In vitro transcriptional probes of heterotic rat liver chromatin.
DNA-dependent RNA polymerase I from E. coli has been used as probe for determining the capacity of purified chromatin isolated from inbred and hybrid rats during the course of postweaning development to serve as template for RNA synthesis in vitro. An analysis of variance reveals both strain- and age-specific differences in the incorporation of [3H]UTP into RNA. The ability of inbred chromatin to support synthesis exceeds that of the hybrid at every age examined except 50 days, with values in the inbred line approaching those in the hybrid line with increasing age. These data suggest that template characteristics may vary substantially with regard to strain and age and may contribute to differences in heterotic development.


The role of nuclei, polyribosomes and cytosol factors in the onset of the acute-phase reaction in the liver cell.
Nuclei isolated from livers of turpentine-treated rats show an increased RNA synthesis, reaching a maximum at 10 h after treatment. The stimulation affects both alpha-amanitin-resistant and alpha-amanitin-sensitive activities, suggesting that pre-ribosomal and pre-messenger RNA formation are activated at the same time and to the same extent. The amount of ribosomal RNA, which is still normal 10 h after treatment, increases significantly at 24 h, but the increase is limited to the bound ribosomes, in keeping with the fact that the acute phase reactants are export proteins. These ribosomes, however, are not more active per se and the stimulation of protein synthesis in cell-free preparations depends essentially on an increased activity of soluble factors located in the cytosol. In living cells these soluble factors co-operate with an increased amount of some specific mRNAs and an expanded population of membrane-bound polyribosomes, thus leading to the increased protein synthesis peculiar to the liver of turpentine-treated rats.


Phylogenetic independence in the variations in leaf functional traits among different plant life forms in an arid environment.
Leaf traits of global plants reveal the fundamental trade-offs in plant resource acquisition to conservation strategies. However, which leaf traits are consistent, converged, or diverged among herbs, shrubs, and subshrubs in an arid environment remains unclear. In the present study, we evaluated the trade-offs in six leaf functional traits (LFTs): leaf fresh mass (LFM), leaf dry mass (LDM), leaf dry matter content (LDMC), leaf area (LA), specific leaf area (SLA), and leaf thickness (LTh) of 37 desert plant species. LFTs differed between different plant life forms; LFM, LDM, and LA were slightly higher in herbs, LDMC and LTh in shrubs, and SLA in subshrubs. Conversely, the correlations among LFTs were inconsistent in different life forms, which may indicate their different adaptation strategies in an arid environment. Legumes and C3 plants exhibited slightly higher LDMC, LA, and SLA than non-legumes and C4 plants, whereas non-legumes and C4 plants showed higher (nonsignificant) LFM, LDM, and LTh than legumes and C3 plants. A significant phylogenetic signal (PS) and maximum K-value were found for SLA (K = 0.32). LFTs exhibited convergent and divergent variations among different life forms. However, these variations in LFTs were not influenced by phylogeny. Together, these findings increase our understanding of the variations in ecological adaptations of desert plants as well as adaption strategies of different life forms in an arid environment.


Comparative effectiveness of devices for transcatheter closure of atrial septal defects: Systematic review and network meta-analysis.
Atrial septal defect is a common congenital heart disease, producing a left-to-right shunt in the atrial septum; the current preferred treatment is transcatheter device closure. The aim is to conduct a systematic review to synthesize information on the comparative effectiveness and safety of atrial septal defect closure devices. The methods used: a comprehensive search of Ovid MEDLINE®, Embase, and Cochrane Central databases was conducted. Studies comparing procedural and follow-up outcomes of atrial septal defect devices were included. Network meta-analyses were conducted to generate direct and indirect evidence for comparative effectiveness and safety outcomes between devices. The results are as follows: Twelve studies met our inclusion criteria and were compared in network meta-analyses. The meta-analyses evaluated contemporary devices: the AMPLATZER Septal Occluder; the GORE CARDIOFORM Septal Occluder; the Figulla Flexible II Occluder; the CeraFlex Septal Occluder; and the HELEX Septal Occluder. These studies represented 3998 patients. The primary safety and efficacy outcomes were device embolization and follow-up residual shunt, respectively. Secondary clinical outcomes included procedural success and major and minor complications. No differences were found between devices in terms of device embolization and secondary clinical outcomes. Follow-up residual shunt was higher with the HELEX Septal Occluder compared with the AMPLATZER Septal Occluder (odds ratio 2.92, 95% confidence interval 1.12-7.61). To conclude: although most outcomes were similar between devices, evidence was largely based on observational low-quality studies. There were inconsistencies in outcome reporting and definitions; this merits future studies, with head-to-head device comparisons and standardization of outcomes.


