Biomechanical factors influencing successful self-righting in the pleurodire turtle Emydura subglobosa.
Self-righting performance is a key ability for most terrestrial animals, and has been used as a metric of fitness, exhaustion and thermal limits in a variety of taxa. However, there is little understanding of the underlying mechanisms that drive variation in self-righting performance. To evaluate the mechanical factors that contribute to success versus failure when animals attempt to self-right, we compared force production and kinematic behavior in the rigid-bodied, pleurodire turtle Emydura subglobosa between successful and unsuccessful self-righting efforts. We found that the moment exerted during efforts to roll the body and the velocity of that roll are the primary drivers behind self-righting success. Specifically, turtles that self-righted successfully produced both larger moments and faster rolls than turtles that failed. In contrast, the angle at which the head was directed to lever the body and the extent of yaw that was incorporated in addition to roll had little impact on the likelihood of success. These results show that specific performance metrics can predict the ability of animals to self-right, providing a framework for biomimetic applications as well as future comparisons to test for differences in self-righting performance across animals from different environments, sexes, populations and species.


Sri Lanka in global medical research: a scientific analysis of the Sri Lankan research output during 2000-2009.
Scientific research is an essential component in guiding improvements in health systems. There are no studies examining the Sri Lankan medical research output at international level. The present study evaluated the Sri Lankan research performance in medicine as reflected by the research publications output between years 2000-2009. This study was based on Sri Lankan medical research publication data, retrieved from the SciVerse Scopus® from January 2000 to December 2009. The process of article selection was as follows: Affiliation - 'Sri Lanka' or 'Ceylon', Publication year - 'January 2000 to December 2009' and Subject area - 'Life and Health Sciences'. The articles identified were classified according to disease, medical speciality, institutions, major international collaborators, authors and journals. Sri Lanka's cumulative medical publications output between years 2000-2009 was 1,740 articles published in 160 different journals. The average annual publication growth rate was 9.1%. Majority of the articles were published in 'International' (n = 950, 54.6%) journals. Most articles were descriptive studies (n = 611, 35.1%), letters (n-345, 19.8%) and case reports (n = 311, 17.9%). The articles were authored by 148 different Sri Lankan authors from 146 different institutions. The three most prolific local institutions were Universities of; Colombo (n = 547), Kelaniya (n = 246) and Peradeniya (n = 222). Eighty four countries were found to have published collaborative papers with Sri Lankan authors during the last decade. UK was the largest collaborating partner (n = 263, 15.1%).Malaria (n = 75), Diabetes Mellitus (n = 55), Dengue (n = 53), Accidental injuries (n = 42) and Lymphatic filariasis (n = 40) were the major diseases studied. The 1,740 publications were cited 9,708 times, with an average citation of 5.6 per paper. The most cited paper had 203 citations, while there were 597 publications with no citations. The Sri Lankan authors' contribution to the global medical research output during the last decade was only 0.086%. The Sri Lankan medical research output during the last decade is only a small fraction of the global research output. There it is a necessity to setup an enabling environment for research, with a proper vision, support, funds and training. In addition, collaborations across the region need to be strengthened to face common regional health challenges.


In vitro evaluation of the association of medicinal larvae (Insecta, Diptera, Calliphoridae) and topical agents conventionally used for the treatment of wounds.
Wound healing is a complex process involving multiple biochemical and cellular events and represents a neglected public health issue. As a consequence, millions of people worldwide suffer from chronic wounds. The search for new treatment alternatives is therefore an important issue. In the context of wound healing, Maggot Debridement Therapy (MDT) is an inexpensive treatment with few contraindications and very promising results. This study aimed to evaluate the in vitro feasibility and implications of larvae (= MDT) use when combined with topical agents as a strategy to identify additive or synergistic combinations. The weight and survival rate of Cochliomyia macellaria (Fabricius) (Insecta, Diptera, Calliphoridae) larvae reared in an in vitro wound with either honey, hydrogel, 10% papain gel, essential fatty acids (EFA), collagenase, or silver sulfadiazine were evaluated after 24, 48 and 72 h. Hydrogel (for weight: 24 and 72 h; for survival: 24 h) and 10% papain gel (for weight: 48 h; for survival: 48 and 72 h) demonstrated the least interference in larval weight gain and survival rate, when compared to the control group. The results obtained in this study showed that the combined use of larvae and hydrogel or 10% papain gel may be promising to maximize the tissue repair. Honey, EFA and collagenase could be used to prepare the bed of the dry wounds to receive the MDT.


A case of tuberculous pyomyositis that caused a recurrent soft tissue lesion localized at the forearm.
We present the case of a 20-year-old male who had a non-traumatic soft tissue lesion (4 x 3 cm) with recurrent discharge at his right posteromedial antebrachial muscles; the patient underwent surgery twice, and antibiotic therapy was administered, but no cure was achieved with these treatments. The patient underwent surgery at our medical center. There was no history of pulmonary, gastrointestinal, or genitourinary tuberculosis (TB). Due to suspected pulmonary, genitourinary, and gastrointestinal TB, radiography and computed tomography scans were performed, and these studies disclosed no evidence of a primary origin. The erythrocyte sedimentation rate and the results of purified protein derivate testing were normal. We also detected submandibular lymphadenopathy (LAP) (2 x 3 cm) localized at a submandibular site in our patient 4 months after his first visit to our clinic. Smears were stained with Ehrlich Ziehl Neelsen (EZN) stain and culture were grown for Mycobacterium tuberculosis complex (MTC); the samples used for these assays had been obtained by incisional biopsy of the forearm lesion and by aspiration of the submandibular lymph node, and they were found to be MTC-positive. Then, a culture for MTC, derived from an induced sputum sample, was found to be positive, despite the negative results obtained with a sputum smear subjected to EZN staining. According to these results, the primary focus of the tuberculous pyomyositis and the submandibular LAP was the lungs. The lesion and submandibular LAP were both treated successfully by the administration of antituberculous chemotherapy.


Antibiotic use for community-acquired pneumonia in neonates and children: WHO evidence review.
Background Pneumonia is the most common cause of death in children worldwide, accounting for 15% of all deaths of children under 5 years of age. This review summarises the evidence for the empirical antibiotic treatment of community-acquired pneumonia in neonates and children and puts emphasis on publications since the release of the previous WHO Evidence Summary report published in 2014. Methods A systematic search for systematic reviews and meta-analyses of antibiotic therapy for community-acquired pneumonia was conducted between 1 January 2013 and 10 November 2016. Results The optimal dosing recommendation for amoxicillin remains unclear with limited pharmacological and clinical evidence. There is limited evidence from surveillance to indicate whether amoxicillin or broader spectrum antibiotics (e.g. third-generation cephalosporins) are being used most commonly for paediatric CAP in different WHO regions. Data are lacking on clinical efficacy in the context of pneumococcal, staphylococcal and mycoplasma disease and the relative contributions of varying first-line and step-down options to the selection of such resistance. Conclusion Further pragmatic trials are required to optimise management of hospitalised children with severe and very severe pneumonia.


Biomechanical implications of mild leg length inequality.
The effect of mild leg length inequality (lower extremity length difference less than 3 cm) on posture and gait has been the source of much controversy. Many opinions have been expressed both for and against the need for intervention to reduce the magnitude of the discrepancy. This paper emphasizes the need for accurate and reliable assessment of leg length differences using a clinically functional radiographic technique, and reviews the biomechanical implications of leg length inequality as related to the development of stress fractures, low back pain and osteoarthritis.


Long head BIceps TEnodesis or tenotomy in arthroscopic rotator cuff repair: BITE study protocol.
Optimal treatment of the diseased long head of the biceps (LHB) tendon during rotator cuff repair remains a topic of debate: tenotomy or tenodesis. A recent meta analysis revealed no difference in strength or functional outcome between treatments. The included studies varied in methodological quality, and only two were randomized controlled trials (RCTs). As strong evidence in favor of either tenotomy or tenodesis is still lacking, we designed this randomized controlled trial to compare functional outcomes after tenotomy and tenodesis when performed in adjunct to arthroscopic rotator cuff repair. Patients older than 50 years with a supraspinatus and/or infraspinatus tendon rupture sized smaller than 3 cm, who are encountered with LHB pathology, will be randomized to either LHB tenotomy or LHB tenodesis. Clinical and patient-reported data will be collected pre-operatively, 6 weeks, 3 months and 1 year after surgery. Primary outcome is overall shoulder function evaluated with the Constant score at 1 year after surgery. As additional measures of shoulder function, two patient reported outcomes (the Dutch Oxford Shoulder Test and the Disabilities of the Arm Shoulder and Hand questionnaire) will be assessed. Other evaluations include cosmetic appearance evaluated by the "Popeye" deformity, elbow flexion strength, arm cramping pain, MRI-based location of the biceps tendon, quality of life, and duration of surgery. To detect non-inferiority with a one-sided, two-sample t-test with 80 % power and a significance level (alpha) of 0.025, the required sample size is 98 patients. Treatment of LHB tendon lesions is performed differently around the world and meta analyses do not provide conclusive evidence in favor of one of these treatments. This study will strengthen evidence on the risks and benefits of LHB tenotomy and tenodesis in adjunct to a rotator cuff repair, which is important for managing patient expectations. Dutch Trial Register ( NTR3255 ) January 12, 2012, ClinicalTrials.gov (ID NCT02655848 ) January 14, 2016, retrospectively registered.


Lupus nephritis: enigmas, conflicting models and an emerging concept.
Autoantibodies to components of chromatin, which include double-stranded DNA (dsDNA), histones and nucleosomes, are central in the pathogenesis of lupus nephritis. How anti-chromatin autoantibodies exert their nephritogenic activity, however, is controversial. One model assumes that autoantibodies initiate inflammation when they cross-react with intrinsic glomerular structures such as components of membranes, matrices or exposed nonchromatin ligands released from cells. Another model suggests glomerular deposition of autoantibodies in complex with chromatin, thereby inducing classic immune complex-mediated tissue damage. Recent data suggest acquired error of renal chromatin degradation due to the loss of renal DNaseI enzyme activity is an important contributing factor to the development of lupus nephritis in lupus-prone (NZBxNZW)F1 mice and in patients with lupus nephritis. Down-regulation of DNaseI expression results in reduced chromatin fragmentation and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals who produce IgG anti-chromatin autoantibodies. The main focus of the present review is to discuss whether exposed chromatin fragments in glomeruli are targeted by potentially nephritogenic anti-dsDNA autoantibodies or if the nephritogenic activity of these autoantibodies is explained by cross-reaction with intrinsic glomerular constituents or if both models coexist in diseased kidneys. In addition, the role of silencing of the renal DNaseI gene and the biological consequences of reduced chromatin fragmentation in nephritic kidneys are discussed.


