Neurocognitive Aging and the Hippocampus across Species.
There is extensive evidence that aging is associated with impairments in episodic memory. Many of these changes have been ascribed to neurobiological alterations to the hippocampal network and its input pathways. A cross-species consensus is beginning to emerge suggesting that subtle synaptic and functional changes within this network may underlie the majority of age-related memory impairments. In this review we survey convergent data from animal and human studies that have contributed significantly to our understanding of the brain-behavior relationships in this network, particularly in the aging brain. We utilize a cognitive as well as a neurobiological perspective and synthesize data across approaches and species to reach a more detailed understanding of age-related alterations in hippocampal memory function.


Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry.
The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids 'not as prescribed'. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N = 132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed positive genetic correlations with the two largest available GWAS of OUD and opioid dependence (rg = 0.64, 0.80, respectively). We also identified numerous additional genetic correlations with POU, including alcohol dependence (rg = 0.74), smoking initiation (rg = 0.63), pain relief medication intake (rg = 0.49), major depressive disorder (rg = 0.44), chronic pain (rg = 0.42), insomnia (rg = 0.39), and loneliness (rg = 0.28). Although POU was positively genetically correlated with risk-taking (rg = 0.38), conditioning POU on risk-taking did not substantially alter the magnitude or direction of these genetic correlations, suggesting that POU does not simply reflect a genetic tendency towards risky behavior. Lastly, we performed phenome- and lab-wide association analyses, which uncovered additional phenotypes that were associated with POU, including respiratory failure, insomnia, ischemic heart disease, and metabolic and blood-related biomarkers. We conclude that opioid misuse can be measured in population-based cohorts and provides a cost-effective complementary strategy for understanding the genetic basis of OUD.


Guild structure in water mites (Unionicola spp.) inhabiting freshwater mussels: choice, competitive exclusion and sex.
Unionicolid water mites inhabit freshwater unionid mussels during the nymphal and adult stages of their life-cycle. Regular sampling of mussels from two sites in St. Mark's River, Fl. established that each of four species of water mite (Unionicola abnormipes, U. fossulata, U. serrata and U. formosa) occurred mainly in one or two of the mussel species available at each site.The role of preference for particular mussel species during host location was assessed for the first three mite species by choice experiments, in which mites were offered different mussel species simultaneously. In five out of six experiments, mites entered normally unused mussels as often as they did normally used ones. Additionally, a sexual difference in choice was found for U. fossulata, with males preferring one mussel species and females showing no preference. One mussel species, (Anodonta imbecilis), normally unused but chosen by mite species during the lab. experiments, is inhabited exclusively by the fourth mite species, U. formosa, in the field. An experiment showed that U. formosa excludes other mite species aggressively from Anodonta imbecilis.The results illustrate the sometimes misleading nature of simple sampling data as an indication of host specificity or host preference in parasites. They suggest also that the population dynamics of some parasites might be more fruitfully compared to unrelated, free-living species than to other parasites.


HPLC determination of 1,2-diethyl-3-hydroxypyridin-4-one (CP94), its iron complex [Fe(III) (CP94)3] and glucuronide conjugate [CP94-GLUC] in serum and urine of thalassaemic patients.
Sensitive and selective high performance liquid chromatographic (HPLC) methods for the quantification of 1,2-diethyl-3-hydroxypyridin-4-one (CP94), its iron complex [Fe(III) (CP94)3] and glucuronide metabolite (CP94-GLUC) in urine and serum of thalassaemic patients are described. Three separate analyses are involved. The first assay quantifies both CP94 and its iron complex. This procedure requires the conversion of the iron complex to the free ligand and is carried out using diethylenetriaminepentaacetic acid (DTPA). CP94 and the internal standard, 1-propyl-2-ethyl-3-hydroxypyridin-4-one (CP95) present in either serum or urine are then extracted at pH 7.0 with dichloromethane. Extraction efficiency is 96.0 +/- 5.6% and 100 +/- 7.1% for CP94 and CP95, respectively, and 31.2 +/- 2.1% at 30 microM and 53.2 +/- 4.2% at 300 microM for the corresponding iron complex. In the second assay, samples are incubated (16 h) with beta-glucuronidase and processed as before. In this assay, the drug, its iron complex and glucuronide conjugate are measured. In the third assay the iron complex of CP94, [Fe(III) (CP94)3] is quantified. From the three separate analyses it is possible to calculate the individual concentrations of the three separate components present in serum and urine of thalassaemic patients. Calibration for both components, i.e. CP94 (assays 1 and 2) and its iron complex (assay 3) are linear with correlation coefficients > 0.99 and are reproducible over the required concentration range of 0-500 microM for the free ligand and 0-100 microM for the iron complex. The minimum quantifiable level is 0.5 microM for the free ligand and 1.0 microM for the iron complex.


Use of prophylactic stoma mesh is a risk factor for developing rectus abdominis muscle atrophy.
The aim of this study was to evaluate the possible risk factors for developing a parastomal hernia (PSH) in a cohort of rectal cancer patients with and without the application of a retro-muscular prophylactic mesh. The evaluated risk factors included the position of the stoma in the rectus abdominis muscle (RAM), RAM atrophy and shift of abdominal wall midline structures. Rectal cancer patients treated with an abdominoperineal excision or Hartmann's procedure between 2002 and 2015 at Västmanland Hospital, Sweden was included. Postoperative CT examinations were retrospectively reviewed regarding the presence of PSH and RAM atrophy and for measurements such as position of the stoma in the RAM. 116 patients were included, with a median age of 71 years. 70 patients received a prophylactic stoma mesh. 55 patients (47%) had a parastomal hernia at three-year follow-up. Rectus abdominis muscle atrophy was significantly higher in the mesh group compared with the non-mesh group (37% vs 2%; P = 0.04). RAM atrophy was a significant independent protective factor for developing a PSH (P = 0.007; OR 0.15; 95% CI 0.03-0.55). Placement of a prophylactic retro-muscular stoma mesh resulted in a high frequency of RAM atrophy distal to the stomal aperture and patients with such atrophy had a lower risk of developing a PSH.


On the relation between surface area and partitioning of particulates in two-polymer aqueous phase systems.
Partitioning in dextran-poly(ethylene glycol) aqueous two-phase systems is an established method for the separation of biomaterials. Size and surface properties are generally regarded as parameters which contribute to the determination of the materials' partition coefficients, K. While molecular weight or surface area can be one of the determinants of the K value of biomaterials in the size range of macromolecules to very small particulates (e.g. some viruses), partitioning liposomes of identical surface properties and different but distinct sizes indicate that surface areas greater than about 0.2 microns 2 do not affect the K value obtained. Analysis of available partitioning data of much larger particulates (i.e. cells) reveals that surface properties per unit area outweight surface area per se in determining the K value in non-charge-sensitive, charge-sensitive and biospecific affinity phase systems.


Zoledronic acid in genitourinary cancer.
Bone metastases are a common complication of advanced prostate cancer and while they are less common in non-prostate genitourinary (GU) malignances, they have been reported in up to 35 % of patients with advanced renal cell carcinoma and bladder cancer. Furthermore, they may occur in more than two-thirds of those patients with bladder cancer who develop distant metastases. In the absence of bone-targeted therapies, approximately 50 % of all patients with metastatic bone disease from GU cancers experience at least one skeletal-related event within their lifetime. Zoledronic acid is a bisphosphonate that has been shown to delay or prevent the development of skeletal complications in patients with bone metastases and reduce bone pain in these patients. Furthermore, zoledronic acid has also demonstrated the ability to prevent osteopenia, which may occur with the prolonged use of some pharmacological interventions in patients with cancer.


Economic Evaluation of a Geriatric Oncology Clinic.
Geriatric assessment (GA) is supported by recent trials and guidelines yet rarely implemented due to a lack of resources. We performed an economic evaluation of a geriatric oncology clinic. Pre-GA proposed treatments and post-GA actual treatments were obtained from a detailed chart review of patients seen at a single academic centre. GA-based costs for investigations and referrals were calculated. Unit costs were obtained for surgical, radiation, systemic therapy, laboratory, imaging, physician, nursing, and allied health care (all in 2019 Canadian dollars). A six-month time horizon and government payer perspective were used. Consecutive patients aged 65 years or older (n = 152, mean age 82 y) and referred in the pre-treatment setting between July 2016 and June 2018 were included. Treatment plans were modified for 51% of patients. Costs associated with planned treatment were CAD 3,655,015. Costs associated with GA and related interventions were CAD 95,798. Final treatment costs were CAD 2,436,379. Net savings associated with the clinic were CAD 1,122,837, or CAD 7387 per patient seen. Findings were robust in multiple sensitivity analyses. Combined with mounting trial data demonstrating the clinical benefits of GA, our data can inform a strong business case for geriatric oncology clinics in health care environments similar to ours, but additional studies in diverse health care settings are warranted.


Disparities in knowledge of heart attack and stroke symptoms among adult men: an analysis of behavioral risk factor surveillance survey data.
The staggering burden of myocardial infarction and stroke in men and for men of African-American descent in particular provided the impetus for this study. Morbidity and mortality from these vascular disorders can be reduced by early treatment, which requires correct prehospital identification of symptoms. The purpose of this study was to assess current knowledge of myocardial infarction and stroke symptoms and to examine if there were disparities in knowledge of these among U.S. males. This is a cross-sectional study analyzing public use 2003-2005 Behavioral Risk Factor Surveillance Survey data. Univariate, bivariate and multivariate techniques were used. Random-digit-dial telephone survey focused on health risk factors and behaviors. Data collection was done under the direction of the Centers for Disease Control and Prevention. Data collections targeted noninstitutionalized U.S. adults 18-90 years of age. This study focused on the adult male population. From the 13 heart attack and stroke symptom knowledge questions asked on the survey, a heart attack and stroke knowledge score was computed for each respondent. Multivariate analysis revealed that both Caucasian and African-American men earning low scores on the knowledge questions were more likely to: have less than a high-school education, have deferred medical care in the past 12 months because of cost and not have health insurance in the past 12 months. African-American men were also more likely to live in households with annual incomes < $35,000 and were more likely to not have a primary care provider; this was not true for Caucasian men. There is a disparity in myocardial infarction and stroke symptom knowledge along racial and socioeconomic lines. African-American males, poorer individuals and those with lower levels of education had significantly lower scores. Since these subgroups are also among those at higher risk for stroke and myocardial infarction, targeting measures to enhance knowledge in these groups might yield more benefit than programs aimed at the general male populace.


