Mutations in the dimer interface of dihydrolipoamide dehydrogenase promote site-specific oxidative damages in yeast and human cells.
Dihydrolipoamide dehydrogenase (DLD) is a multifunctional protein well characterized as the E3 component of the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes. Previously, conditions predicted to destabilize the DLD dimer revealed that DLD could also function as a diaphorase and serine protease. However, the relevance of these cryptic activities remained undefined. We analyzed human DLD mutations linked to strikingly different clinical phenotypes, including E340K, D444V, R447G, and R460G in the dimer interface domain that are responsible for severe multisystem disorders of infancy and G194C in the NAD(+)-binding domain that is typically associated with milder presentations. In vitro, all of these mutations decreased to various degrees dihydrolipoamide dehydrogenase activity, whereas dimer interface mutations also enhanced proteolytic and/or diaphorase activity. Human DLD proteins carrying each individual mutation complemented fully the respiratory-deficient phenotype of yeast cells lacking endogenous DLD even when residual dihydrolipoamide dehydrogenase activity was as low as 21% of controls. However, under elevated oxidative stress, expression of DLD proteins with dimer interface mutations greatly accelerated the loss of respiratory function, resulting from enhanced oxidative damage to the lipoic acid cofactor of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase and other mitochondrial targets. This effect was not observed with the G194C mutation or a mutation that disrupts the proteolytic active site of DLD. As in yeast, lipoic acid cofactor was damaged in human D444V-homozygous fibroblasts after exposure to oxidative stress. We conclude that the cryptic activities of DLD promote oxidative damage to neighboring molecules and thus contribute to the clinical severity of DLD mutations.


Investigation of the role of flocculation conditions in recuperative thickening on dewatering performance and biogas production.
There is considerable interest in recuperative thickening (RT), the recycling of partially digested solids in an anaerobic digester outlet stream back into the incoming feed, as a 'high-performance' process to increase biogas production, increase system capacity, and improve biosolids stabilization. While polymer flocculation is commonly used in full-scale RT operations, no studies have investigated the effect of flocculation conditions on RT process performance. Our goal was to investigate the effect of polymer type and dosage conditions on dewatering performance and biogas production in a lab-scale RT system. The type of polymer flocculant significantly affected dewatering performance. For example, the 440 LH polymer (low molecular weight (MW) polyacrylamide) demonstrated lower capillary suction time (CST) and filtrate total suspended solids (TSS) values than the C-6267 polymer (high MW polyacrylamide). An examination of the dewatering performance of RT digesters with different polymers found a strong correlation between CST and filtrate TSS. The type of polymer flocculant had no significant effect on biogas productivity or composition; the methane content was greater than 60% in good agreement with typical results. The optimization of the polymer flocculation conditions is a critical task for which the lab-scale RT system used in this work is ideally suited.


ROADTRIPS: case-control association testing with partially or completely unknown population and pedigree structure.
Genome-wide association studies are routinely conducted to identify genetic variants that influence complex disorders. It is well known that failure to properly account for population or pedigree structure can lead to spurious association as well as reduced power. We propose a method, ROADTRIPS, for case-control association testing in samples with partially or completely unknown population and pedigree structure. ROADTRIPS uses a covariance matrix estimated from genome-screen data to correct for unknown population and pedigree structure while maintaining high power by taking advantage of known pedigree information when it is available. ROADTRIPS can incorporate data on arbitrary combinations of related and unrelated individuals and is computationally feasible for the analysis of genetic studies with millions of markers. In simulations with related individuals and population structure, including admixture, we demonstrate that ROADTRIPS provides a substantial improvement over existing methods in terms of power and type 1 error. The ROADTRIPS method can be used across a variety of study designs, ranging from studies that have a combination of unrelated individuals and small pedigrees to studies of isolated founder populations with partially known or completely unknown pedigrees. We apply the method to analyze two data sets: a study of rheumatoid arthritis in small UK pedigrees, from Genetic Analysis Workshop 15, and data from the Collaborative Study of the Genetics of Alcoholism on alcohol dependence in a sample of moderate-size pedigrees of European descent, from Genetic Analysis Workshop 14. We detect genome-wide significant association, after Bonferroni correction, in both studies.


Common reservoirs for Penicillium marneffei infection in humans and rodents, China.
Human penicilliosis marneffei is an emerging infectious disease caused by the fungus Penicillium marneffei. High prevalence of infection among bamboo rats of the genera Rhizomys and Cannomys suggest that these rodents are a key facet of the P. marneffei life cycle. We trapped bamboo rats during June 2004-July 2005 across Guangxi Province, China, and demonstrated 100% prevalence of infection. Multilocus genotypes show that P. marneffei isolates from humans are similar to those infecting rats and are in some cases identical. Comparison of our dataset with genotypes recovered from sites across Southeast Asia shows that the overriding component of genetic structure in P. marneffei is spatial, with humans containing a greater diversity of genotypes than rodents. Humans and bamboo rats are sampling an as-yet undiscovered common reservoir of infection, or bamboo rats are a vector for human infections by acting as amplifiers of infectious dispersal stages.


Clinical and genetic characterization of frontorhiny: report of 3 novel cases and discussion of the surgical management.
To (1) define the nasal, columellar, and lip deformities of 3 patients with characteristics consistent with frontorhiny; (2) illustrate the embryologic correlation of the oronasal findings to the development of the median nasal prominence; (3) report the clinical manifestation in 3 patients from 2 unrelated families; (4) report a novel Y214X mutation in ALX3 ; and (5) describe the surgical reconstruction. In this case series, we report 3 novel cases of frontorhiny from 2 different families. The surgical reconstruction technique is reviewed. Extension of the columellar medial crural cartilage into the upper lip cleft is examined histologically. Signed consent was granted for all patient photographs and specimens, and the study was approved by the institutional review committee of the University of California Davis The genetic sequencing of the ALX3 homeobox gene was performed in 2 of our 3 cases using standard commercially available sequencing kits. The genetic material in our third case was not available for analysis. Patients 1 and 2 were brothers from the same family. Both exhibited bifidity of their columella, a widened philtrum, poor nasal tip development, and low hairlines. Genetic sequencing in the 2 brothers confirmed the presence of a novel ALX3 homeobox mutation at the second exon (mutation Y214X). Patient 3 was a 4-year-old girl. She presented with an underdeveloped, widened nasal tip and a bifid columella. Her philtrum was widened and had a left-sided cartilaginous prominence. She also had a widened nasal root. Family history revealed no family members with the same features. Frontorhiny represents a new syndromic frontonasal malformation with consistent characteristic features. The genetic abnormality has now been found in 14 different patients. Careful scrutiny and classification of frontonasal deformities will expand our understanding of causes, genetic susceptibility, and treatment options.


Screening and selection of high carotenoid producing in vitro tomato cell culture lines for [13C]-carotenoid production.
Isotopically labeled tomato carotenoids, phytoene, phytofluene, and lycopene, are needed for mammalian bioavailability and metabolism research but are currently commercially unavailable. The goals of this work were to establish and screen multiple in vitro tomato cell lines for carotenoid production, test the best producers with or without the bleaching herbicides, norflurazon and 2-(4-chlorophenyl-thio)triethylamine (CPTA), and to use the greatest carotenoid accumulator for in vitro 13C-labeling. Different Solanum lycopersicum allelic variants for high lycopene and varying herbicide treatments were compared for carotenoid accumulation in callus and suspension culture, and cell suspension cultures of the hp-1 line were chosen for isotopic labeling. When grown with [U]-13C-glucose and treated with CPTA, hp-1 suspensions yielded highly enriched 13C-lycopene with 45% of lycopene in the M+40 form and 88% in the M+35 to M+40 isotopomer range. To the authors' knowledge this is the first report of highly enriched 13C-carotenoid production from in vitro plant cell culture.


Identifying transcriptional cis-regulatory modules in animal genomes.
Gene expression is regulated through the activity of transcription factors (TFs) and chromatin-modifying proteins acting on specific DNA sequences, referred to as cis-regulatory elements. These include promoters, located at the transcription initiation sites of genes, and a variety of distal cis-regulatory modules (CRMs), the most common of which are transcriptional enhancers. Because regulated gene expression is fundamental to cell differentiation and acquisition of new cell fates, identifying, characterizing, and understanding the mechanisms of action of CRMs is critical for understanding development. CRM discovery has historically been challenging, as CRMs can be located far from the genes they regulate, have few readily identifiable sequence characteristics, and for many years were not amenable to high-throughput discovery methods. However, the recent availability of complete genome sequences and the development of next-generation sequencing methods have led to an explosion of both computational and empirical methods for CRM discovery in model and nonmodel organisms alike. Experimentally, CRMs can be identified through chromatin immunoprecipitation directed against TFs or histone post-translational modifications, identification of nucleosome-depleted 'open' chromatin regions, or sequencing-based high-throughput functional screening. Computational methods include comparative genomics, clustering of known or predicted TF-binding sites, and supervised machine-learning approaches trained on known CRMs. All of these methods have proven effective for CRM discovery, but each has its own considerations and limitations, and each is subject to a greater or lesser number of false-positive identifications. Experimental confirmation of predictions is essential, although shortcomings in current methods suggest that additional means of validation need to be developed. For further resources related to this article, please visit the WIREs website. The authors have declared no conflicts of interest for this article.


Severe lower respiratory tract infection in infants and toddlers from a non-affluent population: viral etiology and co-detection as risk factors.
Lower respiratory tract infection (LRTI) is a major cause of pediatric morbidity and mortality, especially among non-affluent communities. In this study we determine the impact of respiratory viruses and how viral co-detections/infections can affect clinical LRTI severity in children in a hospital setting. Patients younger than 3 years of age admitted to a tertiary hospital in Brazil during the months of high prevalence of respiratory viruses had samples collected from nasopharyngeal aspiration. These samples were tested for 13 different respiratory viruses through real-time PCR (rt-PCR). Patients were followed during hospitalization, and clinical data and population characteristics were collected during that period and at discharge to evaluate severity markers, especially length of hospital stay and oxygen use. Univariate regression analyses identified potential risk factors and multivariate logistic regressions were used to determine the impact of specific viral detections as well as viral co-detections in relation to clinical outcomes. We analyzed 260 episodes of LRTI with a viral detection rate of 85% (n = 222). Co-detection was observed in 65% of all virus-positive episodes. The most prevalent virus was Respiratory Syncytial Virus (RSV) (54%), followed by Human Metapneumovirus (hMPV) (32%) and Human Rhinovirus (HRV) (21%). In the multivariate models, infants with co-detection of HRV + RSV stayed 4.5 extra days (p = 0.004), when compared to infants without the co-detection. The same trends were observed for the outcome of days of supplemental oxygen use. Although RSV remains as the main cause of LRTI in infants our study indicates an increase in the length of hospital stay and oxygen use in infants with HRV detected by RT-PCR compared to those without HRV. Moreover, one can speculate that when HRV is detected simultaneously with RSV there is an additive effect that may be reflected in more severe clinical outcome. Also, our study identified a significant number of children infected by recently identified viruses, such as hMPV and Human Bocavirus (HBov), and this is a novel finding for poor communities from developing countries.