Cloning the interleukin 1 receptor from human T cells.
cDNA clones of the interleukin 1 (IL-1) receptor expressed in a human T-cell clone have been isolated by using a murine IL-1 receptor cDNA as a probe. The human and mouse receptors show a high degree of sequence conservation. Both are integral membrane proteins possessing a single membrane-spanning segment. Similar to the mouse receptor, the human IL-1 receptor contains a large cytoplasmic region and an extracellular, IL-1 binding portion composed of three immunoglobulin-like domains. When transfected into COS cells, the human IL-1 receptor cDNA clone leads to expression of two different affinity classes of receptors, with Ka values indistinguishable from those determined for IL-1 receptors in the original T-cell clone. An IL-1 receptor expressed in human dermal fibroblasts has also been cloned and sequenced and found to be identical to the IL-1 receptor expressed in T cells.


Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice.
Hepatic lipase (HL) has a well-established role in lipoprotein metabolism. However, its role in atherosclerosis is poorly understood. Here we demonstrate that HL deficiency raises the proatherogenic apoB-containing lipoprotein levels in plasma but reduces atherosclerosis in lecithin cholesterol acyltransferase (LCAT) transgenic (Tg) mice, similar to results previously observed with HL-deficient apoE-KO mice. These findings suggest that HL has functions that modify atherogenic risk that are separate from its role in lipoprotein metabolism. We used bone marrow transplantation (BMT) to generate apoE-KO and apoE-KO x HL-KO mice, as well as LCAT-Tg and LCAT-Tg x HL-KO mice, chimeric for macrophage HL gene expression. Using in situ RNA hybridization, we demonstrated localized production of HL by donor macrophages in the artery wall. We found that expression of HL by macrophages enhances early aortic lesion formation in both apoE-KO and LCAT-Tg mice, without changing the plasma lipid profile, lipoprotein lipid composition, or HL and lipoprotein lipase activities. HL does, however, enhance oxidized LDL uptake by peritoneal macrophages. These combined data demonstrate that macrophage-derived HL significantly contributes to early aortic lesion formation in two independent mouse models and identify a novel mechanism, separable from the role of HL in plasma lipoprotein metabolism, by which HL modulates atherogenic risk in vivo.


GDF15/MIC1 and MMP9 Cerebrospinal Fluid Levels in Parkinson's Disease and Lewy Body Dementia.
Based on animal and ex-vivo experiments, Growth/Differentiation Factor-15 (GDF15, also called Macrophage Inhibitory Cytokine-1, MIC1), a member of the transforming growth factor-beta family, and Matrix Metalloproteinase-9 (MMP9), a member of the matrix metalloprotease family may be potential markers for Lewy body disorders, i.e. Parkinson's disease with (PDD) and without dementia (PDND) and Lewy body dementia (DLB). GDF15 has a prominent role in development, cell proliferation, differentiation, and repair, whereas MMP9 degrades, as a proteolytic enzyme, components of the extracellular matrix. In this study, cerebrospinal fluid GDF15 and MMP9 levels of 59 PDND, 17 PDD and 23 DLB patients, as well as of 95 controls were determined, and associated with demographic, clinical and biochemical parameters. Our analysis confirmed the already described association of GDF15 levels with age and gender. Corrected GDF15 levels were significantly higher in PDD than in PDND patients, and intermediate in DLB patients. Within Lewy body disorders, GDF15 levels correlated positively with age at onset of Parkinsonism and dementia, Hoehn & Yahr stage and cerebrospinal fluid t-Tau and p-Tau levels, and negatively with the Mini Mental State Examination. Remarkably, it does not relevantly correlate with disease duration. MMP9 was not relevantly associated with any of these parameters. Cerebrospinal GDF15, but not MMP9, may be a potential marker of and in Lewy body disorders.


A new entity: Chiari Zero malformation and its surgical method.
Recently, Iskandar et al described "Chiari Zero malformation" to characterize some kind of syringomyelia that exhibits classic Chiari-type symptoms with little to no herniation, but there is some dilemma about whether it is actually present. We presented a 38-year-old-man with a diagnosis of cervical syringomyelia. In his neurological examination, there was monoparesia at the left leg together with hypoesthesia below thoracal 7. He had initially been treated with syringopleural shunting successfully. Nine months after surgery, his syringomyelia had regrown and he clinically deteriorated. It was accepted as "a Chiari zero malformation". We performed craniovertebral decompression only. Although there was no tonsillar herniation, his syringomyelia was completely resolved and his neurological status was improved six months after the craniovertebral decompression, This case suggested that "Chiari zero malformation" description is remarkable and craniovertebral decompression is a suitable surgical approach for this entity.


CO adsorption, oxidation and carbonate formation mechanisms on Fe3O4 surfaces.
By means of density functional theory calculations that account for the on-site Coulomb interaction via a Hubbard term (DFT+U), we systematically investigated CO adsorption on Fe3O4 surfaces at different coverages. It has been found that more than one CO can coadsorb on one surface iron atom on both Fetet1 and Feoct2 terminations of Fe3O4(111). The uncapped oxygen atom is the active site for CO oxidation on both Fetet1 and Feoct2 terminations of Fe3O4(111). For Fe3O4(110), two CO molecules prefer to coadsorb on one surface iron atom on the A layer; CO prefers to adsorb at the bridge site of the surface octahedral iron atoms at low coverage, while CO prefers to adsorb at the surface tetrahedral iron atom at high coverage on the B layer. It has been found that the surface oxygen atom which is not coordinated to the tetrahedral iron atom is the active site for CO oxidation on the B termination of Fe3O4(001). On the Fe3O4 surfaces, the formation of carbonate has been found to be very stable thermodynamically, which agrees well with experiments. The adsorption mechanism has been analyzed on the basis of projected density of states (PDOS).


SNP discovery and haplotype analysis in the segmentally duplicated DRD5 coding region.
The dopamine receptor 5 gene (DRD5) holds much promise as a candidate locus for contributing to neuropsychiatric disorders and other diseases influenced by the dopaminergic system, as well as having potential to affect normal behavioral variation. However, detailed analyses of this gene have been complicated by its location within a segmentally duplicated chromosomal region. Microsatellites and SNPs upstream from the coding region have been used for association studies, but we find, using bioinformatics resources, that these markers all lie within a previously unrecognized second segmental duplication (SD). In order to accurately analyze the DRD5 locus for polymorphisms in the absence of contaminating pseudogene sequences, we developed a fast and reliable method for sequence analysis and genotyping within the DRD5 coding region. We employed restriction enzyme digestion of genomic DNA to eliminate the pseudogenes prior to PCR amplification of the functional gene. This approach allowed us to determine the DRD5 haplotype structure using 31 trios and to reveal additional rare variants in 171 unrelated individuals. We clarify the inconsistencies and errors of the recorded SNPs in dbSNP and HapMap and illustrate the importance of using caution when choosing SNPs in regions of suspected duplications. The simple and relatively inexpensive method presented herein allows for convenient analysis of sequence variation in DRD5 and can be easily adapted to other duplicated genomic regions in order to obtain good quality sequence data.


Conditions for polarization elements to be dichroic and birefringent.
The polarization of light when it passes through optical media can change as a result of change in the amplitude (dichroism) or phase shift (birefringence) of the electric vector. The anisotropic properties of media can be determined from these two optical features. We derive the conditions required for polarization elements to be dichroic and birefringent. Our derivation starts from commonly accepted assumptions for dichroism and birefringence. Our main conclusions are that (i) the generalized Jones matrix for dichroic elements has in general nonorthogonal eigenpolarizations and (ii) in the general case, the birefringent and dichroic properties of polarization elements have no direct association with the corresponding phase and dichroic polar forms derived in the polar decomposition of the polarization elements' Jones matrices.


The effect of neonatal vitamin A supplementation on morbidity and mortality at 12 months: a randomized trial.
: Neonatal vitamin A supplementation (NVAS) is an intervention hypothesized to reduce infant morbidity and mortality. The objective of this study was to assess the efficacy of neonatal vitamin A supplementation in reducing infant morbidity and mortality and assess potential sources of heterogeneity of the effect of NVAS. : We completed an individually randomized, double-blind, placebo-controlled trial in Tanzania. Infants were randomized within 3 days of birth to a single dose of vitamin A (50 000 IU) or placebo. We assessed infants at 1 and 3 days after supplementation, as well as 1, 3, 6 and 12 months after supplementation. We included all live births in the analysis and used relative risks (RR) and 95% confidence intervals (CI) to assess the risks of mortality and hospitalization by 12 months. We used general estimating equations to assess the incidence of morbidities during infancy. : A total of 31 999 infants were enrolled in the study between August 2010 and March 2013. At 12 months, vitamin A did not reduce all-cause infant mortality (RR 1.04; 95% CI 0.92-1.16), nor affect hospitalization (RR 1.09; 95% CI 0.97-1.22) or all-cause morbidity (RR 1.00; 95% CI 0.96-1.05). Postpartum maternal vitamin A supplementation modified the effect of neonatal vitamin A supplementation on mortality at 12 months ( P -value, test for interaction = 0.04). Among infants born to women who received a mega-dose of vitamin A after delivery, NVAS appeared to increase the risk of death (RR 1.12; 95% CI 0.98-1.29), whereas the risk of death among infants born to women who did not receive a mega-dose was reduced (RR 0.86; 95% CI 0.70-1.06). We noted no modification of the effect of NVAS by infant gender, birthweight or maternal HIV status. : NVAS did not affect the risk of death or incidence of common childhood morbidities. However, this study sheds light on potential sources of heterogeneity of the effect of neonatal vitamin A supplementation which should be further examined in a pooled analysis of all NVAS trials.