Isoxazolylthioamides as potential immunosuppressants a combinatorial chemistry approach.
A library of thioamide derivatives of leflunomide 1a and of its bioactive metabolite 1b has been synthesised on solid phase. Thus, para-substituted phenylacetic acids were coupled to TentaGel and were subsequently reacted with aromatic isothiocyanates. Treatment of the resulting enaminothioamides with hydroxylamine led to their simultaneous cyclisation and cleavage from the resin affording 2-25. Their in vitro profiling demonstrated that the amide-thioamide isologous substitution was detrimental of the biological activity.


Retraction notice to "Histological, ultrastructural and immunohistochemical studies on the ameliorative role of Cinnamon zeylanicum against high cholesterol diet-induced hypercholesterolemia in the kidney of adult male albino rats" [Heliyon 8, (2022) Article e10401].
[This retracts the article DOI: 10.1016/j.heliyon.2022.e10401.].


No positive effects of OP-1 device on the incorporation of impacted graft materials after 8 weeks: a bone chamber study in goats.
Bone morphogenetic proteins (BMPs) have the potential to improve clinical outcome after hip revision surgery by improving graft incorporation and implant fixation. However, impaction of cancellous bone grafts and TCP/HA bone substitute mixed with OP-1 device in a bone chamber in goats in a previous study led to reduced fibrous tissue ingrowth after 4 weeks. New bone formation was not promoted by OP-1. In the current study we examined whether this reduction represented a final loss of ingrowth or was just a delay, and whether the reduction can be overcome and ultimately results in a better late ingrowth. Bone chambers with impacted allografts and impacted TCP/HA granules mixed with 2 doses of OP-1 device were implanted in proximal medial goat tibias. Impacted allografts and TCP/HA not treated with OP-1 served as controls. After 8 weeks, the incorporation was evaluated using histology and histomorphometry. Histology revealed evidence of bone graft incorporation, which proceeded in a similar way in both allografts and TCP/HA, with and without the addition of OP-1. After 8 weeks, no difference in bone ingrowth was found between the OP-1 groups and their controls. It was only in the allografts that the addition of OP-1 resulted in more fibrous tissue ingrowth. We conclude that the previously observed delay in fibrous tissue ingrowth can be only partially overcome.


Endocytic apparatus and transcytosis in epithelial cells of the vas deferens in the rat.
The apex of the principal epithelial cells lining the vas deferens of the rat contains coated pits in continuity with the apical plasma membrane and large subsurface-coated vesicles (100-125 nm). In the apical cytoplasm, large, pale, uncoated vesicles (150-300 nm), small coated and uncoated vesicles (50-60 nm), uncoated vesicles about 75-90 nm, and membranous apical tubules are present, in addition to large, vacuolar, pale, multivesicular bodies, dense multivesicular bodies, and secondary lysosomes seen deeper in the cytoplasm amongst numerous ER cisternae, saccules of the Golgi apparatus, and mitochondria. The endocytic activity of these cells was investigated by using cationic ferritin (CF) as a marker of adsorptive endocytosis and native ferritin (NF) for demonstrating fluid-phase endocytosis. These tracers were injected separately into the lumen of the vas deferens, and the animals were killed at various time intervals thereafter from 2 to 90 minutes. At 2 minutes CF was seen bound predominantly to microvilli and to areas of the apical plasma membrane delimiting coated pits as well as in large, coated vesicles. At 5 and 15 minutes the tracers were seen in apical tubules and pale multivesicular bodies; at 30 minutes moderately dense multivesicular bodies were labeled. At 1 hour and longer time intervals dense multivesicular bodies and secondary lysosomes were labeled. NF followed the same pathway as CF; however, no binding to microvilli or areas delimiting coated pits was observed. The numerous other vesicular structures, i.e., the large uncoated vesicles (150-300 nm) and the small coated and uncoated vesicles (50-60 nm), never became labeled with the tracers and therefore were not involved in the endocytic process. There was, however, an exception in the case of several small (75-90 nm) uncoated vesicles seen deeper in the apical cytoplasm of these cells which were labeled exclusively with CF. With time such vesicles appeared along the lateral and basal surfaces of these cells and discharged their content of CF into the lateral intercellular space or the connective tissue space at the base of these cells. Thus the principal epithelial cells in addition to sequestering the endocytosed tracers within secondary lysosomes where they are presumably degraded also appear to be involved in the transcytosis of material from the lumen of the vas deferens to the underlying lamina propria.


Electron donors and acceptors based on 2,7-functionalized pyrene-4,5,9,10-tetraone.
An efficient synthesis of 2,7-dibromo- and diiodo-pyrene(4,5,8,19)-tetraones led to strong donors and acceptors based on pyrene. They are versatile building blocks for conjugated materials and can be further applied in molecular electronics.


Simulations of the p97 complex suggest novel conformational states of hydrolysis intermediates.
The vitally important AAA (ATPases associated with various cellular activities) protein p97 is involved in cellular functions ranging from replication to degradation of misfolded proteins and has recently been proposed as a novel chemotherapeutic target. p97 is a large molecular machine that has been shown to hexamerize in vitro, with each monomer consisting of an N domain responsible for binding to effector proteins and two AAA repeats (D1 and D2). However, structural studies are inconclusive or in disagreement with one another on several important features such as the locations of the N domains, the relative orientations of the D1 and D2 rings, and the dimensions of the central pore. Here, we present atomic-scale simulations of the p97 hexamer in the prehydrolysis, transition, and post-hydrolysis states. To improve the agreement between low- and high-resolution experimental studies, we first use a biased simulation technique, molecular dynamics flexible fitting (MDFF), to improve the correlation between the structures described in these experiments. We follow this with extended, classical molecular dynamics simulations, which not only show that structures generated in the MDFF phase are stable, but reveal insights into the dynamics important to each state. Simulation results suggest a hybrid model for hydrolysis, in which the N and D2 domains are dynamic while the D1 domains are relatively static, salt bridges stabilize the position of the N domains in the pre-hydrolysis state, and the rings formed by D1 and D2 rotate relative to one another.


UPLC-MS/MS analysis and biological activity of the potato cyst nematode hatching stimulant, solanoeclepin A, in the root exudate of Solanum spp.
Solanoeclepin A is a hatching stimulant for potato cyst nematode in very low (pM) concentrations. We report a highly sensitive method for the analysis of SolA in plant root exudates using UHPLC-MS/MS and show that there is considerable natural variation in SolA production in Solanum spp. corresponding with their hatching inducing activity. Potato cyst nematode (PCN) is a plant root sedentary endoparasite, specialized in the infection of solanaceous species such as potato (Solanum tuberosum) and tomato (Solanum lycopersicum). Earlier reports (Mulder et al. in Hatching agent for the potato cyst nematode, Patent application No. PCT/NL92/00126, 1996; Schenk et al. in Croat Chem Acta 72:593-606, 1999) showed that solanoeclepin A (SolA), a triterpenoid metabolite that was isolated from the root exudate of potato, induces the hatching of PCN. Its low concentration in potato root exudate has hindered progress in fully understanding its hatching inducing activity and exploitation in the control of PCN. To further investigate the role of SolA in hatching of PCN, the establishment of a highly sensitive analytical method is a prerequisite. Here we present the efficient single-step extraction and UHPLC-MS/MS based analysis for rapid determination of SolA in sub-nanomolar concentrations in tomato root exudate. This method was used to analyze SolA production in different tomato cultivars and related solanaceous species, including the trap crop Solanum sisymbriifolium. Hatching assays with PCN, Globodera pallida, with root exudates of tomato genotypes revealed a significant positive correlation between SolA concentration and hatching activity. Our results demonstrate that there is natural variation in SolA production within solanaceous species and that this has an effect on PCN hatching. The analytical method we have developed can potentially be used to support breeding for crop genotypes that induce less hatching and may therefore display reduced infection by PCN.


Transcriptional regulation of the 5'-flanking region of the human transcription factor Sp3 gene by NF-1, c-Myb, B-Myb, AP-1 and E2F.
We analyzed in detail the proximal promoter of transcription factor Sp3, which expands 281 bp from the translational start. This sequence contains putative binding sites for Sp1, NF-Y, NF-1, Myb, AP-1 and E2F transcription factors. In this work, we further explored the role of these boxes on the regulation of the Sp3 gene. Gel-shift and competition assays showed specific binding of NF-1, Myb, AP-1 and E2F. Furthermore, chromatin immunoprecipitation assays demonstrated that Sp1, Sp3, NF-Y, NF-1, c-Myb, B-Myb, c-Jun and E2F1 actually occupied the Sp3 promoter in HeLa cells. Transient transfections and luciferase assays revealed activation of the Sp3 proximal promoter upon overexpression of NF-1, c-Myb, B-Myb, c-Jun and c-Fos, and repression after overexpression of E2F/DP1. Point mutation of the binding sites for NF1, Myb, AP1 and E2F and cell incubation with specific siRNAs further confirmed the role of these transcription factors in the regulation of the Sp3 promoter. The regulation of the endogenous Sp3 gene was also observed at the mRNA level when the studied transcription factors were overexpressed or knocked down by siRNA incubation. These results help to explain the complex regulation of the Sp3 gene, which depends, at least in part, on the relative amount of Sp1, Sp3, NF-Y, NF-1, c-Myb, B-Myb, AP-1, and E2F proteins in the cell.


Chronic illness, life style and emotional health in adolescence: results of a cross-sectional survey on the health of 15-20-year-olds in Switzerland.
The objective was to evaluate the prevalence of chronic conditions (CC) in adolescents in Switzerland; to describe their behaviour (leisure, sexuality, risk taking behaviour) and to compare them to those in adolescents who do not have CC in order to evaluate the impact of those conditions on their well-being. The data were obtained from the Swiss Multicentre Adolescent Survey on Health, targeting a sample of 9268 in-school adolescents aged 15 to 20 years, who answered a self-administered questionnaire. Some 11.4% of girls and 9.6% of boys declared themselves carriers of a CC. Of girls suffering from a CC, 25% (versus 13% of non carriers; P=0.007) and 38% of boys (versus 25%; P=0.002) proclaimed not to wear a seatbelt whilst driving. Of CC girls, 6.3% (versus 2.7%; P=0.000) reported within the last 12 months to have driven whilst drunk. Of the girls, 43% (versus 36%; P=0.004) and 47% (versus 39%; P=0.001) were cigarette smokers. Over 32% of boys (versus 27%; P=0.02) reported having ever used cannabis and 17% of girls (versus 13%; P=0.013) and 43% of boys (versus 36%; P=0.002) admitted drinking alcohol. The burden of their illness had important psychological consequences: 7.7% of girls (versus 3.4%; P=0.000) and 4.9% of boys (versus 2.0%; P=0.000) had attempted suicide during the previous 12 months. experimental behaviours are not rarer in adolescents with a chronic condition and might be explained by a need to test their limits both in terms of consumption and behaviour. Prevention and specific attention from the health caring team is necessary.