Results From Mexico's 2016 Report Card on Physical Activity for Children and Youth.
The 2016 Mexican Report Card on Physical Activity for Children and Youth aims to assess how Mexico is doing in terms of providing physical activity (PA) opportunities for Mexican children and youth. The purpose of this article is to summarize results from the Mexican 2016 Report Card. A literature search was conducted in Spanish and English languages using major databases, and complemented with a review of government/nongovernment documents, websites, and national health surveys. Information on the 9 indicators outlined in the Global Matrix of Report Card Grades was extracted. A team of Mexican experts met to discuss and assign a grade on each indicator based on the best available evidence and established benchmarks. Daily behaviors grades were Overall PA (C), Organized Sport Participation (D), Active Play (D-), Active Transportation (C), and Sedentary Behavior (D). For Settings and Sources of Influence, grades were Family and Peers (INC), School (D-), and Community and Environment (D). Strategies and Investments grades were Government Strategies (C) and Non-Government (F). PA and sedentary behaviors among Mexican children and youth remain below the recommended levels. Government and communities are far from providing appropriate and sufficient physical activity opportunities for children and youth.


Practice patterns among United States cardiologists for managing adults with atrial fibrillation (from the AFFECTS Registry).
The Atrial Fibrillation: Focus on Effective Clinical Treatment Strategies (AFFECTS) Registry was designed to examine atrial fibrillation (AF) treatment by United States cardiologists in the context of the American College of Cardiology, American Heart Association, and European Society of Cardiology guidelines after recent landmark clinical trials. Most patients in AFFECTS had AF without clinically significant structural heart disease or only uncomplicated hypertension. Among the all-enrolled population (n = 1,461), initial treatment strategies assigned were rhythm control in 64% and rate control in 36%. Among patients with either paroxysmal (n = 1,165) or persistent (n = 273) AF, 67% and 55%, respectively, were assigned rhythm control. The trend to assign rhythm control as the initial treatment goal decreased with age. In the rhythm-control group, most patients (74%) also received a rate-control agent during the registry, while 25% of those assigned to rate control received antiarrhythmic drugs. Most first prescriptions of antiarrhythmic drugs were for first-line therapy compliant with 2001 (76%) and 2006 (86%) guidelines. Most second prescriptions were for first-line therapies as well. Rates of serious adverse events were low. In conclusion, data from this study provide insight into community treatment patterns in patients with AF, most without clinically significant structural heart disease or with only uncomplicated hypertension.


SU-E-I-101: Initial Implementation and Evaluation of AAPM TG-150 Draft Image Receptor Non-Uniformity Testing Recommendations.
To implement in software the procedures described in AAPM Task Group 150's draft recommendations for image receptor performance testing, and to evaluate the effectiveness and practicality of these procedures. Images of flat fields were acquired using digital x-ray image receptors at 6 cooperating institutions. Four flat field images obtained with each detector spanned a range of input detector air kerma. Software based on AAPM TG150's draft report processed the test images and generated results. Image receptor response and several measures of non-uniformity were evaluated. Images were divided into 10 mm square regions, after eliminating 10 mm borders. For each region, signal (mean), noise (standard deviation) and SNR were calculated. Characteristic signal, noise and SNR were calculated based on average values from all regions. Local non-uniformity for signal (SLN), noise (NLN) and SNR (SNRLN) were expressed as the maximum ratio of the absolute difference between each region's value and its 4 nearest neighbors, to the respective characteristic value. Global non-uniformity (SGN, NGN, SNRGN) were expressed similarly but differences between maximum and minimum values obtained from the regions were used (without comparison to local neighbors). TG150 tests discriminated between good and poorly performing detectors. Improper detector calibration was detectable, with noise non-uniformity proving to be a more sensitive measure than signal or SNR non-uniformity. Detector rotation relative to calibration conditions produced a greater change in signal non-uniformity than the other measures. Image receptor structured noise was characterized by an increase in noise non-uniformity with incident air kerma. AAPM TG150's proposed approach to image receptor testing was implemented and evaluated. The approach appears to be an effective and practical one for routine quality assurance testing of digital radiographic image receptors.


Effects of posture and spinal bracing on respiratory function in neuromuscular disease.
Effects of posture and spinal bracing on lung function were studied in 40 children with neuromuscular disease, 20 of whom had scoliosis and were non-ambulant. Change from sitting to supine position had little effect on lung function in ambulant children, but caused a significant 12% reduction in forced vital capacity in a group of 16 non-ambulant children with scoliosis, suggesting diaphragmatic weakness in some. Spinal bracing, using a rigid supporting jacket, resulted in a significant reduction in mean vital capacity of 22%. The degree of impairment in forced vital capacity was proportional to the severity of the scoliosis (as measured by the Cobb's angle), to the amount of correction achieved by the brace, and to the degree of diaphragmatic weakness. Spinal bracing in a child with established severe scoliosis causes appreciable respiratory impairment, and this may explain why it is less likely to be tolerated than early prophylactic bracing.


Acute disseminated encephalomyelitis: MR and CT features.
We describe three cases of acute disseminated encephalomyelitis (an immune-mediated inflammatory demyelinating disease of the central nervous system) and their histology, showing different radiological features. One appearance is a few ring-shaped enhancing lesions, which are found predominantly in the supratentorial white matter, the other is solid disseminated lesions.


Highly efficient HIV transmission to young women in South Africa.
Young women in sub-Saharan Africa are at very high risk of HIV acquisition, and high prevalence levels have been observed among women reporting one lifetime partner and few sexual contacts. Such findings have led to hypotheses that the probability of HIV transmission from men to women must be far higher than previously appreciated. We used the data from a cross-sectional national household survey of HIV among South African women aged 15-24 years to estimate the per-partnership transmission probability from men to women. Estimates were obtained using maximum likelihood methods and a transmission probability model allowing for random error in the self-reported number of lifetime partners. Sensitivity analyses were employed to assess the robustness of the per-partnership transmission probability estimates to the assumed HIV prevalence in male partners. HIV prevalence in women was 21.2% (95% confidence interval 17.9-24.5). The mean reported number of lifetime partners was 2.3. A significant increase in prevalence was observed with increasing lifetime partner numbers (P = 0.02). For a range of plausible values of the partner prevalence, the estimated per-partnership transmission probability varied from 0.74 to 1.00 with 95% confidence intervals ranging from 0.56 to 1.00. The per-partnership probability of HIV transmission from men to women in this population was very high. Before this, the majority of studies examining per-partnership transmission probabilities estimated values below 50%. Identifying the factors that may drive the efficient spread of HIV in sub-Saharan Africa is essential for the development of effective prevention interventions.


Arthroscopic management of calcific tendinitis of the subscapularis tendon.
Calcific tendinitis is a common disorder of the rotator cuff. Conservative treatment is frequently successful. For the patients remaining symptomatic after conservative treatment, excision of the calcium deposits offers a generally reliable pain relief. While calcific tendinitis is seen commonly affecting the supraspinatus tendon, it has been rarely reported involving the subscapularis tendon. We report on the clinical features, radiographic findings, arthroscopic treatment and results of one patient who presented a calcific tendonitis involving the subscapularis tendon of the left shoulder unresponsive to conservative treatment and associated subcoracoid stenosis and coracoid impingement.


The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis.
In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways in colorectal cancer is uncertain, which led us to systematically review the impact of alterations in KRAS (outside of exon 2), NRAS, BRAF, PIK3CA and PTEN in relation to the clinical benefit from anti-EGFR treatment. In total, 22 studies that include 2395 patients formed the basis for a meta-analysis on alterations in KRAS exons 3 and 4, NRAS, BRAF, and PIK3CA and PTEN and outcome of anti-EGFR treatment. Odds ratios for objective response rate (ORR) and hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) were calculated. Mutations in KRAS exons 3 and 4, BRAF, PIK3CA and non-functional PTEN (mutations or loss of protein expression) significantly predicted poor ORR (OR = 0.26, OR = 0.29, OR = 0.39, and OR = 0.41, respectively). Significantly shorter PFS applied to mutations in KRAS exons 3 and 4 (HR = 2.19), NRAS (HR = 2.30) and BRAF (HR = 2.95) and non-functional PTEN (HR = 1.88). Significantly shorter OS applied to mutations in KRAS exons 3 and 4 (HR = 1.78), NRAS (HR = 1.85), BRAF (HR = 2.52), PIK3CA (HR = 1.43) and alterations in PTEN (HR = 2.09). Meta-analysis suggests that mutations in KRAS exons 3 and 4, NRAS, BRAF and PIK3CA and non-functional PTEN predict resistance to anti-EGFR therapies and demonstrates that biomarker analysis beyond KRAS exon 2 should be implemented for prediction of clinical benefit from anti-EGFR antibodies in metastatic colorectal cancer.


Discovery of a strongly apoptotic ruthenium complex through combinatorial coordination chemistry.
A strategy for combinatorial parallel coordination chemistry is introduced that provides access to libraries of tris-heteroleptic ruthenium complexes in an economical fashion. Using this method, a library of 560 constitutionally unique, monocationic ruthenium complexes was synthesized, followed by a screening for anticancer activity and resulting in the identification of three hits with promising cytotoxic properties in HeLa cancer cells. A subsequent structure-activity relationship led to the discovery of the surprisingly simple anticancer complex [Ru(tBu(2)bpy)(2)(phox)]PF(6) (complex 1), with tBu(2)bpy = 4,4'-di-tert-buty-2,2'-bipyridine and Hphox = 2-(2'-hydroxyphenyl)oxazoline, displaying an LC(50) value in HeLa cells of 1.3 microM and 0.3 microM after incubation for 24 and 72 h, respectively. Complex 1 also shows remarkable antiproliferative and apoptotic properties at submicromolar concentrations in more clinically relevant Burkitt-like lymphoma cells. A reduction of the mitochondrial membrane potential by 1 indicates the involvement of the intrinsic pathway of programmed cell death. Further investigations reveal that 1 requires caspase-3 for the induction of apoptosis but is insensitive to the proapoptotic and antiapoptotic proteins Smac and Bcl-2, respectively.