Epidemiology of severe childhood eye injuries that required hospitalisation.
We conducted a retrospective study of all paediatric ocular injuries that were treated at the Prince of Wales Hospital between October 1991 and January 1997. Of the 60 injuries reviewed, eight (13.3%) resulted in some degree of visual deficit. The mean age was 5.5 years and the average male to female ratio was 2.75:1. The distribution of injuries was as follows: contusions, 29 (48.3%); non-penetrating lacerations, 14 (23.3%); penetrating lacerations, six (10.0%); chemical burns, six (10%) and superficial foreign bodies, five (8.3%). Thirteen (21.7%) ocular injuries were associated with common household items, seven (11.7%) injuries were due to toy gun pellets, and five (8.3%) injuries were sports-related. A total of 28 operations were performed on 21 patients, and the mean duration of hospital stay was 3.6 days. The visual outcome depended mainly on the type and severity of the injury. Some childhood eye injuries are preventable by means of more public education, improved safety measures, and closer adult supervision.


Hepatocellular carcinoma at the University of Puerto Rico Liver Transplant Clinic.
The aim of this study was to determine the prevalence of hepatocellular carcinoma (HCC) in our liver transplant clinic, and describe the risk factors, predictors and treatment outcomes of primary liver cancer. 459 of 469 records of patients attending the UPR Liver Transplant Clinic from September 1999 to January 2005 were reviewed. Frequency distributions were computed to describe the study group. 35 patients (7%) were included. 33 patients were diagnosed during the pre-transplant evaluation and 2 were diagnosed in the explant. Mean age at diagnosis in males was 54.5 years and 61.3 years in females. The main cause of liver disease was hepatitis C plus ethanolism in 42.9% (15 cases). The frequency of HCC in patients with a BMI > or = 25 Kg/m2 was more than twice that of patients with a BMI < 25 Kg/m2. Predominant presenting symptoms were ascites (40%), abdominal pain and jaundice (25%). Normal alpha-fetoprotein was found in 25%. 76% had a MELD score < 20. Treatment modalities included trans-arterial embolization (TAE/TACE) (49%), conservative treatment (34%), liver transplant (OLT, 23%), partial resection (9%) and systemic chemotherapy (3%). Eight patients underwent OLT and one developed primary graft failure, needing a second transplant. Two had T1N0M0 score, with a 100% survival at 2 yrs, and 6 patients had a T2N0M0 score, 5 of which underwent TAE before OLT, with an overall survival of 67%. Partial resection had an overall survival of 66%. The population of our clinic is similar in gender and age distribution, etiology of chronic liver disease, and clinical presentation of HCC to other studies previously described. The treatment outcomes and mortality rates compare with those observed in the literature.


Crushing hope: Short term responses to tragedy vary by hopefulness.
This paper explores the consequences of hopefulness when the environment changes. Much literature has documented the importance of a positive outlook in pursuing investments in health and education that pay off in the future. A question that has received less attention is whether a positive outlook creates resilience in the face of setbacks or whether a positive outlook may be a disadvantage in extreme circumstances, especially when there is a large mismatch between expectations and reality. This paper uses the coincidental interview schedule of the Add Health data (N = 15,024) around the terrorist attack of September 11, 2001 to examine interactions with this environmental shock and previously elicited measures of hopefulness. The results suggest that increases in depressive symptoms following the attack are concentrated among those young adults who initially expressed the most hopefulness in the future as teenagers.


Improved efficiency of bulk heterojunction hybrid solar cells by utilizing CdSe quantum dot-graphene nanocomposites.
We present a significant efficiency enhancement of hybrid bulk heterojunction solar cells by utilizing CdSe quantum dots attached to reduced graphene oxide (rGO) as the electron accepting phase, blended with the PCPDTBT polymer. The quantum dot attachment to rGO was achieved following a self-assembly approach, recently developed, using thiolated reduced graphene oxide (TrGO) to form a TrGO-CdSe nanocomposite. Therefore, we are able to obtain TrGO-CdSe quantum dot/PCPDTBT bulk-heterojunction hybrid solar cells with power conversion efficiencies of up to 4.2%, compared with up to 3% for CdSe quantum dot/PCPDTBT devices. The improvement is mainly due to an increase of the open-circuit voltage from 0.55 V to 0.72 V. We found evidence for a significant change in the heterojunction donor-acceptor blend nanomorphology, observable by a more vertical alignment of the TrGO-quantum dot nanocomposites in the z-direction and a different nanophase separation in the x-y direction compared to the quantum dot only containing device. Moreover, an improved charge extraction and trap state reduction were observed for TrGO containing hybrid solar cells.


Ftm is a novel basal body protein of cilia involved in Shh signalling.
In this study we show in mice that Ftm (Rpgrip1l) is located at the ciliary basal body. Our data reveal that Ftm is necessary for developmental processes such as the establishment of left-right asymmetry and patterning of the neural tube and the limbs. The loss of Ftm affects the ratio of Gli3 activator to Gli3 repressor, suggesting an involvement of Ftm in Shh signalling. As Ftm is not essential for cilia assembly but for full Shh response, Ftm can be considered as a novel component for cilium-related Hh signalling. Furthermore, the absence of Ftm in arthropods underlines the divergence between vertebrate and Drosophila Hh pathways.


Modulation of the immune system and the response against pathogens with bovine colostrum concentrates.
The growth, development and health conditions for children living under deprived conditions in developing countries are so adverse that immediate public health measures to reduce morbidity and improve nutrition are urgently needed. Preventing and shortening the course of diarrhoeal episodes, eliminating protozoal colonization, and balancing intestinal microflora would all contribute to these goals. The consumption by humans of part of the colostrum produced when a dairy animal gives birth is an established tradition in many traditional societies. Recent advances in food technology in industrial dairying allow for continuous availability of stabilized bovine colostrum concentrate, both natural and hyperimmunized against specific human pathogens. This is safe for the calves of the producers themselves, for laboratory animals, and generally for humans, with the caveat of the milk-allergic. Moreover, substantial amounts of orally ingested bovine colostrum concentrate survive their passage through the stomach to remain intact and active in the lower reaches of the bowel. Studies in animals, human volunteers and naturally infected humans have demonstrated a therapeutic efficacy of oral bovine colostrum with certain infections. Similarly, attempts to prevent gastrointestinal infections in animals, exposed volunteers and at-risk populations have met with limited success with specific pathogens. It is time to begin to assess the feasibility and potential effectiveness and efficiency of employing seasonal or chronic bovine colostrum feeding in populations of deprived infantile populations to reduce the rates of recurrent gastroenteritis and decrease immunostimulation to improve vitality and nutritional status in early life.


Clinicopathologic findings predictive of relapse in children with stage III favorable-histology Wilms tumor.
Stage III designation in NWTS-5 (National Wilms Tumor Study-5) was determined by four pathologic criteria: positive lymph nodes (LNs), peritoneal implants, residual disease, and tumor rupture. The objective of this study was to determine the prognostic significance of each of the stage III criteria. Children with stage III Wilms tumor (WT) treated in NWTS-5 were assessed for event-free (EFS) and overall survival (OS). Sites of relapse and molecular status of tumors are reported. EFS and OS are reported 8 years after diagnosis. There were 569 patients with local stage III favorable-histology (FH) WT in this analysis, of whom 109 had overall stage IV disease. LN involvement alone was the most frequent criterion for stage III designation (38%), followed by microscopic residual disease alone (20%), microscopic residual disease and LN involvement (14%), and spill or soilage alone (9%). The 8-year EFS and OS estimates for all patients with local stage III FHWT were 82% and 91%, respectively. Multivariate analysis demonstrated that both LN involvement (relative risk, 1.89; P = .005) and microscopic residual disease (relative risk, 1.87; P = .007) were predictive of EFS, and OS results were similar. There was no apparent difference in pattern of relapse according to stage III subtype. The rate of loss of heterozygosity was higher (6%) for those with positive LNs than for those without (2%; P = .05). LN involvement and microscopic residual are the stage III criteria highly predictive of EFS and OS for patients with stage III FHWT. It is possible that in future studies, patients with different stage III criteria may receive different therapies.


Intrahospital transport of critically ill patients.
This review on the current literature of the intrahospital transport of critically ill patients addresses type and incidence of adverse effects, risk factors and risk assessment, and the available information on efficiency and cost-effectiveness of transferring such patients for diagnostic or therapeutic interventions within hospital. Methods and guidelines to prevent or reduce potential hazards and complications are provided. A Medline search was performed using the terms 'critical illness', 'transport of patients', 'patient transfer', 'critical care', 'monitoring' and 'intrahospital transport', and all information concerning the intrahospital transport of patients was considered. Adverse effects may occur in up to 70% of transports. They include a change in heart rate, arterial hypotension and hypertension, increased intracranial pressure, arrhythmias, cardiac arrest and a change in respiratory rate, hypocapnia and hypercapnia, and significant hypoxaemia. No transport-related deaths have been reported. In up to one-third of cases mishaps during transport were equipment related. A long-term deterioration of respiratory function was observed in 12% of cases. Patient-related risk indicators were found to be a high Therapeutic Intervention Severity Score, mechanical ventilation, ventilation with positive end-expiratory pressure and high injury severity score. Patients' age, duration of transport, destination of transport, Acute Physiology and Chronic Health Evaluation II score, personnel accompanying the patient and other factors were not found to correlate with an increased rate of complications. Transports for diagnostic procedures resulted in a change in patient management in 40-50% of cases, indicating a good risk:benefit ratio. To prevent adverse effects of intrahospital transports, guidelines concerning the organization of transports, the personnel, equipment and monitoring should be followed. In particular, the presence of a critical care physician during transport, proper equipment to monitor vital functions and to treat such disturbances immediately, and close control of the patient's ventilation appear to be of major importance. It appears useful to use specifically constructed carts including standard intensive care unit ventilators in a selected group of patients. To further reduce the rate of inadvertent mishaps resulting from transports, alternative diagnostic modalities or techniques and performing surgical procedures in the intensive care unit should be considered.


The infectious particle of insect-borne totivirus-like Omono River virus has raised ridges and lacks fibre complexes.
Omono River virus (OmRV) is a double-stranded RNA virus isolated from Culex mosquitos, and it belongs to a group of unassigned insect viruses that appear to be related to Totiviridae. This paper describes electron cryo-microscopy (cryoEM) structures for the intact OmRV virion to 8.9 Å resolution and the structure of the empty virus-like-particle, that lacks RNA, to 8.3 Å resolution. The icosahedral capsid contains 120-subunits and resembles another closely related arthropod-borne totivirus-like virus, the infectious myonecrosis virus (IMNV) from shrimps. Both viruses have an elevated plateau around their icosahedral 5-fold axes, surrounded by a deep canyon. Sequence and structural analysis suggests that this plateau region is mainly composed of the extended C-terminal region of the capsid proteins. In contrast to IMNV, the infectious form of OmRV lacks extensive fibre complexes at its 5-fold axes as directly confirmed by a contrast-enhancement technique, using Zernike phase-contrast cryo-EM. Instead, these fibre complexes are replaced by a short "plug" structure at the five-fold axes of OmRV. OmRV and IMNV have acquired an extracellular phase, and the structures at the five-fold axes may be significant in adaptation to cell-to-cell transmission in metazoan hosts.


