Volatile Compounds in Citrus Essential Oils: A Comprehensive Review.
The essential oil fraction obtained from the rind of Citrus spp. is rich in chemical compounds of interest for the food and perfume industries, and therefore has been extensively studied during the last decades. In this manuscript, we provide a comprehensive review of the volatile composition of this oil fraction and rind extracts for the 10 most studied Citrus species: C. sinensis (sweet orange), C. reticulata (mandarin), C. paradisi (grapefruit), C. grandis (pummelo), C. limon (lemon), C. medica (citron), C. aurantifolia (lime), C. aurantium (bitter orange), C. bergamia (bergamot orange), and C. junos (yuzu). Forty-nine volatile organic compounds have been reported in all 10 species, most of them terpenoid (90%), although about half of the volatile compounds identified in Citrus peel are non-terpenoid. Over 400 volatiles of different chemical nature have been exclusively described in only one of these species and some of them could be useful as species biomarkers. A hierarchical cluster analysis based on volatile composition arranges these Citrus species in three clusters which essentially mirrors those obtained with genetic information. The first cluster is comprised by C. reticulata, C. grandis, C. sinensis, C. paradisi and C. aurantium, and is mainly characterized by the presence of a larger abundance of non-terpenoid ester and aldehyde compounds than in the other species reviewed. The second cluster is comprised by C. junos, C. medica, C. aurantifolia, and C. bergamia, and is characterized by the prevalence of mono- and sesquiterpene hydrocarbons. Finally, C. limon shows a particular volatile profile with some sulfur monoterpenoids and non-terpenoid esters and aldehydes as part of its main differential peculiarities. A systematic description of the rind volatile composition in each of the species is provided together with a general comparison with those in leaves and blossoms. Additionally, the most widely used techniques for the extraction and analysis of volatile Citrus compounds are also described.


Role of histamine in short- and long-term effects of methamphetamine on the developing mouse brain.
With the rise in methamphetamine (MA) use among women of childbearing age, the potential consequences of MA exposure to the developing brain for cognition in adulthood is a major concern. Histamine might mediate these MA effects. Following MA administration in neonatal mice, histamine levels in brain were elevated and the hypothalamic-pituitary-adrenal axis was activated. Co-administration of MA with the H3 receptor agonist immepip antagonized these effects. The effects of MA on histamine levels and on hypothalamic-pituitary-adrenal axis activation at P20 were more pronounced in female than male mice. These sex differences could have contributed to the increased susceptibility of female mice to the detrimental long-term cognitive effects of MA and the H3/H4 antagonist thioperamide. Following behavioral testing, mice neonatally treated with MA or thioperamide showed reduced levels of the dendritic marker microtubule-associated protein 2 in the CA3 region of the hippocampus and the enthorhinal cortex. This was not seen in mice neonatally treated with immepip and MA who did not show cognitive impairments, suggesting that these brain areas might be particularly important for the long-term effects of MA on cognitive function. These data support a role for histamine in the effects of MA on the developing brain.


Community Health Workers and community advocacy: addressing health disparities.
The Community Health Worker model is recognized nationally as a means to address glaring inequities in the burden of adverse health conditions that exist among specific population groups in the United States. This study explored Arizona CHW involvement in advocacy beyond the individual patient level into the realm of advocating for community level change as a mechanism to reduce the structural underpinnings of health disparities. A survey of CHWs in Arizona found that CHWs advocate at local, state and federal political levels as well as within health and social service agencies and business. Characteristics significantly associated with advocacy include employment in a not for profit organization, previous leadership training, and a work environment that allows flexible work hours and the autonomy to start new projects at work. Intrinsic characteristics of CHWs associated with advocacy include their belief that they can influence community decisions, self perception that they are leaders in the community, and knowledge of who to talk to in their community to make change. Community-level advocacy has been identified as a core CHW function and has the potential to address structural issues such as poverty, employment, housing, and discrimination. Agencies utilizing the CHW model could encourage community advocacy by providing a flexible working environment, ongoing leadership training, and opportunities to collaborate with both veteran CHWs and local community leaders. Further research is needed to understand the nature and impact of CHW community advocacy activities on both systems change and health outcomes.


Association between Glucocorticoid-Induced Osteoporosis and Myasthenia Gravis: A Cross-Sectional Study.
To investigate the association between glucocorticoid-induced osteoporosis and myasthenia gravis (MG) using a cross-sectional survey in Japan. We studied 363 patients with MG (female 68%; mean age, 57 ± 16 years) who were followed at six Japanese centers between April and July 2012. We evaluated the clinical information of MG and fractures, bone markers, and radiological assessment. Quality of life was measured using an MG-specific battery, MG-QOL15. Glucocorticoids were administered in 283 (78%) of 363 MG patients. Eighteen (6%) of 283 MG patients treated with prednisolone had a history of osteoporotic fractures. The duration of glucocorticoid therapy, but not the dose of prednisolone, was associated with the osteoporotic fractures in MG patients. Bone mineral density was significantly decreased in the MG patients with fractures. The multivariate analyses showed that the total quantitative MG score was the only independent factor associated with osteoporotic fractures (OR = 1.30, 95% CI 1.02-1.67, p = 0.03). MG patients who had experienced fractures reported more severe difficulties in activities of daily living. Glucocorticoid-induced osteoporosis aggravates quality of life in patients with MG.


Cerebral venous-sinus thrombosis: a case series analysis.
Cerebral venous-sinus thrombosis is an uncommon form but important cause of stroke, especially in young-aged women. We performed a retrospective descriptive-analytical study in which 124 patients with cerebral venous-sinus thrombosis, who referred to Nemazee Hospital, Shiraz University of Medical Sciences from January 2000 to March 2008, were included, and their demographic, etiologic, radiological and prognostic characteristics were evaluated. The patients' mean age was 34.01±10.25. Eighty seven (70.16%) were women and 37 (29.83%) were men. The most frequent clinical manifestations were headache, papilledema and seizures. Fifty seven (65.51%) women took oral contraceptive pills. Twenty of 57 women (35.08%) took the pill longer than one month to be able to fast in Ramadan or perform the Hajj ceremonies. In the mean time they developed cerebral venous-sinus thrombosis. Superior sagital sinus, with or without lateral sinuses, was the most involved area (70.96%). High mortality and morbidity rates (14.51% and 35.48%, respectively) were found in patients. Poor prognostic factors at the time of admission were stupor and coma (P=0.001) and evidence of hemorrhage in primary CT scan (P=0.005). Taking oral contraceptive pills was a main factor associated with cerebral venous-sinus thrombosis. Clinical manifestations, prognostic factors, common involved sinuses and image findings of this study were similar to those of other studies. Health care policy makers should design a plan to warn susceptible women of the risk of cerebral venous-sinus thrombosis, and to educate them the ways to prevent it.


In situ insight into the unconventional ruthenium catalyzed growth of carbon nanostructures.
We report on the in situ analysis of the growth process of carbon nanostructures catalyzed by Ru nanoparticles using syngas, a mixture of hydrogen and CO, as the carbon source at a medium temperature (500 °C). The structural modifications of the dual nanotube/nanoparticle system and the general dynamics of the involved processes have been directly followed during the growth, in real time and at the atomic scale, by transmission electron microscopy in an environmental gas cell at atmospheric pressure. After a reduction step under hydrogen and syngas, the particles became very active for the carbon growth. The growth rate is independent of the particle size which mainly influences the nanotube wall thickness. Other subtle information on the general behavior of the system has been obtained, as for instance the fact that the regular changes in the direction of the particle originate generally from the particle shape fluctuation. The main result is the evidence of a new growth mode in relation to the presence and the high instability of the ruthenium carbide phase which acts as a carbon reservoir. For the first time, a relaxation oscillation of the growth rate has been observed and correlated with the metal-carbide structural transition at the particle sub-surface.


Charting the Complexity of the Marine Microbiome through Single-Cell Genomics.
Marine bacteria and archaea play key roles in global biogeochemistry. To improve our understanding of this complex microbiome, we employed single-cell genomics and a randomized, hypothesis-agnostic cell selection strategy to recover 12,715 partial genomes from the tropical and subtropical euphotic ocean. A substantial fraction of known prokaryoplankton coding potential was recovered from a single, 0.4 mL ocean sample, which indicates that genomic information disperses effectively across the globe. Yet, we found each genome to be unique, implying limited clonality within prokaryoplankton populations. Light harvesting and secondary metabolite biosynthetic pathways were numerous across lineages, highlighting the value of single-cell genomics to advance the identification of ecological roles and biotechnology potential of uncultured microbial groups. This genome collection enabled functional annotation and genus-level taxonomic assignments for >80% of individual metagenome reads from the tropical and subtropical surface ocean, thus offering a model to improve reference genome databases for complex microbiomes.


Isotope effects on the spin dynamics of single-molecule magnets probed using muon spin spectroscopy.
Muon spin relaxation (μSR) experiments on a single-molecule magnet enriched in different Dy isotopes detect unambiguously the slowing down of the zero field spin dynamics for the non-magnetic isotope. This occurs in the low temperature regime dominated by quantum tunnelling, in agreement with previous ac susceptibility investigations. In contrast to the latter, however, μSR is sensitive to all fluctuation modes affecting the lifetime of the spin levels.


Viability and infectivity of Cryptosporidium parvum oocysts are retained upon intestinal passage through a refractory avian host.
Six Cryptosporidium-free Peking ducks (Anas platyrhynchos) were each orally inoculated with 2.0 x 10(6) Cryptosporidium parvum oocysts infectious to neonatal BALB/c mice. Histological examination of the stomachs jejunums, ilea, ceca, cloacae, larynges, tracheae, and lungs of the ducks euthanized on day 7 postinoculation (p.i.) revealed no life-cycle stages of C. parvum. However, inoculum-derived oocysts extracted from duck feces established severe infection in eight neonatal BALB/c mice (inoculum dose, 2.5 x 10(5) per mouse). On the basis of acid-fast stained direct wet smears, 73% of the oocysts in duck feces were intact (27% were oocyst shells), and their morphological features conformed to those of viable and infectious oocysts of the original inoculum. The fluorescence scores of the inoculated oocysts, obtained by use of the MERIFLUOR test, were identical to those obtained for the feces-recovered oocysts (the majority were 3+ to 4+). The dynamics of oocyst shedding showed that the birds released a significantly higher number of intact oocysts than the oocyst shells (P < 0.01). The number of intact oocysts shed (87%) during the first 2 days p.i. was significantly higher than the number shed during the remaining 5 days p.i. (P < 0.01) and significantly decreased from day 1 to day 2 p.i. (P < 0.01). The number of oocyst shells shed during 7 days p.i. did not vary significantly (P > 0.05). The retention of infectivity of C. parvum oocysts after intestinal passage through an aquatic bird has serious epidemiological and epizootiological implications. Waterfowl may serve as mechanical vectors for the waterborne oocysts and may enhance contamination of surface waters with C. parvum. As the concentration of Cryptosporidium oocysts in source waters is attributable to watershed management practices, the watershed protection program should consider waterfowl as a potential factor enhancing contamination of the source water with C. parvum.


