designs avoiding the sharp ends of Wallstents and Palmaz stents should be considered.


Outcomes after liver transplantation for alcoholic hepatitis are similar to alcoholic cirrhosis: exploratory analysis from the UNOS database.
Data on liver transplantation for patients with alcoholic hepatitis are limited. Using the United Network for Organ Sharing database (2004-2010), adults undergoing liver transplantation for a listing diagnosis of alcoholic hepatitis were matched for age, gender, ethnicity, and model for endstage disease (MELD) score, donor risk index, and year of transplantation with three patients transplanted for a listing diagnosis of alcoholic cirrhosis. Study outcomes of graft and patient survival on follow-up were also analyzed for cohorts based on the diagnosis of the explant (46 alcoholic hepatitis and 138 alcoholic cirrhosis) and diagnosis at both listing as well as of the explant (11 alcoholic hepatitis and 33 alcoholic cirrhosis). Five-year graft and patient survival of alcoholic hepatitis and alcoholic cirrhosis patients were 75% and 73% (P = 0.97) and 80% and 78% (P = 0.90), respectively. Five-year graft and patient survival rates were also similar for cohorts based on diagnosis of the explant and diagnosis at listing as well as explant. Cox proportional regression analysis adjusting for other variables showed no impact of the etiology of liver disease (alcoholic hepatitis versus alcoholic cirrhosis) on the graft and patient survival. The causes of graft loss and patient mortality were similar in the two groups, and were not alcohol-related in any patient. Compared with alcoholic cirrhosis, patients with alcoholic hepatitis have similar posttransplantation graft and patient survival. Based on these preliminary findings, liver transplantation may be considered in a select group of patients with alcoholic hepatitis who fail to improve with medical therapy. Prospective studies are needed to assess the long-term outcome after liver transplantation in patients with alcoholic hepatitis.


NLRP14 deficiency causes female infertility with oocyte maturation defects and early embryonic arrest by impairing cytoplasmic UHRF1 abundance.
Oocyte maturation is vital to attain full competence required for fertilization and embryogenesis. NLRP14 is preferentially expressed in mammalian oocytes and early embryos. Yet, the role and molecular mechanism of NLRP14 in oocyte maturation and early embryogenesis are poorly understood, and whether NLRP14 deficiency accounts for human infertility is unknown. Here, we found that maternal loss of Nlrp14 resulted in sterility with oocyte maturation defects and early embryonic arrest (EEA). Nlrp14 ablation compromised oocyte competence due to impaired cytoplasmic and nuclear maturation. Importantly, we revealed that NLRP14 maintained cytoplasmic UHRF1 abundance by protecting it from proteasome-dependent degradation and anchoring it from nuclear translocation in the oocyte. Furthermore, we identified compound heterozygous NLRP14 variants in women affected by infertility with EEA, which interrupted the NLRP14-UHRF1 interaction and decreased UHRF1 levels. Our data demonstrate NLRP14 as a cytoplasm-specific regulator of UHRF1 during oocyte maturation, providing insights into genetic diagnosis for female infertility.


Cold stress-induced modulation of inflammatory responses and intracerebral cytokine mRNA expression in acute murine toxoplasmosis.
The effects of a physical stressor, cold water stress (CWS), within the central nervous system were investigated in the acute phase of infection with Toxoplasma gondii. Female BALB/c mice were subjected to CWS for 5 min each day for 8 days prior to oral infection with 20 cysts of the low virulent ME 49 strain. Animals were killed at 10-day intervals to detect inflammation, gliosis, and expression of intracerebral cytokine mRNAs. Zones of inflammation were detected by Nissl staining and gliosis by immunoreactivity to glial fibrillary acidic protein. Larger zones of inflammation and reactive astrogliosis were consistently observed in mice subjected to CWS and infected (CWS +INF) compared to control infected (INF) mice. Expression of interleukin (IL)-1beta, IL-2, IL-12, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and inducible nitric oxide synthase (iNOS) were decreased in CWS+INF mice at 10 days postinoculation (PI), followed by a gradual increase after day 20 PI. This was in contrast to increased expression of these cytokines at 10 days PI in INF mice with a gradual decline thereafter. Inflammation and astrogliosis in CWS+INF mice were associated with an increased expression of IL-1beta, IL-6, IL-12, and TNF-alpha between 20 and 30 days PI. These findings correlated with the continuous gene expression of tachyzoite surface antigen (SAG)-1 mRNA in CWS+INF mice compared to its sharp decline in INF mice after 20 days PI. These results suggest that CWS delays regulation and control of intracerebral Toxoplasma gondii during acute infection in BALB/c mice by decreasing the early expression of IFN-gamma, IL-2, TNF-alpha, iNOS, IL-1beta, and IL-12, while increasing the expression of IL-6, a counterregulatory cytokine.