Plastic ingestion in aquatic-associated bird species in southern Portugal.
Excessive use of plastics in daily life and the inappropriate disposal of plastic products are severely affecting wildlife species in both coastal and aquatic environments. Birds are top-predators, exposed to all threats affecting their environments, making them ideal sentinel organisms for monitoring ecosystems change. We set a baseline assessment of the prevalence of marine plastic litter affecting multi-species populations of aquatic birds in southern Portugal. By examining 160 stomach contents from 8 species of aquatic birds, we show that 22.5% were affected by plastic debris. Plastic was found in Ciconia ciconia, Larus fuscus and L. michahellis. Ciconia ciconia ingested the highest amount (number of items and total mass) of plastic debris. Polydimethylsiloxane (PDMS, silicones) was the most abundant polymer and was recorded only in C. ciconia. Plastic ingestion baseline data are of crucial importance to evaluate changes through time and among regions and to define management and conservation strategies.


Induced vertical disparity effects on local and global stereopsis.
Although significant amounts of vertical misalignment could have a noticeable effect on visual performance, there is no conclusive evidence about the effect of very small amount of vertical disparity on stereopsis and binocular vision. Hence, the aim of this study was to investigate the effects of induced vertical disparity on local and global stereopsis at near. Ninety participants wearing best-corrected refraction had local and global stereopsis tested with 0.5 and 1.0 prism diopter (Δ) vertical prism in front of their dominant and non-dominant eye in turn. This was compared to local and global stereopsis in the same subjects without vertical prism. Data were analyzed in SPSS.17 software using the independent samples T and the repeated measures ANOVA tests. Induced vertical disparity decreases local and global stereopsis. This reduction is greater when vertical disparity is induced in front of the non-dominant eye and affects global more than local stereopsis. Repeated measures ANOVA showed differences in the mean stereopsis between the different measured states for local and global values. Local stereopsis thresholds were reduced by 10 s of arc or less on average with 1.0Δ of induced vertical prism in front of either eye. However, global stereopsis thresholds were reduced by over 100 s of arc by the same 1.0Δ of induced vertical prism. Induced vertical disparity affects global stereopsis thresholds by an order of magnitude (or a factor of 10) more than local stereopsis. Hence, using a test that measures global stereopsis such as the TNO is more sensitive to vertical misalignment than a test such as the Stereofly that measures local stereopsis.


The effect of a low-frequency sound source (acoustic thermometry of the ocean climate) on the diving behavior of juvenile northern elephant seals, Mirounga angustirostris.
Changes in the diving behavior of individual free-ranging juvenile northern elephant seals, Mirounga angustirostris, exposed to the acoustic thermometry of the ocean climate (ATOC) sound source were examined using data loggers. Data loggers were attached to the animals and measured swim speed, maximum depth of dive, dive duration, surface interval, descent and ascent rate, and descent and ascent angle along with sound pressure level (SPL). The ATOC sound source was at a depth of 939 m and transmitted at 195 dB re: 1 microPa at 1 m centered at 75 Hz with a 37.5-Hz bandwidth. Sound pressure levels (SPL) measured at the seal during transmissions averaged 128 dB and ranged from 118 to 137 dB re: 1 microPa for the 60-90 Hz band, in comparison to ambient levels of 87-107 dB within this band. In no case did an animal end its dive or show any other obvious change in behavior upon exposure to the ATOC sound. Subtle changes in diving behavior were detected, however. During exposure, deviations in descent rate were greater than 1 s.d. of the control mean in 9 of 14 seals. Dive depth increased and descent velocity increased in three animals, ascent velocity decreased in two animals, ascent rate increased in one animal and decreased in another, and dive duration decreased in only one animal. There was a highly significant positive correlation between SPL and descent rate. The biological significance of these subtle changes is likely to be minimal. This is the first study to quantify behavioral responses of an animal underwater with simultaneous measurements of SPL of anthropogenic sounds recorded at the animal.


The Adenoid Microbiome in Recurrent Acute Otitis Media and Obstructive Sleep Apnea.
To compare the microbial flora of adenoids from patients with recurrent acute otitis media (AOM) and patients with obstructive sleep apnea (OSA). This study was prospective and controlled. Adenoids were obtained from children undergoing adenoidectomy for recurrent AOM (n=7) or OSA (n=13). Specimens were processed for total deoxyribonucleic acid (DNA) isolation. 16s DNA 454-pyrosequencing was performed on AOM (n=5) and OSA (n=5) specimens. All specimens were analyzed by real-time polymerase chain reaction for the quantification of the oral commensal bacteria, Streptococcus salivarius. All adenoid specimens had evidence of microbes. Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus were among the dominant species in all samples. S. salivarius, Prevotella sp. and Terrahaemophilus aromaticivorans were more common on adenoids from OSA patients (p<0.05). Bradyrhizobium sp. was more common on adenoids from patients with recurrent AOM (p<0.05). The microbial profiles associated with recurrent AOM were different from, but overlapped with OSA. S. salivarius quantified by real-time PCR was not different between the two groups. Microbes are present on all adenoid specimens, though the microbial profile differs between recurrent AOM and OSA. The clinical significance of these differences remains to be determined.


Transcriptome analysis of rice root heterosis by RNA-Seq.
Heterosis is a phenomenon in which hybrids exhibit superior performance relative to parental phenotypes. In addition to the heterosis of above-ground agronomic traits on which most existing studies have focused, root heterosis is also an indispensable component of heterosis in the entire plant and of major importance to plant breeding. Consequently, systematic investigations of root heterosis, particularly in reproductive-stage rice, are needed. The recent advent of RNA sequencing technology (RNA-Seq) provides an opportunity to conduct in-depth transcript profiling for heterosis studies. Using the Illumina HiSeq 2000 platform, the root transcriptomes of the super-hybrid rice variety Xieyou 9308 and its parents were analyzed at tillering and heading stages. Approximately 391 million high-quality paired-end reads (100-bp in size) were generated and aligned against the Nipponbare reference genome. We found that 38,872 of 42,081 (92.4%) annotated transcripts were represented by at least one sequence read. A total of 829 and 4186 transcripts that were differentially expressed between the hybrid and its parents (DGHP) were identified at tillering and heading stages, respectively. Out of the DGHP, 66.59% were down-regulated at the tillering stage and 64.41% were up-regulated at the heading stage. At the heading stage, the DGHP were significantly enriched in pathways related to processes such as carbohydrate metabolism and plant hormone signal transduction, with most of the key genes that are involved in the two pathways being up-regulated in the hybrid. Several significant DGHP that could be mapped to quantitative trait loci (QTLs) for yield and root traits are also involved in carbohydrate metabolism and plant hormone signal transduction pathways. An extensive transcriptome dataset was obtained by RNA-Seq, giving a comprehensive overview of the root transcriptomes at tillering and heading stages in a heterotic rice cross and providing a useful resource for the rice research community. Using comparative transcriptome analysis, we detected DGHP and identified a group of potential candidate transcripts. The changes in the expression of the candidate transcripts may lay a foundation for future studies on molecular mechanisms underlying root heterosis.


Improved targeting of photosensitizers by intratumoral administration of immunoconjugates.
Biodistribution of technetium (99mTc) labeled hematoporphyrin derivative (HpD, Photosan-3) conjugated to a monoclonal antibody to carcinoembryonic antigen (anti-CEA) was compared following intravenous (i.v.) and intratumoral (i.t.) administration in solid Ehrlich ascites tumor bearing mice. Images of mice at different time intervals were acquired after injection of radiolabeled PS-3 in either conjugated or unconjugated forms. Quantitative estimation of the radiolabel in different tissues was performed by selecting the different region of interests (ROIs). Maximum accumulation of both free and antibody conjugated PS-3 following i.v. administration was observed in liver followed by tumor. Tumor/muscle (T/N) ratio was more with free PS-3 compared to conjugated PS-3. Pharmacokinetics of free and conjugated PS-3 was also different with faster accumulation of conjugated PS-3 in the tumor. With intratumoral administration of anti-CEA-PS-3-99mTc, specific accumulation and retention of the sensitizer was observed in the tumor tissue. Since, direct injection of antibody conjugated photosensitizer into the tumor resulted in longer retention of the dye in the tumor with no accumulation in the normal tissues, the present results imply that the toxicity to normal tissues could be reduced significantly with selective destruction of the tumor following photodynamic treatment with the use of i.t. administration of specific antibodies conjugated to photosensitizers.


Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection.
Neonatal infections are frequent complications of extremely low-birth-weight (ELBW) infants receiving intensive care. To determine if neonatal infections in ELBW infants are associated with increased risks of adverse neurodevelopmental and growth sequelae in early childhood. Infants weighing 401 to 1000 g at birth (born in 1993-2001) were enrolled in a prospectively collected very low-birth-weight registry at academic medical centers participating in the National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth outcomes were assessed at a comprehensive follow-up visit at 18 to 22 months of corrected gestational age and compared by infection group. Eighty percent of survivors completed the follow-up visit and 6093 infants were studied. Registry data were used to classify infants by type of infection: uninfected (n = 2161), clinical infection alone (n = 1538), sepsis (n = 1922), sepsis and necrotizing enterocolitis (n = 279), or meningitis with or without sepsis (n = 193). Cognitive and neuromotor development, neurologic status, vision and hearing, and growth (weight, length, and head circumference) were assessed at follow-up. The majority of ELBW survivors (65%) had at least 1 infection during their hospitalization after birth. Compared with uninfected infants, those in each of the 4 infection groups were significantly more likely to have adverse neurodevelopmental outcomes at follow-up, including cerebral palsy (range of significant odds ratios [ORs], 1.4-1.7), low Bayley Scales of Infant Development II scores on the mental development index (ORs, 1.3-1.6) and psychomotor development index (ORs, 1.5-2.4), and vision impairment (ORs, 1.3-2.2). Infection in the neonatal period was also associated with impaired head growth, a known predictor of poor neurodevelopmental outcome. This large cohort study suggests that neonatal infections among ELBW infants are associated with poor neurodevelopmental and growth outcomes in early childhood. Additional studies are needed to elucidate the pathogenesis of brain injury in infants with infection so that novel interventions to improve these outcomes can be explored.