Anti-inflammatory, anti-tumor-promoting, and cytotoxic activities of constituents of marigold (Calendula officinalis) flowers.
Ten oleanane-type triterpene glycosides, 1-10, including four new compounds, calendulaglycoside A 6'-O-methyl ester (2), calendulaglycoside A 6'-O-n-butyl ester (3), calendulaglycoside B 6'-O-n-butyl ester (5), and calendulaglycoside C 6'-O-n-butyl ester (8), along with five known flavonol glycosides, 11-15, were isolated from the flowers of marigold (Calendula officinalis). Upon evaluation of compounds 1-9 for inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice, all of the compounds, except for 1, exhibited marked anti-inflammatory activity, with ID50 values of 0.05-0.20 mg per ear. In addition, when 1-15 were evaluated against the Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA, compounds 1-10 exhibited moderate inhibitory effects (IC50 values of 471-487 mol ratio/32 pmol TPA). Furthermore, upon evaluation of the cytotoxic activity against human cancer cell lines in vitro in the NCI Developmental Therapeutics Program, two triterpene glycosides, 9 and 10, exhibited their most potent cytotoxic effects against colon cancer, leukemia, and melanoma cells.


Periodontal tissue reaction to customized nano-hydroxyapatite block scaffold in one-wall intrabony defect: a histologic study in dogs.
This study evaluated histologically the tissue responses to and the effects of a customized nano-hydroxyapatite (n-HA) block bone graft on periodontal regeneration in a one-wall periodontal-defect model. A customized block bone for filling in the standardized periodontal defect was fabricated from prefabricated n-HA powders and a polymeric sponge. Bilateral 4×4×5 mm (buccolingual width×mesiodistal width×depth), one-wall, critical-size intrabony periodontal defects were surgically created at the mandibular second and fourth premolars of five Beagle dogs. In each dog, one defect was filled with block-type HA and the other served as a sham-surgery control. The animals were sacrificed following an 8-week healing interval for clinical and histological evaluations. Although the sites that received an n-HA block showed minimal bone formation, the n-HA block was maintained within the defect with its original hexahedral shape. In addition, only a limited inflammatory reaction was observed at sites that received an n-HA block, which might have been due to the high stability of the customized block bone. In the limitation of this study, customized n-HA block could provide a space for periodontal tissue engineering, with minimal inflammation.


Development of the perceived barriers scale: a new instrument identifying barriers to career development and employment for young adult survivors of pediatric CNS tumors.
Given the significant employment disparities for survivors of pediatric brain tumors, there is increased need to conduct vocational and career research with this group. The purpose of the present study was to construct an instrument, the Perceived Barriers Scale, that is psychometrically sound and has both clinical and research application related to career and employment issues of pediatric brain tumor survivors. The participants consisted of 110 young adult central nervous system survivors of childhood cancer aged between 18 and 30 years old (M = 23.05, SD = 3.36) who were identified by the DFCI Pediatric Brain Tumor Clinic. The 12-item Perceived Barriers Scale was developed from a comprehensive literature review, clinical interviews conducted with survivors of pediatric brain tumors, and feedback from multidisciplinary providers. Exploratory factor analysis and correlations were completed to examine the initial psychometric properties of the scale. Exploratory factors analysis identified two factors that accounted for 57.92% with the two factors labeled as internal barriers and external barriers. All factors loaded significantly onto their respective factors (.48 to .88). The results of the correlational analysis found significant relationships between both internal barrier and external barrier subscales and CSE and WHODAS-2 providing initial support for the construct validity of the Perceived Barriers Scale. Overall, the study findings indicate good psychometrics with the brevity of the scale increasing potential application and utilization in both research and clinical settings. Identification of employment barriers for brain tumor survivors provides opportunity for more targeted vocational intervention.


[Mortality due to neoplasms in Brazil (1980/1983/1985): grouping by states, behavior and trends].
Mortality caused by neoplasms in Brazil was examined by means of official Ministry of Health data covering 26 of the Federal Units and 13 different tumoral sites and referring to the years 1980, 1983 and 1985. Both cluster analyses and those of principal components have shown heterogeneous behaviour as between the different regions of the country in relation to the 13 variants studied. The main discriminatory elements are the trachea/bronchus/lung malign neoplasms followed by those of stomach, pancreas, colon and larynx. Complementary analyses have demonstrated a tendency to an increase in the mortality rate due to prostate malign neoplasms (17.74%), followed by those of trachea/bronchus/lung (15.22%), breast (11.32%), pancreas (10.23%), colon (8.08%), uterine colon (6.45%) and larynx (6.36). There has been a decrease of the mortality due to benign neoplasms/carcinoma "in situ"/others (27.37%), malign rectus neoplasms of the sigmoid/anus (7.67%), stomach (5.31%), of other non-specific locations in the uterus (2.56%), of leukaemia (0.70%) and malign neoplasms of the oesophagus (0.44%). Maling neoplasms of the stomach have been the main cause of cancer mortality in Brazil accounting for 21.27% of the mean total, followed by of the malign neoplasms trachea/bronchus/lung (17.52% of the general average). The mortality rates by esophageal malign neoplasms in Rio Grande do Sul is stressed.


Exercise Improves V˙O2max and Body Composition in Androgen Deprivation Therapy-treated Prostate Cancer Patients.
Prostate cancer is the most common cancer in men, and patients treated with androgen deprivation therapy (ADT) experience unfavorable changes in body composition and associated metabolic complications, which can increase the risk of cardiovascular disease. We examined the effect of a 6-month program of aerobic and resistance exercise aimed at improving body composition and cardiorespiratory health in this population. Ninety-seven men (43-90 yr) with localized prostate cancer receiving ADT were randomized to either exercise (EX, n = 50) or usual care (CON, n = 47). Supervised exercise was undertaken twice weekly at moderate to high intensity. Measures of cardiorespiratory capacity (V˙O2max), resting metabolic rate, central blood pressure, hemodynamic variables, blood markers, and body composition were assessed. There was a significant group-time interaction present for V˙O2max (P = 0.033) with a treatment effect for EX of 0.11 L·min (95% confidence interval [CI] = 0.04-0.19) (relative to body mass = 1.3 mL·kg·min, 95% CI = 0.3-2.3) and fat oxidation (P = 0.037) of 12.0 mg·min (95% CI = 2.3-21.7). Similarly, there was a significant improvement in glucose (P < 0.001) for EX of -0.5 mmol·L (95% CI = -0.8 to -0.3), with no change in prostate-specific antigen or testosterone as a result of exercise. Body composition was enhanced for EX with adjusted mean differences in lean mass (P = 0.015) of 0.8 kg (95% CI = 0.3-1.3), total fat mass (P = 0.020) of -1.1 kg (95% CI = -1.8 to -0.5), and trunk fat mass (P < 0.001) of -1.0 kg (95% CI = -1.4 to -0.6). A 6-month combined aerobic and resistance exercise program has a significant favorable effect on cardiorespiratory capacity, resting fat oxidation, glucose, and body composition despite the adverse effects of hormone suppression. Combined aerobic and resistance training should be considered a key adjuvant component in men undergoing ADT for the treatment of prostate cancer.


Heterozygosity-fitness correlations in a wild mammal population: accounting for parental and environmental effects.
HFCs (heterozygosity-fitness correlations) measure the direct relationship between an individual's genetic diversity and fitness. The effects of parental heterozygosity and the environment on HFCs are currently under-researched. We investigated these in a high-density U.K. population of European badgers (Meles meles), using a multimodel capture-mark-recapture framework and 35 microsatellite loci. We detected interannual variation in first-year, but not adult, survival probability. Adult females had higher annual survival probabilities than adult males. Cubs with more heterozygous fathers had higher first-year survival, but only in wetter summers; there was no relationship with individual or maternal heterozygosity. Moist soil conditions enhance badger food supply (earthworms), improving survival. In dryer years, higher indiscriminate mortality rates appear to mask differential heterozygosity-related survival effects. This paternal interaction was significant in the most supported model; however, the model-averaged estimate had a relative importance of 0.50 and overlapped zero slightly. First-year survival probabilities were not correlated with the inbreeding coefficient (f); however, small sample sizes limited the power to detect inbreeding depression. Correlations between individual heterozygosity and inbreeding were weak, in line with published meta-analyses showing that HFCs tend to be weak. We found support for general rather than local heterozygosity effects on first-year survival probability, and g2 indicated that our markers had power to detect inbreeding. We emphasize the importance of assessing how environmental stressors can influence the magnitude and direction of HFCs and of considering how parental genetic diversity can affect fitness-related traits, which could play an important role in the evolution of mate choice.


Single-photon emission computed tomography/computed tomography in abdominal diseases.
Single-photon emission computed tomography (SPECT) studies of the abdominal region are established in conventional nuclear medicine because of their easy and large availability, even in the most peripheral hospitals. It is well known that SPECT imaging demonstrates function, rather than anatomy. It is useful in the diagnosis of various disorders because of its ability to detect changes caused by disease before identifiable anatomic correlates and clinical manifestations exist. However, SPECT data frequently need anatomic landmarks to precisely depict the site of a focus of abnormal tracer uptake and the structures containing normal activity; the fusion with morphological studies can furnish an anatomical map to scintigraphic findings. In the past, software-based fusion of independently performed SPECT and CT or magnetic resonance images have been demonstrated to be time consuming and not useful for routine clinical employment. The recent development of dual-modality integrated imaging systems, which provide SPECT and CT images in the same scanning session, with the acquired images co-registered by means of the hardware, has created a new scenario. The first data have been mainly reported in oncology patients and indicate that SPECT/CT is very useful because it is able to provide further information of clinical value in several cases. In SPECT studies of abdominal diseases, hybrid SPECT/CT can play a role in the differential diagnosis of hepatic hemangiomas located near vascular structures, in precisely detecting and localizing active splenic tissue caused by splenosis in splenectomy patients, in providing important information for therapy optimization in patients submitted to hepatic arterial perfusion scintigraphy, in accurately identifying the involved bowel segments in patients with inflammatory bowel diseases, and in correctly localizing the bleeding sites in patients with gastrointestinal bleeding.