Effect of indapamide on the baroreceptor reflex in essential hypertension.
The effect of chronic treatment with indapamide on blood pressure (BP), baroreceptor sensitivity (BRS) and vascular reactivity (VR) were investigated in 10 patients with essential hypertension. After 3 months of therapy with indapamide 2.5 mg/d the mean arterial pressure (MAP) had decreased from 135 +/- 6 to 112 +/- 2 mmHg (p less than 0.001); the heart rate (HR) had not changed, VR had decreased from 6.1 +/- 1.2 to 4.8 +/- 1.8 (pg . min . kg)-1 (p less than 0.05), and BRS had increased from 8.3 +/- 3.7 to 12.2 +/- 5.3 ms/mmHg (p less than 0.005), with a leftshift of the relationship between BP and heart period. An inverse correlation was found between the pre-treatment systolic blood pressure and the change in baroreceptor sensitivity after indapamide (r = 0.59; p less than 0.05). In conclusion, chronic treatment with indapamide enhances BRS and resets the reflex. The resetting may account for the lack of tachycardia at rest observed after treatment with indapamide. The mechanism by which indapamide interferes with the baroreceptor reflex requires further investigations.


Abrupt drainage basin reorganization following a Pleistocene river capture.
River capture is a dramatic natural process of internal competition through which mountainous landscapes evolve and respond to perturbations in tectonics and climate. River capture may occur when one river network grows at the expense of another, resulting in a victor that steals the neighboring headwaters. While river capture occurs regularly in numerical models, field observations are rare. Here we document a late Pleistocene river capture in the Yimeng Mountains, China that abruptly shifted 25 km2 of drainage area from one catchment to another. River terraces and imbricated cobbles indicate that the main channel incised 27 m into granitic bedrock within 80 kyr, following the capture event, and upstream propagating knickpoints and waterfalls reversed the flow direction of a major river. Topographic analysis shows that the capture shifted the river basins far from topographic equilibrium, and active divide migration is propagating the effects of the capture throughout the landscape.


Cervical cerclage for the prevention of preterm birth.
Contemporary evidence supports the concept that cervical insufficiency is anything but a well-defined and distinct clinical entity. Instead, it is only 1 component of the larger and more complex preterm birth syndrome. Premature cervical ripening, as evidenced by shortening and effacement beginning at the internal os, provides strong evidence that parturition has begun and is the result of multiple interrelated pathways and inciting factors. Ultrasonographic screening of the cervix and treatment with cerclage for cervical shortening in the mid-trimester is reserved for women with prior spontaneous preterm birth (Fig. 1). Although cerclage benefit increases as the cervix shortens to less than 25 mm, it is appropriate to offer cerclage to women with shortened cervical length of less than 25 mm, and particularly those with a coexistent U-shaped funnel.


Comprehensive analysis and validation of contemporary survival prognosticators in Korean patients with metastatic renal cell carcinoma treated with targeted therapy: prognostic impact of pretreatment neutrophil-to-lymphocyte ratio.
In line with the era of targeted therapy (TT), an increasing number of prognosticators are becoming available for patients with metastatic renal cell carcinoma (mRCC). Here, potential prognosticators of cancer-specific survival (CSS) were identified based on the contemporary literature and were comprehensively validated in an independent cohort of patients treated for mRCC. Data were collected from 478 patients treated with TT for mRCC between January 1999 and July 2013 at a single institution. The analysis included 25 clinicopathological covariates that included both traditional and contemporary prognosticators. Multivariate Cox regression models were used to quantify the effect of covariates on CSS. Median survival from the initial diagnosis of metastasis was 24.5 (IQR, 11.5-55.7) months. There were 303 (63.4 %) cancer-specific deaths, yielding a 2-year CSS rate of 62.5 %. Low Karnofsky performance status (KPS), hypercalcemia, neutrophil-to-lymphocyte ratio (NLR), the number of metastatic sites (≥2), and the presence of brain metastases were independent adverse prognosticators of CSS. The C-index of the model was 0.78. Patients with at least one adverse prognosticator demonstrated lower 2-year CSS rates compared to those with no prognosticators (53.9 vs. 70.6 %; log rank p < 0.001). Together with traditional prognosticators such as KPS, hypercalcemia, and the number and location of metastases, the NLR was an independent predictor of CSS in patients with mRCC treated with TT. Our findings could be useful for guiding clinical decision making including stratification of patients for TT and inclusion in clinical trials.


Electroencephalographic abnormalities in patients with normal contrast computerised axial tomography brain scans.
The present investigation shows how, in certain circumstances, electroencephalography is capable of detecting the presence of cerebral dysfunction when CT head scanning fails to reveal that any abnormality is present.


Vapor pressures and enthalpies of sublimation of 17 polychlorinated dibenzo-p-dioxins and five polychlorinated dibenzofurans.
An apparatus for vapor pressure measurement with a very small cell by the mass-loss Knudsen effusion technique was tested with solid benzoic acid and anthracene. The vapor pressure and enthalpy of sublimation results of the two reference compounds were in good agreement with accepted literature data. The vapor pressures at different temperatures of 17 polychlorinated dibenzo-p-dioxins (including dibenzo-p-dioxin) and five polychlorinated dibenzofurans (including dibenzofuran) were measured with the apparatus, and the enthalpies of sublimation of the 22 dioxins and furans were derived from the temperature dependence of vapor pressure. The results were systematically compared with the literature data.


A comparative study of Greek nondeletional hereditary persistence of fetal hemoglobin and beta-thalassemia compound heterozygotes.
The coexistence of beta- and gamma-globin gene mutations in the compound heterozygous state presents a rare in vivo model that provides important data on gene regulation of clinical interest. In this unique comparative study we present the hematological, biosynthetic, and molecular data from six adult compound heterozygotes for the Greek nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH, Agamma-117 G-->A) and four frequent beta-thalassemia mutations (IVS I-110 G-->A, Cd 39 C-->T, IVS I-1 G-->A, and IVS I-6 T-->C) found in the Hellenic population. Fetal hemoglobin (HbF) levels were found to be considerably higher (25-50%) than in 19 Greek nd-HPFH heterozygotes (HbF=9.7+/-1.7%) and, interestingly, to depend on the type of the respective beta-thalassemia mutation, in trans to the nd-HPFH allele. All cases presented a typical beta-thalassemia heterozygote's phenotype despite the increased HbF and the normal HbA2 levels, as indicated by both the hematological indices and the biosynthetic ratios. These data were compared with those from two unique cases of Greek origin: a homozygous case of the Greek nd-HPFH and a compound heterozygote with HbS. Our data suggest that in these compound heterozygous cases the beta-thalassemic chromosome indirectly determines the final outcome of the gamma- and of the in cis beta-globin gene expression, most likely at the post-transcriptional level.


An intriguing association between dental and mental pathology in addicted and control subjects: a cross-sectional survey.
Recent clinical studies suggest that substance use may be associated with an acceleration of the ageing process, possibly related to a deficit of stem cell number or function. As this clinic had access to both medical and drug dependent patients, we tested the hypothesis that there may be an association between previously identified deficits. A cross-sectional survey was performed looking at both dental and mental dysfunction. Both a dental index (DI) and a mental index (MI) were defined as previously described and utilised as summary measures of such pathology. From 249 substance use disorder (SUD) and 134 general medical controls (N-SUD), 248 and 91 patients were selected with ages less than 57 years as the primary focus of analysis. The mean (+/- S.D.) ages (32.59 +/- 7.98 vs 35.65 +/- 15.45 years) were similar. The DI was found to correlate with the MI in a significant manner in SUD (R = 0.14, p = 0.03), N-SUD (R = 0.27, p = 0.009) and in the whole group (R = 0.17, p = 0.001). The (univariate) association of MI with DI (p = 0.019) and DI with MI (p = 0.0037) remained highly significant at multivariate regression after adjustment for psychiatric diagnoses and measures of dose-duration exposure to common addictive drugs. The qualitative appearance of the surfaces of best fit for the relationship between age, DI and MI was different in the two groups. These results suggest that the robust statistical association between dental and mental pathology may be related to common underlying pathophysiological mechanisms such as a progeroid or stem cell deficiency process in clinical addiction.


Analysis of T cell subsets in cancer patients treated with interferon.
T cell subsets were analyzed in 33 patients with advanced cancer who were treated with either of two interferon preparations: a partially purified human leukocyte interferon (HulFN-alpha (Le] and a highly purified recombinant interferon (lFLrA). Included in the lFLrA-treated group were eight patients with immunodeficiency and Kaposi's sarcoma. The OKT4+/OKT8+ ratio was used to define the balance between helper/inducer and suppressor/cytotoxic T cell subsets. With both interferon preparations, the mean OKT4+/OKT8+ ratio decreased 24 hours after the first interferon dose. Within the HulFN-alpha (Le) group, the decrease in ratio was related to an increase in OKT8+ cells; in the lFLrA group, it was accompanied by a small decrease in the proportion of OKT4+ cells that was greater than the decrease in OKT8+ cells. Patients treated with lFLrA were followed for the first three weeks of therapy. Most patients treated with lFLrA at all dose levels, ranging from 1 X 10(6) to 54 X 10(6) units per day, had a decrease in OKT4+/OKT8+ ratio on Day 1. No substantial change in the ratio was observed on Days 7, 14, and 22. Patients with immunodeficiency and Kaposi's sarcoma had responses similar to those of patients with other cancers treated with lFLrA. In conclusion, although both HulFN-alpha (Le) and lFLrA induce immediate decreases in the OKT4+/OKT8+ ratio, the T cell subset(s) primarily responsible for the decrease varies with the source of interferon.