Overlap between dental anxiety and blood-injury fears: psychological characteristics and response to dental treatment.
The relationship between dental anxiety and blood/body injury (BI) fears was examined in a sample of 1420 adults. Based on their responses to two mail questionnaires, they were classified into one of four groups: Group 1--neither dentally anxious nor BI fearful; Group 2--BI fearful only; Group 3--dentally anxious only; Group 4--both dentally anxious and BI fearful. Overall, only 16% of dentally anxious subjects were BI fearful while 31.6% of those with high levels of BI fears were dentally anxious. While subjects in Group 2 were more fearful of dentistry than those in Group 1, they were substantially less so than subjects in Groups 3 and 4. Moreover, even BI stimuli in the dental setting evoked lower levels of anxiety for subjects in Group 2 compared to Group 3 and 4. However, rates of fainting or near fainting experiences in the dental situation were similar for all three groups. Group 3 and 4 were similar in terms of fear evoking stimuli and patterns of anxiety response. Subjects in Group 4 had more agoraphobic symptoms and social interaction fears and had higher scores on the Anxiety Sensitivity Index and Speilberger Trait Anxiety Index. This suggests that Group 4 is comprised of individuals who are more likely to be multiphobic and exhibit generalized anxiety states. Although BI fears are a significant component of dental anxiety, their overall contribution is relatively small.


Prospective screening by a panfungal polymerase chain reaction assay in patients at risk for fungal infections: implications for the management of febrile neutropenia.
Invasive fungal infections are a major cause of mortality in neutropenic cancer patients. To determine whether a polymerase chain reaction (PCR)-based assay enabled the identification of patients at risk for invasive fungal infections, a prospective monitoring once per week was performed during 92 neutropenic episodes in patients receiving chemotherapy for acute leukaemia or high-dose therapy followed by allogeneic or autologous stem cell transplantation, with the investigators blinded to clinical and microbiological data. PCR positivity was documented in 34 out of 92 risk episodes. All patients developing proven invasive fungal infection were found PCR positive, and PCR was found to be the earliest indicator of invasive fungal infection preceding clinical evidence by a mean of 5.75 d (range 0-14 d). In febrile neutropenic patients without a prior history of invasive fungal infection, a sensitivity of 100% and a specificity of 73% of the PCR assay for the development of proven or probable invasive fungal infection was documented. In conclusion, panfungal PCR performed prospectively once a week enabled the identification of patients at high risk for invasive fungal infections.


Phase II study of megestrol acetate in the treatment of hepatocellular carcinoma.
This is a report of a phase II study of megestrol acetate (160 mg/day, orally) in the treatment of hepatocellular carcinoma (HCC). Forty-six patients with advanced HCC were studied and tumour response, changes in appetite, bodyweight, a feeling of well-being, survival and toxicity were evaluated. Thirty-two patients were able to be evaluated for response; there were no complete responders or partial responders. Twelve patients (38%) had stable disease and seven of these patients had a minor response with a median size reduction in the tumour of 18%. Twenty patients (62%) had progressive disease. Five of 24 (21%) patients had a median reduction in alpha-fetoprotein levels of 59 ng/mL. The overall median survival was 4 months (range 1 week to 27 months). Twenty of 32 (62%) patients had an increased appetite and feeling of well-being. Fourteen of 22 (64%) patients had a median lean bodyweight gain of 5 kg (range 1-14 kg). Toxicities were minimal. Tests for glucocorticoid receptors were performed in 10 patients. Four of five patients who were positive for glucocorticoid receptors in the tumour had a stable disease and all five patients who were negative for glucocorticoid receptors had progressive disease. Megestrol acetate had no significant effect on the tumour in HCC patients. However, megestrol acetate is useful in the palliative management of HCC patients, with improvements in appetite, bodyweight and a feeling of well-being with minimal side effects. Some patients had stable disease, a minor reduction of tumour size and a prolonged survival after megestrol acetate treatment and this response may be related to the presence of glucocorticoid receptors in the HCC tumour.


The posttraumatic stiff elbow.
The development of joint contracture is a well-recognized complication of elbow injury. Precise causes of the propensity of this joint for ankylosis are understood poorly. Yet, treatment is emerging and therefore the indications and willingness on the part of the surgeon to address this problem is improving. Limited open procedures have emerged during the past several years that are safe and effective by improving arcs of motion of 50-70 degrees in approximately 80-90% of patients. For severe injuries that involve the articular surface, interposition arthroplasty is less documented but has been shown to be effective but constitutes one of the most challenging technical procedures. Joint replacement arthroplasty generally should not be considered as a treatment for posttraumatic stiffness unless the patient is older than 65 years. The experience with this procedure indicates that with linked semiconstrained implants, approximately 80% of patients will achieve a near functional arc of motion. Arthroscopic intervention shows the greatest activity of investigation and clinical expansion. The learning curve is defined by a concern of complications to the neural structures and the fear of this complication has limited the application but the emerging documentation of the safeness of this option also has been associated with improved effectiveness. Therefore, arthroscopic intervention for the stiff elbow, particularly those with soft tissue extrinsic involvement, is emerging as the treatment of choice in many instances. The investigation regarding the medical treatment of altering the tendency of the soft tissue to go through such intense contracture is in its infancy but suggests that this could be a long-term solution at least for many patients.


Self DNA perpetuates IPF lung fibroblast senescence in a cGAS-dependent manner.
Senescence and mitochondrial stress are mutually reinforcing age-related processes that contribute to idiopathic pulmonary fibrosis (IPF); a lethal disease that manifests primarily in the elderly. Whilst evidence is accumulating that GMP-AMP synthase (cGAS) is crucial in perpetuating senescence by binding damaged DNA released into the cytosol, its role in IPF is not known. The present study examines the contributions of cGAS and self DNA to the senescence of lung fibroblasts from IPF patients (IPF-LFs) and age-matched controls (Ctrl-LFs). cGAS immunoreactivity was observed in regions of fibrosis associated with fibroblasts in lung tissue of IPF patients. Pharmacological inhibition of cGAS or its knockdown by silencing RNA (siRNA) diminished the escalation of IPF-LF senescence in culture over 7 days as measured by decreased p21 and p16 expression, histone 2AXγ phosphorylation and/or IL-6 production (P < 0.05, n = 5-8). The targeting of cGAS also attenuated etoposide-induced senescence in Ctrl-LFs (P < 0.05, n = 5-8). Levels of mitochondrial DNA (mDNA) detected by qPCR in the cytosol and medium of IPF-LFs or senescence-induced Ctrl-LFs were higher than Ctrl-LFs at baseline (P < 0.05, n = 5-7). The addition of DNAse I (100 U/ml) deaccelerated IPF-LF senescence (P < 0.05, n = 5), whereas ectopic mDNA or the induction of endogenous mDNA release augmented Ctrl-LF senescence in a cGAS-dependent manner (P < 0.05, n = 5). In conclusion, we provide evidence that cGAS reinforces lung fibroblast senescence involving damaged self DNA. The targeting of cGAS to supress senescent-like responses may have potential important therapeutic implications in the treatment of IPF.


Lipid-specific T cells and the skin.
Langerhans cells express constitutively high levels of CD1a, a member of the CD1 family of molecules which are known to present lipid antigens to T cells. Whilst much human skin immunology research has focussed on the function of T cells which recognise peptides presented by HLA molecules, in contrast few studies have addressed the role of CD1a and lipid antigens in the pathogenesis of inflammatory skin disease. House dust mite and bee and wasp venom extracts were found to generate CD1a reactivity, but paradoxically this function was within the protein and not lipid fraction. This unexpected finding was explained by the presence of phospholipases within the house dust mite and insect venoms which generated antigenic lipids on contact with skin. The lipids then bind to CD1a on Langerhans cells which are recognised by T cells, which in turn contribute to skin inflammation. This newly identified pathway of skin inflammation defines several potential points for therapeutic intervention.


Regulation of insulin-like growth factor-I (IGF-I) delivery by IGF binding proteins and receptors.
Delivery of growth factors via the bloodstream for the treatment of various diseases is regulated in part by interactions with cell surface binding elements. Understanding the kinetics of growth factor binding and transport by cells would, therefore, be advantageous. This report quantifies the binding, internalization, and transport of insulin-like growth factor-I (IGF-I) across bovine aortic endothelial cells (BAEC) cultured in vitro. Binding analysis indicated that IGF binding proteins (IGFBPs), primarily localized with the extracellular matrix, were the primary IGF-I binding elements in our system, with twice as many binding sites (8.0 +/- 1.9 x 10(4) per cell) as IGF-I receptors (IGF-IR) (3.9 +/- 0.6 x 10(4) per cell). Internalization of IGF-I by IGF-IR, but not IGFBPs, was detected, however both receptor and IGFBP binding were shown to inhibit rather than enhance the transport of intact IGF-I, albeit in different ways. IGFBPs retained IGF-I in the apical region while IGF-IR binding led to protein degradation. Based on our computational modeling and experimental data, we hypothesize that IGFBPs could function as a reservoir for IGF-I, sequestering it for later release and transport, and that this reservoir function of the IGFBPs could be used to promote controlled localized delivery of IGF-I.


Chemically Induced Vinylphosphonothiolate Electrophiles for Thiol-Thiol Bioconjugations.
Herein we introduce vinylphosphonothiolates as a new class of cysteine-selective electrophiles for protein labeling and the formation of stable protein-protein conjugates. We developed a straightforward synthetic route to convert nucleophilic thiols into electrophilic, thiol-selective vinylphosphonothiolates: In this protocol, intermediately formed disulfides can be chemoselectively substituted with vinylphosphonites under acidic conditions to yield the desired vinylphosphonothiolates. Notably, this reaction sequence enables the installation of vinylphosphonothiolate electrophiles directly on cysteine side chains within peptides and proteins. In addition to labeling the monoclonal antibody trastuzumab with excellent cysteine-selectivity, we applied our protocol for the site-specific conjugation of two proteins with unique cysteine residues yielding a nonhydrolyzable phosphonothiolate-linked diubiquitin and an ubiquitin-α-synuclein conjugate. The latter was recognized as a substrate in a subsequent enzymatic ubiquitination reaction.