Types of unintended consequences related to computerized provider order entry.
To identify types of clinical unintended adverse consequences resulting from computerized provider order entry (CPOE) implementation. An expert panel provided initial examples of adverse unintended consequences of CPOE. The authors, using qualitative methods, gathered and analyzed additional examples from five successful CPOE sites. Using a card sort method, the authors developed a categorization scheme for the 79 unintended consequences initially identified and then iteratively modified the scheme to categorize 245 additional adverse consequences resulting from fieldwork. Because the focus centered on consequences requiring prevention or remedial action, the authors did not further analyze reported unintended beneficial (positive) consequences. Unintended adverse consequences (UACs) fell into nine major categories (in order of decreasing frequency): 1) more/new work for clinicians; 2) unfavorable workflow issues; 3) never ending system demands; 4) problems related to paper persistence; 5) untoward changes in communication patterns and practices; 6) negative emotions; 7) generation of new kinds of errors; 8) unexpected changes in the power structure; and 9) overdependence on the technology. Clinical decision support features introduced many of these unintended consequences. Identifying and understanding the types and in some instances the causes of unintended adverse consequences associated with CPOE will enable system developers and implementers to better manage implementation and maintenance of future CPOE projects.


Towards Visualization Thumbnail Designs That Entice Reading Data-Driven Articles.
As online news increasingly include data journalism, there is a corresponding increase in the incorporation of visualization in article thumbnail images. However, little research exists on the design rationale for visualization thumbnails, such as resizing, cropping, simplifying, and embellishing charts that appear within the body of the associated article. Therefore, in this paper we aim to understand these design choices and determine what makes a visualization thumbnail inviting and interpretable. To this end, we first survey visualization thumbnails collected online and discuss visualization thumbnail practices with data journalists and news graphics designers. Based on the survey and discussion results, we then define a design space for visualization thumbnails and conduct a user study with four types of visualization thumbnails derived from the design space. The study results indicate that different chart components play different roles in attracting reader attention and enhancing reader understandability of the visualization thumbnails. We also find various thumbnail design strategies for effectively combining the charts' components, such as a data summary with highlights and data labels, and a visual legend with text labels and Human Recognizable Objects (HROs), into thumbnails. Ultimately, we distill our findings into design implications that allow effective visualization thumbnail designs for data-rich news articles. Our work can thus be seen as a first step toward providing structured guidance on how to design compelling thumbnails for data stories.


High-power 980-nm pump laser modules for erbium-doped fiber amplifiers.
High-power fiber-coupled pump modules with an emission wavelength of 980 nm and output powers in excess of 200 mW, as measured at the fiber end, have been fabricated. Laser-to-fiber coupling efficiencies in excess of 77% are observed to be in excellent agreement with a mathematical model. Also, the output power stability of these modules has been monitored during severe temperature cycling, and the relative power variation was less than 4% for all the tested modules.


Hepatitis B core antibody positive donors as a safe and effective therapeutic option to increase available organs for lung transplantation.
The use of hepatitis B core antibody (HBcAb+) and hepatitis C antibody (HCV Ab+) positive donors represents one strategy to increase available donor organs, but this remains controversial because of concern for viral transmission to recipients. We hypothesized that isolated HBcAb+ donors represent minimal risk of viral transmission in vaccinated lung transplant (LTx) recipients. A retrospective study was performed of LTx recipients who received HBcAb+ or HCV Ab+ pulmonary allografts. We analyzed liver function studies, viral hepatitis screening tests, quantitative polymerase chain reaction for hepatitis B viral DNA (HBV DNA) and hepatitis C viral RNA (HCV RNA), freedom from bronchiolitis obliterans syndrome, acute rejection, and survival. Between April 1992 and August 2003, 456 LTx operations were performed. Twenty-nine patients (HB group) received HBcAb+ allograft transplants with a median posttransplant follow-up of 24.5 months. Three critically ill patients (HC group) received HCV Ab+ allografts with a median follow-up of 21.5 months. One-year survival for the HB group is 83% versus 82% for all patients who received non-HB organs (P=0.36). No patient in the HB group developed clinical liver disease because of viral hepatitis, and all patients alive (n=21) at follow-up are, to date, HBV DNA and/or HBcAb negative. All patients in the HC group tested HCV RNA positive; one patient died of liver failure at 22 months. Risk of viral transmission with HCV Ab+ allografts seems high after LTx. However, the use of HBcAb+ pulmonary allografts in recipients with prior hepatitis B vaccination seems to be a safe and effective strategy to increase organ availability.


The multifaceted mineralocorticoid receptor.
The primary adrenal cortical steroid hormones, aldosterone, and the glucocorticoids cortisol and corticosterone, act through the structurally similar mineralocorticoid (MR) and glucocorticoid receptors (GRs). Aldosterone is crucial for fluid, electrolyte, and hemodynamic homeostasis and tissue repair; the significantly more abundant glucocorticoids are indispensable for energy homeostasis, appropriate responses to stress, and limiting inflammation. Steroid receptors initiate gene transcription for proteins that effect their actions as well as rapid non-genomic effects through classical cell signaling pathways. GR and MR are expressed in many tissues types, often in the same cells, where they interact at molecular and functional levels, at times in synergy, others in opposition. Thus the appropriate balance of MR and GR activation is crucial for homeostasis. MR has the same binding affinity for aldosterone, cortisol, and corticosterone. Glucocorticoids activate MR in most tissues at basal levels and GR at stress levels. Inactivation of cortisol and corticosterone by 11β-HSD2 allows aldosterone to activate MR within aldosterone target cells and limits activation of the GR. Under most conditions, 11β-HSD1 acts as a reductase and activates cortisol/corticosterone, amplifying circulating levels. 11β-HSD1 and MR antagonists mitigate inappropriate activation of MR under conditions of oxidative stress that contributes to the pathophysiology of the cardiometabolic syndrome; however, MR antagonists decrease normal MR/GR functional interactions, a particular concern for neurons mediating cognition, memory, and affect.


Combined transplantation of small and large bowel. FK506 versus cyclosporine A in a porcine model.
Clinically, FK506 is superior to CsA after solitary small bowel transplantation (SBTx). Development of diarrhea after SBTx has been the rationale for adding the colon to small bowel grafts. However, the additional lymphoid and bacterial content transferred with total small plus large bowel transplants (TBTx) might aggravate the alloimmune response-rejection and graft-versus-host disease (GVHD)-and increase the risk of infection. We studied the incidence of rejection, GVHD, and infection after TBTx and the impact of CsA versus FK506. We performed orthotopic TBTx with portal drainage after total enterectomy in outbred Yorkshire Landrace pigs, divided into 3 groups: control pigs (n=6) received no immunosuppression; CsA pigs (n= 14) received CsA (5 mg/kg), antilymphocyte globulin (10 mg/kg for 10 days), prednisone (2 mg/kg), and AZA (2.5 mgtkg); and FK506 pigs (n=9) received FK506 (0.2 mg/kg) and prednisone (2 mg/kg). Trough CsA whole blood levels were >400 ng/ml for the first 7 days and >200 ng/ml thereafter. FK506 levels were > 15 ng/ml. We excluded from further analysis 5 early deaths (<3 days) due to anesthesiologic (n=2) or technical reasons (n=3). Median survival of control pigs was 9.5 days (range, 4-13). Cyclosporine did not extend survival: median, 9 days (range, 5-31) (P=0.6). FK506 prolonged survival: median, 37 days (range, 21-49) (P<0.001 vs. control and CsA pigs). Of FK506 pigs, 60% gained weight (+75 g/day), whereas 100% of controls and 75% of CsA pigs lost weight (-550 g/day and -300 g/day, respectively). All control pigs died of rejection within 2 weeks versus none of the FK506 pigs. However, 36% of CsA pigs died of rejection. Groupwise comparison showed less rejection in FK506 versus control pigs (P<0.001) and in FK506 versus CsA pigs (P<0.03), but no difference between CsA and control pigs. None of the control pigs died of GVHD versus 18% of CsA pigs (by day 31) and 37% of FK506 pigs (by day 49). Groupwise comparison showed increased GVHD in FK506 versus control pigs (P<0.001) and a tendency toward increased GVHD in FK506 versus CsA pigs (P=0.08). None of the control pigs died of infection alone versus 22% of CsA pigs (by day 31) and 67% of FK506 pigs (by day 49). Groupwise comparison showed increased infection in FK506 versus control pigs (P<0.001). We detected significant endotoxemia early and late postoperatively. But we saw no specific correlation between endotoxemia, rejection, GVHD, or infection. Based on this study, we have drawn several conclusions: (1) In untreated pigs, TBTx provokes a severe rejection response, but no lethal GVHD. (2) Cyclosporine and particularly FK506 pigs have a high incidence of infection and lethal GVHD, a complication that we had not seen after solitary SBTx. (3) FK506 is superior to CsA in controlling rejection and in prolonging graft and recipient survival; FK506, however, does not reduce GVHD, but rather tends to augment it. (4) TBTx causes endotoxemia. As with solitary SBTx, FK506 is superior to CsA after TBTx. However, longterm survival is difficult to achieve on FK506 recipients because of the development of GVHD and infection.


Electromagnetic scattering by fully ordered and quasi-random rigid particulate samples.
In this paper we have analyzed circumstances under which a rigid particulate sample can behave optically as a true discrete random medium consisting of particles randomly moving relative to each other during measurement. To this end, we applied the numerically exact superposition T-matrix method to model far-field scattering characteristics of fully ordered and quasi-randomly arranged rigid multiparticle groups in fixed and random orientations. We have shown that, in and of itself, averaging optical observables over movements of a rigid sample as a whole is insufficient unless it is combined with a quasi-random arrangement of the constituent particles in the sample. Otherwise, certain scattering effects typical of discrete random media (including some manifestations of coherent backscattering) may not be accurately replicated.