Integrating Sequence Evolution into Probabilistic Orthology Analysis.
Orthology analysis, that is, finding out whether a pair of homologous genes are orthologs - stemming from a speciation - or paralogs - stemming from a gene duplication - is of central importance in computational biology, genome annotation, and phylogenetic inference. In particular, an orthologous relationship makes functional equivalence of the two genes highly likely. A major approach to orthology analysis is to reconcile a gene tree to the corresponding species tree, (most commonly performed using the most parsimonious reconciliation, MPR). However, most such phylogenetic orthology methods infer the gene tree without considering the constraints implied by the species tree and, perhaps even more importantly, only allow the gene sequences to influence the orthology analysis through the a priori reconstructed gene tree. We propose a sound, comprehensive Bayesian Markov chain Monte Carlo-based method, DLRSOrthology, to compute orthology probabilities. It efficiently sums over the possible gene trees and jointly takes into account the current gene tree, all possible reconciliations to the species tree, and the, typically strong, signal conveyed by the sequences. We compare our method with PrIME-GEM, a probabilistic orthology approach built on a probabilistic duplication-loss model, and MrBayesMPR, a probabilistic orthology approach that is based on conventional Bayesian inference coupled with MPR. We find that DLRSOrthology outperforms these competing approaches on synthetic data as well as on biological data sets and is robust to incomplete taxon sampling artifacts.


Involvement of oxidants and AP-1 in angiotensin II-activated NFAT3 transcription factor.
Cardiomyocyte hypertrophy is associated with multiple pathophysiological cardiovascular conditions. Recent studies have substantiated the finding that oxidants may contribute to the development of cardiomyocyte hypertrophy. Activation of the nuclear factor of activated T cells-3 (NFAT3) transcription factor has been shown to result from endocrine inducers of cardiomyocyte hypertrophy such as angiotensin II (ANG II) and serves as an important molecular regulator of cardiomyocyte hypertrophy. In this study, we found that antioxidant enzyme catalase and antioxidants N-acetyl-l-cysteine, alpha-phenyl-N-tert-butylnitrone, and lipoic acid prevent ANG II from activating NFAT3 promoter-luciferase. H(2)O(2) induces a time- and dose-dependent activation of NFAT3 transcription factor. A dominant negative form of NFAT3 transcription factor inhibited H(2)O(2) from activating NFAT3 promoter. An inhibitor of ERKs, but not phosphoinositide 3-kinase or p38 MAPKs, blocked NFAT3 activation by H(2)O(2). The NFAT3 binding site in the promoters of most genes contains a weak activator protein-1 (AP-1) binding site adjacent to the core consensus NFAT binding sequence. ERK inhibitor PD98059 was found previously to inhibit AP-1 activation by H(2)O(2). Inactivation of AP-1 transcription factor by cotransfection of a dominant negative c-Jun, TAM67, prevented H(2)O(2) or ANG II from activating NFAT3 promoter. NFAT3 promoter containing the core NFAT cis-element without AP-1 binding site failed to show activation by H(2)O(2) treatment. Our data suggest that hypertrophy inducers ANG II and H(2)O(2) may activate NFAT3 in cardiomyocyte through an AP-1 transcription factor-dependent mechanism.


Simultaneous ingestion of high-methoxy pectin from apple can enhance absorption of quercetin in human subjects.
Chronic ingestion of apple pectin has been shown to increase the absorption of quercetin in rats. The present study was designed to elucidate whether the simultaneous ingestion of quercetin with apple pectin could enhance the absorption of quercetin in humans, and the effects of dose dependency and degree of pectin methylation on quercetin absorption were also investigated. Healthy volunteers (n 19) received 200 ml of 0.5 mg/ml of quercetin drinks with or without 10 mg/ml of pectin each in a randomised cross-over design study with over 1-week intervals; urine samples from all the subjects were collected within 24 h after ingestion of the test drinks, and urinary deconjugated quercetin and its metabolites were determined using HPLC. The sum of urinary quercetin and its metabolites excreted was increased by 2.5-fold by the simultaneous ingestion of pectin. The metabolism of methylated quercetin (isorhamnetin and tamarixetin) was not affected by pectin ingestion. In six volunteers, who received quercetin drinks containing 0, 3 and 10 mg/ml of pectin, the sum of urinary quercetin and its metabolites excreted also increased in a pectin dose-dependent manner. Furthermore, the simultaneous ingestion of quercetin with low-methoxy and high-methoxy pectin, respectively, increased the sum of urinary excretion of quercetin and its metabolites by 1.69-fold and significantly by 2.13-fold compared with the ingestion of quercetin without pectin. These results elucidated that apple pectin immediately enhanced quercetin absorption in human subjects, and that its enhancing effect was dependent on the dose and degree of pectin methylation. The results also suggested that the viscosity of pectin may play a role in the enhancement of quercetin absorption.