Enzymic and immunochemical properties of lysozyme. X. Conformation, enzymic activity and immunochemistry of lysozyme reduced at two carboxyl groups.
Reduction of lysozyme by diborane, followed by air oxidation of the reduced disulfides and chromatography on CM-cellulose, yielded a homogeneous derivative. In the derivative, the carboxyl groups of aspartic acid 119 and the end-chain leucine residue were reduced to their corresponding alcohols. Correct re-forming of the disulfide bonds was demonstrated by peptide mapping of the tryptic hydrolysates of the derivative and lysozyme without breaking the disulfide bonds, followed by identification of the disulfide-containing peptides. Correct disulfide pairing in the two-disulfide peptide in the tryptic hydrolysate was established from its immunochemical behavior. Preparations of the two-disulfide fragment from lysozyme and derivative had equal inhibitory activities (26 or 32%) of the reaction of lysozyme with two homologous antisera. In ORD measurements, lysozyme and the derivative had equal rotatory powers at neutral pH. However, the bo value for the derivative decreased by about 10%. Below pH 6.4 and above pH 8.0, the derivative was less rotatory than native lysozyme. In CD measurements at neutral pH, the negative ellipticity bands at 220 and 208 nm showed little or no decrease in the derivative relative to the native protein. Although conformational differences between the derivative and its parent protein were almost undetectable by ORD and CD measurements, they were readily detected by chemical monitoring of the conformation. In the derivative, both accessibility to tryptic hydrolysis and reducibility of the disulfide bonds increased markedly. The enzymic activity of the derivative was decreased but retained the same pH optimum. With antisera to lysozyme or antisera to the derivative, lysozyme and its derivative possessed equal antigenic reactivities. The immunochemical findings further confirm the correct refolding of the disulfides. Also, they indicate that aspartic acid 119 and the C-terminal leucine residue are not part of an antigenic reactive region in lysozyme.


A brief spiritual beliefs inventory for use in quality of life research in life-threatening illness.
This paper reports on the initial efforts to validate a brief self-report inventory, the Systems of Belief Inventory(SBI-15R), for use in quality of life (QOL) and psychosocial research studying adjustment to illness. The SBI-15R was designed to measure religious and spiritual beliefs and practices, and the social support derived from a community sharing those beliefs. The authors proposed this scale to address the need for greater exploration of spiritual and religious beliefs in QOL, stress and coping research. Phase I: Item generation. The research team identified four domains comprised of 35 items that make up spiritual and religious beliefs and practices. The instrument was piloted in a structured interview format on 12 hospitalized patients with varying sites of cancer. Phase II: Formation of SBI-54. After these initial efforts, the research team increased the number of items to 54 and adopted a self-report format. To assess patients reactions to the questionnaire, the new version was piloted on 50 outpatients with malignant melanoma. Phase III: Initial validation. To begin establishing validation, 301 healthy individuals with no history of cancer or serious illness in the prior year were asked to complete the SBI-54 and several other instruments. A principal components analysis with varimax rotation of the SBI-54 identified two factors, in contrast to the four which were hypothesized, one measuring spiritual beliefs and practices, the other measuring social support related to the respondent's religious community. Phase IV: Item reduction of the SBI-54. A shortened version of the SBI-54 with 15 items, five from the items identifying factor I and ten from those identifying factor II, was developed to lessen patient burden. The new SBI-15 correlated highly with the SBI-54, and demonstrated convergent, divergent, and discriminant validity. Revision of SBI-15. The investigators rephrased one statement in order to broaden the applicability of the SBI-15 to patients other than those with a diagnosis of cancer, and to healthy individuals. DISCUSSION. The SBI-15R met tests of internal consistency, test-retest reliability, and convergent, divergent, and discriminant validity in both physically healthy and physically ill individuals. The SBI-15R may have value in measuring religious and spiritual beliefs as a potentially mediating variable in coping with life-threatening illness, and in the measurement of QOL.


Factors affecting the response rate of frequency volume chart: A prospective nonrandomized controlled study.
To evaluate if compliance with frequency volume charts can be improved if a physician explains its importance and to identify factors affecting compliance and accurate responses to frequency volume chart (FVC). We identified patients ≥18 years of age with voiding dysfunction reported from July 2013 to February 2014. Patients were explained the importance of frequency volume charts by a doctor and then a nurse explained how to fill it (group A). Others were only explained how to fill it (group B). A total of 137 patients were enrolled. The response rate to frequency volume charts was higher in group A than in group B (94.3% vs 82.9%, P = .038). Patients ≥70 years of age, without a private health insurance, with high school education or higher, and without past medical history had a higher response rate in group A than in group B. In the multivariate binary logistic regression analysis, group A (odds ratio [OR], 4.87; 95% confidence interval [95% CI], 1.04-22.89; P = .045) and QoL (OR, 2.28; 95% CI, 1.16-4.46; P = .017) were factors associated with the response rate. In addition, group A (OR, 3.46; 95% CI, 1.03-11.70; P = .045) and being 60's years old (vs 50's years, OR, 7.01; 95% CI, 1.36-36.23; P = .020) were related to FVC complete response rate. Frequency volume chart compliance can be improved if physicians explain its importance for lower urinary tract symptoms diagnosis and management. The explanation and severe lower urinary tract symptoms are factors affecting compliance and the explanation and being 60's years old are related to accurate response.


A phage-based system to select multiple protein-protein interactions simultaneously from combinatorial libraries.
Selectively infective phage (SIP) can be used to identify protein-protein interactions. SIP was modified to facilitate the simultaneous selection of interacting protein pairs from large combinatorial libraries. An interference-resistant phage was constructed which non-covalently, but stably links the genetic information of an interacting pair, encoded separately on phage and phagemid vectors, by co-packaging into heteropolyphages. In a model system, the interaction between a SIP-selected peptide and the intracellular domain of the p75 neurotrophin receptor was detected in the presence of a 10(4)-fold excess of a non-interacting control pair (jun leucine zipper and p75 intracellular domain) via SIP hetero-polyphage transductants. To minimize the redundancy of transductants and to minimize possible ligand exchange generated in a solution-based SIP screening, a filter-based in situ infectivity screening was developed. The combination of the above techniques may provide a powerful system for rapid screening of very large sequence spaces.


Experience with a triple-lumen catheter for autologous stem-cell transplantation.
We relate our experience with the Cook (Cook Medial Inc., Bloomington, IN, USA), triple-lumen hyperalimentation (HAS) catheter for treatment related to autologous stem-cell transplant. Nineteen HAS catheters were implanted in the right jugular vein, and tunneled to the right anterior chest wall, under imaging guidance. Retrospectively, we reviewed each catheter. Three patient's experienced "ballooning" of the middle (white) lumen of the HAS catheter during routine use. We assessed, time in situ, follow-up imaging, chemotherapy regimen, possibility of systemic or device infection, tissue pathology of the patient's malignancy, and other factors to attempt to determine if there were any associations that could explain the catheter lumen failure. After this pilot study of the HAS-catheter in these 19 patients, we discontinued use of this device at our facility due to mechanical problems of ballooned and obstructed middle lumens. There was no obvious cause, or association, detected to explain the ballooning identified.


Comparative analysis of cell cycle events in zygotic and somatic embryos of Cyclamen persicum indicates strong resemblance of somatic embryos to recalcitrant seeds.
Embryo development and germination of Cyclamen persicum have been comparatively characterized for zygotic and somatic embryos with regard to mitotic activity and morphology in order to identify developmental abnormalities in somatic embryogenesis. Zygotic embryo development proved to be highly synchronous with distinct periods of cell division, cell elongation and embryo maturation within a total period of 17 weeks of seed development. Somatic embryo development was accomplished within only 3 weeks, resulting in a mixture of morphologically highly variable embryos. No distinct developmental periods could be identified and no reduction of the mitotic activity was discovered for non-desiccated somatic embryos. Controlled desiccation of somatic embryos severely reduced their germination rate, demonstrating resemblance of somatic embryos to recalcitrant seeds, whereas zygotic Cyclamen seeds could be characterized as typically orthodox.


A β-sheet structure interacting peptide for intracellular protein delivery into human pluripotent stem cells and their derivatives.
The advance in stem cell research relies largely on the efficiency and biocompatibility of technologies used to manipulate stem cells. In our previous study, we had designed an amphipathic peptide RV24 that can deliver proteins into cancer cell lines efficiently without significant side effects. Encouraged by this observation, we moved forward to test whether RV24 could be used to deliver proteins into human embryonic stem cells and human induced pluripotent stem cells. RV24 successfully mediated protein delivery into these pluripotent stem cells, as well as their derivatives including neural stem cells and dendritic cells. Based on NMR studies and particle surface charge measurements, we proposed that hydrophobic domain of RV24 interacts with β-sheet structures of the proteins, followed by formation of "peptide cage" to facilitate delivery across cellular membrane. These findings suggest the feasibility of using amphipathic peptide to deliver functional proteins intracellularly for stem cell research.


Elevated content of p53 protein in the absence of p53 gene mutations as a possible prognostic marker for human renal cell tumors.
p53 tumour suppressor gene expression was estimated immunohistochemically using DO-1 monoclonal antibody (recognising both wild-type and mutant p53 in 88 human renal tumours. Single strand conformation polymorphism (SSCP) analysis of possible mutations within exons 4-8 of the p53 gene was performed in 29 of the tumours (mostly immunostaining-positive cases). Obviously elevated p53 content was detected with DO-1 antibody in chromophobic cell carcinomas and most clear/chromophilic cell tumours (in chromophilic cell populations). In contrast, clear cell carcinomas demonstrated either complete absence of p53 expression or the presence of single immunopositive nuclei. Oncocytomas were completely negative. Additional immunostaining of the positive samples with mutant p53-specific Pab240 monoclonal antibody failed to detect immunopositive material. No p53 mutation was found in any of the samples analysed by SSCP. Our results suggest that the elevated p53 content in human renal cell carcinomas does not result from gene mutation and the p53 gene alterations are probably not an important mechanism in the development of human renal cell carcinomas. Accumulation of the wild-type p53 protein may be a useful prognostic marker indicating neoplastic progression malignancy.


Analysis of the gene-expression profile regarding the progression of human gastric carcinoma.
Tumor tissue consists of a variable mixture of tumor and host-cell populations. Recent developments in laser microdissection (LMD) and cDNA microarray analysis have encouraged us to study the differential gene expression profiles among normal cells, primary carcinoma cells, and metastatic carcinoma cells in cases of gastric carcinoma. Total RNA was extracted from the cells obtained by means of LMD from the primary carcinoma, the corresponding gastric epithelium, and the lymph node metastasis in 5 cases of primary gastric carcinoma. RNA was amplified by the T7-based amplification system to be applied to a cDNA microarray. Thereafter, the differentially expressed genes among the 3 populations were evaluated. cDNA samples for microarray studies were successfully obtained from each cell population of 5 cases. The cDNA microarray demonstrated that several interesting genes, such as cell-cycle regulators and growth factors, were overexpressed in the metastatic cells compared with in the primary carcinoma cells. Oncogenes and cell-adhesion molecules were more overexpressed in the primary carcinoma cells than in the normal cells. On the other hand, caspase 8 and cadherin were more suppressed in the primary carcinoma cells than in the normal cells. Interestingly, among the matrix metalloproteinase family, only MMP7 was identified as a differentially overexpressed gene in both the primary carcinoma and the metastatic cells in comparison with the normal cells. This study demonstrated that the combined use of LMD, T7-based amplification, and a cDNA microarray enabled us to identify genes directly associated with each population of tumor tissue. The method will open up new possibilities for the precise gene analysis of tumor progression and metastasis.