Adult and adolescent exposure to tobacco and alcohol content in contemporary YouTube music videos in Great Britain: a population estimate.
We estimate exposure of British adults and adolescents to tobacco and alcohol content from a sample of popular YouTube music videos. British viewing figures were generated from 2 representative online national surveys of adult and adolescent viewing of the 32 most popular videos containing content. 2068 adolescents aged 11-18 years (1010 boys, 1058 girls), and 2232 adults aged 19+years (1052 male, 1180 female) completed the surveys. We used the number of 10 s intervals in the 32 most popular videos containing content to estimate the number of impressions. We extrapolated gross and per capita impressions for the British population from census data and estimated numbers of adults and adolescents who had ever watched the sampled videos. From video release to the point of survey, the videos delivered an estimated 1006 million gross impressions of alcohol (95% CI 748 to 1264 million), and 203 million of tobacco (95% CI 151 to 255 million), to the British population. Per capita exposure was around 5 times higher for alcohol than for tobacco, and nearly 4 times higher in adolescents, who were exposed to an average of 52.1 (95% CI 43.4 to 60.9) and 10.5 (95% CI 8.8 to 12.3) alcohol and tobacco impressions, respectively, than in adults (14.1 (95% CI 10.2 to 18.1) and 2.9 (95% CI 2.1 to 3.6)). Exposure rates were higher in girls than in boys. YouTube music videos deliver millions of gross impressions of alcohol and tobacco content. Adolescents are exposed much more than adults. Music videos are a major global medium of exposure to such content.


Ultrastructural localization of the Pasteurella multocida toxin in a toxin-producing strain.
Toxigenic strains of Pasteurella multocida produce the 147 kDa protein Pasteurella multocida toxin (PMT) which is responsible for the osteoclastic bone resorption in progressive atrophic rhinitis in pigs and induces such resorption in all experimental animals tested so far. In the present study we have carried out immunocytochemistry on formaldehyde- and glutaraldehyde-fixed ultracryocut P. multocida using a pool of monoclonal antibodies against different epitopes on PMT as the first layer and affinity purified rabbit anti-mouse IgG as the second layer. Goat anti-rabbit IgG conjugated with 5 nm gold particles was used as marker. The gold particles were silver-enhanced prior to examination in the transmission electron microscope. Whole bacteria were also immunostained after fixation and critical point drying and examined by scanning transmission electron microscopy. The results showed that PMT was located in the cytoplasm of P. multocida. PMT could not be detected on intact, undamaged P. multocida by scanning electron microscopy. Neither pili nor flagella could be detected on the surface of the negatively stained P. multocida strains investigated. PMT has a series of characteristics encompassed in the definition of an exotoxin. However, that PMT was not secreted by living intact P. multocida is unexpected for an exotoxin.


The commensal bacterium Faecalibacterium prausnitzii is protective in DNBS-induced chronic moderate and severe colitis models.
The abundance of Faecalibacterium prausnitzii, an abundant and representative bacterium of Firmicutes phylum, has consistently been observed to be lower in patients with Crohn's disease than in healthy individuals. We have shown that both F. prausnitzii and its culture supernatant (SN) have anti-inflammatory and protective effects in a TNBS-induced acute colitis mouse model. Here, we tested the effects of both F. prausnitzii and its SN in moderate and severe DNBS-induced chronic colitis mouse models. Colitis was induced by intrarectal administration of DNBS. After either 4 or 10 days of recovery (severe and moderate protocols, respectively), groups of mice were intragastrically administered either with F. prausnitzii A2-165 or with its culture SN for 7 or 10 days. Three days before being sacrificed, colitis was reactivated by administration of a lower dose of DNBS. The severity of colitis at the time of being sacrificed was assessed by weight loss and macroscopic and microscopic scores. Myeloperoxidase (MPO) activity, cytokine levels, lymphocyte populations, and changes in microbiota were studied. Intragastric administration of either F. prausnitzii or its SN led to a significant decrease in colitis severity in both severe and moderate chronic colitis models. The lower severity of colitis was associated with down-regulation of MPO, pro-inflammatory cytokines, and T-cell levels. We show, for the first time, protective effects of both F. prausnitzii and its SN during both the period of recovery from chronic colitis and colitis reactivation. These results provide further evidence that F. prausnitzii is an anti-inflammatory bacterium with therapeutic potential for patients with inflammatory bowel disease.


Clinical and pathologic responses of American crows (Corvus brachyrhynchos) and fish crows (C ossifragus) to experimental West Nile virus infection.
West Nile virus (WNV)-associated disease has a range of clinical manifestations among avian taxa, the reasons for which are not known. Species susceptibility varies within the avian family Corvidae, with estimated mortality rates ranging from 50 to 100%. We examined and compared virologic, immunologic, pathologic, and clinical responses in 2 corvid species, the American crow (Corvus brachyrhynchos) and the fish crow (C ossifragus), following experimental WNV inoculation. Unlike fish crows, which remained clinically normal throughout the study, American crows succumbed to WNV infection subsequent to dehydration, electrolyte and pH imbalances, and delayed or depressed humoral immune responses concurrent with marked, widespread virus replication. Viral titers were approximately 3,000 times greater in blood and 30,000 to 50,000 times greater in other tissues (eg, pancreas and small intestine) in American crows versus fish crows. Histologic lesion patterns and antigen deposition supported the differing clinical outcomes, with greater severity and distribution of lesions and WNV antigen in American crows. Both crow species had multiorgan necrosis and inflammation, although lesions were more frequent, severe, and widespread in American crows, in which the most commonly affected tissues were small intestine, spleen, and liver. American crows also had inflammation of vessels and nerves in multiple tissues, including heart, kidney, and the gastrointestinal tract. WNV antigen was most commonly observed within monocytes, macrophages, and other cells of the reticuloendothelial system of affected tissues. Collectively, the data support that WNV-infected American crows experience uncontrolled systemic infection leading to multiorgan failure and rapid death.


3.42 µm lasing in heavily-erbium-doped fluoride fibers.
In this paper, we investigate laser emission at 3.4μm in heavily-erbium-doped fluoride fibers using dual-wavelength pumping. To this extent, a monolithic 7 mol% erbium-doped fluoride fiber laser bounded by intracore fiber Bragg gratings at 3.42 μm is used to demonstrate a record efficiency of 38.6 % with respect to the 1976 nm pump. Through numerical modeling, we show that similar laser performances at 3.4 μm can be expected in fluoride fibers with erbium concentrations ranging between 1 - 7 mol%, although power scaling should rely on lightly-doped fibers to mitigate the heat load. Moreover, this work studies transverse mode-beating of the 1976 nm core pump and its role in the generation of a periodic luminescent grating and in the trapping of excitation in the metastable energy levels of the erbium system. Finally, we also report on the bistability of the 3.42 μm output power of the 7 mol% erbium-doped fluoride fiber laser.


Cardiotocography plus ST analysis of fetal electrocardiogram compared with cardiotocography only for intrapartum monitoring: a randomized controlled trial.
To estimate the effectiveness of intrapartum fetal monitoring by cardiotocography plus ST analysis using a strict protocol for performance of fetal blood sampling. We performed a multicenter randomized trial among laboring women with a high-risk singleton pregnancy in cephalic presentation beyond 36 weeks of gestation. Participants were assigned to monitoring by cardiotocography with ST analysis (index) or cardiotocography only (control). Primary outcome was metabolic acidosis, defined as an umbilical cord artery pH below 7.05 combined with a base deficit calculated in the extracellular fluid compartment above 12 mmol/L. Secondary outcomes were metabolic acidosis in blood, operative deliveries, Apgar scores, neonatal admissions, and hypoxic-ischemic encephalopathy. We randomly assigned 5,681 women to the two groups (2,832 index, 2,849 control). The fetal blood sampling rate was 10.6% in the index compared with 20.4% in the control group (relative risk 0.52; 95% [CI] 0.46-0.59). The primary outcome occurred 0.7% in the index compared with 1.1% in the control group (relative risk 0.70; 95% CI 0.38-1.28; number needed to treat 252). Using metabolic acidosis calculated in blood, these rates were 1.6% and 2.6%, respectively (relative risk 0.63; 95% CI 0.42-0.94; number needed to treat 100). The number of operative deliveries, low Apgar scores, neonatal admissions, and newborns with hypoxic-ischemic encephalopathy was comparable in both groups. Intrapartum monitoring by cardiotocography combined with ST analysis does not significantly reduce the incidence of metabolic acidosis calculated in the extracellular fluid compartment. It does reduce the incidence of metabolic acidosis calculated in blood and the need for fetal blood sampling without affecting the Apgar score, neonatal admissions, hypoxic-ischemic encephalopathy, or operative deliveries. I.


Effect of Nursing Assessment on Predictive Delirium Models in Hospitalised Patients.
Delirium is an acute neuropsychiatric syndrome which is common in elderly patients during their hospitalisation and is associated with an increased mortality and morbidity. Since delirium is a) often underdiagnosed and b) preventable if early signs are detected,igh expectations are set in delirium risk assessment during hospital admission. In our latest studies, we showed that delirium prediction using machine learning algorithms is possible based on the patients' health history. The aim of this study is to compare the influence of nursing assessment data on prediction models with clinical and demographic data. We approached the problem by a) comparing the performance of predictive models including nursing data with models based on clinical and demographic data only and b) analysing the feature importance of all available features. From our results we concluded that nursing assessment data can improve the performance of delirium prediction models better than demographic, laboratory, diagnosis, procedures, and previous transfers' data alone.


The expression of intercellular adhesion molecule-1 and the beta 1-integrins in asthma.
Expression of intercellular adhesion molecule-1 (ICAM-1) appears to be important to the development of bronchial hyperresponsiveness and eosinophilia in Ascaris sensitized monkeys. Beta 1-integrins are expressed on epithelial cells, and may contribute to adherence of epithelial cells to the basement membrane. The aim of this study was to determine whether adhesion receptor expression was altered in human asthmatic bronchial epithelium. Using monoclonal antibody staining, we have examined the expression of ICAM-1 and the alpha 1-alpha 6-subunits of the beta 1-integrin family in bronchial mucosal biopsies from 33 asthmatic and 13 nonasthmatic subjects. The epithelium was positive for ICAM-1 in 26 out of 33 asthmatics, although negative in all 13 nonasthmatics. ICAM-1 expression was not associated with bronchial responsiveness or with medication requirements. Beta 1-integrin staining showed that alpha 2-, alpha 3- and alpha 6-subunits stained the epithelium in all cases. Alpha 4 staining was weakly positive in the epithelium in five asthmatics. Alpha 5 staining was weak in asthmatics and normals. Alpha 4 and alpha 6-subunits also stained inflammatory cells. Epithelial upregulation of ICAM-1 is present in asthma. Beta 1-integrins with alpha 2-, alpha 3- and alpha 6-subunits appear to be constitutively expressed in bronchial epithelium.