Mannose-Functionalized Hyperbranched Polyglycerol Loaded with Zinc Porphyrin: Investigation of the Multivalency Effect in Antibacterial Photodynamic Therapy.
The antibacterial photodynamic activity of hyperbranched polyglycerol (hPG) loaded with zinc porphyrin photosensitizers and mannose units was investigated. hPG, with a MW of 19.5 kDa, was functionalized with about 15 molecules of the photosensitizer {5,10,15-tris(3-hydroxyphenyl)-20-[4-(prop-2-yn-1-ylamino)tetrafluorophenyl]porphyrinato}-zinc(II) by using copper(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC). These nanoparticle conjugates were functionalized systematically with increasing loadings of mannose in the range of approximately 20 to 110 groups. With higher mannose loadings (ca. 58-110 groups) the water-insoluble zinc porphyrin photosensitizer could thus be transferred into a water-soluble form. Targeting of the conjugates was proven in binding studies to the mannose-specific lectin concanavalin A (Con A) by using surface plasmon resonance (SPR). The antibacterial phototoxicity of the conjugates on Staphylococcus aureus (as a typical Gram-positive germ) was investigated in phosphate-buffered saline (PBS). It was shown that conjugates with approximately 70-110 mannose units exhibit significant antibacterial activity, whereas conjugates with approximately 20-60 units did not induce bacterial killing at all. These results give an insight into the multivalency effect in combination with photodynamic therapy (PDT). On addition of serum to the bacterial cultures, a quenching of this antibacterial phototoxicity was observed. In fluorescence studies with the conjugates in the presence of increasing bovine serum albumin (BSA) concentrations, protein-conjugate associations could be identified as a plausible cause for this quenching.


A fatal case of Behcet's disease with rare complications.
Behcet's disease BD may involve in any large or small artery, vein. We present a case of BD with multiple venous thromboses, cardiac and pulmonary involvements, and renal failure. A 22-year-old man admitted with progressive dyspnea and edema on his face and neck. He had the history of recurrent oral and genital ulcers, and pustular skin lesions for 4 years. Doppler ultrasonography revealed right internal jugular vein thrombosis. Transthoracic echocardiography showed a pericardial effusion, decreased left ventricular ejection fraction. While his symptoms were regressing moderately with a pulse cyclophosphamide, prednisolone, and low molecular weight heparin treatment, new thromboses occurred in vena cava inferior, and bilateral renal veins after the third and 7th dosages of pulse cyclophosphamide. Creatinine levels increased progressively, which required hemodialysis. However, he died after the second session of hemodialysis. Patients with BD should be followed up for new developing thrombosis even during an immunosuppressive treatment.


Pharmacodynamics of propranolol in renal failure.
The pharmacodynamics of propranolol were studied in patients with renal functional impairment. (14)C-labelled propranolol was given either intravenously or by mouth and the disappearance rates of propranolol, 4-hydroxypropranolol, and total radioactive metabolites measured. The renal clearance of total radioactive compounds is directly related to renal function. The half-life of total radioactivity is greatly lengthened in the presence of severe renal failure while the half-lives of the pharmacologically active propranolol and 4-hydroxymetabolite are slightly reduced. There is a suggestion that the absorption of propranolol is delayed in renal failure. No known pharmacological action or side effects from the other metabolic products of propranolol have been recognized. There is still too little well-documented evidence concerning the beta-blocking activity of the unidentified major metabolites of propranolol to suggest any alteration in the dosage regimen used in renal failure.


Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.