Atypical teratoid rhabdoid tumor in a child with neurofibromatosis type 2: A novel dual diagnosis.
Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by the development of tumors of the nervous system and is associated with NF2 gene alterations. Atypical teratoid rhabdoid tumor (ATRT) is a malignant central nervous system tumor that occurs primarily in children less than 3 years of age. The majority of cases of ATRT demonstrate genomic alterations of SMARCB1, a core member of the SWI/SNF chromatin-remodeling complex and tumor suppressor gene. SMARCB1 inactivation in ATRT is occasionally associated with somatic NF2 deletion; however, concurrent germline NF2 mutations have not been reported. Herein, we describe the case of a 3-year-old patient who presented with an intracranial mass. Next generation sequencing analysis of tumor identified homozygous deletions of the entire SMARCB1 gene and exon 7 to exon 14 of NF2 gene with whole chromosome 22 loss of heterozygosity (LOH). Multiplex Ligation-dependent Probe Amplification (MLPA) assay performed on blood identified a germline heterozygous intragenic deletion of NF2 exon 7 to exon 14; a somatic chromosome 22 LOH led to the homozygous deletion. SMARCB1 MLPA assay of blood showed no deletion. This cascade represents a novel, "four-hit" mechanism of SMARCB1 inactivation resulting in ATRT and the first known dual diagnosis of NF2 and ATRT.


Glycation-induced inactivation of aspartate aminotransferase, effect of uric acid.
Glycation is common posttranslational modification of proteins impairing their function, which occurs during diabetes mellitus and aging. Beside extracellular glycation of long-lived proteins, intracellular modifications of short-lived proteins by more reactive sugars like fructose are possible. The process includes free oxygen radicals (glycoxidation). In an attempt to reduce glycoxidation and formation of advanced glycation products (AGE), influence of 0.2-1.2 mM uric acid as endogenous antioxidant on glycoxidation of purified pig heart aspartate aminotransferase (AST) by 50 mM and 500 mM D-fructose in vitro was studied. Uric acid at 1.2 mM concentration reduced AST activity decrease and formation of total AGE products caused by incubation in vitro of the enzyme with sugar up to 25 days at 37 degrees C. The results thus support the hypothesis that uric acid has beneficial effects in controlling protein glycoxidation. The in vitro system AST-fructose proved to be a useful tool for investigation of glycation process.


Management of locoregional and systemic recurrence of breast cancer: to stage or not to stage and how.
The surveillance of breast cancer patients after potentially curative treatment may result in the identification of locoregional or distant recurrence. While many patients expect frequent imaging studies to monitor for recurrence, there are no data supporting aggressive imaging surveillance beyond mammography. However, when recurrent disease is suspected, it is appropriate to undertake re-staging to develop a rational management plan. The rationale and methods for appropriate surveillance and re-staging are discussed.


Amino acid control mechanism for bacitracin formation by Bacillus licheniformis.
Several amino acids affected the amount of bacitracin produced by Bacillus licheniformis ATCC 10716 and the high-yielding mutant B. licheniformis AL. The possibility of an amino acid control mechanism for bacitracin biosynthesis is discussed. The two strains showed a different response to the addition of some amino acids. This indicate that they may have differences in their amino acid control mechanism.


Predicting the orientation of eukaryotic membrane-spanning proteins.
We have developed a rule to predict the orientation of the first internal signal-anchor sequence in eukaryotic transmembrane proteins synthesized on the rough endoplasmic reticulum. The difference in the charges of the 15 residues flanking the first internal signal-anchor determines its orientation, with the more positive portion facing the cytosol. In proteins that span the membrane more than once, the orientation of all subsequent transmembrane segments would be determined by that of the most N-terminal one.


Sequential fluctuation pattern of serum des-gamma-carboxy prothrombin levels detected by high-sensitive electrochemiluminescence system as an early predictive marker for hepatocellular carcinoma in patients with cirrhosis.
Serum concentration levels of des-gamma-carboxy prothrombin (DCP), alpha-fetoprotein (AFP) and Lens culinaris agglutinin-reactive fraction (AFP-L3) are useful tumor markers for the diagnosis of hepatocellular carcinoma (HCC). Recently, a novel immunoassay using the electrochemiluminescence (ECLIA) was developed to enable measurement of low-concentration of DCP. This study investigated the usefulness of high-sensitive DCP for the early diagnosis of HCC. The subjects consisted of 90 patients with viral cirrhosis who could be followed for at least 24 months from 1992 to 1997. Fifty-six of these patients developed HCC and 34 patients had not by 1998. We measured the serum levels of high-sensitive DCP, AFP and %AFP-L3 every 3 months during 2 years before the detection of tumor in patients with HCC and during 2 years from 1995 to 97 in patients without HCC. Youden's index was calculated for evaluation of the ideal cut-off levels. The patterns of serial changes during 2 years were divided into two types: fluctuating type and non-fluctuating type. Cut-off levels of 40 mAU/ml for high-sensitive DCP (Youden's index = 0.435), 20 ng/ml for AFP (Youden's index = 0.442) and 10% for %AFP-L3 (Youden's index = 0.364) gave the highest index for each marker. When these markers were combined, the combination of high-sensitive DCP, AFP and %AFP-L3 gave the highest accuracy (sensitivity = 82.1%, specificity = 82.4%, accuracy = 82.2%). Fluctuating type of high-sensitive DCP, AFP and %AFP-L3 levels were found in 15 (17%), 29 (32%) and 11 (12%) patients, respectively. The rate of complication with HCC in the patients who showed the fluctuating type of high-sensitive DCP levels was significantly greater than that in the patients who showed non-fluctuating type (P<0.01). These results suggest that periodic measurement of serum DCP levels using ECLIA method is very useful for HCC screening and predicting the development of HCC.


Massive hemorrhage and infarction complicating focal nodular hyperplasia of the liver.
Spontaneous infarction or hemorrhage of focal nodular hyperplasia (FNH) has rarely been reported in the literature. A 43-year-old woman presented with upper abdominal pain and anemia. CT scan showed an enormous perihepatic hematoma. Trisegmentectomy successfully dealt with the problem. Although conservative management of FNH is often adopted, this case illustrates that these lesions can undergo massive bleeding.


Synthetic apomixis enables stable transgenerational transmission of heterotic phenotypes in hybrid rice.
In hybrid plants, heterosis often produces large, vigorous plants with high yields; however, hybrid seeds are generated by costly and laborious crosses of inbred parents. Apomixis, in which a plant produces a clone of itself via asexual reproduction through seeds, may produce another revolution in plant biology. Recently, synthetic apomixis enabled clonal reproduction of F1 hybrids through seeds in rice (Oryza sativa), but the inheritance of the synthetic apomixis trait and superior heterotic phenotypes across generations remained unclear. Here, we propagated clonal plants to the T4 generation and investigated their genetic and molecular stability at each generation. By analyzing agronomic traits, as well as the genome, methylome, transcriptome, and allele-specific transcriptome, we showed that the descendant clonal plants remained stable. Unexpectedly, in addition to normal clonal seeds, the plants also produced a few aneuploids that had eliminated large genomic segments in each generation. Despite the identification of rare aneuploids, the observation that the synthetic apomixis trait is stably transmitted through multiple generations helps confirm the feasibility of using apomixis in the future.


The expression of embryonic primary mesenchyme genes of the sea urchin, Strongylocentrotus purpuratus, in the adult skeletogenic tissues of this and other species of echinoderms.
Adult tissues of the sea urchin, Strongylocentrotus purpuratus, were analyzed for the products of a set of genes whose expression, in the embryo, is restricted to the skeletogenic primary mesenchyme (PM). Three embryonic PM-specific mRNAs were found to be abundant in adult skeletal tissues (test and lantern), but not in a variety of soft tissues. Homologous mRNAs were also found in skeletal tissues of the congeneric sea urchin, S. droebachiensis, as well as a more distantly related echinoid, Dendraster excentricus, and an asteroid, Evasterias troschellii. The distributions of two of these RNAs were analyzed in regenerating spines of adult S. purpuratus using in situ hybridization. These gene products were localized primarily in the calcoblasts that accumulated at the regeneration site. In nonregenerating spines SpLM 18 RNAs, the most abundant of these gene products, were localized in a small population of noncalcoblast cells scattered through the spine shaft, and were absent from calcoblasts. These observations suggest that a program of gene expression associated with the process of calcification is conserved both developmentally through the period of metamorphosis and evolutionarily among the echinoderms.


Cost-effectiveness of cognitive-behavioural therapy and drug interventions for major depression.
Antidepressant drugs and cognitive-behavioural therapy (CBT) are effective treatment options for depression and are recommended by clinical practice guidelines. As part of the Assessing Cost-effectiveness -- Mental Health project we evaluate the available evidence on costs and benefits of CBT and drugs in the episodic and maintenance treatment of major depression. The cost-effectiveness is modelled from a health-care perspective as the cost per disability-adjusted life year. Interventions are targeted at people with major depression who currently seek care but receive non-evidence based treatment. Uncertainty in model inputs is tested using Monte Carlo simulation methods. All interventions for major depression examined have a favourable incremental cost-effectiveness ratio under Australian health service conditions. Bibliotherapy, group CBT, individual CBT by a psychologist on a public salary and tricyclic antidepressants (TCAs) are very cost-effective treatment options falling below 10,000 Australian dollars per disability-adjusted life year (DALY) even when taking the upper limit of the uncertainty interval into account. Maintenance treatment with selective serotonin re-uptake inhibitors (SSRIs) is the most expensive option (ranging from 17,000 Australian dollars to 20,000 Australian dollars per DALY) but still well below 50,000 Australian dollars, which is considered the affordable threshold. A range of cost-effective interventions for episodes of major depression exists and is currently underutilized. Maintenance treatment strategies are required to significantly reduce the burden of depression, but the cost of long-term drug treatment for the large number of depressed people is high if SSRIs are the drug of choice. Key policy issues with regard to expanded provision of CBT concern the availability of suitably trained providers and the funding mechanisms for therapy in primary care.