Primary T-cell lymphoma of the thyroid.
A rare case of non-Hodgkin's malignant T-cell lymphoma of the thyroid in a 79-year-old woman is reported. Light microscopically, the tumor showed diffuse proliferation of lymphoid cells, revealing prominent nuclear irregularity and occasional multilobulated nuclei, and was diagnosed as a diffuse lymphoma of medium-sized cell type. Electron microscopically, the tumor cells were seen to possess irregularly indented nuclei. Immunologic surface marker studies showed that the lymphoma cells were positive for T-lymphocyte-lineage antigens, OKT4 and OKT11, and did not react with B-lymphocyte-associated antigens. These findings indicated that the lymphoma had a T-cell phenotype.


Impaired endothelium independent vasodilation in the cutaneous microvasculature of young obese adults.
Microvascular dysfunction contributes to the development of cardiovascular and metabolic disease. This study tested the hypothesis that young obese (BMI>30 kg m(-2)), otherwise healthy, adults (N=15) have impaired microvascular function relative to age and sex matched, lean (BMI<25 kg m(-2)) individuals (N=14). Participants were instrumented with two microdialysis probes in the cutaneous vasculature of one forearm; one for a wide dose range of infusions of the endothelium-dependent vasodilator methacholine (MCh) and the other for the endothelium-independent vasodilator sodium nitroprusside (SNP). Local temperature at each site was clamped at 33 °C and cutaneous blood flow was indexed by laser Doppler flowmetry (LDF). LDF was recorded while 7 doses of each drug (MCh: 10(-6)-1M; SNP: 5 × 10(-8)-5 × 10(-2)M) were infused at a rate of 2 μl/min for 8 min per dose. Both sites finished with heating to 43 °C and 5 × 10(-2)M SNP to achieve site specific maximal vasodilation. Mean arterial blood pressure (MAP) was assessed in the last minute of each dose and was used for subsequent calculation of cutaneous vascular conductance (CVC; LDF/MAP) and responses were normalized to each individual site's maximal response (%CVCmax). Group four-parameter dose response curves were compared with an extra sum of squares F-test. SNP EC50 was greater in obese relative to lean (-2.931 ± 0.10 vs -3.746 ± 0.18 Log[SNP]M, P<0.001); however, there was no difference in MCh EC50 between groups (-3.796 ± 0.23 vs -3.852 ± 0.25 Log[MCh]M, P=0.81). Additionally, baseline and maximal CVC in both sites were similar between groups (all P>0.05). These results suggest attenuated endothelium-independent response to nitric oxide while endothelium-dependent vasodilation function is maintained.


Rabbit model of uveal Greene melanoma: morphologic studies of metastatic lesions.
We studied the morphology of metastatic tumors in three rabbits with implanted choroidal Greene melanoma. The tumor-bearing eyes were perforated and destroyed by the expanding tumors 10 to 12 weeks after implantation. The animals then lost body weight and became cachectic; they were suspected of having metastases and were sacrificed. The interval between the destruction of the eye and the discovery of metastases was 1 to 14 weeks. Widespread metastases involved the liver, lungs, kidneys, and subcutaneous tissue, with the greatest number of tumors in the liver and lungs. Histopathologic findings in the metastases and primary tumors were identical. This model may be considered appropriate for study of human uveal melanoma because (1) the biological behavior is similar to that of human uveal melanoma, (2) the primary and metastatic tumors are histologically similar, and (3) the large size of the rabbit's eye facilitates observation and manipulation.


Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights.
The first consensus guidelines for scoring the histopathological growth patterns (HGPs) of liver metastases were established in 2017. Since then, numerous studies have applied these guidelines, have further substantiated the potential clinical value of the HGPs in patients with liver metastases from various tumour types and are starting to shed light on the biology of the distinct HGPs. In the present guidelines, we give an overview of these studies, discuss novel strategies for predicting the HGPs of liver metastases, such as deep-learning algorithms for whole-slide histopathology images and medical imaging, and highlight liver metastasis animal models that exhibit features of the different HGPs. Based on a pooled analysis of large cohorts of patients with liver-metastatic colorectal cancer, we propose a new cut-off to categorise patients according to the HGPs. An up-to-date standard method for HGP assessment within liver metastases is also presented with the aim of incorporating HGPs into the decision-making processes surrounding the treatment of patients with liver-metastatic cancer. Finally, we propose hypotheses on the cellular and molecular mechanisms that drive the biology of the different HGPs, opening some exciting preclinical and clinical research perspectives.


Estimation of octanol-water partition coefficients for neutral and weakly acidic compounds by microemulsion electrokinetic chromatography using dynamically coated capillary columns.
Microemulsion electrokinetic chromatography (MEEKC) using dynamically coated capillary columns is shown to be suitable for estimating the octanol-water partition coefficient (log P) for neutral and weakly acidic compounds at pH 3. The solvation parameter model is used to demonstrate that the retention properties of sodium dodecyl sulfate (1.4% w/v), n-butanol (8% v/v) and n-heptane (1.2% v/v) microemulsion are strongly correlated with the octanol-water partition system. For compounds of varied structure and log P values from 0.3 to 5.15, the correlation model is able to estimate log P to better than 0.25 log units. The dynamically coated columns consisting of a bilayer of poly(vinylsulfonate) adsorbed on top of polybrene provide a suitable electroosmotic flow at pH 3 without interfering in the retention properties of the microemulsion. For automated measurements the microemulsion run buffer should be replenished after 10 runs to maintain a stable cycle time and the coated columns replaced after 40-70 runs, depending on sample properties.


Factors Associated with Timing of Initiation of Antiretroviral Therapy among HIV-1 Infected Adults in the Niger Delta Region of Nigeria.
Based on growing evidence mainly from countries outside Sub-Saharan Africa, the World Health Organisation (WHO) now recommends initiation of antiretroviral therapy (ART) in HIV-infected individuals in developing countries when CD4 cell count (CD4+) is ≤ 500 cells/ul. Nigeria accounts for about 14% of the estimated HIV/AIDS burden in Sub-Saharan Africa. We evaluated the factors associated with timing of initiation of ART among treatment-ineligible HIV-infected adults from Nigeria. We retrospectively reviewed the hospital records of ART ineligible HIV-infected adults who enrolled into HIV care between January 2008 and December 2012 at two major tertiary hospitals in Bayelsa State, South-South Nigeria. Demographic, clinical and laboratories data were obtained at presentation, at each subsequent visit at 6 monthly intervals and at time of initiation of ART. Cox proportional regression and Kaplan-Meier survival analysis were used to evaluate independent predictors of time to initiation of ART. Amongst the 280 study participants, 70.6% were females, 62.6% had CD4+ ≥500 cells/ul, 48.4% had WHO HIV Stage 1 disease and 34.3% were lost to follow up. In a cohort of 180 participants followed up for ≥3 months, participants with CD4+ of 351-500 cells/ul and stage 2 disease were more likely to start ART earlier than those with CD4+ > 500 cells/ul (Hazard ratio [HR]-1.7, 95% confidence interval [CI] of 1.0-2.9) and stage 1 disease (HR-2.3 (95% CI-1.3-4.2) respectively. HIV-infected adults with faster CD4+ decay required earlier ART initiation, especially in the first year of follow up. ART-ineligible HIV-infected adults on follow up in South-South Nigeria are more likely to require earlier initiation of ART if they have stage 2 HIV disease or CD4+ ≤500 cells/ul at presentation. Our findings suggest faster progression of HIV-disease in these groups of individuals and corroborate the growing evidence in support for earlier initiation of ART.