In vivo tracking and fate of intra-articularly injected superparamagnetic iron oxide particle-labeled multipotent stromal cells in an ovine model of osteoarthritis.
In this study, superparamagnetic iron oxide (SPIO) particle-labeled mesenchymal stromal cells (MSCs) were injected intra-articularly into osteoarthritic knee joints. Their fate and distribution were evaluated using magnetic resonance imaging (MRI) and macroscopic and histologic postmortem examination. Osteoarthritis was induced in 12 sheep by bilateral meniscectomy. After 6 weeks, one knee joint received 10 × 10(6) SPIO-labeled MSCs (Molday Ion Rhodamine B). Contralateral knees received a control injection of a) PBS, b) SPIO in PBS, c) 10 × 10(6) nonvital SPIO-labeled MSCs in PBS, or d) no injection. MR images were acquired immediately after injection and 1, 4, 8, and 12 weeks thereafter using a 0.5-T unit and a T2* sequence. Signal intensity of synovial fluid and synovial lining was assessed semiquantitatively using a scoring system. Viable SPIO-labeled MSCs produced a strong hypointense signal in the synovial fluid immediately after injection, but normal signal intensity of the synovial fluid was observed 1 week later. Synovial lining maintained its hypointensity throughout the study period. Nonvital SPIO-labeled MSCs induced hypointense signals of the synovial fluid; synovial lining appeared weak and inconsistently hypointense in the following weeks. Pure SPIO produced a strong hyperintense signal in the synovial fluid at the time of injection only. Histologically, in all knee joints receiving viable SPIO-labeled MSCs, SPIO particles were detected (Prussian blue) within the synovial lining, dorsal fat pad, and neomeniscus tissue, but not in osteochondral samples. Few SPIO particles were detected in joints injected with nonvital SPIO-labeled MSCs. Immunohistologically, no increased cell death (TUNEL) was observed in the area of detected SPIO particles, but we did observe potential chondrogenic cell differentiation (Safranin O or S100β). We conclude that viable SPIO-labeled MSCs remain detectable within the joint for 12 weeks and attach themselves to some but not all diseased joint structures.


Deep metazoan phylogeny.
We reconstructed a robust phylogenetic tree of the Metazoa, consisting of almost 1,500 taxa, by profile neighbor joining (PNJ), an automated computational method that inherits the efficiency of the neighbor joining algorithm. This tree supports the one proposed in the latest review on metazoan phylogeny. Our main goal is not to discuss aspects of the phylogeny itself, but rather to point out that PNJ can be a valuable tool when the basal branching pattern of a large phylogenetic tree must be estimated, whereas traditional methods would be computationally impractical.


Development of dual fluorescent stage specific reporter strain of Toxoplasma gondii to follow tachyzoite and bradyzoite development in vitro and in vivo.
Toxoplasma gondii is a protozoan that infects 30% of humans as intermediate hosts. T Sexual reproduction can occur only within the intestinal tract of felines, however, infection in other mammals and birds is associated with asexual replication and interconversion between the tachyzoite and bradyzoite stages. Bradyzoites are slow growing forms found in tissue cysts in latent infection. Recently, our group described the biological behavior of the EGS strain that forms thick walled cysts spontaneously in tissue culture, constituting a useful tool for examining the developmental biology of T. gondii. To further improve the usefulness of this model, we constructed genetically modified EGS parasites that express fluorescent tags under the control of stage specific promoters. The promoter regions for SAG-1 (tachyzoite specific), BAG-1 and LDH-2 (bradyzoite specific) were amplified by PCR and plasmids were constructed with mCherry (redT) and sfGFP (greenB) sequences, respectively. Strains of parasites were selected using FACS to arrive at single fluorescent and dual fluorescent strains of EGS expressing tags in a stage specific manner. In cell cultures, vacuoles labeled by immunofluorescence assay using anti-CST-1 a marker for T. gondii cyst wall contained parasites that were positive for BAG1-GFP and negative for SAG1-mCherry. Tachyzoites and bradyzoites harvested from the mice expressed stage specific mCherry and GFP proteins, respectively. These new dual fluorescent transgenic EGS strains are a promising tool to elucidate the mechanisms of T. gondii differentiation both in vitro and in vivo.


Tcf3 governs stem cell features and represses cell fate determination in skin.
Many stem cells (SCs) respond to Wnt signaling, but whether beta-catenin's DNA binding partners, the Tcfs, play a role in SCs in the absence of Wnts, is unknown. In adult skin, quiescent multipotent progenitors express Tcf3 and commit to a hair cell fate in response to Wnt signaling. We find that embryonic skin progenitors also express Tcf3. Using an inducible system in mice, we show that upon Tcf3 reactivation, committed epidermal cells induce genes associated with an undifferentiated, Wnt-inhibited state and Tcf3 promotes a transcriptional program shared by embryonic and postnatal SCs. Further, Tcf3-repressed genes include transcriptional regulators of the epidermal, sebaceous gland and hair follicle differentiation programs, and correspondingly, all three terminal differentiation pathways are suppressed when Tcf3 is induced postnatally. These data suggest that in the absence of Wnt signals, Tcf3 may function in skin SCs to maintain an undifferentiated state and, through Wnt signaling, directs these cells along the hair lineage.


Spatiotemporal dynamics of the epidemic transmission in a predator-prey system.
Epidemic transmission is one of the critical density-dependent mechanisms that affect species viability and dynamics. In a predator-prey system, epidemic transmission can strongly affect the success probability of hunting, especially for social animals. Predators, therefore, will suffer from the positive density-dependence, i.e., Allee effect, due to epidemic transmission in the population. The rate of species contacting the epidemic, especially for those endangered or invasive, has largely increased due to the habitat destruction caused by anthropogenic disturbance. Using ordinary differential equations and cellular automata, we here explored the epidemic transmission in a predator-prey system. Results show that a moderate Allee effect will destabilize the dynamics, but it is not true for the extreme Allee effect (weak or strong). The predator-prey dynamics amazingly stabilize by the extreme Allee effect. Predators suffer the most from the epidemic disease at moderate transmission probability. Counter-intuitively, habitat destruction will benefit the control of the epidemic disease. The demographic stochasticity dramatically influences the spatial distribution of the system. The spatial distribution changes from oil-bubble-like (due to local interaction) to aggregated spatially scattered points (due to local interaction and demographic stochasticity). It indicates the possibility of using human disturbance in habitat as a potential epidemic-control method in conservation.


Effects of iron ions, protons and X rays on human lens cell differentiation.
We have investigated molecular changes in cultured differentiating human lens epithelial cells exposed to high-energy accelerated iron-ion beams as well as to protons and X rays. In this paper, we present results on the effects of radiation on gene families that include or are related to DNA damage, cell cycle regulators, cell adhesion molecules, and cell cytoskeletal function. A limited microarray survey with a panel of cell cycle-regulated genes illustrates that irradiation with protons altered the gene expression pattern of human lens epithelial cells. A focus of our work is CDKN1A (p21(CIP1/WAF1)), a protein that we demonstrate here has a role in several pathways functionally related to LET-responsive radiation damage. We quantitatively assessed RNA and protein expression in a time course before and after single 4-Gy radiation doses and demonstrated that transcription and translation of CDKN1A are both temporally regulated after exposure. Furthermore, we show qualitative differences in the distribution of CDKN1A immunofluorescence signals after exposure to X rays, protons or iron ions, suggesting that LET effects likely play a role in the misregulation of gene function in these cells. A model of molecular and cellular events is proposed to account for precataractous changes in the human lens after exposure to low- or high-LET radiations.


Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects cortical neurons from dying following a traumatic brain injury.
The therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) gene delivery was examined in a rodent model of traumatic brain injury (TBI), the controlled cortical impact (CCI). An adenoviral vector harboring human GDNF (AdGDNF) or green fluorescent protein (AdGFP) was injected unilaterally into the forelimb sensorimotor cortex (FL-SMC) of the rat one week prior to a unilateral CCI. Tests of forelimb function and asymmetry were administered for 2 weeks post-injury. At 2 weeks post-injury, animals were sacrificed and contusion size, neuronal survival, neurodegeneration, and virally-mediated GDNF and GFP protein expression were measured. Rats injected with AdGDNF had significantly smaller contusions, more surviving neurons, and less neurodegeneration than AdGFP injected and uninjected injured animals. GDNF gene delivery also resulted in significantly faster recovery of forelimb coordination and a smaller initial preference for the uninjured forelimb during exploration of the walls of a platform. However, overall recovery of symmetrical forelimb use was not achieved. The discrepancy between neural protection and behavioral recovery suggests that while GDNF gene delivery provided a high degree of protection of damaged cortical neurons in this model of TBI, it may not have fully protected their terminals and synaptic functioning, resulting in only mild protection against behavioral deficits.


Internet-based survey of the nature and perceived causes of injury to dogs participating in agility training and competition events.
To characterize injuries (on the basis of type and severity of injury and affected region of the body) among dogs participating in agility training and competition events and examine associations between injury characteristics and perceived causes of injury. Internet-based, retrospective, cross-sectional survey. 3,801 privately owned dogs participating in agility training or trials. A retrospective electronic survey was developed to investigate demographic factors for dogs and handlers, frequency of participation in agility training and competition, and perceived causes and characteristics of injuries acquired by dogs during agility-related activities. Respondents were handlers recruited through member lists of large canine agility associations in Canada and the United Kingdom and through promotion on an agility blog site. Associations between cause and anatomic site or type of injury and between injury severity (mild vs severe) and setting (competition vs practice) were investigated. Surveys were received from 1,669 handlers of 3,801 agility dogs internationally. Handler-reported data indicated 1,209 of 3,801 (32%) dogs had ≥ 1 injury; of 1,523 analyzed injuries, the shoulder (349 injuries), back (282), and neck (189) regions and phalanges (202) were predominantly affected. Soft tissue injuries (eg, strain [muscle or tendon injury; 807], sprain [ligament injury; 312], and contusion [200]) were common. Injuries were most commonly incurred during interactions with bar jumps, A-frames, and dog walk obstacles (260, 235, and 177 of 1,602 injuries, respectively). Anatomic site and type of injury were significantly associated with perceived cause of injury. These findings provided a basis for further experimental studies to identify specific mechanisms of various types of injury in dogs that participate in agility activities.