Championing eHealth in Clinical Care.
Since 1959, the rate of technological advancements, which has been buoyed by the evolution of microprocessors that stimulate innovation, has grown exponentially, doubling every 12 to 18 months (Roser & Ritchie, 2020). In 2020, it is impossible to walk down the street without seeing people checking their smartphones. However, it was only four decades ago that the personal computer was first introduced into the marketplace. It has been a little more than a decade since the first smartphone-the iPhone by Apple-was released in 2007, followed by the release of the iPad in 2010 (Zimmermann, 2017). As of 2019, an estimated 269 million people in the United States use smartphones (Holst, 2019). Increased technological advancements, as well as the widespread availability of these technologies and their application to Americans' daily lives, have become the norm. In the clinical nursing care of patients with cancer, the use of technology is also gaining momentum. This supplement to the Clinical Journal of Oncology Nursing explores how technology in health care can extend and enhance clinical oncology nursing care.


Novel agents in development for pediatric sarcomas.
The survival curves for many pediatric sarcomas have remained flat for the past 2 decades or more and novel therapeutics - those small molecule medicines that selectively inhibit specific signaling molecules - have been slow to enter into pediatric practice. The preclinical basis for their use is reviewed here. Preclinical and phase I studies showing efficacy of antiinsulin-like growth factor receptor 1 therapies for Ewing sarcoma have led to numerous ongoing clinical trials using these agents for Ewing and other sarcomas. Early studies of ERBB signaling as a target in sarcoma therapy have been tantalizing, but progress in this area has been controversial. In-vitro analysis of Src inhibitors suggested that these agents would prevent metastasis in osteosarcoma, whereas in-vivo analysis showed no effect on metastasis, underscoring the need for thorough preclinical investigations of promising new therapies to guide future clinical trials. Antiangiogenic and immunomodulatory therapies are gaining momentum in the pediatric arena and should be tested in combination with traditional cytotoxic agents for recurrent and high-risk primary pediatric sarcomas. Pediatric sarcomas have diverse biology and distinct signaling pathways, making detailed preclinical evaluation of small molecule inhibitors essential to guiding the design of further clinical investigations.


The transcription factor ETS-1: its role in tumour development and strategies for its inhibition.
Transcription factors are an important group of proteins. Changes in expression or activity of transcription factors result in diverse and manifold effects on the whole transcriptome of the cell. Therefore transcription factors are of special interest in physiological as well as pathological processes particularly tumour development and progression. In this review we focus on Ets-1, the prototype of the ETS family of transcription factors. ETS family members play important roles in development, differentiation and proliferation of cells in general and they are involved in apoptosis and tissue remodelling as well. Most of them are downstream nuclear targets of Ras-MAP kinase signalling and the deregulation of ets genes results in malignant transformation of different cells. Several ets genes are rearranged in human leukaemia, Ewing tumours and prostate cancer to produce chimeric oncoproteins. Furthermore, an aberrant expression of several ets genes is often observed in various types of human malignant tumours. With regard to the involvement of some ETS transcription factors, especially Ets-1, in malignant transformation and tumour progression (including invasion, metastasis and neoangiogenesis) through transactivation of cancer related genes, they are potential molecular targets for selective cancer therapy. In this review we focus on the roles of Ets-1 for tumour development and progression with special emphasis on tumour vascularization and invasion. We then discuss specific strategies for Ets-1 inhibition as a potential tool for cancer treatment.


Rehabilitation benefits highly motivated patients: a six-year prospective cost-effectiveness study.
To compare the six-year outcome of a multidisciplinary rehabilitation program with continued care within primary care in terms of health-related quality of life and cost-effectiveness. Furthermore, predictors of total costs to society were examined. A prospective, matched, controlled, six-year follow-up was designed. The study included 236 patients (42 men, 194 women) nineteen to sixty-one years of age with prolonged musculoskeletal disorders. The intervention comprised a four-week multidisciplinary rehabilitation and an active one-year follow-up based on a bio-psycho-social approach. The control group received continued care within primary care. The main outcome measures were quality of life measured using the Nottingham Health Profile, motivation identified by an interview and patient-specific total costs to society. Differences in mean costs between groups and cost-effectiveness were evaluated by applying nonparametric bootstrapping techniques. Total costs per treated patient in the rehabilitation group and the control group were pound 43,464 (SD = 31,093) and pound 44,123 (SD = 33,333), respectively (p = .896). Multidisciplinary rehabilitation improved quality of life somewhat more cost-effectively. Motivation was revealed as a predictor of total costs. In the long-run, the evaluated multidisciplinary rehabilitation improved the highly motivated patients' quality of life most cost-effectively. The latently motivated patients may require rehabilitation, which is less intensive and with a longer duration, to improve their health in a whole-person perspective. The burden of prolonged musculoskeletal disorders to society was reaffirmed. Motivation could be a predictor of total costs, a factor which has to be taken into account in the examination procedure.


Biological relativity revisited: the pre-eminent role of values.
Multilevel interpretations of development and evolution take to heart the contextual nature of both those processes, and so necessarily assume top-down causation occurs, right down to the physics level. In this article we revisit the Principle of Biological Relativity proposed by Noble in 2012, where all emergent levels of organisation are equally causally valid. While this is true in general for physical interactions between levels, we argue that in the case of conscious organisms making rational choices, there is indeed a preferred causal origin - namely the overall embracing influence of meaning and values. This is the opposite of what is suggested by a reductionist viewpoint, where it is the bottom-most physical level that is stated to be causally preferred (by some physicists), or the genetic level (by some evolutionary theorists). Charles Darwin was therefore correct to distinguish between Artificial (conscious) Selection, where values enter, and Natural Selection. The Modern Synthesis was wrong to exclude Darwin's distinction.


Non-phonological Strategies in Spelling Development.
This paper investigated the role that types of knowledge beyond phonology have on spelling development, such as knowledge of morpheme-to-grapheme mappings, of orthographic patterns, and of word-specific orthographic patterns. It is based on the modern view that children do not learn spelling in discrete stages but, rather, they apply different types of strategies from early on. The goals of the paper were threefold: (1) to determine the relative difficulty of different types of non-phonological spelling strategies, (2) to examine the contribution of non-phonological strategies (specifically, morphological, morphophonological, orthographic, and lexical) to conventional spelling scores, and (3) to determine the role of children's educational level and population type (first- vs. second-language learners) on spelling strategy use. A large sample of 982 children (497 boys), speakers of Catalan (a Romance language similar to Spanish but with a less consistent orthography), participated in the study. They were administered a bespoke dictation task aimed to test their conventional and phonographic accuracy skill, as well as to determine their ability to use different types of non-phonological strategies for the spelling of ambiguous phonemes. Data were analyzed with a series of multigroup, multilevel SEMs. Results showed that (1) children across groups found morphological and lexical strategies harder to apply than orthographic and morphophonological strategies and (2) all types of non-phonological strategies contributed greatly to spelling accuracy scores, even after controlling for children's phonographic skills. Efficient strategy use increased as a function of schooling level, while second-language learners had a worse performance throughout, but no group showed a specific pattern of results. In conclusion, the paper offers substantial evidence that non-phonological strategies are paramount to learning to spell at least during the early and intermediate elementary school years. It is suggested that the teaching of writing should therefore be multidimensional in nature and target particularly the strategies with which children struggle the most: knowledge of morpho-graphemic mappings and word-specific lexical representations. Theoretical implications are also discussed.


Cancer-on-a-chip for Drug Screening.
The oncology pharmaceutical research spent a shocking amount of money on target validation and drug optimization in preclinical models because many oncology drugs fail during clinical trial phase III. One of the most important reasons for oncology drug failures in clinical trials may due to the poor predictive tool of existing preclinical models. Therefore, in cancer research and personalized medicine field, it is critical to improve the effectiveness of preclinical predictions of the drug response of patients to therapies and to reduce costly failures in clinical trials. Three dimensional (3D) tumor models combine micro-manufacturing technologies mimic critical physiologic parameters present in vivo, including complex multicellular architecture with multicellular arrangement and extracellular matrix deposition, packed 3D structures with cell-cell interactions, such as tight junctions, barriers to mass transport of drugs, nutrients and other factors, which are similar to in vivo tumor tissues. These systems provide a solution to mimic the physiological environment for improving predictive accuracy in oncology drug discovery. This review gives an overview of the innovations, development and limitations of different types of tumor-like construction techniques such as self-assemble spheroid formation, spheroids formation by micro-manufacturing technologies, micro-dissected tumor tissues and tumor organoid. Combination of 3D tumor-like construction and microfluidic techniques to achieve tumor on a chip for in vitro tumor environment modeling and drug screening were all included. Eventually, developmental directions and technical challenges in the research field are also discussed. We believe tumor on chip models have provided better sufficient clinical predictive power and will bridge the gap between proof-of-concept studies and a wider implementation within the oncology drug development for pathophysiological applications.


Hemolysate-induced contraction in smooth muscle cells of the guinea pig basilar artery.
The hemolysate (10(-5)-10(-2) times dilution; original hemoglobin concentration was 0.83 +/- 0.10 X 10(-3)M) evoked the contraction in a dose dependent manner, and this contraction was composed of low and high sensitive responses as estimated from the Eadie-Hofstee's plot. Indomethacin (10(-7)-10(-5)M) inhibited the latter component in the hemolysate-induced contraction. The membrane potential of smooth muscle cells was -50 mV and the cell was electrically quiescent. The hemolysate (greater than 10(-2) times dilution) depolarized the membrane and increased the ionic conductance of membrane. In rare occasions, the spike potential was triggered on the hemolysate-induced depolarization. The hemolysate (10(-5)-3 X 10(-3) times dilution) produced the contraction with no change in the membrane property. Carbocyclic thromboxane A2 ( cTXA2 ; 2.8 X 10(-10)M) produced the contraction without depolarization of the membrane, yet the TXA2 synthesis inhibitor, OKY-1581 (10(-5)M), had no effect on the hemolysate-induced contraction. PGE1, PGE2 and PGF2 alpha (2.8 X 10(-6)M) produced the contraction with no change in the membrane property. The contraction evoked by 2.8 X 10(-6)M PGF2 alpha corresponded well with that evoked by 3 X 10(-3) times dilution of the hemolysate. Removal of the endothelium by mechanical rubbing modified the hemolysate-induced contraction. Under the assumption that OKY-1581 is a selective inhibitor for TXA2 synthesis, the major part of the contraction (the indomethacin sensitive component) of the basilar artery is postulated to be due to synthesis of the primary PG rather than TXA2 by the hemolysate, yet the hemolysate itself, has to some extent a direct action in evoking the small contraction.