A novel hypothesis on metal dyshomeostasis and mitochondrial dysfunction in amyotrophic lateral sclerosis: Potential pathogenetic mechanism and therapeutic implications.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor dysfunctions resulting from the loss of upper (UMNs) and lower (LMNs) motor neurons. While ALS symptoms are coincidental with pathological changes in LMNs and UMNs, the causal relationship between the two is unclear. For example, research on the extra-motor symptoms associated with this condition suggests that an imbalance of metals, including copper, zinc, iron, and manganese, is initially induced in the sensory ganglia due to a malfunction of metal binding proteins and transporters. It is proposed that the resultant metal dyshomeostasis may promote mitochondrial dysfunction in the satellite glial cells of these sensory ganglia, causing sensory neuron disturbances and sensory symptoms. Sensory neuron hyperactivation can result in LMN impairments, while metal dyshomeostasis in spinal cord and brain stem parenchyma induces mitochondrial dysfunction in LMNs and UMNs. These events could prompt intracellular calcium dyshomeostasis, pathological TDP-43 formation, and reactive microglia with neuroinflammation, which in turn activate the apoptosis signaling pathways within the LMNs and UMNs. Our model suggests that the degeneration of LMNs and UMNs is incidental to the metal-induced changes in the spinal cord and brain stem. Over time psychiatric symptoms may appear as the metal dyshomeostasis and mitochondrial dysfunction affect other brain regions, including the reticular formation, hippocampus, and prefrontal cortex. It is proposed that metal dyshomeostasis in combination with mitochondrial dysfunction could be the underlying mechanism responsible for the initiation and progression of the pathological changes associated with both the motor and extra-motor symptoms of ALS.


The relative rotation of the ends of Bacillus subtilis during growth.
Observation of long single filaments of Bacillus subtilis 168 in depression slide cultures demonstrated that one end rotated relative to the other during growth. This was observed with suspended filaments, filaments attached to glass surfaces and single stranded filaments folded back on themselves growing as a double stranded helix. This extends Mendelson's 1976 conclusion to cases with no alternative interpretation to the hypothesis that as each cell grows, the structure of the peptidoglycan changes to rotate one end relative to the other.


FEASIBILITY OF INSPIRATORY MUSCLE TRAINING FOR PATIENTS WITH PERSISTENT DYSPNOEA AFTER COVID-19 INFECTION: A PILOT STUDY.
This study investigates the feasibility of delivering inspiratory muscle training as part of the physical therapy treatment for patients with post-COVID dyspnoea. Mixed-methods pilot study. Patients with complaints of dyspnoea after COVID-19 infection and their physical therapists. The Amsterdam University of Applied Sciences and the Amsterdam University Medical Centers conducted this study. Participants performed daily inspiratory muscle training at home for 6 weeks, consisting of 30 repetitions against a pre-set resistance. The primary outcome was feasibility assessed as acceptability, safety, adherence and patient- and professional experience obtained through diaries and semi-structured interviews. The secondary outcome was maximal inspiratory pressure. Sixteen patients participated. Nine patients and 2 physical therapists partook in semi-structured interviews. Two patients dropped out before initiating the training. Adherence was 73.7%, and no adverse events occurred. Protocol deviations occurred in 29.7% of the sessions. Maximal inspiratory pressure changed from 84.7% of predicted at baseline to 111.3% at follow-up. Qualitative analysis identified barriers to training: 'Getting acquainted with the training material' and 'Finding the right schedule'. Facilitators were: 'Support from physical therapists' and 'Experiencing improvements'. Delivering inspiratory muscle training to patients with post-COVID dyspnoea seems feasible. Patients valued the simplicity of the intervention and reported perceived improvements. However, the intervention should be carefully supervised, and training parameters adjusted to individual needs and capacity.


[Survival of Bacillus anthracis spores in baths using modern technologic tannery processes].
The influence of skin tannery baths, according as wet-blue, wet-white and plant technology, on B. anthracis spores survival was investigated. As a result of this study there was explained that lime bath do not inactivated of all spores that are present in infected bath. As a result of these experiments the spores were inactivated completely not before pickle bath.


Visual outcome and complications of pars plana vitrectomy for dislocated intraocular lenses.
To report factors predicting the visual outcome and complications in eyes that underwent pars plana vitrectomy (PPV) to manage dislocated intraocular lenses (IOLs). A retrospective chart review was performed. Clinical data recorded from the patient charts include, demographic, preoperative, intraoperative, and postoperative, with emphasis on visual acuity, interval between IOL dislocation and pars plana vitrectomy, surgical method and complications. Patients with follow-up of less than three months were excluded. Ninety-four patients were identified, 63 males and 31 females. Age ranged from 2 to 85 years (mean 52.6). The range of follow-up was 3 to 108 months (mean ± SD 19.4 ± 17.4 months). The final visual acuity was 20/50 or better in 52 (55.3%) eyes. Our analysis indicated that visual rehabilitation with IOL was significantly associated with better visual acuity as compared with eyes that were left aphakic (P = 0.0092). There was a trend toward a better visual outcome when PPV was performed within two weeks from the diagnosis of the dislocated IOL which was associated with good visual outcome (20/200 or better) in 85.7% of eyes compared with 78.8% of eyes. Management of IOL by interofixation was associated in (90.0%) of eyes with good vision (20/200 or better) compared to 76.1% eyes that had exchange of IOL through the limbus. Postoperative complications include cystoid macular edema in 9 (9.6%), glaucoma in 9 (9.6%), bullous keratopathy in 8 (8.5%), retinal detachments in 6 (6.4%) eyes, and relapsing uveitis in 2 (2%). In this series, the final visual outcomes were improved and the rate of postoperative complications were low. Eyes that were pseudophakic had significantly good visual outcome compared with eyes that were left aphakic. To the best of our knowledge, this may be the largest study on dislocated IOL removal by PPV with good visual results compared to other studies.


Glioblastoma microenvironment contains multiple hormonal and non-hormonal growth-stimulating factors.
The growth of malignant tumors is influenced by their microenvironment. Glioblastoma, an aggressive primary brain tumor, may have cysts containing fluid that represents the tumor microenvironment. The aim of this study was to investigate whether the cyst fluid of cystic glioblastomas contains growth-stimulating factors. Identification of such growth factors may pave the way for the development of targeted anti-glioblastoma therapies. We performed hormone analysis of cyst fluid from 25 cystic glioblastomas and proteomics analysis of cyst fluid from another 12 cystic glioblastomas. Glioblastoma cyst fluid contained hormones within wide concentration ranges: Insulin-like growth factor 1 (0-13.7 nmol/L), insulin (1.4-133 pmol/L), erythropoietin (4.7-402 IU/L), growth hormone (0-0.93 µg/L), testosterone (0.2-10.1 nmol/L), estradiol (0-1.0 nmol/L), triiodothyronine (1.0-11.5). Tumor volume correlated with cyst fluid concentrations of growth hormone and testosterone. Survival correlated inversely with cyst fluid concentration of erythropoietin. Several hormones were present at concentrations that have been shown to stimulate glioblastoma growth in vitro. Concentrations of erythropoietin and estradiol (in men) were higher in cyst fluid than in serum, suggesting formation by tumor or brain tissue. Quantitatively, glioblastoma cyst fluid was dominated by serum proteins, illustrating blood-brain barrier leakage. Proteomics identified several proteins that stimulate tumor cell proliferation and invasiveness, others that inhibit apoptosis or mediate adaption to hypoxia and some that induce neovascularization or blood-brain barrier leakage. The microenvironment of glioblastomas is rich in growth-stimulating factors that may originate from the circulation, the tumor, or the brain. The wide variation in cyst fluid hormone concentrations may differentially influence tumor growth.


Compatibility of a novel temperature-controlled, irrigated radiofrequency catheter with ultra-high-density mapping.
Compatibility of DiamondTemp (DT) radiofrequency (RF) catheter with the Rhythmia mapping system has not been manufacturer-reported nor its tracking accuracy reported. Consecutive patients undergoing macroreentrant atrial tachycardia ablation guided by Rhythmia and ablated using DT were prospectively enrolled. Following catheter configuration, ablation lines were performed and remapped to measure the RF tag to effective-ablation-line-center (RFT-ALC) distance. Among 20 consecutive patients (54 maps), 40 ablation lines were evaluated. Overall, the RFT-ALC distance was 3.88 ± 2.95 mm, and the operator assessment of accuracy was high. No complications occurred. The use of DT catheter guided by the Rhythmia mapping system is feasible and accurate.


Association of medication use with falls and mortality among long-term care residents: a longitudinal cohort study.
Falls in long-term care are common. The aim of our study was to explore how medication use is associated with incidence of falls, related consequences, and all-cause mortality among long-term care residents. Five hundred thirty two long-term care residents aged 65 years or older participated in this longitudinal cohort study in 2018-2021. Data on medication use were retrieved from medical records. Polypharmacy was defined as use of 5-10 medications and excessive polypharmacy as use of > 10 medications. The numbers of falls, injuries, fractures, and hospitalizations were collected from medical records over 12 months following baseline assessment. Participants were followed for three years for mortality. All analysis were adjusted for age, sex, Charlson Comorbidity Index, Clinical dementia rating, and mobility. A total of 606 falls occurred during the follow-up. Falls increased significantly with the number of medications used. Fall rate was 0.84/person-years (pyrs) (95% CI 0.56 to 1.13) for the non-polypharmacy group, 1.13/pyrs (95% CI 1.01 to 1.26) for the polypharmacy group, and 1.84/pyrs (95% CI 1.60 to 2.09) for the excessive polypharmacy group. Incidence rate ratio for falls was 1.73 (95% CI 1.44 to 2.10) for opioids, 1.48 (95% CI 1.23 to 1.78) for anticholinergic medication, 0.93 (95% CI 0.70 to 1.25) for psychotropics, and 0.91 (95% CI 0.77 to 1.08) for Alzheimer medication. The three-year follow-up showed significant differences in mortality between the groups, the lowest survival rate (25%) being in the excessive polypharmacy group. Polypharmacy, opioid and anticholinergic medication use predicted incidence of falls in long-term care. The use of more than 10 medications predicted all-cause mortality. Special attention should be paid to both number and type of medications when prescribing in long-term care.