The role of biotin and oxamate in the carboxyltransferase reaction of pyruvate carboxylase.
Pyruvate carboxylase (PC) is a biotin-dependent enzyme that catalyzes the MgATP-dependent carboxylation of pyruvate to oxaloacetate, an important anaplerotic reaction in central metabolism. During catalysis, carboxybiotin is translocated to the carboxyltransferase domain where the carboxyl group is transferred to the acceptor substrate, pyruvate. Many studies on the carboxyltransferase domain of PC have demonstrated an enhanced oxaloacetate decarboxylation activity in the presence of oxamate and it has been shown that oxamate accepts a carboxyl group from carboxybiotin during oxaloacetate decarboxylation. The X-ray crystal structure of the carboxyltransferase domain from Rhizobium etli PC reveals that oxamate is positioned in the active site in an identical manner to the substrate, pyruvate, and kinetic data are consistent with the oxamate-stimulated decarboxylation of oxaloacetate proceeding through a simple ping-pong bi bi mechanism in the absence of the biotin carboxylase domain. Additionally, analysis of truncated PC enzymes indicates that the BCCP domain devoid of biotin does not contribute directly to the enzymatic reaction and conclusively demonstrates a biotin-independent oxaloacetate decarboxylation activity in PC. These findings advance the description of catalysis in PC and can be extended to the study of related biotin-dependent enzymes.


Tissue-specific alternative splicing of turkey preprovasoactive intestinal peptide messenger ribonucleic acid, its regulation, and correlation with prolactin secretion.
Although vasoactive intestinal peptide (VIP) is a well characterized physiological PRL-releasing factor in avian species, its regulated expression is not fully understood. We cloned complementary DNAs encoding the prepro-turkey VIP (prepro-tVIP) molecule from an adult turkey hypothalamic complementary DNA library. When the amino acid sequence of the prepro-tVIP was compared to chicken and mammalian sequence, it was found that the isolated tVIP molecules lacked the 27-amino acid peptide histidine isoleucine (PHI) portion of the precursor protein. Several tissues showed an alternatively spliced tVIP transcript that lacked the PHI sequence. Only in the hypothalamus did tVIP-specific primer pairs and reverse transcription-polymerase chain reaction produce two alternatively spliced fragments. The larger hypothalamus-specific fragment was subjected to nucleotide sequence analysis and identified as containing the alternatively spliced PHI-containing exon, which encoded a 27-amino acid PHI peptide in addition to the 8 amino acids that flanked the peptide. Hypothalamic tVIP expression was shown to be up-regulated during the incubation phase of the reproductive cycle. The increased steady state level of tVIP messenger RNA appears to be regulated by nesting behavior, because nest deprivation dramatically suppressed its expression. Levels of the minor tVIP transcript containing both the PHI- and VIP-encoding exons did not significantly change between reproductive stages and were maintained at approximately 4-6% of the total tVIP transcript level. Our findings provide further evidence that VIP is the most important PRL-releasing factor in birds. Our study should serve as a useful model for determining whether PHI contributes in any way to the physiological role of PRL regulation. Revealing the tissue distribution of VIP and PHI gene expression and tissue-specific alternative splicing could contribute to an understanding of the physiological functions of the two peptides as well as their relative roles in PRL regulation.


[Oral ferric ammonium citrate solution in MRCP for diagnosing low-level obstructive jaundice].
To evaluate the value of oral ferric ammonium citrate solution as a gastrointestinal contrast agent in diagnosing low-level obstructive jaundice. Thirty-six patients who were suspected of low-level obstructive jaundice were performed with magnetic resonance cholangiopancreatography (MRCP) and conventional MRI before and after the administration of oral ferric ammonium citrate solution. The diagnostic accuracy for evaluating the site and the cause of obstruction was compared with other diagnostic modalities. The image qualities of single-slice and multi-slice MRCP were improved markedly. The accuracy of MRCP for evaluating the site of obstruction was 97.22%, which was superior to US (P<0.05). There were no significant differences among the MRCP, CT, and ERCP. Oral ferric ammonium citrate solution can significantly improve the image quality of MRCP. FAC-MRCP is a simple, safe, and noninvasive technique with excellent accuracy in the diagnosis of low-level obstructive jaundice.


Moving temporary wall in microfluidic devices.
This paper describes the formation of a temporary wall between two fluid streams in a microfluidic channel. Diffusion of ions from one fluid stream into a costreaming thermally responsive polymer solution is used to lower the local gelation temperature of the polymer, leading to formation of a gel wall in the center of the flow channel. The mechanisms driving either the generation or removal of the wall on its both sides are described and discussed. This wall allows well-controlled transport of particles from one stream into the other.


Gas-solid reactions of single crystals: a study of reactions of NH3 and NO2 with single crystalline organic substrates by infrared microspectroscopy.
Reaction of single crystals of benzoic and trans-cinnamic acids with 200 Torr pressure of ammonia gas in a sealed glass bulb at 20 degrees C generates the corresponding ammonium salts; there is no sign of any 1:2 adduct as has been reported previously for related systems. Isotopic substitution using ND3 has been used to aid identification of the products. Adipic acid likewise reacts with NH3 gas to form a product in which ammonium salts are formed at both carboxylic acid groups. Reaction of 0.5 Torr pressure of NO2 gas with single crystals of 9-methylanthracene and 9-anthracenemethanol in a flow system generates nitrated products where the nitro group appears to be attached at the 10-position, i.e. the position trans to the methyl or methoxy substituent on the central ring. Isotopic substitution using 15NO2 has been used to confirm the identity of the bands arising from the coordinated NO2 group. The products formed when single crystals of hydantoin are reacted with NO2 gas under similar conditions depend on the temperature of the reaction. At 20 degrees C, a nitrated product is formed, but at 65 degrees C this gives way to a product containing no nitro groups. The findings show the general applicability of infrared microspectroscopy to a study of gas-solid reactions of organic single crystals.


The effectiveness of an education program on stages of smoking behavior for workers at a factory in Turkey.
The aim of the study was to determine the smoking behavior based on "stages of change" model of the workers and to assess the effectiveness of a education program at a workplace. The first step was descriptive and the second step was an experimental study. The intervention group received an smoking cessation education. Before intervention 36% of the intervention group were at precontemplation stage. Six months after the intervention decline the percentage of those at precontemplation stage was significantly lower. In the control group there was not a significant reduction in the percentages of smokers at precontemplation stage before and after the intervention. After the 6 months the "maintenance" stage rates were 6% and 2% in the intervention and control groups, respectively. The study showed that the education in factory for workers could not be successful in quiting, however it impacted the intention and preparation of to quit in the future.


Association of physical capacity with heart rate variability based on a short-duration measurement of resting pulse rate in older adults with obesity.
Obesity can limit physical capacity and lower physical activity levels in elderly people. Low physical activity levels may be mediated by autonomic dysfunction with decreased heart rate variability (HRV). However, the relationship between autonomic dysfunction and low physical capability remains unclear. This cross-sectional study investigated the association of low physical capability with HRV in older adults with obesity. We recruited 231 old man and 210 old women with a mean (range) age of 65.5 (51-78) and 62.9 (52-76) years, respectively. Physical capability was measured using mobility tasks, including functional reach, single-leg stance (SLS), gait speed (GS), timed up and go, and timed chair rise (TCR), and the scores on these tasks were merged and transformed into a global physical capability score (GPCS). HRV was measured using a 7-min resting pulse-based technique, and the time- and frequency-domain indices of HRV were obtained including standard deviation of normal-to-normal intervals (SDNN), root mean square of successive differences at rest (rMSSD), and high-frequency (HF) power. All HRV indices were natural log (ln) transformed for analysis. Participants were divided into high, moderate, and low physical-capability groups according to their physical performance. Multivariate analysis of covariance was performed to test differences in HRV indices among physical-capability groups with participants' characteristics serving as covariates. A stepwise regression model was established to identify the determinants of HRV indices. We used hierarchical regression analysis to identify the association of the GPCS with HRV indices. In both men and women, the low physical-capability group exhibited significantly increased heart rate (P <0.05) and decreased HRV in terms of a decreased ln[SDNN] (P <0.001), ln[rMSSD] (P <0.05) and ln[HF] (P <0.05), compared with the high physical-capability group. GS positively predicted ln[SDNN], whereas SLS, GS, and TCR were determinants of ln[HF], regardless of gender. The GPCS in older men and women independently accounted for 29.9% (P <0.001) and 23.7% (P <0.001), respectively, in variance in ln[SDNN]. A low physical-capability level is an independent determinant of decreased HRV in older adults with obesity.


Design, synthesis and antibacterial evaluation of a polycationic calix[4]arene derivative alone and in combination with antibiotics.
The growing antibiotic resistance phenomenon continues to stimulate the search for new compounds and strategies to combat bacterial infections. In this study, we designed and synthesized a new polycationic macrocyclic compound (2) bearing four N-methyldiethanol ammonium groups clustered and circularly organized by a calix[4]arene scaffold. The in vitro activity of compound 2, alone and in combination with known antibiotics (ofloxacin, chloramphenicol or tetracycline), was assessed against strains of Staphylococcus aureus (ATCC 6538 and methicillin-resistant isolate 15), S. epidermidis (ATCC 35984 and methicillin-resistant isolate 57), and Pseudomonas aeruginosa (ATCC 9027 and antibiotic-resistant isolate 1). Calix[4]arene derivative 2 showed significant antibacterial activity against ATCC and methicillin-resistant Gram positive Staphylococci, improved the stability of tetracycline in water, and in combination with antibiotics enhanced the antibiotic efficacy against Gram negative P. aeruginosa by an additive effect.