Corticosteroid injections in the management of subacromial pain: Experiences and decision making of physiotherapists.
Despite ongoing debate in the literature regarding their efficacy, corticosteroid injections remain a common treatment intervention for physiotherapists to consider for patients with subacromial pain. Very little is known about what factors and how clinician's experiences inform decision making in this area. To investigate the experiences and decision making of physiotherapists in relation to the use of corticosteroid injections for subacromial pain. A qualitative study using semi-structured interviews, which were then analysed using thematic analysis. A social enterprise organisation delivering NHS primary care musculo-skeletal physiotherapy services. Nine physiotherapists. Three broad codes were identified: (1) initial management; (2) patient factors; (3) therapist beliefs. Within these three codes, seven sub-themes were identified. Confidence in diagnosis and satisfaction that conservative management had been attempted was important. Features of a patient's presentation were key to decision making, i.e. pain severity, function and effect on sleep. Patient engagement with rehabilitation was also considered important, as was consideration of the effect of psychosocial factors. Therapist beliefs and experiences around the efficacy of corticosteroid injections was also considered influential on decision making. Some dissuasive factors were also discussed. Some of the key factors in the decision making of physiotherapists in relation to the use of corticosteroid injections for subacromial pain have been identified, such as patient presentation and engagement, clinician experience and consideration of current literature. Further research is indicated to explore this subject further to enable better understanding around clinical decision making and the use of corticosteroid injections.


Calcium-chloride-assisted approach towards green and sustainable synthesis of hierarchical porous carbon microspheres for high-performance supercapacitive energy storage.
Spherical carbon materials exhibit great competence as electrode materials for electrochemical energy storage, owing to the high packing density, low surface to volume ratio, and excellent structure stability. How to utilize renewable biomass precursor by green and efficient strategy to fabricate porous carbon microspheres remains a great challenge. Herein, we report a KOH-free and sustainable strategy to fabricate porous carbon microspheres derived from cassava starch with high specific surface area, high yield, and hierarchical structure, in which potassium oxalate monohydrate (K2C2O4·H2O) and calcium chloride (CaCl2) are employed as novel activator. The green CaCl2 activator is crucial to regulate the graphitization degree, specific surface area, and porosity of the carbon microspheres for improving the electrochemical performance. The as-prepared carbon microspheres exhibit high specific surface area (1668 m2 g-1), wide pore size distribution (0.5-60 nm), high carbon content (95%), and exfoliated surface layer. The hierarchical porous carbon microspheres show high specific and areal capacitance (17.1 μF cm-2), superior rate performance, and impressive cycling stability. Moreover, the carbon microspheres based symmetric supercapacitor exhibits high capacitance and excellent cycling performance (100% after 20 000 cycles at a current density of 5 A g-1). This green and novel approach holds great promise to realize low-cost, high-efficient and scalable of renewable cassava starch-derived carbon materials for advanced supercapacitive energy storage applications.


Chimeric Pestivirus Experimental Vaccines.
Chimeric pestiviruses have shown great potential as marker vaccine candidates against pestiviral infections. Exemplarily, we describe here the construction and testing of the most promising classical swine fever vaccine candidate "CP7_E2alf" in detail. The description is focused on classical cloning technologies in combination with reverse genetics.