Multiplex DNA sensor for BRAF and BRCA detection.
In this article, a kind of simple, sensitive, and rapid quantum dots (QDs)-based multiplex DNA sensor is developed for the simultaneous detection of BRAF and BRCA DNA based on the "nano-on-micro" technique. In our strategy, capture DNA(BRCA) and DNA(BRAF) are simultaneously immobilized on the surface of amino-modified silica microbeads. After blocking with bovine serum albumin (BSA), different concentrations of target DNA(BRCA) and DNA(BRAF) are introduced to hybrid with complementary capture DNA(BRCA) and DNA(BRAF). After hybridization, QDs546-labeled probe DNA(BRAF) and QDs657-labeled probe DNA(BRCA) were added into the above solution so that the unreacted capture DNA(BRCA) and DNA(BRAF) could be detected by QDs657-labeled probe DNA(BRCA) and QDs546-labeled probe DNA(BRAF) simultaneously. We demonstrate that the proposed method is effective for detecting BRAF and BRCA DNA with high sensitivity. The sensor has great potential to expand its application to the early diagnosis of cancers such as breast cancer, ovarian cancer, and papillary thyroid carcinoma.


Injection augmentation of type I laryngeal clefts.
To describe a series of children diagnosed with type I congenital laryngeal clefts (LC-I) and treated, due to various presentations, with endoscopic injection augmentation (IA). Case series with chart review. Tertiary care academic children's hospital in Edmonton, Canada. All pediatric patients diagnosed with LC-I and treated with IA in a single tertiary care practice. The children were identified from a prospectively collected database. Only those who were treated with IA and had a minimum follow-up of 3 months were included. The authors collected demographics, diagnoses, surgical procedures, number of IA procedures, clinical outcomes, and complications. Over a period of 8 years, 43 patients were diagnosed with LC-I. Eighteen had undergone IA over the past 4 years. Mean age at IA was 37.11 ± 32.68 months with a male-to-female ratio of 1.25:1. The indications were swallowing dysfunction (13), atypical croup (2), chronic cough (1), cyanotic spells (1), and asthma (1). Seven patients required repeated injections (mean, 2.57 injections). A total of 13 patients responded with resolution of symptoms in question. A single postoperative complication was recorded. IA is a brief, simple management option that succeeds in a number of children with LC-I. It is minimally morbid and supplements other conservative approaches to treat the condition.


Reconstructing archaeological palaeolandscapes using geophysical and geomatic survey techniques: An example from Red Lily Lagoon, Arnhem Land, Australia.
Arnhem Land is a key region for understanding the Pleistocene colonisation of Australia, due to the presence of the oldest sites in the continent. Despite this, conventional archaeological survey has not been effective at locating additional pre-Holocene sites in the region due to a complex distribution of geomorphic units caused by sea level rise and coastal aggradation. This research uses geophysical and geomatic techniques to map the subsurface distribution of the geomorphic units in the Red Lily Lagoon region in eastern Arnhem Land. This reveals a complex Pleistocene landscape, which offers the potential to locate additional archaeological sites and so reveal more about the lifeways of the earliest Australians.


Diastology 2010: clinical approach to diastolic heart failure.
The role of echocardiography in the evaluation of left ventricular diastolic function is increasingly important in both systolic and diastolic heart failure. In routine clinical practice, the diastolic dysfunction associated with diastolic heart failure can mainly be evaluated by Doppler echocardiography. In order to use echocardiographic techniques for this purpose, one should recognize the definition, terminology, epidemiology, and pathophysiology of diastolic dysfunction and diastolic heart failure. There are various echocardiographic parameters for this purpose, including transmitral flow velocity, pulmonary venous flow velocity, mitral annular velocity, flow propagation velocity, left atrial size, strain, strain rate, twist, and so on. However, no single Doppler echocardiographic index has yielded a robust criterion for diastolic dysfunction and elevated left ventricular filling pressure. Thus, multiple indices are required to increase the sensitivity of the diagnosis. Clinicians who take care of heart failure patients should continue to make critical use of a current Doppler echocardiographic evaluation and utilize this information to improve survival and quality of life in these patients.


Parent-ramet connections in Agave deserti: influences of carbohydrates on growth.
Agave deserti, a monocarpic perennial occurring in the northwestern Sonoran Desert, produces ramets on rhizomes that extend from the base of a parent plant. Shading ramtes to light compensation for two years did not decrease their relative growth rate (RGR) compared with unshaded ramets. However, the parents experienced a 30% decrease in total nonstructural carbohydrate (TNC) level, suggesting that carbohydrates were translocated from parents to ramets. Shaded parents had RGR's similar to unshaded parents, due in large part to consumption of 50% of the TNC reserves of shaded parents, but about 10% of the growth of the shaded parents was attributed to TNC received from their attached ramets. Estimates of parent and ramet growth separately, based on changes in TNC levels (converted to dry weight using a measured production value), net CO2 uptake of unfolded leaves, and respiration of roots, stems, and folded leaves, were similar to measured growth of parents and ramets combined, suggesting that parents and ramets are physiologically integrated and grow as a unit. Large TNC reserves, which were also shown to support growth during conditions of water limitation in the field, enhance the growth of ramets in an environment where seedling establishment is rare.


Mycotic aortic aneurysm: A case of an unlikely location and an unlikely pathogen.
This is an unusual case of a mycotic aortic aneurysm located in the ascending aorta caused by Neisseria meningitidis. The diagnosis was made using two-dimensional (2D) and three-dimensional (3D) transoesophageal echocardiogram (TOE) and cardiovascular magnetic resonance (CMR). Management was with prolonged antibiotics followed by surgical resection. The ascending aorta was replaced with Dacron tube graft. The contribution of multimodality imaging in clearly defining the pathology, its location and directing the timing of surgery, was a striking aspect of this case.


[Bone morphogenetic proteins in the skeletal system].
Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta superfamily. Their potential for organ and tissue regeneration and repair has been intensively investigated in recent years. Studies on fetal development have demonstrated the important role of these proteins for the development and differentiation of different organs. Miss-expression or mutation of BMPs may lead to severe abnormalities or even abortion. However, a regenerative potential has also been recognized for the adult organism. BMPs support fracture healing and may contribute to treatment of joint diseases. Thus, BMP-7 is one of the first BMPs approved for clinical application in non-unions of bone fractures resistant to conventional therapy. In degenerative and inflammatory joint diseases, experimental data suggest a decrease of BMP expression in cartilage tissue. Therefore, BMPs could be promising therapeutic candidates in these diseases, although more detailed analyses are necessary. In this review we will focus on bone morphogenetic proteins and discuss present and putative future clinical applications.


ICD-10 coding in otorhinolaryngological malformations: Analyses of 2342 Q-diagnoses.
The 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) includes more than 14,400 codes. The aim of this study was to study the prevalence and demographics of otorhinolaryngological congenital malformations in an outpatient clinic based of the ICD-10 Q-diagnoses used for congenital malformations, deformations and chromosomal abnormalities. Electronic hospital records covering six years (2007-2013) were searched to identify all patients with ICD-10 Q-diagnosis. 2342 patients were identified. Malformations of the face and neck were most prevalent (30%). The gender distribution was equal except malformations of tongue, mouth and pharynx, where 70% of the patients were male. There seems to be a significant excess of ICD-10 codes for otorhinolaryngological malformations. Ten most common otorhinolaryngological malformation codes cover more than 94% of the diagnoses. In addition, the illogicalities and the possibility of coding by diagnosis, symptoms or clinical findings makes the coding suboptimal for the purposes it was originally created for. Malformations of the nose and larynx are rare compared to other anatomic localizations. The age at diagnosis of branchial cysts differs significantly from all other congenital malformations supporting the theory of cystic transformation of cervical lymph nodes.


(2S,3'S,3a'R,5'R,7a'R)-5'-[(E)-5-(Furan-3-yl)-2-methyl-pent-1-en-1-yl]-3-hy-droxy-3',4,7'-trimethyl-1',2',3',3a',5',7a'-hexa-hydro-5H-spiro-[furan-2,4'-inden]-5-one.
The title compound, ircinianin, C25H32O4, belongs to the sesterterpene tetronic acid compound family and was isolated from the marine sponge Ircinia wistarii. These chemical scaffolds are pharmacologically relevant, since they represent a new class of glycine receptor modulators. The furan ring makes a dihedral angle of 35.14 (12)° to the 4-hy-droxy-3-methyl-furan-2(5H)-one ring. The crystal packing is characterized by inter-molecular O-H⋯O hydrogen bonds, which generate [010] chains.


Subgaleal Drain Placement Improves Surgical Outcomes After Primary Cranioplasty in Craniosynostosis Patients.
There is no published data addressing the use of postoperative subgaleal drains in patients undergoing primary cranioplasty for craniosynostosis. We conducted a retrospective chart review in this population of patients, comparing outcomes of those who received postoperative drains with those who did not. We hypothesize that the subgaleal drains can significantly diminish postoperative facial edema and reduce the length of hospital stay. We conducted a retrospective chart review of all patients undergoing primary cranioplasty for craniosynostosis with subgaleal drain placement (May 2010-March 2012). A comparison group without drain placement was matched appropriately to establish a comparison of outcomes. We determined whether subgaleal drainage led to improvement in postoperative facial edema, reduced length of hospital stay, postoperative changes in hematocrit (Hct), and complication rates. Of the 50 patients in this cohort, 25 patients had received subgaleal drains. The mean length of stay was 2.4 versus 3.5 days for the respective drained and undrained cohorts (P = 0.03). There was no significant difference in the mean decline in Hct between drained and undrained patients, with the mean Hct drop of 4.8% versus 5.0%, respectively (P = 0.83). Postoperative seroma formation developed in 3 undrained patients (17%) versus none in the drained cohort (0%). Although subjective, drained patients were observed to achieve quicker resolution of facial swelling and earlier recovery of eye opening. There is clinical benefit in subgaleal drain placement as earlier resolution of postoperative facial edema and a significantly shortened length of hospital stay was found among the drained cohort. Future studies warrant prospective clinical trials to establish the safety and efficacy of using subgaleal drains in cranial remodeling procedures of craniosynostosis.