Eggshell particle-reinforced hydrogels for bone tissue engineering: an orthogonal approach.
Hydrogel-based biomimetic scaffolds have generated broad interest due to their tunable physical, chemical, and biological properties for bone tissue engineering applications. We fabricated eggshell microparticle (ESP) reinforced gelatin-based hydrogels to obtain mechanically stable and biologically active three-dimensional (3D) constructs that can differentiate pre-mature cells into osteoblasts. Physical properties including swelling ratio, degradation, and mechanical properties of the composite hydrogels were investigated. Pre-osteoblasts were encapsulated within the ESP-reinforced hydrogels to study their differentiation and evaluate mineral deposition by these cells. The ESP-reinforced gels were then subcutaneously implanted in a rat model to determine their biocompatibility and degradation behaviors. The composite hydrogels have shown outstanding tunability in physical and biological properties holding substantial promise for engineering mineralized tissues (e.g. bone, cartilage, tooth, and tendon). These 3D scaffolds enabled the differentiation of pre-osteoblasts without the use of specialized osteogenic growth medium. The ESP-reinforced gels exhibited significant enhancement in mineralization by pre-osteoblasts. These behaviors are positively correlated with increasing concentrations of ESP. Findings suggest that our novel composite hydrogel exhibits superior mechanical properties and indicates a favorable in vivo response by subcutaneous implantation in a rat model.


The evolution of male traits in social insects.
Pair formation in social insects mostly happens early in adult life and away from the social colony context, which precludes promiscuity in the usual sense. Termite males have continuous sperm production, but males of social Hymenoptera have fixed complements of sperm, except for a few species that mate before female dispersal and show male-fighting and lifelong sperm production. We develop an evolutionary framework for testing sexual selection and sperm competition theory across the advanced eusocial insects (ants, wasps, bees, termites) and highlight two areas related to premating sexual selection (sexual dimorphism and male mate number) that have remained understudied and in which considerable progress can be achieved with relatively simple approaches. We also infer that mating plugs may be relatively common, and we review further possibilities for postmating sexual selection, which gradually become less likely in termite evolution, but for which eusocial Hymenoptera provide unusual opportunities because they have clonal ejaculates and store viable sperm for up to several decades.


Exposure to perfluoroalkyl substances and longitudinal changes in bone mineral density in adolescents and young adults: A multi-cohort study.
Per- and polyfluoroalkyl substances (PFAS) may impair bone development in adolescence, which impacts life-long bone health. No previous studies have examined prospective associations of individual PFAS and their mixture with bone mineral density (BMD) changes in Hispanic young persons, a population at high risk of osteoporosis in adulthood. To examine associations of individual PFAS and PFAS mixtures with longitudinal changes in BMD in an adolescent Hispanic cohort and examine generalizability of findings in a mixed-ethnicity young adult cohort (58.4% Hispanic). Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; n = 304; mean follow-up = 1.4 years) and young adults from the Southern California Children's Health Study (CHS; n = 137; mean follow-up = 4.1 years) were included in this study. Plasma PFAS were measured at baseline and dual x-ray absorptiometry scans were performed at baseline and follow-up to measure BMD. We estimated longitudinal associations between BMD and five PFAS via separate covariate-adjusted linear mixed effects models, and between BMD and the PFAS mixture via quantile g-computation. In SOLAR adolescents, baseline plasma perfluorooctanesulfonic acid (PFOS) was associated with longitudinal changes in BMD. Each doubling of PFOS was associated with an average -0.003 g/cm2 difference in change in trunk BMD per year over follow-up (95% CI: -0.005, -0.0002). Associations with PFOS persisted in CHS young adults, where each doubling of plasma PFOS was associated with an average -0.032 g/cm2 difference in total BMD at baseline (95% CI -0.062, -0.003), though longitudinal associations were non-significant. We did not find associations of other PFAS with BMD; associations of the PFAS mixture with BMD outcomes were primarily negative though non-significant. PFOS exposure was associated with lower BMD in adolescence and young adulthood, important periods for bone development, which may have implications on future bone health and risk of osteoporosis in adulthood.


Inconsistencies in TTO and VAS values for EQ-5D health states.
Most EQ-5D health states can be ordered logically. When people assign values to different health states, they may violate this logical order, which can be seen as inconsistencies. The aim of this study was to assess the effect of inconsistently valued EQ-5D health states on mean visual analog scale (VAS) and time trade-off (TTO) values. The authors also examined the effect of removing respondents with high numbers of inconsistent states on the estimation of tariffs, which is used to interpolate values to all possible EQ-5D states from the direct valuation of a subset of states. Data from the Dutch EQ-5D valuation study were used. A representative sample of 309 Dutch adults valued 17 EQ-5D health states by VAS and TTO. A state was valued inconsistently when it had a higher value than at least 1 logically better state. Mean values of groups with various numbers of inconsistently valued states were compared. Of the respondents, 65% had inconsistencies for VAS and 89% for TTO. The mean VAS values of consistent respondents tend to be lower. For TTO, those with inconsistencies gave lower values. Removing data of respondents with the highest number of inconsistently valued states for VAS (13%) and TTO (9%) did not result in statistically significant different coefficients in the estimated tariff using all data. The majority of respondents valued at least 1 state inconsistently. For both VAS and TTO, the presence of these inconsistencies did not affect the estimated tariffs.


Alterations in the vitamin D endocrine system during pregnancy: A longitudinal study of 855 healthy Norwegian women.
To ensure optimal calcium accrual in the fetal skeleton, a substantial rise occurs in 1,25-dihydroxyvitamin D (1,25(OH)2D), but is dependent on sufficient 25-hydroxyvitamin (25(OH)D). Large longitudinal studies addressing free 25(OH)D and 1,25(OH)2D during pregnancy are scarce. We aimed to assess levels of and relationship between 25(OH)D, 1,25(OH)2D, vitamin D-binding protein (DBP), parathyroid hormone (PTH), and free 25(OH)D during pregnancy; determinants of vitamin D status; and association between vitamin D indices or PTH and pregnancy outcomes (gestational diabetes mellitus and birthweight). Altogether 855 pregnant Norwegian Caucasian women from Trondheim and Stavanger (latitude 63°N and 58°N) were recruited; 94 were lost to follow-up. The study was originally a randomized controlled trial (2007-2009) with gestational diabetes as primary outcome. Data were collected in second and third trimester. In third trimester, 246 (34%) had vitamin D insufficiency and 52 (7%) deficiency (25(OH)D <50 and <30nmol/L, respectively). During wintertime in third trimester, 61 (47%) from Trondheim and 23 (51%) from Stavanger exhibited vitamin D insufficiency. PTH was elevated in 27 (3.7%). Estimate of change between trimesters was (95% CI): 25(OH)D -1.8 (-2.8 to -0.7) nmol/L, DBP 0.62 (0.57 to 0.66) μmol/L, calculated free 25(OH)D -1.7 (-2.0 to -1.4) pmol/L, PTH 0.81 (0.72 to 0.90) pmol/L, 1,25(OH)2D (sub-analysis) 31.4 (CI 24.7 to 38.2) pmol/L. A decrease in 1,25(OH)2D occurred in 45% of those with vitamin D deficiency, and they also exhibited lower levels than women with adequate vitamin D status. No association of vitamin D indices and PTH with pregnancy outcomes was observed. Women in Trondheim displayed lower 25(OH)D levels, despite minor latitudinal differences. Less than one-fifth adhered to the authorities' vitamin D recommendations. These findings demonstrate that hypovitaminosis D is prevalent among pregnant women living in northern latitudes, especially during the dark season, and there is an unmet need to ensure adequate vitamin D intake.


Microtubules and the endoplasmic reticulum are highly interdependent structures.
The interrelationships of the endoplasmic reticulum (ER), microtubules, and intermediate filaments were studied in the peripheral regions of thin, spread fibroblasts, epithelial, and vascular endothelial cells in culture. We combined a fluorescent dye staining technique to localize the ER with immunofluorescence to localize microtubules or intermediate filaments in the same cell. Microtubules and the ER are sparse in the lamellipodia, but intermediate filaments are usually completely absent. These relationships indicate that microtubules and the ER advance into the lamellipodia before intermediate filaments. We observed that microtubules and tubules of the ER have nearly identical distributions in lamellipodia, where new extensions of both are taking place. We perturbed microtubules by nocodazole, cold temperature, or hypotonic shock, and observed the effects on the ER distribution. On the basis of our observations in untreated cells and our experiments with microtubule perturbation, we conclude that microtubules and the ER are highly interdependent in two ways: (a) polymerization of individual microtubules and extension of individual ER tubules occur together at the level of resolution of the fluorescence microscope, and (b) depolymerization of microtubules does not disrupt the ER network in the short term (15 min), but prolonged absence of microtubules (2 h) leads to a slow retraction of the ER network towards the cell center, indicating that over longer periods of time, the extended state of the entire ER network requires the microtubule system.


Disruption of an RNA-binding hinge region abolishes LHP1-mediated epigenetic repression.
Epigenetic maintenance of gene repression is essential for development. Polycomb complexes are central to this memory, but many aspects of the underlying mechanism remain unclear. LIKE HETEROCHROMATIN PROTEIN 1 (LHP1) binds Polycomb-deposited H3K27me3 and is required for repression of many Polycomb target genes in Arabidopsis Here we show that LHP1 binds RNA in vitro through the intrinsically disordered hinge region. By independently perturbing the RNA-binding hinge region and H3K27me3 (trimethylation of histone H3 at Lys27) recognition, we found that both facilitate LHP1 localization and H3K27me3 maintenance. Disruption of the RNA-binding hinge region also prevented formation of subnuclear foci, structures potentially important for epigenetic repression.


dsRNA Molecules From the Tobacco Mosaic Virus p126 Gene Counteract TMV-Induced Proteome Changes at an Early Stage of Infection.
Exogenous application of double-stranded RNA (dsRNA) in the tobacco-Tobacco mosaic virus (TMV) pathosystem was shown previously to induce resistance against TMV providing an alternative approach to transgenesis. In the present study, we employed proteomics technology to elucidate the effect of TMV on tobacco as well as the effect of exogenous application of TMV p126 dsRNA molecules (dsRNAp126) at an early stage of the tobacco-TMV interaction. The proteome of tobacco leaf at 15 min post inoculation (mpi) in the presence or absence of dsRNAp126 molecules was studied. Thirty-six tobacco proteins were differentially accumulated in TMV-infected vs. healthy tobacco leaf tissue. The identified main differential TMV-responsive proteins were found to be involved in photosynthesis, energy metabolism, stress, and defense responses. Most of the virus-induced changes in the tobacco leaf proteome were not observed in the leaves treated with dsRNAp126 + TMV. The results indicated that the protein changes induced by TMV infection were counteracted by the exogenous application of dsRNAp126 molecules. Moreover, using small RNA sequencing, we showed that the exogenously applied dsRNAp126 was efficiently processed in tobacco as early as 15 min post application (mpa) to produce small interfering RNAs (siRNAs); the dicing pattern was not affected by the presence of TMV. The presence of dsRNAp126 reduced TMV p126 RNA abundance suggesting virus titer reduction via a sequence-specific mechanism, since a non-homologous dsRNA did not protect from TMV infection nor affect TMV accumulation.