Amelioration of diabetic nephropathy in db/db mice treated with tibetan medicine formula Siwei Jianghuang Decoction Powder extract.
Siwei Jianghuang Decoction Powder (SWJH) documented originally in the Four Medical Tantras-Blue Glaze exhibited beneficial effects on diabetic nephropathy (DN) via combined synergistically action of multiple formula components including Curcumae longae Rhizoma, Berberidis dictyophyllae Cortex, Phyllanthi Fructus and Tribuli Fructus. This study investigated the effects of SWJH on DN in db/db mice and possible underlying mechanisms. The ten weeks old db/db mice treated with SWJH by intra-gastric administration once a day for 8 weeks. After 8 weeks, body weight, water and food intake of mice were recorded. The level of fasting blood glucose (FBG) was measured. Serum creatinine (Scr), blood urea nitrogen (BUN), urine microalbumin (UMAlb), serum uric acid (UA) and urinary albumin excretion (UAE) were detected. An enzyme-linked immunosorbent assay was performed to test serum vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1). Real-time PCR and Western blot analysis were used to test mRNA and protein expression of hypoxia inducible factor-1α (HIF-1α), VEGF and TGF-β1 in kidney tissue. SWJH treatment significantly reduced the levels of FBG, Scr, BUN, UMAlb, UA and UAE and retarded renal fibrosis. SWJH treatment further significantly reduced serum TGF-β1 level and downregulated the expression of HIF-1α, VEGF and TGF-β1 at both mRNA and protein levels. Principal component analysis and partial least squares regression and hierarchical cluster analysis demonstrated that SWJH treatment significantly ameliorated renal damage in DN mice. These consequences suggested that SWJH formulations were effective in the treatment of DN through regulating the HIF-1α, VEGF and TGF-β1 overexpression.


Choroid plexus papilloma-A case highlighting the challenges of extrapolating pediatric chemotherapy regimens to adult populations.
The treatment of adults who present with rare pediatric tumors is not characterized well in the literature. We report an instance of a 40-year-old African American woman with a diagnosis of choroid plexus carcinoma admitted to the intensive care unit for severe sepsis seven days after receiving chemotherapy consisting of carboplatin (350 mg/m(2) on Days 1 and 2 plus etoposide 100 mg/m(2) on Days 1-5). Her laboratory results were significant for an absolute neutrophil count of 0/µL and blood cultures positive for Capnocytophagia species. She was supported with broad spectrum antibiotics and myeloid growth factors. She eventually recovered and was discharged in stable condition. The management of adults with malignancies most commonly seen in pediatric populations presents substantial challenges. There are multiple age-specific differences in renal and hepatic function that explain the need for higher dosing in pediatric patients without increasing the risk of toxicity. Furthermore, differences in pharmacokinetic parameters such as absorption, distribution, and clearance are present but are less likely to affect patients. It is expected that the pediatric population will have more bone marrow reserve and, therefore, less susceptible to myelosuppression. The extrapolation of pediatric dosing to an adult presents a problematic situation in treating adults with malignancies that primarily effect pediatric patients. We recommend extrapolating from adult treatment regimens with similar agents rather than extrapolating from pediatric treatment regimens to reduce the risk of toxicity. We also recommend the consideration of adding myeloid growth factors. If the treatment is tolerated without significant toxicity, dose escalation can be considered.


Proteomic Analysis of Microtubule Interacting Proteins over the Course of Xylem Tracheary Element Formation in Arabidopsis.
Plant vascular cells, or tracheary elements (TEs), rely on circumferential secondary cell wall thickenings to maintain sap flow. The patterns in which TE thickenings are organized vary according to the underlying microtubule bundles that guide wall deposition. To identify microtubule interacting proteins present at defined stages of TE differentiation, we exploited the synchronous differentiation of TEs in Arabidopsis thaliana suspension cultures. Quantitative proteomic analysis of microtubule pull-downs, using ratiometric (14)N/(15)N labeling, revealed 605 proteins exhibiting differential accumulation during TE differentiation. Microtubule interacting proteins associated with membrane trafficking, protein synthesis, DNA/RNA binding, and signal transduction peaked during secondary cell wall formation, while proteins associated with stress peaked when approaching TE cell death. In particular, CELLULOSE SYNTHASE-INTERACTING PROTEIN1, already associated with primary wall synthesis, was enriched during secondary cell wall formation. RNAi knockdown of genes encoding several of the identified proteins showed that secondary wall formation depends on the coordinated presence of microtubule interacting proteins with nonoverlapping functions: cell wall thickness, cell wall homogeneity, and the pattern and cortical location of the wall are dependent on different proteins. Altogether, proteins linking microtubules to a range of metabolic compartments vary specifically during TE differentiation and regulate different aspects of wall patterning.


An Observed Effect of p53 Status on the Bystander Response to Radiation-Induced Cellular Photon Emission.
In this study, we investigated the potential influence of p53 on ultraviolet (UV) signal generation and response of bystander cells to the UV signals generated by beta-irradiated cells. Five cell lines of various p53 status (HaCaT, mutated; SW48, wild-type; HT29, mutated; HCT116+/+, wild-type; HCT116-/-, null) were irradiated with beta particles from tritium. Signal generation (photon emission at 340 ± 5 nm) was quantified from irradiated cells using a photomultiplier tube. Bystander response (clonogenic survival) was assessed by placing reporter cell flasks directly superior to irradiated signal-emitting cells. All cell lines emitted significant quantities of UV after tritium exposure. The magnitudes of HaCaT and HT29 photon emission at 340 nm were similar to each other while they were significantly different from the stronger signals emitted from SW48, HCT116+/+ and HCT116-/- cells. In regard to the bystander responses, HaCaT, HCT116+/+ and SW48 cells demonstrated significant reductions in survival as a result of exposure to emission signals. HCT116-/- and HT29 cells did not exhibit any changes in survival and thus were considered to be lacking the mechanisms or functions required to elicit a response. The survival response was found not to correlate with the observed signal strength for all experimental permutations; this may be attributed to varying emission spectra from cell line to cell line or differences in response sensitivity. Overall, these results suggest that the UV-mediated bystander response is influenced by the p53 status of the cell line. Wild-type p53 cells (HCT116+/+ and SW48) demonstrated significant responses to UV signals whereas the p53-null cell line (HCT116-/-) lacked any response. The two mutated p53 cell lines exhibited contrasting responses, which may be explained by unique modulation of functions by different point mutations. The reduced response (cell death) exhibited by p53-mutated cells compared to p53 wild-type cells suggests a possible role of the assessed p53 mutations in radiation-induced cancer susceptibility and reduced efficacy of radiation-directed therapy.


Does long-term care subsidization reduce hospital admissions and utilization?
We use quasi-experimental evidence on the expansion of the public subsidization of long-term care to examine the causal effect of a change in caregiving affordability on the delivery of hospital care. More specifically, we examine a reform that both introduced a new caregiving allowance and expanded the availability of publicly funded home care services, on both hospital admissions (both on the internal and external margin) and length of stay. We find robust evidence of a reduction in both hospital admissions and utilization among both those receiving a caregiving allowance and, albeit less intensely, among beneficiaries of publicly funded home care, which amounts to 11% of total healthcare costs. These effects were stronger when regions had an operative regional health and social care coordination plan in place. Consistently, a subsequent reduction in the subsidy, five years after its implementation, is found to significantly attenuate such effects. We investigate a number of potential mechanisms, and show a number of falsification and robustness checks.


Protective Effect of Carvacrol on Oxidative Stress and Cellular DNA Damage Induced by UVB Irradiation in Human Peripheral Lymphocytes.
Exposure to ultraviolet B (UVB; 280-320 nm) radiation induces the formation of reactive oxygen species (ROS) in the biological system. In this study, we examined the protective effect of carvacrol on UVB-induced lipid peroxidation and oxidative DNA damage with reference to alterations in cellular an-tioxidant status in human lymphocytes. A series of in vitro assays (hydroxyl radical, superoxide, nitric oxide, DPPH (2,2-Diphenyl-1-picryl hydrazyl), and ABTS (2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging assays) demonstrate antioxidant property of carvacrol in our study. UVB exposure significantly increased thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LHPs), % tail DNA and tail moment; decreased % cell viability and antioxidant status in UVB-irradiated lymphocytes. Treatment with carvacrol 30 min prior to UVB-exposure resulted in a significant decline of TBARS, LHP, % tail DNA, and tail moment and increased % cell viability as carvacrol concentration increased. UVB irradiated lymphocytes with carvacrol alone (at 10 μg/mL) gave no significant change in cell viability, TBARS, LHP, % tail DNA, and tail moment when compared with normal lymphocytes. On the basis of our results, we conclude that carvacrol, a dietary antioxidant, mediates its protective effect through modulation of UVB-induced ROS.


Energetics of Shaker K channels block by inactivation peptides.
A synthetic peptide of the NH2-terminal inactivation domain of the ShB channel blocks Shaker channels which have an NH2-terminal deletion and mimics many of the characteristics of the intramolecular inactivation reaction. To investigate the role of electrostatic interactions in both peptide block and the inactivation process we measured the kinetics of block of macroscopic currents recorded from the intact ShB channel, and from ShB delta 6-46 channels in the presence of peptides, at different ionic strengths. The rate of inactivation and the association rate constants (k(on)) for the ShB peptides decreased with increasing ionic strength. k(on) for a more positively charged peptide was more steeply dependent on ionic strength consistent with a simple electrostatic mechanism of enhanced diffusion. This suggests that a rate limiting step in the inactivation process is the diffusion of the NH2-terminal domain towards the pore. The dissociation rates (k(off)) were insensitive to ionic strength. The temperature dependence of k(on) for the ShB peptide was very high, (Q10 = 5.0 +/- 0.58), whereas k(off) was relatively temperature insensitive (Q10 approximately 1.1). The results suggest that at higher temperatures the proportion of time either the peptide or channel spends in the correct conformation for binding is increased. There were two components to the time course of recovery from block by the ShB peptide, indicating two distinct blocked states, one of which has similar kinetics and dependence on external K+ concentration as the inactivated state of ShB. The other is voltage-dependent and at -120 mV is very unstable. Increasing the net charge on the peptide did not increase sensitivity to knock-off by external K+. We propose that the free peptide, having fewer constraints than the tethered NH2-terminal domain binds to a similar site on the channel in at least two different conformations.