Treatments for neuropathic pain differentially affect delayed matching accuracy by macaques: effects of amitriptyline and gabapentin.
Current clinical treatments for neuropathic pain include amitriptyline, a tricyclic antidepressant with mixed pharmacology that is also clinically reported to impair cognitive performance; and gabapentin, a compound that selectively interacts with alpha2delta-1 calcium channel subunits. Since few assessments of cognitive performance have been made in non-human primates with these marketed treatments, the purpose of this study was to determine their relative abilities to alter working memory as measured in mature macaques in their performance of a delayed matching-to-sample task. Four delay intervals of increasing duration provided increasing impairment in task accuracies during vehicle sessions. Administration of clinically relevant doses of amitriptyline significantly decreased task accuracy at the highest dose tested (3mg/kg). Administration of gabapentin increased mean task accuracy, though the effect was not statistically significant until intra-subject variability was reduced by selecting the individual best dose for each animal (which averaged 12.8mg/kg). Most of the effect was obtained during the presentation of long delay trials (18.2% above vehicle). Task improvement was sustained during sessions run 24h after gabapentin administration. In a series that used a task-relevant distractor to determine gabapentin's effect on attention, drug treatment reversed distractor-impaired accuracy during long delay trials (25.4% above vehicle). The selective improvement in long delay accuracy in both paradigms suggests improvement in encoding or retention components of working memory. It is currently unclear whether the ability of acute administration of gabapentin to modestly improve working memory occurs by a mechanism that could be related to its anti-allodynic mechanism of action.


Extreme Diversity of Diplonemid Eukaryotes in the Ocean.
The world's oceans represent by far the largest biome, with great importance for the global ecosystem [1-4]. The vast majority of ocean biomass and biodiversity is composed of microscopic plankton. Recent results from the Tara Oceans metabarcoding study revealed that a significant part of the plankton in the upper sunlit layer of the ocean is represented by an understudied group of heterotrophic excavate flagellates called diplonemids [5, 6]. We have analyzed the diversity and distribution patterns of diplonemid populations on the extended set of Tara Oceans V9 18S rDNA metabarcodes amplified from 850 size- fractionated plankton communities sampled across 123 globally distributed locations, for the first time also including samples from the mesopelagic zone, which spans the depth from about 200 to 1,000 meters. Diplonemids separate into four major clades, with the vast majority falling into the deep-sea pelagic diplonemid clade. Remarkably, diversity of this clade inferred from metabarcoding data surpasses even that of dinoflagellates, metazoans, and rhizarians, qualifying diplonemids as possibly the most diverse group of marine planktonic eukaryotes. Diplonemids display strong vertical separation between the photic and mesopelagic layers, with the majority of their relative abundance and diversity occurring in deeper waters. Globally, diplonemids display no apparent biogeographic structuring, with a few hyperabundant cosmopolitan operational taxonomic units (OTUs) dominating their communities. Our results suggest that the planktonic diplonemids are among the key heterotrophic players in the largest ecosystem of our biosphere, yet their roles in this ecosystem remain unknown.


Tunable T cell immunity towards a protein antigen using polymersomes vs. solid-core nanoparticles.
Using poly(propylene sulfide) (PPS) and poly(ethylene glycol) (PEG) as components of a nanocarrier platform, we sought to compare immune responses induced by PPS-bl-PEG polymersomes (PSs; watery-core structures, with antigen incorporated within the PSs) and PEG-stabilized PPS nanoparticles (NPs; solid-core structures, with antigen conjugated upon the NP surface). We have previously shown strong CD8(+) T cell responses to antigen conjugated to NPs via a disulfide link, and here we investigated the extent to which antigen incorporated within oxidatively-sensitive PSs could induce CD4(+) or CD8(+) T cell responses. C57BL/6 mice were subcutaneously immunized with free ovalbumin (OVA) as a model antigen, or equivalent doses of OVA-loaded into PSs, conjugated onto NPs, or given as a mixture of the two. Free CpG was used as an adjuvant. Antigen-loaded PSs induced enhanced frequencies of antigen-specific CD4(+) T cells in the spleen, lymph nodes and lungs as compared to the NP formulation, whereas antigen-conjugated NPs induced stronger CD8(+) T cell responses. Co-administration of both PSs and NPs elicited T cell immunity characteristic of the two nanocarriers at the same time, i.e. both strong CD4(+) and CD8(+) T cell responses. These results have important implications for particulate-based vaccine design and highlight the potential of using different antigen-delivery systems for the induction of both T helper and cytotoxic T lymphocyte immune responses.


A comparison of lower genital tract glycogen and lactic acid levels in women and macaques: implications for HIV and SIV susceptibility.
Understanding factors that affect heterosexual transmission of HIV in women is of great importance. Lactobacilli in the lower genital tract of women utilize glycogen in vaginal epithelial cells as an energy source and produce lactic acid. The resultant vaginal acidity is believed to provide protection against HIV infection. Conversely, bacterial vaginosis (BV) is characterized by less lactic acid and a higher pH, and is associated with increased susceptibility to HIV infection. Because vaginal infection of macaques with simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) is used as a model to study HIV sexual transmission, and because previous studies have shown a paucity of lactobacilli in rhesus macaques' lower genital tract, we compared lactic acid and glycogen levels in the genital fluid of rhesus and pigtail macaques with levels found in humans. The levels of lactic acid were lower in both rhesus (median=1.2 mol lactate/mg protein) and pigtail macaques (median=0.7 mol/mg) compared to women with healthy genital microbiota (median=4.2 mol/mg). Glycogen levels were significantly lower in both rhesus (median=0.004 μg glycogen/μg protein) and pigtail macaques (median=0 μg/μg) than in women (median=0.2 μg/μg). No significant differences in glycogen or lactate levels were observed comparing longitudinally collected samples from cycling pigtail macaques. These data show that the previously reported scarcity of lactobacilli in macaques correlates with low glycogen and lactic acid levels. These findings have important implications for studies of vaginal infection of macaques with SIV or SHIV and further our understanding of how the bacterial microbiota influences HIV infection.


Therapy for lower-risk MDS.
Lower-risk myelodysplastic syndromes (MDS) are characterized by the presence of dysplasia, low bone marrow blast percentage, low number and depth of cytopenia(s), and relatively good-risk karyotpic and molecular abnormalities. A score of ≤3.5 on the Revised International Prognostic Scoring System classifies patients as lower-risk MDS. Information from a mutational profile of the MDS at time of diagnosis (and over serial time points) can be reassuring for predicted behavior of lower-risk MDS compared with one expected to progress more rapidly (higher-risk MDS). Supportive care continues to be the crux of treatment, although the options to reduce transfusion needs have improved in 2020. Erythropoiesis stimulating agents, lenalidomide, and luspatercept address the most frequent (and symptomatic) cytopenia (anemia) and are started only when patients are transfusion dependent. Patients can derive long-term benefits (years) from these approaches but will often progress to higher-risk MDS. Interestingly, some patients with lower-risk MDS can present with an isolated thrombocytopenia for which thrombopoietin receptor analogs such as romiplostim and eltrombopag are options (as long as blast counts are low). The presence of pancytopenia and or intensifying and unremitting clinical symptoms are often treated with hypomethylating agents or (anti-thymocyte globulin if hypocellular MDS is of concern). Targeted therapies are emerging for small subsets of MDS patients with specific somatic mutations (ie, TP53, IDH1/2, FLT3), although currently, there are no approved, mutation-directed medications to treat MDS.


Effects of intensive longitudinal data collection on pregnancy and contraceptive use.
We use an experiment based on the Relationship Dynamics and Social Life (RDSL) study of sexual behavior, pregnancy, and contraceptive use to investigate whether participation in weekly self-reports over one year result in differential effects on related behaviors and attitudes, compared to participation in a one-time follow-up interview requiring retrospective self-reporting for the prior year. We randomly assigned 200 subjects to either a control group or a journal group. All subjects were interviewed at the beginning of the study (baseline interview) and 12 months later (closeout interview). Subjects in the journal group also completed a five-minute web- or phone-based survey every week during the 12-month study period. We found no statistically significant difference in pregnancy rates across the two groups at closeout. Contrary to our expectation, the control group experienced a slightly larger increase in having ever used a contraceptive method, although this was mainly due to increases in the least effective methods, such as condoms and withdrawal. Respondents in the weekly interview group became slightly more positive toward childbearing in terms of one specific attitude measure, but not for the vast majority of measures. We conclude that intensive longitudinal data collection does not appear to have a large or consistent impact on respondents' pregnancy, contraceptive use, or related attitudes, relative to the more standard longitudinal approach.


The ecology of microscopic life in household dust.
We spend the majority of our lives indoors; yet, we currently lack a comprehensive understanding of how the microbial communities found in homes vary across broad geographical regions and what factors are most important in shaping the types of microorganisms found inside homes. Here, we investigated the fungal and bacterial communities found in settled dust collected from inside and outside approximately 1200 homes located across the continental US, homes that represent a broad range of home designs and span many climatic zones. Indoor and outdoor dust samples harboured distinct microbial communities, but these differences were larger for bacteria than for fungi with most indoor fungi originating outside the home. Indoor fungal communities and the distribution of potential allergens varied predictably across climate and geographical regions; where you live determines what fungi live with you inside your home. By contrast, bacterial communities in indoor dust were more strongly influenced by the number and types of occupants living in the homes. In particular, the female : male ratio and whether a house had pets had a significant influence on the types of bacteria found inside our homes highlighting that who you live with determines what bacteria are found inside your home.


Human papillomavirus vaccine safety in Australia: experience to date and issues for surveillance.
Australia was one of the first countries to licence a quadrivalent human papillomavirus (HPV) vaccine, rapidly followed by a federally funded program of universal vaccination of a broad age group of females through schools (12 to 18 years) and primary care (19 to 26 years). As of August 2009, more than 5.8 million doses of Gardasil((R)) (quadrivalent; Merck, New Jersey, USA) have been distributed in Australia and a total of 1394 suspected adverse events following immunisation (AEFI) have been reported to the passive surveillance system. Most reports are of common and expected reactions. Case series of more uncommon and serious AEFI, both known to be potentially vaccine related (anaphylaxis, conversion disorders and lipoatrophy) and otherwise (multiple sclerosis and pancreatitis) have been published.


Amphibian orientation: an unexpected observation.
The study of homing movements of displaced newts (Taricha rivularis) revealed unexpected features of the migratory behavior of amphibians. Newts leaving the breeding stream in the spring move not directly uphill but at an angle carrying them upstream. When they emerge after summer estivation this tendency is not evident in captures made during the autumn and winter. During the latter period, however, newly metamorphosed frogs (Rana boylii) show the same pronounced upstream migration that characterizes T. rivularis in the spring.