[Salt Stress Response in Arabidopsis thaliana Plants with Defective Jasmonate Signaling].
The effects of exogenous jasmonic acid (JA) on antioxidant enzymes in four-week-old leaves of wild-type Arabidopsis thaliana L. (Columbia-0) and jin1 (jasmonate insensitive 1) mutant plants with defective jasmonate signaling were investigated under normal conditions and under salt stress (200 mM NaCl, 24 h). The wild-type plants responded to JA by an increase in the activities of Cu/Zn superoxide dismutase, catalase, and guaiacol peroxidase, while there was no change in the case of the mutant plants. In response to the salt stress of both the wild-type and mutant genotypes, the activities of superoxide dismutase, catalase, and guaiacol peroxidase were unchanged, decreased, and increased, respectively. The JA-treated wild type plants showed the highest activity of all three enzymes as compared with the mutant plants. Salinity caused a decrease in chlorophyll content in the wild-type and jin 1 plants. Preliminary JA treatment of the Col-0 plants resulted in a normal content of photosynthetic pigments after the salt stress, while the positive JA effect was insignificant in the jin 1 mutants. It was concluded that the MYC2/JIN 1 protein is involved in the JA signal transduction and plant adaptation to salt stress.


Are there real advantages of induction therapy with basiliximab in renal transplantation?
Randomized clinical trials have supported the use of interleukin-2 receptor (IL-2R) antagonists as induction therapy in renal transplantation. This strategy has reduced the incidence of acute rejection episodes (ARE) but not improved graft survival. Our objective was to investigate the impact of induction therapy using the IL-2R antagonist basiliximab, as compared with no induction therapy, on relevant clinical outcomes-initial length of stay, incidence of ARE, long-term graft function, and graft survival. We retrospectively reviewed the medical records of patients transplanted in a tertiary care center between 1996 and 2011. We selected patients who received cyclosporine, mycophenolate mofetil, and prednisolone (n = 334) to classify as: no induction therapy (n = 131; group 1); induction therapy with basiliximab (n = 203; group 2). Estimated glomerular filtration rate (eGFR) was assessed with the 4-variable Modification of Diet in Renal Disease (MDRD) equation. Mean follow-up was 72.7 ± 35.4 months. Patients who received basiliximab had a shorter mean hospital stay (19.2 versus 22.5 days; P = .02), lower incidence of ARE (10.8% versus 23.7%; P = .02) and better graft function post transplantation at 12 months (mean eGFR 59.4 ± 18.4 versus 54.8 ± 18.7 mL/min/1.73 m(2); P = .015) and 5 years (mean eGFR 64.1 ± 21.5 versus 55.4 ± 19.6 mL/min/1.73 m(2); P = .009). On multivariate analysis, induction therapy with basiliximab was independently associated with a lower incidence of ARE and better graft function at 1 and 5 years after transplantation. There was no difference in 5-year graft survival between the two groups (log-rank: P = .54). Induction therapy with basiliximab was associated with a reduced incidence of ARE and better long-term graft function but no difference in 5-year graft survival.


A greatly simplified method of establishing B-lymphoblastoid cell lines.
Ten lymphoblastoid cell lines were established by Epstein-Barr virus-induced transformation directly from 0.04 to 0.15 ml of peripheral whole blood of one patient with xeroderma pigmentosum and four normal healthy adults. All these lines expressed B-lymphocyte characteristics. The advantages of this method are: (a) only a few drops of blood are required for establishing a permanent line; (b) damage and loss of cells in separation procedures are minimal; and (c) the method is simple, reliable, and applicable, if desired, to any patient, even babies.


Suicide in England and Wales, 1975-1984.
An investigation of the suicide rate in the decade 1975-1984 in England and Wales revealed an increase in rate for males of all ages, and a small decrease for young females. The increase for males has been greatest in the 25-54 years group. There has been a decrease in the number of suicides by poisoning with solids and liquids (including overdoses) for both sexes. Rates for poisoning by vehicle exhaust gas and by hanging, strangulation and suffocation have increased substantially during this period. In males, suicides by these methods now exceed those due to poisoning by solids and liquids.


Synthesis of oligodeoxyribonucleotides containing 2'-deoxypseudouridine: inhibition of uracil-DNA glycosylase.
2'-Deoxypseudouridine (1) was synthesized starting from thymidine in a 23% overall yield via a silylated furanoid glycal. Compound 1 was introduced to oligodeoxyribonucleotides (ODNs) by the solid phase phosphoramidite chemistry. The ODNs containing 1 inhibited uracil-DNA glycosylase (UDG) reaction.