Higher adenoma detection rates with endocuff-assisted colonoscopy - a randomized controlled multicenter trial.
The Endocuff is a device mounted on the tip of the colonoscope to help flatten the colonic folds during withdrawal. This study aimed to compare the adenoma detection rates between Endocuff-assisted (EC) colonoscopy and standard colonoscopy (SC). This randomized prospective multicenter trial was conducted at four academic endoscopy units in Germany. 500 patients (235 males, median age 64[IQR 54-73]) for colon adenoma detection purposes were included in the study. All patients were either allocated to EC or SC. The primary outcome measure was the determination of the adenoma detection rates (ADR). The ADR significantly increased with the use of the Endocuff compared to standard colonoscopy (35.4%[95% confidence interval{CI} 29-41%] vs. 20.7%[95%CI 15-26%], p<0.0001). Significantly more sessile polyps were detected by EC. Overall procedure time and withdrawal time did not differ. Caecal and ileum intubation rates were similar. No major adverse events occurred in both groups. In multivariate analysis, age (odds ratio [OR] 1.03; 95%[CI] 1.01-1.05), male sex (OR 1.74; 95%CI 1.10-2.73), withdrawal time (OR 1.16; 95%CI 1.05-1.30), procedure time (OR 1.07; 95%CI 1.04-1.10), colon cleanliness (OR 0.60; 95%CI 0.39-0.94) and use of Endocuff (OR 2.09; 95%CI 1.34-3.27) were independent predictors of adenoma detection rates. EC increases the adenoma detection rate by 14.7%(95%CI 6.9-22.5%). EC is safe, effective, easy to handle and might reduce colorectal interval carcinomas. ClinicalTrials.gov NCT02034929.


Acting via a cell surface receptor, thyroid hormone is a growth factor for glioma cells.
Recent evidence suggests that the thyroid hormone L-thyroxine (T4) stimulates growth of cancer cells via a plasma membrane receptor on integrin alphaVbeta3. The contribution of this recently described receptor for thyroid hormone and receptor-based stimulation of cellular mitogen-activated protein kinase [MAPK; extracellular signal-regulated kinase 1/2 (ERK1/2)] activity, to enhancement of cell proliferation by thyroid hormone was quantitated functionally and by immunologic means in three glioma cell lines exposed to T4. At concentrations of 1 to 100 nmol/L, T4 caused proliferation of C6, F98, and GL261 cells, measured by accumulation of proliferating cell nuclear antigen (PCNA) and radiolabeled thymidine incorporation. This effect was inhibited by the T4 analogue, tetraiodothyroacetic acid, and by an alphaVbeta3 RGD recognition site peptide, both of which block T4 binding to integrin alphaVbeta3 but are not agonists. Activation of MAPK by T4 was similarly inhibited by tetraiodothyroacetic acid and the RGD peptide. The thyroid hormone 3,5,3'-triiodo-L-thyronine (T3) and T4 were equipotent stimulators of PCNA accumulation in C6, F98, and GL261 cells, but physiologic concentrations of T3 are 50-fold lower than those of T4. In conclusion, our studies suggest that glioblastoma cells are thyroid hormone dependent and provide a molecular basis for recent clinical observations that induction of mild hypothyroidism may improve duration of survival in glioblastoma patients. The present experiments infer a novel cell membrane receptor-mediated basis for the growth-promoting activity of thyroid hormone in such tumors and suggest new therapeutic approaches to the treatment of patients with glioblastoma.


Rapid development of non-alcoholic steatohepatitis in Psammomys obesus (Israeli sand rat).
A major impediment to establishing new treatments for non-alcoholic steatohepatitis is the lack of suitable animal models that accurately mimic the biochemical and metabolic characteristics of the disease. The aim of this study was to explore a unique polygenic animal model of metabolic disease as a model of non-alcoholic steatohepatitis by determining the effects of 2% dietary cholesterol supplementation on metabolic and liver endpoints in Psammomys obesus (Israeli sand rat). P. obesus were provided ad libitum access to either a standard rodent diet (20% kcal/fat) or a standard rodent diet supplemented with 2% cholesterol (w/w) for 4 weeks. Histological sections of liver from animals on both diets were examined for key features of non-alcoholic steatohepatitis. The expression levels of key genes involved in hepatic lipid metabolism were measured by real-time PCR. P. obesus fed a cholesterol-supplemented diet exhibited profound hepatomegaly and steatosis, and higher plasma transaminase levels. Histological analysis identified extensive steatosis, inflammation, hepatocyte injury and fibrosis. Hepatic gene expression profiling revealed decreased expression of genes involved in delivery and uptake of lipids, and fatty acid and triglyceride synthesis, and increased expression of genes involved in very low density lipoprotein cholesterol synthesis, triglyceride and cholesterol export. P. obesus rapidly develop non-alcoholic steatohepatitis when fed a cholesterol-supplemented diet that appears to be histologically and mechanistically similar to patients.


Administration of hydrogen-rich saline in mice with allogeneic hematopoietic stem-cell transplantation.
Hydrogen, as a novel antioxidant, has been shown to selectively reduce the level of hydroxyl radicals and alleviate acute oxidative stress in many animal experiments. Hydrogen-rich saline provides a high concentration of hydrogen that can be easily and safely applied. Allogeneic hematopoietic stem-cell transplantation (HSCT) has been the most curative therapy for hematological malignancies. However, acute graft-versus-host disease (aGVHD) is the main cause of death in post-transplantation patients. In this study, we examined whether hydrogen-rich saline would show favorable effects on acute GVHD in mice. After lethal irradiation, BALB/c mice received bone marrow transplantation from C57BL/6 mice. Hydrogen-rich saline (5 ml/kg) was given to recipient mice in the hydrogen group once a day by intraperitoneal injection, and saline (5 ml/kg) was given to recipient mice in the saline group. Survival rates were monitored, clinical and pathological scores of aGVHD were determined after bone marrow transplantation (BMT), and the serum cytokine levels were examined on the 7th day after BMT. This study proves that hydrogen-rich saline increased the survival rate, reduced clinical and histopathological scores of aGVHD, promoted the recovery of white blood cells, reduced the serum cytokine levels, and reversed tissue damage after transplantation in mice. Hydrogen has potential as an effective and safe therapeutic agent in aGVHD.


How much does a verbal autopsy based mortality surveillance system cost in rural India?
This paper aims to determine the cost of establishing and sustaining a verbal-autopsy based mortality surveillance system in rural India. Deaths occurring in 45 villages (population 185,629) were documented over a 4-year period from 2003-2007 by 45 non-physician healthcare workers (NPHWs) trained in data collection using a verbal autopsy tool. Causes of death were assigned by 2 physicians for the first year and by one physician for the subsequent years. Costs were calculated for training of interviewers and physicians, data collection, verbal autopsy analysis, project management and infrastructure. Costs were divided by the number of deaths and the population covered in the year. Verbal-autopsies were completed for 96.7% (5786) of all deaths (5895) recorded. The annual cost in year 1 was INR 1,133,491 (USD 24,943) and the total cost per death was INR 757 (USD 16.66). These costs included training of NPHWs and physician reviewers Rs 67,025 (USD 1474), data collection INR 248,400 (USD 5466), dual physician review for cause of death assignment INR 375,000 (USD 8252), and project management INR 341,724 (USD 7520). The average annual cost to run the system each year was INR 822,717 (USD18104) and the cost per death was INR 549 (USD 12) for the next 3 years. Costs were reduced by using single physician review and shortened re-training sessions. The annual cost of running a surveillance system was INR 900,410 (USD 19814). This study provides detailed empirical evidence of the costs involved in running a mortality surveillance site using verbal-autopsy.


Accuracy of Jump-Mat Systems for Measuring Jump Height.
Vertical-jump tests are commonly used to evaluate lower-limb power of athletes and nonathletes. Several types of equipment are available for this purpose. To compare the error of measurement of 2 jump-mat systems (Chronojump-Boscosystem and Globus Ergo Tester) with that of a motion-capture system as a criterion and to determine the modifying effect of foot length on jump height. Thirty-one young adult men alternated 4 countermovement jumps with 4 squat jumps. Mean jump height and standard deviations representing technical error of measurement arising from each device and variability arising from the subjects themselves were estimated with a novel mixed model and evaluated via standardization and magnitude-based inference. The jump-mat systems produced nearly identical measures of jump height (differences in means and in technical errors of measurement ≤1 mm). Countermovement and squat-jump height were both 13.6 cm higher with motion capture (90% confidence limits ±0.3 cm), but this very large difference was reduced to small unclear differences when adjusted to a foot length of zero. Variability in countermovement and squat-jump height arising from the subjects was small (1.1 and 1.5 cm, respectively, 90% confidence limits ±0.3 cm); technical error of motion capture was similar in magnitude (1.7 and 1.6 cm, ±0.3 and ±0.4 cm), and that of the jump mats was similar or smaller (1.2 and 0.3 cm, ±0.5 and ±0.9 cm). The jump-mat systems provide trustworthy measurements for monitoring changes in jump height. Foot length can explain the substantially higher jump height observed with motion capture.


Ambient air pollution and low birth weight - are some women more vulnerable than others?
Ambient air pollution is controllable, and it is one of the greatest environmental threats to human health. Studies conducted worldwide have provided evidence that maternal exposure to ambient air pollution during pregnancy enhances the risk of low birth weight at term (TLBW, <2500g among infants born ≥37 completed weeks of gestation), a maker of intrauterine growth restriction (IUGR), and suggest that some subgroups of pregnant women who are smoking, of low or high body-mass index (BMI), low socioeconomic status (SES) or asthma are more vulnerable towards the effect of ambient air pollution. The aim of this commentary is to review the published literature on the association between ambient air pollution and TLBW regarding increased vulnerability for the above-mentioned subgroups. Although more than fifty epidemiological studies have examined the associations between ambient air pollution and TLBW to date, we only identified six studies that examined the potential effect modification of the association between ambient air pollution and TLBW by the above listed maternal risk factors. Two studies assessed effect modification caused by smoking on the association between ambient air pollution and TLBW. The adjusted odds ratio (OR) for TLBW associated with exposure to ambient air pollution were in one study higher among women who smoked during pregnancy, as compared to the OR of non-smoking women, while in the other study the association was in the opposite direction. The association of ambient air pollution and TLBW were higher among women characterized by extreme BMI (two studies) and low SES compared to non-obese women or women of higher SES (four studies), respectively. Only one study reported the estimated effects among asthmatic and non-asthmatic women and no statistically significant effect modification was evident for the risk of TLBW associated with ambient air pollution. The current epidemiologic evidence is scarce, but suggests that pregnant women who are smoking, being underweight, overweight/obese or having lower SES are a vulnerable subpopulation when exposed to ambient air pollution, with and increased risk of having a child with TLBW. The limited evidence precludes for definitive conclusions and further studies are recommended.