Meeting Report from the Genomic Standards Consortium (GSC) Workshops 6 and 7.
This report summarizes the proceedings of the 6th and 7th workshops of the Genomic Standards Consortium (GSC), held back-to-back in 2008. GSC 6 focused on furthering the activities of GSC working groups, GSC 7 focused on outreach to the wider community. GSC 6 was held October 10-14, 2008 at the European Bioinformatics Institute, Cambridge, United Kingdom and included a two-day workshop focused on the refinement of the Genomic Contextual Data Markup Language (GCDML). GSC 7 was held as the opening day of the International Congress on Metagenomics 2008 in San Diego California. Major achievements of these combined meetings included an agreement from the International Nucleotide Sequence Database Consortium (INSDC) to create a "MIGS" keyword for capturing "Minimum Information about a Genome Sequence" compliant information within INSDC (DDBJ/EMBL /Genbank) records, launch of GCDML 1.0, MIGS compliance of the first set of "Genomic Encyclopedia of Bacteria and Archaea" project genomes, approval of a proposal to extend MIGS to 16S rRNA sequences within a "Minimum Information about an Environmental Sequence", finalization of plans for the GSC eJournal, "Standards in Genomic Sciences" (SIGS), and the formation of a GSC Board. Subsequently, the GSC has been awarded a Research Co-ordination Network (RCN4GSC) grant from the National Science Foundation, held the first SIGS workshop and launched the journal. The GSC will also be hosting outreach workshops at both ISMB 2009 and PSB 2010 focused on "Metagenomics, Metadata and MetaAnalysis" (M(3)). Further information about the GSC and its range of activities can be found at http://gensc.org, including videos of all the presentations at GSC 7.


Wave speed and intensity in the canine aorta: analysis with and without the Windkessel-wave system.
The Windkessel model, coupled with the wave propagation theory, was applied to data measured in the ascending aorta of 11 anaesthetised dogs during total aortic occlusion at the thoracic and diaphragm levels. Wave speed and wave intensity were calculated using the measured pressure (P) and velocity (U), and separately using the pressure due to the wave (P(ex)) and U in the aorta approximately 1 cm distal to the aortic valve. Results show that wave speed, determined using the PU-loop method, is higher during thoracic than in diaphragm occlusion (p<0.001). On average wave speed calculated using P (c) is higher than that determined using P(ex) (c(WK)) in both occlusion sites (p<0.001). During aortic occlusion at the thoracic level, the intensity of backward waves was almost negligible using the Windkessel-wave system. Backward waves were observed during the occlusion at the diaphragm level, but their magnitude is lower compared to that determined with P. The Windkessel-wave system seems to reduce the magnitude of reflected waves during total aorta occlusion, notably if the occlusion sites are close to the ascending aorta.


Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system.
Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKCα. We therefore screened drugs for their potential to overcome this differentiation block. From our screening, tamoxifen emerges as a potent inducer of OPC differentiation in vitro. We show that the effects of tamoxifen rely on modulation of the estrogen receptors ERα, ERβ, and GPR30. Furthermore, we demonstrate that administration of tamoxifen to demyelinated rats in vivo accelerates remyelination. Tamoxifen is a well-established drug and is thus a promising candidate for a drug to regenerate myelin, as it will not require extensive safety testing. In addition, Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models. Our results highlight the importance of appropriate controls when using such models.


Effects of Chiropractic Care on Strength, Balance, and Endurance in Active-Duty U.S. Military Personnel with Low Back Pain: A Randomized Controlled Trial.
Objectives: To investigate whether chiropractic care influences strength, balance, and/or endurance in active-duty United States military personnel with low back pain (LBP). Design: This study employed a prospective randomized controlled trial using a pragmatic treatment approach. Participants were randomly allocated to 4 weeks of chiropractic care or to a wait-list control. Interventions: Chiropractic care consisted of spinal manipulation, education, advice, and reassurance. Settings/Location: Naval Air Technical Training Center branch clinic at the Naval Hospital Pensacola Florida. Subjects: One hundred ten active-duty military personnel 18-40 years of age with self-reported LBP. Outcome measures: Isometric pulling strength from a semisquat position was the primary outcome. Secondary outcomes were single-leg balance with eyes open and eyes closed, and trunk muscle endurance using the Biering-Sorensen test. Patient-reported outcomes such as pain severity and disability were also measured. Outcomes were measured at baseline and 4 weeks. Linear mixed-effects regression models over baseline and 4 weeks were used for analysis. Results: Participants had mean age of 30 years (18-40), 17% were female, 33% were non-white, and 86% reported chronic LBP. Mean maximum pulling strength in the chiropractic group increased by 5.08 kgs and decreased by 7.43 kgs in the wait-list group, with a statistically significant difference in mean change between groups (p = 0.003). Statistically significant differences in mean change between groups were also observed in trunk muscle endurance (13.9 sec, p = 0.002) and balance with eyes closed (0.47 sec, p = 0.01), but not in balance with eyes open (1.19 sec, p = 0.43). Differences in mean change between groups were statistically significant in favor of chiropractic for LBP-related disability, pain intensity and interference, and fear-avoidance behavior. Conclusions: Active-duty military personnel receiving chiropractic care exhibited improved strength and endurance, as well as reduced LBP intensity and disability, compared with a wait-list control.


Frozen Density Embedding with External Orthogonality in Delocalized Covalent Systems.
Frozen density embedding (FDE) has become a popular subsystem density functional theory (DFT) method for systems with weakly overlapping charge densities. The failure of this method for strongly interacting and covalent systems is due to the approximate kinetic energy density functional (KEDF), although the need for approximate KEDFs may be eliminated if each subsystem's Kohn-Sham (KS) orbitals are orthogonal to the other, termed external orthogonality (EO). We present an implementation of EO into the FDE framework within the Amsterdam density functional program package, using the level-shift projection operator method. We generalize this method to remove the need for orbital localization schemes and to include multiple subsystems, and we show that the exact KS-DFT energies and densities may be reproduced through iterative freeze-and-thaw cycles for a number of systems, including a charge delocalized benzene molecule starting from atomic subsystems. Finally, we examine the possibility of a truncated basis for systems with and without charge delocalization, and found that subsystems require a basis that allows them to correctly describe the supermolecular delocalized orbitals.


Acinetobacter spp. colonization and infection risk factors in surgical patients.
The results of numerous studies carried out over the last two decades have increasingly important cause of intrahospital infections (IHI). The aim of the study was to determine potential differences in distribution of individual risk factors between the group of patients in whom multiresistant Acinetobacter spp. was isolated and the group of patients in whom it was not. A prospective cohort study of 64 patients hospitalized with recorded IHI at the University Hospital for Digestive Surgery, Clinical Center of Serbia in the period between January and July 2011. The subjects were divided into two groups: patients with IHI in whom multiresistant Acinetobacter spp. was isolated from the biological material samples, and those with IHI without the presence of Acinetobacter spp. Univariate data analysis indicated presence of statistically significant difference in distribution of certain types of surgeries (esophageal, pancreatic and hepatobiliary) among the two groups of subjects, distribution of CVC placement, application of mechanical ventilation and nasogastric tube placement, length of stay in ICU, lethal outcomes and administration of third generation cephalosporins. The results of multivariate analysis indicated that length of hospitalization in ICU (> 7 days), CVC, mechanical ventilation, esophageal, pancreatic and hepatobiliary surgeries as well as administration of third generation cephalosporins are independent risk factors for colonization and infection of patients with Acinetobacter spp. Colonized or infected patients with Acinetobacter spp. play a major role in contamination of hands of the medical staff in the course of care and treatment, while inadequate hand hygiene of the staff leads to cross transmission of the causative organism to infection-free patients. Selective antibiotic pressure, particularly administration of quinolones and broad-spectrum cephalosporins, favor onset of multiresistant species of Acinetobacter spp., and therefore appropriate prophylaxis and treatment represent basic preventive measures against the onset and spreading of the causative organisms.