Autonomous identification of freezing of gait in Parkinson's disease from lower-body segmental accelerometry.
We have previously published a technique for objective assessment of freezing of gait (FOG) in Parkinson's disease (PD) from a single shank-mounted accelerometer. Here we extend this approach to evaluate the optimal configuration of sensor placement and signal processing parameters using seven sensors attached to the lumbar back, thighs, shanks and feet. Multi-segmental acceleration data was obtained from 25 PD patients performing 134 timed up and go tasks, and clinical assessment of FOG was performed by two experienced raters from video. Four metrics were used to compare objective and clinical measures; the intraclass correlation coefficient (ICC) for number of FOG episodes and the percent time frozen per trial; and the sensitivity and specificity of FOG detection. The seven-sensor configuration was the most robust, scoring highly on all measures of performance (ICC number of FOG 0.75; ICC percent time frozen 0.80; sensitivity 84.3%; specificity 78.4%). A simpler single-shank sensor approach provided similar ICC values and exhibited a high sensitivity to FOG events, but specificity was lower at 66.7%. Recordings from the lumbar sensor offered only moderate agreement with the clinical raters in terms of absolute number and duration of FOG events (likely due to musculoskeletal attenuation of lower-limb 'trembling' during FOG), but demonstrated a high sensitivity (86.2%) and specificity (82.4%) when considered as a binary test for the presence/absence of FOG within a single trial. The seven-sensor approach was the most accurate method for quantifying FOG, and is best suited to demanding research applications. A single shank sensor provided measures comparable to the seven-sensor approach but is relatively straightforward in execution, facilitating clinical use. A single lumbar sensor may provide a simple means of objective FOG detection given the ubiquitous nature of accelerometers in mobile telephones and other belt-worn devices.


Latitudinal variation in incidence and type of first central nervous system demyelinating events.
Increasing prevalence and variable geographic patterns of occurrence of multiple sclerosis suggest an environmental role in causation. There are few descriptive, population-level, data on whether such variability applies to first demyelinating events (FDEs). We recruited 216 adults (18-59 years), with a FDE between 1 November 2003 and 31 December 2006 in a multi-center incident case-control study in four locations on the south-eastern and eastern seaboard of Australia, spanning latitudes 27 degrees south to 43 degrees south. Population denominators were obtained from the Australian Bureau of Statistics censuses of 2001 and 2006. Age and sex adjusted FDE incidence rates increased by 9.55% (95% confidence interval (CI) 7.37-11.78, p < 0.001) per higher degree of latitude. The incidence rate gradient per higher degree of latitude varied by gender (male: 14.69% (95% CI 9.68-19.94, p < 0.001); female 8.13% (95% CI 5.69-10.62, p < 0.001)); and also by the presenting FDE type: optic neuritis 11.39% (95% CI 7.15-15.80, p < 0.001); brainstem/cerebellar syndrome 9.47% (95% CI 5.18-13.93, p < 0.001); and spinal cord syndrome 5.36% (95% CI 1.78-9.06, p = 0.003). Differences in incidence rate gradients were statistically significant between males and females (p = 0.02) and between optic neuritis and spinal cord syndrome (p = 0.04). The male to female ratio varied from 1 : 6.7 at 27 degrees south to 1 : 2.5 at 43 degrees south. The study establishes a positive latitudinal gradient of FDE incidence in Australia. The latitude-related factor(s) influences FDE incidence variably according to subtype and gender, with the strongest influence on optic neuritis presentations and for males. These descriptive case analyses show intriguing patterns that could be important for understanding the etiology of multiple sclerosis.


Interactions between heme d and heme b595 in quinol oxidase bd from Escherichia coli: a photoselection study using femtosecond spectroscopy.
Femtosecond spectroscopy was performed on CO-liganded (fully reduced and mixed-valence states) and O(2)-liganded quinol oxidase bd from Escherichia coli. Substantial polarization effects, unprecedented for optical studies of heme proteins, were observed in the CO photodissociation spectra, implying interactions between heme d (the chlorin ligand binding site) and the close-lying heme b(595) on the picosecond time scale; this general result is fully consistent with previous work [Vos, M. H., Borisov, V. B., Liebl, U., Martin, J.-L., and Konstantinov, A. A. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 1554-1559]. Analysis of the data obtained under isotropic and anisotropic polarization conditions and additional flash photolysis nanosecond experiments on a mutant of cytochrome bd mostly lacking heme b(595) allow to attribute the features in the well-known but unusual CO dissociation spectrum of cytochrome bd to individual heme d and heme b(595) transitions. This renders it possible to compare the spectra of CO dissociation from reduced and mixed-valence cytochrome bd under static conditions and on a picosecond time scale in much more detail than previously possible. CO binding/dissociation from heme d is shown to perturb ferrous heme b(595), causing induction/loss of an absorption band centered at 435 nm. In addition, the CO photodissociation-induced absorption changes at 50 ps reveal a bathochromic shift of ferrous heme b(595) relative to the static spectrum. No evidence for transient binding of CO to heme b(595) after dissociation from heme d is found in the picosecond time range. The yield of CO photodissociation from heme d on a time scale of < 15 ps is found to be diminished more than 3-fold when heme b(595) is oxidized rather than reduced. In contrast to other known heme proteins, molecular oxygen cannot be photodissociated from the mixed-valence cytochrome bd at all, indicating a unique structural and electronic configuration of the diheme active site in the enzyme.