Superinfection exclusion in cells infected with hepatitis C virus.
Superinfection exclusion is the ability of an established virus infection to interfere with infection by a second virus. In this study, we found that Huh-7.5 cells acutely infected with hepatitis C virus (HCV) genotype 2a (chimeric strain J6/JFH) and cells harboring HCV genotype 1a, 1b, or 2a full-length or subgenomic replicons were resistant to infection with cell culture-produced HCV (HCVcc). Replicon-containing cells became permissive for HCVcc infection after treatment with an HCV-specific protease inhibitor. With the exception of cells harboring a J6/JFH-FLneo replicon, infected or replicon-containing cells were permissive for HCV pseudoparticle (HCVpp) entry, demonstrating a postentry superinfection block downstream of primary translation. The surprising resistance of J6/JFH-FLneo replicon-containing cells to HCVpp infection suggested a defect in virus entry. This block was due to reduced expression of the HCV coreceptor CD81. Further analyses indicated that J6/JFH may be toxic for cells expressing high levels of CD81, thus selecting for a CD81(low) population. CD81 down regulation was not observed in acutely infected cells, suggesting that this may not be a general mechanism of HCV superinfection exclusion. Thus, HCV establishes superinfection exclusion at a postentry step, and this effect is reversible by treatment of infected cells with antiviral compounds.


First Report of Penicillium expansum Causing Postharvest Blue Mold of Fresh Date Palm Fruit (Phoenix dactylifera) in Spain.
A survey of postharvest losses of commercially handled and cold-stored fruit of fresh date palm (Phoenix dactylifera L.), cvs. Medjool and Hayani, was conducted in the 2009 and 2010 seasons in the grove of Elx (Alacant Province, Southeast Spain). Disease symptoms consisting of circular, light brown, soft spots located in any part of the fruit skin were observed in 2 to 5% of the fruit. At room temperature, the lesions expanded rapidly and blue mold symptoms were apparent. The potential causal agent (isolate IVIA NiAA-2) was transferred to PDA and incubated at 25°C. The identification was performed at the Spanish Type Culture Collection (CECT, University of Valencia, Spain) based on colony morphology of the isolate grown on Czapeck yeast extract agar (CYA) and malt extract agar (MEA) at 26°C. Colonies were circular (average diameter of 40 mm at 7 days), radially sulcate, with dense velvety white mycelium, and very abundant, bluish green conidia. The underside of the plates showed light brown and pale green colonies on CYA and MEA, respectively. On CYA, but not on MEA, a light yellow exudate was produced and a brownish pigment diffused into the medium. At 5 and 37°C on CYA, white microcolonies and no colonies were observed, respectively. Conidia were ellipsoidal to subglobose, smooth and thin walled, measuring 3.0 to 3.5 × 2.5 to 3.0 μm (n = 50) (4). Based on these morphological characteristics, the isolate IVIA NiAA-2 was tentatively identified as Penicillium expansum L. To confirm the identity, we amplified and sequenced the rDNA internal transcribed spacer (ITS) region with primers ITS1 and ITS4 (GenBank Accession No. KC169942). A BLAST search showed 99% identity and 100% query coverage with P. expansum strain NRRL 6069 (DQ339562) (2). Selected healthy dates cv. Medjool were surface disinfected by dipping in 0.5% sodium hypochlorite for 2 min followed by thorough rinsing in deionized water. Pathogenicity was tested by pipetting 20 μl of a spore suspension (1 × 106 spores per ml), prepared from 7-day PDA cultures, onto fresh skin wounds, which were made on disinfected fruit using a sterile, stainless steel rod with a probe tip 1 mm in width × 2 mm in length (one wound on each of nine dates, incubated in one humid chamber). Disinfected, wounded, and non-inoculated dates were used as controls. The procedure was repeated three times. Disease symptoms were observed on all inoculated fruit (average lesion size of 6, 15, and 22 mm after 4, 7, and 10 days of incubation at 20°C, respectively) and P. expansum was consistently reisolated, thereby fulfilling Koch's postulates. No decay was observed on any of the non-inoculated fruit. Unidentified species of Penicillium have been reported to cause date palm fruit rot (1,3). To our knowledge, this is the first report of P. expansum causing postharvest decay of date palm fruit in Spain. References: (1) M. Djerbi. Diseases of the Date Palm. FAO Regional Project, Rome, 1983. (2) M. A. Dombrink-Kurtzman. Antonie Van Leeuwenhoek 91:179, 2007. (3) S. Ibrahim and M. A. Rahma. Bayero J. Pure Appl. Sci. 2:127, 2009. (4) R. A. Samson et al. Introduction to Food-Borne Fungi. Centraalbureau voor Schimmelcultures, Baarn, the Netherlands, 1995.


Increased dentate neurogenesis after grafting of glial restricted progenitors or neural stem cells in the aging hippocampus.
Neurogenesis in the dentate gyrus (DG) declines severely by middle age, potentially because of age-related changes in the DG microenvironment. We hypothesize that providing fresh glial restricted progenitors (GRPs) or neural stem cells (NSCs) to the aging hippocampus via grafting enriches the DG microenvironment and thereby stimulates the production of new granule cells from endogenous NSCs. The GRPs isolated from the spinal cords of embryonic day 13.5 transgenic F344 rats expressing human alkaline phosphatase gene and NSCs isolated from embryonic day 9 caudal neural tubes of Sox-2:EGFP transgenic mice were expanded in vitro and grafted into the hippocampi of middle-aged (12 months old) F344 rats. Both types of grafts survived well, and grafted NSCs in addition migrated to all layers of the hippocampus. Phenotypic characterization revealed that both GRPs and NSCs differentiated predominantly into astrocytes and oligodendrocytic progenitors. Neuronal differentiation of graft-derived cells was mostly absent except in the dentate subgranular zone (SGZ), where some of the migrated NSCs but not GRPs differentiated into neurons. Analyses of the numbers of newly born neurons in the DG using 5'-bromodeoxyuridine and/or doublecortin assays, however, demonstrated considerably increased dentate neurogenesis in animals receiving grafts of GRPs or NSCs in comparison with both naïve controls and animals receiving sham-grafting surgery. Thus, both GRPs and NSCs survive well, differentiate predominantly into glia, and stimulate the endogenous NSCs in the SGZ to produce more new dentate granule cells following grafting into the aging hippocampus. Grafting of GRPs or NSCs therefore provides an attractive approach for improving neurogenesis in the aging hippocampus. Disclosure of potential conflicts of interest is found at the end of this article.


Effects of cervical adjustments on lateral-flexion passive end-range asymmetry and on blood pressure, heart rate and plasma catecholamine levels.
The biomechanical and physiological effects of a single, unilateral lower cervical spinal adjustment delivered to the most restricted side of cervical lateral-flexion passive end-range were examined. Only healthy, asymptomatic male subjects who exhibited goniometrically verified lateral-flexion passive range of motion asymmetries of 10 degrees or greater on the morning of the experiment were chosen for the study. Posttreatment goniometric measurements revealed that in sham-adjusted controls, mean lateral-flexion asymmetries had not changed significantly during the 4-hr time period examined. However, in subjects who received lower cervical adjustments, dramatic ameliorations of asymmetry magnitude were observed which persisted throughout the entire 4-hr posttreatment time period. On the other hand, in the face of this rather robust biomechanical effect, heart rate and blood pressure measurements obtained at -60 and -15 min prior to treatments, and at 5, 30, 60, 120 and 240 min following treatments, revealed no significant differences between adjusted and sham-adjusted subjects at any of the time periods examined. Consistent with this, analysis of the plasma concentrations of norepinephrine, epinephrine and dopamine in serial blood samples collected at these same times also failed to reveal significant differences between treatment groups at any of the time periods examined. The results of this investigation indicate that lower cervical adjustments are capable, at least in asymptomatic subjects, of inducing relatively robust biomechanical effects related to passive cervical end-range capability without simultaneously inducing significant alterations in the overall activity of the sympathetic nervous system.


Effects of methionine and guanidinoacetic acid supplementation on performance and energy metabolites in breast muscle of male broiler chickens fed corn-soybean diets.
1. Guanidinoacetic acid (GAA) is the single endogenous precursor of creatine, which plays a critical role in energy homeostasis of cells. Since GAA is endogenously converted to creatine by methylation, it was hypothesised that the effects of dietary GAA supplementation might determine the methionine (Met) availability in corn-soybean based diets. 2. A total of 540, one-day-old male Ross 308 broilers were allocated to nine dietary treatments with six replicates (10 birds each) in a 3 × 3 factorial arrangement with three graded levels of supplementary Met (+0.4 g/kg per level), whilst cystine was equal across groups, resulting in a low, medium and high level of total sulphur amino acids, and with three levels of GAA (0, 0.6 and 1.2 g/kg). Birds were fed for 42 days. 3. Increasing levels of supplemental Met enhanced performance indices in all rearing periods, although there was no effect on feed conversion ratio in the grower or feed intake in the finisher periods. Final body weight was 8.8% and 14.6% higher in the birds fed medium and high Met diets, respectively, compared to the low Met level. Relative breast weight and protein content in muscle on d 25 linearly increased with higher levels of Met. At low and high Met levels, growth in the finisher phase was negatively affected by supplementing GAA at 1.2 g/kg. It was suggested that disturbances in methylation homeostasis and/or changes in Arg metabolism might explain these findings. At the end of the grower phase, muscle creatine content was higher when feeding GAA at 0.6 and 1.2 g/kg (4464 and 4472, respectively, vs. 4054 mg/kg fresh muscle in the control group). 4. The effects of dietary GAA supplementation were influenced by the dietary Met level only in the finisher period, which indicates the need for proper sulphur amino acid formulation in diets when feeding GAA.