Prevalence of Generalized Ligamentous Laxity in Patients Undergoing Hip Arthroscopy: A Prospective Study of Patients' Clinical Presentation, Physical Examination, Intraoperative Findings, and Surgical Procedures.
Recent studies identified microinstability in the hip as a pathoetiology of painful hip conditions, and it was proposed that generalized ligamentous laxity conditions may predispose patients to such microinstability. To study the relationship of generalized ligamentous laxity with patient characteristics, clinical presentation, intraoperative findings, and surgical treatments in a cohort of patients undergoing hip arthroscopy. Cross-sectional study; Level of evidence, 3. Registry data were prospectively collected and retrospectively reviewed between February 2014 and November 2017 for patients who underwent primary hip arthroscopy and had a documented Beighton score to assess generalized ligamentous laxity. Patients with a history of an ipsilateral hip condition or ipsilateral hip surgery, those with Tönnis grade >1, and those who had simultaneous arthroscopic and open procedures were excluded from the study. Two comparisons were made between patients with low and high Beighton scores: Beighton 0 vs ≥1 (B 0 vs B ≥1) and Beighton 0-3 vs ≥4 (B 0-3 vs B ≥4). Patient demographics, symptomatology, physical examination, and intraoperative findings were compared between these low and high Beighton groups. A total of 1381 patients met our inclusion and exclusion criteria. Within this patient population, there were 882 with B 0, 499 with B ≥1, 1120 with B 0-3, and 261 with B ≥4. B 0 was 54.1% female, compared with 84.2% of B ≥1. Similarly, B 0-3 was 58.5% female, while B ≥4 was 92.7% female. The difference in sex makeup was significant between both sets of groups ( P < .0001). The relative risk of having B ≥1 for women versus men was 2.869, and the relative risk of having B ≥4 for women versus men was 6.873. The patients with higher Beighton scores in B ≥1 and B ≥4 had a younger mean age at onset of symptoms ( P < .0001) and lower mean body mass index ( P < .0001) than those in B 0 and B 0-3, respectively. The B ≥1 group had higher preoperative range of motion with internal rotation ( P = .05), external rotation ( P = .017), and flexion ( P < .0001) than B 0 patients, as well as a lower frequency of Trendelenburg gait pattern ( P = .0268). Similarly, the B ≥4 group had higher range of motion than the B 0-3 group with internal rotation ( P = .030), external rotation ( P = .003), flexion ( P < .0001), and abduction ( P = .002). As compared with the lower-score groups, the higher-score groups also had smaller labral size and tear dimension ( P < .0001), and a higher proportion of these patients underwent labral repair, capsular repair, and iliopsoas fractional lengthening. Patients undergoing hip arthroscopy who have generalized ligamentous laxity are overall younger, have a lower body mass index, and are more often female, as compared with patients who have lesser laxity. Patients with higher preoperative Beighton scores had greater hip range of motion and smaller intraoperative labral size and tear dimensions. Additionally, these patients were more likely to undergo labral repair, capsular plication, and iliopsoas fractional lengthening.


Clinical evaluation of dental and periodontal status in a group of oncological patients before chemotherapy.
To evaluate the dental status of 88 cancer patients before chemotherapy. Eighty-eight patients with cancer in different body locations were studied and compared with a control group. Dental plaque was assessed by means of the Silness and Löe index, dental status with the DMFT index, and periodontal status with the modified CPI index. In the oncological patients the mean Silness and Löe index was 1.28-/+0.11. Patients showed multiple missing teeth (mean number 7.55-/+0.80); the mean number of decayed teeth was 2.10-/+0.36; and the mean number of filled teeth was 2.27-/+0.37. As to periodontal status, the mean modified CPI index was 1.45-/+0.11. In the control group, the mean Silness and Löe index was 0.94-/+0.00. The mean number of decayed teeth was 1.21-/+0.25; the mean number of missing teeth was 4.97-/+0.67; and the mean number of filled teeth was 4.82-/+0.44. The mean modified CPI index was 1.29-/+0.10. Oncological patients in our study showed more dental plaque versus healthy patients and more decayed and missing teeth. However, patients in the control group showed more filled teeth than cancer patients. Periodontal status as determined by the modified CPI index was similar in both patient groups.


d-Sotalol: a new potent class III anti-arrhythmic agent.
We have compared the effect of a new drug d-sotalol which has minimal beta-blocking action with the parent (beta-blocking) compound dl-sotalol on monophasic action potential (MAP) duration in open-chested dogs. In seven experiments d-sotalol was administered in intravenous bolus doses of 1.5, 3 and 6 mg/kg given at 10 min intervals. In a further seven experiments dl-sotalol was administered using the same dosage regimen. The animals were anaesthetized with chloralose and urethane. Atrioventricular block was created by injection of the bundle of His with 0.1 ml of 40% formalin in order to ensure capture by ventricular pacing. After prior beta-blockade with propranolol (0.25 mg/kg), simultaneous epicardial and endocardial MAP were recorded at paced heart rates of 100 and 150 beats/min after each bolus injection. d-Sotalol and dl-sotalol showed similar prolongation of MAP duration (measured at 90% repolarization) in both endocardial and epicardial recording at both paced heart rates. These results show that the dextro-isomer of sotalol possesses similar class III action to the parent compound and that this action is homogeneous with respect to left ventricular endocardium and epicardium at heart rates of 100 beats/min and 150 beats/min over a wide dose range. d-Sotalol may be a useful anti-arrhythmic agent in man.


Interaction of [3H]spiperone with rat striatal dopamine D-2 receptors: kinetic evidence for antagonist-induced formation of ternary complex.
The characteristics of [3H]spiperone interactions with rat striatal dopamine D-2 receptor were investigated. Although the association of [3H]spiperone occurred monoexponentially, the pseudo-first order rate constant of association showed a hyperbolic dependence on ligand concentration. The data were therefore analyzed with the assumption of a two-step binding reaction leading to ligand-induced receptor isomerization. For the first equilibrium, the dissociation constant (KD) was 1.2 nM, while for the second equilibrium, the association and the dissociation rate constants were 71.6 X 10(-3) sec-1 and 0.9 X 10(-3) sec-1, respectively. The dissociation rate constant of the overall binding reaction, as determined by inducing the dissociation of [3H]spiperone from its binding sites by 1 microM (+)-butaclamol, was 0.92 X 10(-3) sec-1. However, the kinetically derived KD (15 pM) of the binding reaction differed significantly from the KD (218 pM) obtained from equilibrium binding experiments. This inconsistency between the two KD values appeared to have arisen from using different receptor concentrations in deriving kinetic and equilibrium data. The KD of the equilibrium binding reaction indeed showed significant variation with the receptor concentrations in an inverse way, implicating the involvement of a third component in the two-step binding reaction to form a high affinity ternary complex rather than a simple ligand induced receptor isomerization. Pretreatment of the membrane with 0.1 mM guanosine 5'-imidodiphosphate [Gpp(NH)p] reduced the affinity of the equilibrium binding reaction to a value (KD = 1.2 nM) which corresponded to the kinetically derived KD of the first step of the binding reaction, indicating the involvement of a guanine nucleotide-binding protein or G protein in inducing the formation of the high affinity ternary complex. The affinity of the binding reaction in Gpp(NH)p-pretreated membranes, however, increased with the duration of incubation, indicating that the ligand receptor complex still can couple with the G protein even in the presence of Gpp(NH)p. Pretreatment of the membrane with pertussis toxin irreversibly decreased the affinity of the binding reaction without significantly affecting the total number of binding sites, implying the involvement of the Gi subclass of G protein in the interaction of [3H]spiperone with D-2 receptors. Inhibition of the [3H]spiperone binding by a dopamine receptor agonist, bromocriptine, also yielded a monophasic dose response curve both in the presence and in the absence of Gpp(NH)p.(ABSTRACT TRUNCATED AT 400 WORDS)


Brain metabolic alterations in mice subjected to postnatal traumatic stress and in their offspring.
Adverse environmental and social conditions early in life have a strong impact on health. They are major risk factors for mental diseases in adulthood and, in some cases, their effects can be transmitted across generations. The consequences of detrimental stress conditions on brain metabolism across generations are not well known. Using high-field (14.1 T) magnetic resonance spectroscopy, we investigated the neurochemical profile of adult male mice exposed to traumatic stress in early postnatal life and of their offspring, and of undisturbed control mice. We found that, relative to controls, early life stress-exposed mice have metabolic alterations consistent with neuronal dysfunction, including reduced concentration of N-acetylaspartate, glutamate and γ-aminobutyrate, in the prefrontal cortex in basal conditions. Their offspring have normal neurochemical profiles in basal conditions. Remarkably, when challenged by an acute cold swim stress, the offspring has attenuated metabolic responses in the prefrontal cortex, hippocampus and striatum. In particular, the expected stress-induced reduction in the concentration of N-acetylaspartate, a putative marker of neuronal health, was prevented in the cortex and hippocampus. These findings suggest that paternal trauma can confer beneficial brain metabolism adaptations to acute stress in the offspring.


The North American Layman's Understanding of COVID-19: Are We Doing Enough?
Background: In the absence of an effective vaccine, public health policies are aimed at awareness, and education of the general public in order to contain the quickly spreading COVID-19 pandemic. Most of the recommended precautionary measures are dependent on human behaviors and therefore their effectiveness largely depends on peoples' perception and attitudes toward the disease. This study aimed to assess the level of knowledge, risk perception, and precautionary measures taken in response to COVID-19 in North America. Methods: In this cross-sectional observational study, an online survey targeted to North Americans focused on the public's knowledge of COVID-19, risk perception, and precautionary behaviors taken in response to this pandemic. Descriptive analyses were performed for the whole population and the subgroup analyses contrasted the differences between Americans and Canadians. Results: The cohort comprised 1,264 relatively young participants with an average age of 28.6 ± 9.8 years. The vast majority (>90%) were knowledgeable about COVID-19. Regarding risk perception, about a quarter assumed to be at less risk to contract the disease, and 42.8% considered themselves to be less contagious than others. While the vast majority avoided performing risky behaviors, only a small proportion (13.2%) wore a face mask-which is in line with the public health recommendations of the two countries at the time of data collection. Overall, a larger proportion of Canadian participants (55.8%) were satisfied with the performance of their national public health in response to the current pandemic, compared to their American counterparts (12.2%). Discussion: Data regarding the public's knowledge of COVID-19, risk perception, and behaviors in response to this pandemic is limited. The results of this study highlight that this relatively young and educated sample of North Americans had a high level of knowledge about COVID-19 and a large proportion of them were taking the precautionary measures against this pandemic. However, a significant number of individuals believe to be at less risk of contracting the disease compared to the general population. Educating the public that no one is safe from this disease, could play a role in further limiting risky behaviors and ultimately facilitating disease containment.


Pulmonary embolism in chronic obstructive pulmonary disease: a population-based cohort study.
To evaluate the incidence of pulmonary embolism (PE) in patients with chronic obstructive pulmonary disease (COPD) in Taiwan. This was a retrospective population-based cohort study using data retrieved from Taiwan's National Health Insurance Research Database (2000 to 2008), which contains 99% of Taiwanese healthcare data. The evaluations included 355,878 COPD patients and 355,878 non-COPD patients for comparison. The incidence of PE in the COPD cohort was 12.31 per 10,000 person-years (1.37/10,000 persons/y), which was approximately 4-times higher than in the comparison cohort (0.35/10,000 persons/y). In the COPD cohort, risk of PE was higher in the young age group (20-59 y, HR 4.64, 95% CI 3.06-7.03) than in other age groups. Risk of PE was higher in patients with COPD combined with hypertension, coronary artery disease, and cancer, or those with previous operation (HR 4.16, 4.75, 4.56, and 4.50 respectively) than in those with COPD and no comorbidity. The overall incidence of PE is lower in Taiwan than in western countries. However, the prevalence of PE in COPD patients is higher than in non-COPD patients and increases with age. It is crucial to incorporate PE into the differential diagnosis of COPD exacerbation for clinical physicians.