Multiple insecticide resistance: an impediment to insecticide-based malaria vector control program.
Indoor Residual Spraying (IRS), insecticide-treated nets (ITNs) and long-lasting insecticidal nets (LLINs) are key components in malaria prevention and control strategy. However, the development of resistance by mosquitoes to insecticides recommended for IRS and/or ITNs/LLINs would affect insecticide-based malaria vector control. We assessed the susceptibility levels of Anopheles arabiensis to insecticides used in malaria control, characterized basic mechanisms underlying resistance, and evaluated the role of public health use of insecticides in resistance selection. Susceptibility status of An. arabiensis was assessed using WHO bioassay tests to DDT, permethrin, deltamethrin, malathion and propoxur in Ethiopia from August to September 2009. Mosquito specimens were screened for knockdown resistance (kdr) and insensitive acetylcholinesterase (ace-1(R)) mutations using AS-PCR and PCR-RFLP, respectively. DDT residues level in soil from human dwellings and the surrounding environment were determined by Gas Chromatography with Electron Capture Detector. An. arabiensis was resistant to DDT, permethrin, deltamethrin and malathion, but susceptible to propoxur. The West African kdr allele was found in 280 specimens out of 284 with a frequency ranged from 95% to 100%. Ace-1(R) mutation was not detected in all specimens scored for the allele. Moreover, DDT residues were found in soil samples from human dwellings but not in the surrounding environment. The observed multiple-resistance coupled with the occurrence of high kdr frequency in populations of An. arabiensis could profoundly affect the malaria vector control programme in Ethiopia. This needs an urgent call for implementing rational resistance management strategies and integrated vector control intervention.


Emerging depression is associated with face memory deficits in adolescent girls.
To examine the association between memory for previously encoded emotional faces and depression symptoms assessed over 4 years in adolescent girls. Investigating the interface between memory deficits and depression in adolescent girls may provide clues about depression pathophysiology. Participants were 213 girls recruited from a longitudinal, community-based study; the majority were African American. Scores on depressive screening measures at age 8 were used to increase the base rate of depression. Depression symptoms and diagnoses were assessed annually for 4 years. In year 4, when the girls were 12 to 13 years old, a face emotion encoding task was administered during which ratings were generated in response to sad, fearful, angry, and happy faces. A surprise memory task followed whereby participants identified which of two faces, displaying neutral expressions, they had seen previously. Girls with higher depression symptom levels from ages 9 to 12 years evidenced lower accuracy in identifying previously encoded emotional faces. Controlling for IQ, higher depression symptom level was associated with a memory deficit specific to previously encoded sad and happy faces. These effects were not moderated by race. Individual differences in face memory deficits relate to individual differences in emerging, early adolescent depression, and may be vulnerability markers for depression.


Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people.
To investigate the relationship between neurovascular coupling and cognitive function in elderly individuals with vascular risk factors and to determine whether neurovascular coupling could be modified by cocoa consumption. Sixty older people (aged 72.9 ± 5.4 years) were studied in a parallel-arm, double-blind clinical trial of neurovascular coupling and cognition in response to 24 hours and 30 days of cocoa consumption. Cognitive measures included Mini-Mental State Examination and Trail Making Test A and B. Neurovascular coupling was measured from the beat-to-beat blood flow velocity responses in the middle cerebral arteries to the N-Back Task. In a subset of MRI-eligible participants, cerebral white matter structural integrity was also measured. Neurovascular coupling was associated with Trails B scores (p = 0.002) and performance on the 2-Back Task. Higher neurovascular coupling was also associated with significantly higher fractional anisotropy in cerebral white matter hyperintensities (p = 0.02). Finally, 30 days of cocoa consumption was associated with increased neurovascular coupling (5.6% ± 7.2% vs -2.4% ± 4.8%; p = 0.001) and improved Trails B times (116 ± 78 seconds vs 167 ± 110 seconds; p = 0.007) in those with impaired neurovascular coupling at baseline. There is a strong correlation between neurovascular coupling and cognitive function, and both can be improved by regular cocoa consumption in individuals with baseline impairments. Better neurovascular coupling is also associated with greater white matter structural integrity.


Mono- and trivalent ions around DNA: a small-angle scattering study of competition and interactions.
The presence of small numbers of multivalent ions in DNA-containing solutions results in strong attractive forces between DNA strands. Despite the biological importance of this interaction, e.g., DNA condensation, its physical origin remains elusive. We carried out a series of experiments to probe interactions between short DNA strands as small numbers of trivalent ions are included in a solution containing DNA and monovalent ions. Using resonant (anomalous) and nonresonant small angle x-ray scattering, we coordinated measurements of the number and distribution of each ion species around the DNA with the onset of attractive forces between DNA strands. DNA-DNA interactions occur as the number of trivalent ions increases. Surprisingly good agreement is found between data and size-corrected numerical Poisson-Boltzmann predictions of ion competition for non- and weakly interacting DNAs. We also obtained an estimate for the minimum number of trivalent ions needed to initiate DNA-DNA attraction.


Integrative Phosphoproteomics Links IL-23R Signaling with Metabolic Adaptation in Lymphocytes.
Interleukin (IL)-23 mediated signal transduction represents a major molecular mechanism underlying the pathology of inflammatory bowel disease, Crohn's disease and ulcerative colitis. In addition, emerging evidence supports the role of IL-23-driven Th17 cells in inflammation. Components of the IL-23 signaling pathway, such as IL-23R, JAK2 and STAT3, have been characterized, but elements unique to this network as compared to other interleukins have not been readily explored. In this study, we have undertaken an integrative phosphoproteomics approach to better characterise downstream signaling events. To this end, we performed and compared phosphopeptide and phosphoprotein enrichment methodologies after activation of T lymphocytes by IL-23. We demonstrate the complementary nature of the two phosphoenrichment approaches by maximizing the capture of phosphorylation events. A total of 8202 unique phosphopeptides, and 4317 unique proteins were identified, amongst which STAT3, PKM2, CDK6 and LASP-1 showed induction of specific phosphorylation not readily observed after IL-2 stimulation. Interestingly, quantitative analysis revealed predominant phosphorylation of pre-existing STAT3 nuclear subsets in addition to translocation of phosphorylated STAT3 within 30 min after IL-23 stimulation. After IL-23R activation, a small subset of PKM2 also translocates to the nucleus and may contribute to STAT3 phosphorylation, suggesting multiple cellular responses including metabolic adaptation.


Cerebellar transcranial direct current stimulation effects on saccade adaptation.
Saccade adaptation is a cerebellar-mediated type of motor learning in which the oculomotor system is exposed to repetitive errors. Different types of saccade adaptations are thought to involve distinct underlying cerebellar mechanisms. Transcranial direct current stimulation (tDCS) induces changes in neuronal excitability in a polarity-specific manner and offers a modulatory, noninvasive, functional insight into the learning aspects of different brain regions. We aimed to modulate the cerebellar influence on saccade gains during adaptation using tDCS. Subjects performed an inward (n = 10) or outward (n = 10) saccade adaptation experiment (25% intrasaccadic target step) while receiving 1.5 mA of anodal cerebellar tDCS delivered by a small contact electrode. Compared to sham stimulation, tDCS increased learning of saccadic inward adaptation but did not affect learning of outward adaptation. This may imply that plasticity mechanisms in the cerebellum are different between inward and outward adaptation. TDCS could have influenced specific cerebellar areas that contribute to inward but not outward adaptation. We conclude that tDCS can be used as a neuromodulatory technique to alter cerebellar oculomotor output, arguably by engaging wider cerebellar areas and increasing the available resources for learning.


To Compare and Determine the Diagnostic Accuracy of [18F]-fluorodeoxyglucose Positron Emission Tomography Scan in Predicting Pathological Response in Operated Carcinoma Esophagus Patients after Initial Neoadjuvant Chemoradiation and Neoadjuvant Chemotherapy.
The objective of this study was to determine whether [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan could predict the pathological response in esophageal carcinoma after surgery in patients receiving neoadjuvant concurrent chemoradiation (NACCRT) and neoadjuvant chemotherapy (NACT). A randomized prospective study was carried out from March 2014 to October 2016; thirty patients of histopathologically proven, locally advanced, potentially operable carcinoma esophagus comprising both squamous carcinoma and adenocarcinoma were randomized into NACCRT and NACT arms equally. Both groups had pretreatment FDG-PET-computed tomography (CT) scan and repeat scan after 5-6 weeks of neoadjuvant therapy (NAT). The change in mean %Δmaximum standardized uptake value (%ΔSUVmax) was compared with tumor regression grade (TRG) in the postoperative histology. Patients with TRG 1-2 were deemed responders and 3-5 were nonresponders. Pathologic response was correlated with percentage change in [18F]-FDG uptake (%ΔSUVmax); receiver operating characteristics (ROC) analyses were done to assess sensitivity and specificity of FDG-PET to determine its diagnostic accuracy. The mean SUV in NACCRT group decreased from 15.47 ± 2.92 to 7.31 ± 4.07 (P < 0.001), while in NACT group, mean SUV decreased from 14.74 ± 3.95 to 8.60 ± 3.89 (P < 0.001). Comparison between NACCRT and NACT leads to mean SUV of 57.80 ± 22.40 and 45.92 ± 19.23, respectively (P = 0.13). In NACCRT and NACT, TRG had mean %ΔSUVmax values of 2.53 ± 1.25 and 2.93 ± 1.28 (P = 0.393). However, we found a statistically significant correlation between SUV% reduction and TRG (P = 0.002). ROC curve analysis for FDG-PET-CT suggested an area under the curve of 0.693 and sensitivity and specificity of 80% and 46.7%, respectively. NACCRT and NACT lead to a statistically significant reduction in mean %ΔSUVmax and with statistical significance correlation when compared with pathological response assessment. Hence, PET-CT can be used for differentiating responders and nonresponders to NAT.