A prediction model for outcome in patients with HBV-ACLF based on predisposition, injury, response and organ failure.
We aimed to develop a prediction model based on the PIRO concept (Predisposition, Injury, Response and Organ failure) for patients with Hepatitis B Virus (HBV) related acute-on-chronic liver failure (ACLF). 774 patients with HBV related ACLF defined in the CANONIC study were analyzed according to PIRO components. Variables associated with mortality were selected into the prediction model. Based on the regression coefficients, a score for each PIRO component was developed, and a classification and regression tree was used to stratify patients into different nodes. The prediction model was then validated using an independent cohort (n = 155). Factors significantly associated with 90-day mortality were: P: age, gender and ACLF type; I: drug, infection, surgery, and variceal bleeding; R: systemic inflammatory response syndrome (SIRS), spontaneous bacteria peritonitis (SBP), and pneumonia; and O: the CLIF consortium organ failure score (CLIF-C OFs). The areas under the receiver operating characteristics curve (95% confidence interval) for the combined PIRO model for 90-day mortality were 0.77 (0.73-0.80). Based on the scores for each of the PIRO components and the cut-offs estimated from the classification and regression tree, patients were stratified into different nodes with different estimated death probability. Based on the PIRO concept, a new prediction model was developed for patients with HBV related ACLF, allowing stratification into different clusters using the different scores obtained in each PIRO component. The proposed model will likely help to stratify patients at different risk, defining individual management plans, assessing criteria for specific therapies, and predicting outcomes.


Difference in recognition of right and left hemispheric stroke.
Symptoms of cerebrovascular events differ depending on the hemisphere in which the lesion arises, thereby affecting disease recognition and management. We aimed to establish whether left and right hemispheric strokes are unequally distributed in inpatients. We obtained data from a large hospital-based stroke registry in Germany. 11,328 patients (56%) had left hemispheric events and 8769 (44%) had right-sided lesions (p<0.0001). Age, stroke severity, and time from symptom onset to admission were significantly associated with left hemispheric stroke, suggesting a selection effect. Difficulties in recognition of symptoms due to right hemispheric stroke challenge efforts to optimise stroke management, particularly in the critical early hours of stroke.


Multiple regulation pathways and pivotal biological functions of STAT3 in cancer.
STAT3 is both a transcription activator and an oncogene that is tightly regulated under normal physiological conditions. However, abundant evidence indicates that STAT3 is persistently activated in several cancers, with a crucial position in tumor onset and progression. In addition to its traditional role in cancer cell proliferation, invasion, and migration, STAT3 also promotes cancer through altering gene expression via epigenetic modification, inducing epithelial-mesenchymal transition (EMT) phenotypes in cancer cells, regulating the tumor microenvironment, and promoting cancer stem cells (CSCs) self-renewal and differentiation. STAT3 is regulated not only by the canonical cytokines and growth factors, but also by the G-protein-coupled receptors, cadherin engagement, Toll-like receptors (TLRs), and microRNA (miRNA). Despite the presence of diverse regulators and pivotal biological functions in cancer, no effective therapeutic inventions are available for inhibiting STAT3 and acquiring potent antitumor effects in the clinic. An improved understanding of the complex roles of STAT3 in cancer is required to achieve optimal therapeutic effects.


Bombyx mori cecropin A has a high antifungal activity to entomopathogenic fungus Beauveria bassiana.
A cDNA encoding cecropin A (CecA) was cloned from the larvae of silkworm, Bombyx mori, using RT-PCR. It encodes a protein of 63 amino acids, containing a 22 amino acid signal peptide and a 37 amino acid mat peptide of functional domain. The CecA secondary structure contains two typical amphiphilic α-helices. Real-time qPCR analysis revealed that CecA was expressed in all the tissues tested, including cuticle, fat body, hemocytes, Malpighian tubule, midgut and silk gland in the silkworm larvae with the highest expression in the fat body and hemocytes. The gene expression of B. mori CecA was rapidly induced by Beauveria bassiana challenge and reached maximum levels at 36h after inoculation in third instar larvae. In the fifth instar larvae infected with B. bassiana, the relative expression level of CecA was upregulated in fat body and hemocytes, but not in cuticle, Malpighian tubule, midgut and silk gland. The cDNA segment of the CecA was inserted into the expression plasmid pET-30a(+) to construct a recombinant expression plasmid. Western blot results revealed that his-tagged fusion protein was successfully expressed and purified. Then the mat peptide of CecA was chemically synthesized with C-terminus amidation for in vivo antifungal assay and purity achieved 93.7%. Mass spectrometry and SDS-PAGE showed its molecular weight to be 4046.95Da. Antifungal assays indicated that the B. mori CecA had a high antifungal activity to entomopathogenic fungus B. bassiana both in vitro and in vivo in the silkworm larvae. This is the first report that the CecA is effective to inhibit B. bassiana inside the body of silkworm.


Making a dream come true.
Rachel Wright qualified as a veterinary nurse in England and volunteered extensively in developing countries before setting up an animal hospital in Rajasthan in India.


Inherited disorders of epidermal keratinization.
There have been a number of major discoveries recently in the field of dermatological science which have enabled us to determine the causes of inherited skin diseases of previously unknown etiology. In this paper we will review some important aspects of the biology of epidermal differentiation and the recent advances in understanding of the molecular mechanism underlying genetic diseases of keratinization.


Evaluation of tubomanometry as a routine diagnostic tool for chronic obstructive Eustachian tube dysfunction.
The objective of this study was to demonstrate the reliability of tubomanometry (TMM) described by Estéve in the diagnosis of chronic obstructive Eustachian tube (ET) dysfunction. Combined prospective and retrospective clinical study. Tertiary referral centre, affiliated to university. Two hundred and fifteen healthy subjects were examined once, 25 healthy subjects underwent TMM weekly for 6 weeks, and six healthy subjects were tested three times a day on at least three different days. The results of tubomanometry in healthy subjects were compared to data obtained from 171 patients with chronic obstructive ET dysfunction. In healthy subjects, there was an immediate opening of the ET at 30-50 mbar with an R-value ≤ 1 in at least 94% of the cases. In patients with chronic ET dysfunction, an opening of the ET could be registered in only 42% of patients at 30 mbar and in 58% at 50 mbar. The average of the R-value in these subjects always indicated towards a delayed opening (R > 1). When measurements are repeated in the same subject with a weekly interval, the intraclass correlation (ICC) was 0.49 for the TMM with 30 mbar, 0.51 for the TMM with 40 mbar and 0.52 for the TMM with 50 mbar in healthy people. For the patients with symptoms of ET dysfunction, the ICC for up to four repeated measures was 0.50 for the TMM with 30 mbar, 0.53 for the TMM with 40 mbar and 0.54 for the TMM with 50 mbar. A complete agreement of the results in repeated measurements within seconds was present in 86% for 30 and 40 mbar and in 79% for 50 mbar. The ICC was 0.61 for the TMM with 50 mbar, 0.62 for the TMM with 40 mbar and 0.68 for the TMM with 30 mbar. Tubomanometry can support the diagnosis of ET dysfunction. An R-value ≤ 1 indicates a regular function of the ET, an R-value >1 indicates a delayed opening of the ET, and no definable R-value means no detectable opening of the ET. TMM is a reliable and valid instrument to support the diagnosis of chronic obstructive ET dysfunction.


Global sea level change signatures observed by GRACE satellite gravimetry.
Ice mass loss on land results in sea level rise, but its rate varies regionally due to gravitational self-attraction effects. Observing regional sea level rates by ocean mass change using the Gravity Recovery and Climate Experiment (GRACE) gravity solutions is difficult due to GRACE's spatial resolution (~a few hundred km) and other limitations. Here we estimate regional sea level mass change using GRACE data (without contributions from temperature and salinity variations) by addressing these limitations: restoring spatially spread and attenuated signals in post-processed GRACE data; constraining ocean mass distribution to conform to the changing geoid; and judging specific corrections applied to GRACE data including a new geocenter estimate. The estimated global sea level mass trend for 2003-2014 is 2.14 ± 0.12 mm/yr. Regional trends differ considerably among ocean basins, ranging from -0.5 mm/yr in the Arctic to about 2.4 mm/yr in the Indian and South Atlantic Oceans.


Replacing the refinement for skin sensitization testing: Considerations to the implementation of adverse outcome pathway (AOP)-based defined approaches (DA) in OECD guidelines.
While single non-animal methods have been adopted in OECD test guidelines, combinations of methods (so called defined approaches, DA) are not. Hardly any animal study can be replaced by a single non-animal method, rather DA are needed. The OECD published the Adverse Outcome Pathway (AOP) on skin sensitization in 2012 and is currently discussing the implementation of DA into a guideline. Obviously, it takes thorough considerations and evaluations to validate such DA. Currently we see four preconditions for a proper and expedient implementation of DA in a guideline: (i) The reference data should be selected to allow meaningful evaluations and must not replicate the limitations of the murine local lymph node assay (LLNA) (ii) Methods and prediction models should be validated before they are used in an OECD-adopted DA, (iii) An OECD-adopted DA should follow the respective AOP and (iv) acknowledge regulatory needs and successful toxicological practice. These points still need to be considered in the current discussion at the OECD. A guideline for skin sensitization DA is setting the scene for regulatory acceptance of all new approaches (for any toxicological endpoint) in the future. In this commentary, we are expounding these preconditions to allow a scientifically valid and sustainable application of modern (no-animal) approaches in regulatory toxicology.


Acute myeloblastic leukemia with active tyrosine protein kinase.
High level of tyrosine protein kinase activity was found in a membrane fraction isolated from an acute myeloblastic leukemia, out of 24 leukemias of different origin investigated. The major substrate for tyrosine phosphorylation in vitro was a 58 kDA protein (p58). The phosphorylation proceeded actively at 0 degrees C and was strongly stimulated by Mn2+ ions. Comparison by partial proteolysis of the p58 with similar phosphoproteins from a T-lymphoma line (KE37) and from lectin stimulated lymphocytes showed high similarity. The possible role of the tyrosine kinase activity in this leukemia is discussed.


Dental age assessment of 8.5 to 17 Year-old Saudi children using Demirjian's method.
The aim of this study was to assess the dental age in Saudi children aged 8.5 to 17 years using the Demirjian method. Four hundred ninety panoramic radiographs of boys and girls were reviewed retrospectively. All children were placed in the age group closest to their chronological age. The dental age was scored on all seven left mandibular teeth by one examiner. Both boys and girls in age groups nine to 14 years showed advanced dental age compared to their chronological age which was found to be statistically significant except in age groups nine and 13 years. Saudi boys were 0.3 years and Saudi girls 0.4 years ahead, on average, of French-Canadian children as analyzed by the Demirjian method. The standard values for French-Canadian children provided by Demirjian vary slightly for application to Saudi children. As a result, new graphs and tables were produced to convert these maturity scores, calculated by the Demirjian method, to the dental age for Saudi children.