Lead in paint and soil in Karnataka and Gujarat, India.
Blood lead surveys in several areas of India have found very high percentages of children with elevated blood lead levels. Fifty-three percent of children under 12 years of age in a seven-city screening had blood lead levels equal to or greater than 10 microg/dL, the level currently considered elevated by the U.S. Centers for Disease Control and Prevention (CDC). A number of these surveys focused on populations near lead smelters or in areas with high lead levels from combustion of lead-containing gasoline. There is little information available, however, on the levels of lead in paint in India and in soil. Field portable X-ray fluorescence analyzers were used to determine environmental lead levels in paint, dust, air, soil, and other bulk samples near several lead-using industries and in the residential environments of children with very high blood lead levels, at least four times as high as the CDC limit. Soils near industrial operations, such as secondary lead smelters, and battery dismantling units contained levels up to 100,000 ppm of lead. Four of 29 currently available paints from five manufacturers measured 1.0 mg/cm2 or above--the current U.S. definition of lead-based paint in housing-after the application of a single coat; four others measured at least 1.0 after three coats, and three others likely reached this level after the application of an additional one or two coats. In 5 of 10 homes of the elevated blood lead children, three or more locations in or around the home were found to have lead paint levels of 1.0 mg/cm2 or higher. Soil exceeding the U.S. standard for residential areas (400 ppm) was found at only one of the houses. Other sources of lead exposure, including traditional ayurvedic medicine tablets, were also observed. Similar surveys would be useful elsewhere in India and in other developing countries.


Alemtuzumab induction in kidney transplantation: clinical results and impact on T-regulatory cells.
Alemtuzumab (ALT), a humanized monoclonal anti-CD52 antibody, was introduced in solid organ transplantation as an induction agent. ALT associated with anticalcineurins has provided a low incidence of acute rejection episodes (ARE) and potential tolerogenic properties. We analyzed the clinical outcomes and effects on peripheral Treg of renal transplant recipients treated with ALT. Six-month data on kidney alone or kidney combined with pancreas or liver patients treated with ALT and tacrolimus (TAC) in standard doses were compared with those on renal transplant recipients of similar demography who were not treated with ALT. We evaluated patient and graft survivals, ARE incidence, hematological parameters, renal function, adverse events, and CD4+CD25+FoxP3+ T cells in peripheral blood. Demographics of recipients, donors, and transplants were similar in both groups. Mean HLA mismatch was slightly greater among ALT-treated patients (3.5 vs 2.5). No combined transplantation was performed in the ALT-untreated group. Patient and graft survivals were 100% without rejection or serious infections in both groups. ALT-treated recipients showed anemia and leukopenia in 3 patients as well as severe lymphopenia in 5 recipients, who partially recovered on day 90. Final mean plasma creatinine was 1.4 mg/dL, while calculated creatinine clearance was approximately 65 mL/min in both groups. Mean Treg cell percentage was higher among ALT-treated recipients than the comparative group or healthy controls (P < .05). In conclusion, renal transplantation results obtained using ALT with rigorous immunosuppressive therapy were excellent; serious adverse events and acute rejection were absent. The effect of the increased proportion of Treg cells must be evaluated with longer observation.


Vaporization of protic ionic liquids derived from organic superbases and short carboxylic acids.
This work presents a comprehensive evaluation of the phase behaviour and cohesive enthalpy of protic ionic liquids (PILs) composed of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) organic superbases with short-chain length (acetic, propionic and butyric) carboxylic acids. Glass transition temperatures, Tg, and enthalpies of vaporization, ΔHvap, were measured for six [BH][A] (1 : 1) PILs (B = DBN, DBU; A = MeCOO, EtCOO, nPrCOO), revealing more significant changes upon increasing the number of -CH2- groups in the base than in the acid. The magnitude of ΔHvap evidences that liquid PILs have a high proportion of ions, although the results also indicate that in DBN PILs the concentration of neutral species is not negligible. In the gas phase, these PILs exist as a distribution of ion pairs and isolated neutral species, with speciation being dependent on the temperature and pressure conditions - at high temperatures and low pressures the separated neutral species dominate. The higher Tg and ΔHvap of the DBU PILs are explained by the stronger basicity of DBU (as supported by NMR and computational calculations), which increases the extent of proton exchange and the ionic character of the corresponding PILs, resulting in stronger intermolecular interactions in condensed phases.


Effects of rate of tone-pip stimulation on the evoked K-Complex.
The effects of rate of presentation on the evoked K-Complex were examined. In different conditions, brief duration tone pips were presented every 5, 10 or 30 s. Trials were sorted into those on which a K-Complex was or was not elicited and averaged separately. The evoked K-Complex consisted of two different negative components peaking at approximately 350 and 550 ms (respectively), followed by a positive component peaking at approximately 900 ms. K-Complexes were elicited more often in Stage 2 early and 2 late than in slow-wave sleep although the differences were not significant. K-Complexes were elicited more often in the Long ISI compared to the Short and Medium ISI conditions. When a K-Complex was evoked, the amplitude of N350 and N550 was greater for the Long ISI than for the Short or Medium ISI conditions. P900 amplitude remained invariant regardless of the ISI. A micro-analysis was carried out whenever 3 consecutive occurring K-Complexes were elicited. During the Short and Medium ISI conditions, N350 and N550 following the second and third occurrence of the K-Complex were significantly attenuated compared to the first occurrence. There was no difference in N350 and N550 amplitudes among the 3 consecutive occurrences during the Long ISI condition. The decay in amplitude over consecutive occurrences of the K-Complex might be a reflection of either habituation or refractory processes.


Ambulatory blood pressure, blood pressure variability and the prevalence of carotid artery alteration: the Ohasama study.
To investigate the association between ambulatory blood pressure (BP) variables (level, short-term variability, circadian variation and morning pressor surge) and carotid artery alteration in a general population. We measured ambulatory BP every 30 min in 775 participants (mean age 66.2 +/- 6.2 years, 68.8% women) from the Japanese general population. Short-term BP variability during the daytime and night-time were estimated as within-subject standard deviation of daytime and night-time BP, respectively. Circadian BP variation was calculated as the percentage decline in nocturnal BP. Morning pressor surge was defined as morning BP minus pre-waking BP. The extent of carotid artery alteration was evaluated as the average of common carotid intima-media thickness (IMT) and the presence of focal carotid plaque. Daytime and night-time BP values were more closely associated with carotid artery alteration than casual BP. With mutual adjustment for daytime and night-time BP, the latter (P < 0.0001) was more closely associated with IMT, which represents diffuse arterial thickening and arteriosclerosis, than daytime BP (P = 0.2). Night-time systolic BP variability was positively associated with carotid plaque (focal atherosclerotic lesions) independently of possible confounding factors, including night-time systolic BP (P = 0.01). A diminished nocturnal decline in systolic BP was associated with a greater IMT after adjustment for confounding factors (P = 0.03). A morning pressor surge was not associated with carotid artery alteration. Ambulatory BP levels and BP variability were closely associated with carotid artery alteration, suggesting that these parameters are independent risk factors or predictors of carotid artery alteration.


Exposure of the Heart in Breast Cancer Radiation Therapy: A Systematic Review of Heart Doses Published During 2003 to 2013.
Breast cancer radiation therapy cures many women, but where the heart is exposed, it can cause heart disease. We report a systematic review of heart doses from breast cancer radiation therapy that were published during 2003 to 2013. Eligible studies were those reporting whole-heart dose (ie, dose averaged over the whole heart). Analyses considered the arithmetic mean of the whole-heart doses for the CT plans for each regimen in each study. We termed this "mean heart dose." In left-sided breast cancer, mean heart dose averaged over all 398 regimens reported in 149 studies from 28 countries was 5.4 Gy (range, <0.1-28.6 Gy). In regimens that did not include the internal mammary chain (IMC), average mean heart dose was 4.2 Gy and varied with the target tissues irradiated. The lowest average mean heart doses were from tangential radiation therapy with either breathing control (1.3 Gy; range, 0.4-2.5 Gy) or treatment in the lateral decubitus position (1.2 Gy; range, 0.8-1.7 Gy), or from proton radiation therapy (0.5 Gy; range, 0.1-0.8 Gy). For intensity modulated radiation therapy mean heart dose was 5.6 Gy (range, <0.1-23.0 Gy). Where the IMC was irradiated, average mean heart dose was around 8 Gy and varied little according to which other targets were irradiated. Proton radiation therapy delivered the lowest average mean heart dose (2.6 Gy, range, 1.0-6.0 Gy), and tangential radiation therapy with a separate IMC field the highest (9.2 Gy, range, 1.9-21.0 Gy). In right-sided breast cancer, the average mean heart dose was 3.3 Gy based on 45 regimens in 23 studies. Recent estimates of typical heart doses from left breast cancer radiation therapy vary widely between studies, even for apparently similar regimens. Maneuvers to reduce heart dose in left tangential radiation therapy were successful. Proton radiation therapy delivered the lowest doses. Inclusion of the IMC doubled typical heart dose.


Co-Targeting Prostate Cancer Epithelium and Bone Stroma by Human Osteonectin-Promoter-Mediated Suicide Gene Therapy Effectively Inhibits Androgen-Independent Prostate Cancer Growth.
Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E) containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene. In vitro reporter assays revealed that the hON-522E promoter is highly active in androgen receptor negative and metastatic prostate cancer and bone stromal cells compared to androgen receptor-positive prostate cancer cells. Moreover, in vivo prostate-tumor-promoting activity of the hON-522E promoter was confirmed by intravenous administration of an adenoviral vector containing the hON-522E promoter-driven luciferase gene (Ad-522E-Luc) into mice bearing orthotopic human prostate tumor xenografts. In addition, an adenoviral vector with the hON-522E-promoter-driven herpes simplex virus thymidine kinase gene (Ad-522E-TK) was highly effective against the growth of androgen-independent human prostate cancer PC3M and bone stromal cell line in vitro and in pre-established PC3M tumors in vivo upon addition of the prodrug ganciclovir. Because of the heterogeneity of human prostate tumors, hON-522E promoter-mediated gene therapy has the potential for the treatment of hormone refractory and bone metastatic prostate cancers.