Fracture Rates and Bone Density Among Postmenopausal Veteran and Non-Veteran Women From the Women's Health Initiative.
Postmenopausal osteoporosis can impact quality-of-life even prefracture. To determine whether osteoporosis should be a greater concern in women Veterans versus non-Veterans, we compared fracture rates and bone mineral density (BMD) for Veterans and non-Veterans using Women's Health Initiative data. In this cohort study, participants were women aged 50-79 years. Outcomes were hip, central body, and limb fractures occurring during up to 19 years of follow-up and hip, spine, and whole body BMD collected three times over a 6-year period in a participant subsample. Covariates comprised risk factors for fracture, including fall history and other components of the World Health Organization Fracture Risk Assessment Tool (FRAX). Cox Proportional Hazards models were used to examine fracture rates for Veterans compared with non-Veterans. Of 161,808 women, 145,521 self-identified as Veteran (n = 3,719) or non-Veteran (n = 141,802). Baseline FRAX scores showed that Veterans had higher 10-year probabilities for any major fracture (13.3 vs 10.2; p < .01) and hip fracture (4.1 vs 2.2; p < .01) compared with non-Veterans. The age-adjusted rate of hip fracture per 1,000 person-years for Veterans was 3.3 versus 2.4 for non-Veterans (p < .01). After adjustment, the hazards ratio for hip fracture was 1.24 (95% confidence interval 1.03-1.49) for Veterans versus non-Veterans. Hazards ratios at other anatomic sites did not differ by Veteran status. Mean BMD at baseline and at Years 3 and 6 also did not differ by Veteran status at any site. Women Veterans had an increased hip fracture rate not explained by differences in well-recognized fracture risk factors.


A Novel Tool for Predicting Major Complications After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.
Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has an emerging role in the treatment of peritoneal malignancies. The CRS-HIPEC approach has known treatment-related toxicities. This study sought to determine the predictors of major postoperative complications after CRS-HIPEC in a high-volume center. From a single-institution database, this study investigated complications experienced by patients undergoing CRS-HIPEC. Multiple preoperative and operative factors were analyzed for their ability to predict 60-day Clavien grade 3 and greater (major) complications by logistic regression. A predictive model was created from preoperative factors using multivariate logistic regression. The model was tested by Akaike's information criterion, the Hosmer and Lemeshow Goodness-of-Fit Test, the receiver operating characteristic, and the Youden Index. The study evaluated 247 patients undergoing CRS-HIPEC. The primary tumor site was the appendix in 166 cases (67.2 %), the colorectal area in 51 cases (20.6 %), the peritoneum (mesothelioma) in 22 cases (8.9 %), the ovary in 5 cases (2 %), and the small bowel in 3 cases (1.2 %). The median peritoneal cancer index was 14 (range 0-29), and 235 patients (95.1 %) had a complete (CC-0/1) cytoreduction. Major complications occurred for 41 patients (16.6 %), classified as grade 3 in 33 cases (13.4 %), grade 4 in 5 cases (2 %), and grade 5 (deaths) in 3 cases (1.2 %). The factors predictive of major complications in the multivariate analysis were a Charlson Comorbidity Index (CCI) score higher than 0 [odds ratio (OR), 2.505; p = 0.035], presence of preoperative symptoms (OR 1.951; p = 0.064), and prior resection status [no resection or prior CRS-HIPEC (OR 2.087) vs. prior resection without CRS-HIPEC (OR 3.209); p = 0.046]. These variables were used to create a tool predictive of postoperative complications. Presence of symptoms, CCI, and prior resection status predict major complications and define a low-risk population after CRS-HIPEC.


National single-step genomic method that integrates multi-national genomic information.
The aim of this paper was to develop a national single-step genomic BLUP that integrates multi-national genomic estimated breeding values (EBV) and associated reliabilities without double counting dependent data contributions from the different evaluations. Simultaneous use of all data, including phenotypes, pedigree, and genotypes, is a condition to obtain unbiased EBV. However, this condition is not always fully met, mainly due to unavailability of foreign raw data for imported animals. In dairy cattle genetic evaluations, this issue is traditionally tackled through the multiple across-country evaluation (MACE) of sires, performed by Interbull Centre (Uppsala, Sweden). Multiple across-country evaluation regresses all the available national information onto a joint pedigree to obtain country-specific rankings of all sires without sharing the raw data. In the context of genomic selection, the issue is handled by exchanging sire genotypes and by using MACE information (i.e., MACE EBV and reliabilities), as a valuable source of "phenotypic" data. Although all the available data are considered, these "multi-national" genomic evaluations use multi-step methods assuming independence of various sources of information, which is not met in all situations. We developed a method that handles this by single-step genomic evaluation that jointly (1) uses national phenotypic, genomic, and pedigree data; (2) uses multi-national genomic information; and (3) avoids double counting dependent data contributions from an animal's own records and relatives' records. The method was demonstrated by integrating multi-national genomic EBV and reliabilities of Brown Swiss sires, included in the InterGenomics consortium at Interbull Centre, into the national evaluation in Slovenia. The results showed that the method could (1) increase reliability of a national (genomic) evaluation; (2) provide consistent ranking of all animals: bulls, cows, and young animals; and (3) increase the size of a genomic training population. These features provide more efficient and transparent selection throughout a breeding program.


Health outcomes of children born to mothers with chronic kidney disease: a pilot study.
This study aimed to study the health of children born to mothers with chronic kidney disease. Twenty-four children born to mothers with chronic kidney disease were compared with 39 matched control children born to healthy mothers without kidney disease. The well-being of each child was individually assessed in terms of physical health, neurodevelopment and psychological health. Families participating with renal disease were more likely to be from lower socio-economic backgrounds. Significantly fewer vaginal deliveries were reported for mothers with renal disease and their infants were more likely to experience neonatal morbidity. Study and control children were comparable for growth parameters and neurodevelopment as assessed by the Griffiths scales. There was no evidence of more stress amongst mothers with renal disease or of impaired bonding between mother and child when compared to controls. However, there was evidence of greater externalizing behavioral problems in the group of children born to mothers with renal disease. Engaging families in such studies is challenging. Nonetheless, families who participated appreciated being asked. The children were apparently healthy but there was evidence in this small study of significant antenatal and perinatal morbidity compared to controls. Future larger multi-center studies are required to confirm these early findings.


Specific IgG subclasses in pollinosis.
We studied IgG subclasses in pollinosis in order to determine the possible immunopathological role of these antibodies, especially antigen-specific IgG4. The selection of pollinosic patients allowed us to observe the influence natural antigenic exposure exerts upon antibodies. On the other hand, we intended to study the possible modifications immunotherapy produces on IgG subclasses. For this purpose, we selected 266 patients who were classified into the following groups: Group I, 65 patients without immunotherapy, 35 of whom were studied during the pollen season and 30 outside the pollen season; Group II, 40 nonpollinosic patients with hypersensitization to Dermatophagoides pteronyssinus were taken as atopic controls; Group III, 161 pollinosic patients with from 3 to 42 months of immunotherapy. For every patient, IgG1, IgG2 and IgG3 against Phleum pratense were determined by means of ELAST (Leti), and IgG4 against the same allergen by means of the ELISA technique developed by us. Our results confirm, first, that untreated pollinosic patients present higher concentrations of IgG4 against Phleum than nonpollinosic patients, and second, that immunotherapy produces significant modifications in the production of antigen-specific IgG.


BMI trends, socioeconomic status, and the choice of dataset.
This study is a descriptive investigation of trends in BMI in the USA over time, across race/ethnicity, gender, and socioeconomic status (SES) groups, and across different datasets. The study analyzes micro-level data from three widely used cross-sectional US health datasets: the National Health and Nutrition Examination Survey (NHANES), the National Health Interview Survey (NHIS), and the Behavioral Risk Factor Surveillance System (BRFSS), from the 1970s to 2008. Consistent race/ethnicity and SES groups are constructed for all datasets. SES is measured by education and income. Focusing on adults aged 20-74 years, the study estimates BMI time trends, distributional shifts, and incremental associations (gradients) with SES. SES-BMI gradients are consistently larger for women than for men, differ across race/ethnicity groups, and are similar across datasets. Trends in mean BMI are comparable across White, Black and Hispanic males, while Hispanic females range between White and Black females. Self-reported BMI in the NHANES differs markedly from self-reports in the NHIS and BRFSS. The NHANES, NHIS, and BRFSS provide similar evidence regarding BMI trends over time and across race/ethnicity, gender, and SES groups. Racial disparities in BMI remain after adjusting for SES and should be studied further.


Improving Heart Disease Risk Through Quality-Focused Diet Logging: Pre-Post Study of a Diet Quality Tracking App.
Diet-tracking mobile apps have gained increased interest from both academic and clinical fields. However, quantity-focused diet tracking (eg, calorie counting) can be time-consuming and tedious, leading to unsustained adoption. Diet quality-focusing on high-quality dietary patterns rather than quantifying diet into calories-has shown effectiveness in improving heart disease risk. The Healthy Heart Score (HHS) predicts 20-year cardiovascular risks based on the consumption of foods from quality-focused food categories, rather than detailed serving sizes. No studies have examined how mobile health (mHealth) apps focusing on diet quality can bring promising results in health outcomes and ease of adoption. This study aims to design a mobile app to support the HHS-informed quality-focused dietary approach by enabling users to log simplified diet quality and view its real-time impact on future heart disease risks. Users were asked to log food categories that are the main predictors of the HHS. We measured the app's feasibility and efficacy in improving individuals' clinical and behavioral factors that affect future heart disease risks and app use. We recruited 38 participants who were overweight or obese with high heart disease risk and who used the app for 5 weeks and measured weight, blood sugar, blood pressure, HHS, and diet score (DS)-the measurement for diet quality-at baseline and week 5 of the intervention. Most participants (30/38, 79%) used the app every week and showed significant improvements in DS (baseline: mean 1.31, SD 1.14; week 5: mean 2.36, SD 2.48; 2-tailed t test t29=-2.85; P=.008) and HHS (baseline: mean 22.94, SD 18.86; week 4: mean 22.15, SD 18.58; t29=2.41; P=.02) at week 5, although only 10 participants (10/38, 26%) checked their HHS risk scores more than once. Other outcomes, including weight, blood sugar, and blood pressure, did not show significant changes. Our study showed that our logging tool significantly improved dietary choices. Participants were not interested in seeing the HHS and perceived logging diet categories irrelevant to improving the HHS as important. We discuss the complexities of addressing health risks and quantity- versus quality-based health monitoring and incorporating secondary behavior change goals that matter to users when designing mHealth apps.