What is episodic memory and how do we use it?
What are the neural and computational principles that give rise to episodic memory? Although memory is probably the most studied topic in psychology and cognitive neuroscience, most research has focused on learning at the micro-level. I outline the limitations of this approach and propose a 'molar' approach to tackle episodic memory at the scale of life.


Effects of platelet-activating factor on canine gastric mucosal blood flow and permeability to luminal acid.
Recent studies suggest that platelet-activating factor, a newly described phospholipid released during acute inflammation, may predispose the gastric mucosa to acute ulceration. This study was performed to evaluate whether this substance might contribute to acute injury through its effects on mucosal microcirculation or by increasing permeability of the gastric mucosa to luminal acid. Platelet-activating factor was infused at a rate of 1 microgram/min directly into the artery supplying a chambered segment of canine gastric corpus and both significantly decreased venous outflow and mucosal blood flow and enhanced the efflux of volume, sodium ions, and potassium ions into the lumen. Thus, as in other capillary beds, platelet-activating factor appeared to induce stasis of flow and local accumulation of interstitial fluids which then leaked into the lumen. Platelet-activating factor did not significantly alter the back-diffusion of hydrogen ions into the mucosa. Thus, platelet-activating factor may not directly influence mucosal permeability to luminal acid, and it may predispose the gastric mucosa to acute injury through its effects on the microvasculature and other aspects of the inflammatory process.


Bupivacaine inhibits COX-2 expression, PGE2, and cytokine production in endotoxin-activated macrophages.
Upregulation of cyclooxygenase-2 (COX-2) and resultant prostaglandin E(2) (PGE(2)) overproduction has been shown to play a crucial role in initiating a systemic inflammatory response during sepsis. Sepsis also induces robust production of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 as well as anti-inflammatory cytokine IL-10. We sought to elucidate the effects of bupivacaine on COX-2 expression and production of PGE(2) and cytokines using an endotoxin-activated murine macrophages model. Confluent murine macrophages (RAW264.7 cells) were treated with lipopolysaccharide (LPS, 100 ng/ml) or LPS plus bupivacaine (1, 10, or 100 microM). Bupivacaine was added immediately after LPS. After reacting for 18 h, cell cultures were harvested for subsequent analysis. LPS significantly upregulated COX-2 transcription and PGE(2) production in macrophages. LPS also significantly increased the production of TNF-alpha, IL-1beta, IL-6 and IL-10 in macrophages. Bupivacaine significantly inhibited the effects of LPS on COX-2 transcription and PGE(2) production in a dose-dependent manner. In a dose-dependent manner, bupivacaine also significantly inhibited the effects of LPS on the production of TNF-alpha, IL-1beta, and IL-6. However, bupivacaine exerted no significant effects on LPS-induced IL-10 production. Bupivacaine significantly inhibited COX-2 expression, PGE(2) and cytokine production in endotoxin-activated macrophages.


Patients' perception, views and satisfaction with pharmacists' role as health care provider in community pharmacy setting at Riyadh, Saudi Arabia.
This study will provide guiding information about the population perception, views and satisfaction with pharmacist's performance as health care provider in the community pharmacy setting in Riyadh, Saudi Arabia. The study was conducted in Riyadh, Saudi Arabia, from July through December 2010. A total of 125 community pharmacies in Riyadh city were randomly selected according to their geographical distribution (north, south, east, and west). They represent about 10-15% of all community pharmacies in the city. The questionnaire composed of 8 items about patients' views and satisfaction with the pharmacists' role in the current community pharmacy practice. The questionnaire was coded, checked for accuracy and analyzed using the Statistical Package for Social Sciences (SPSS) version 17.0 for Windows (SPSS Inc., Chicago, Illinois). The response rate was almost 85% where 2000 patients were approached and 1699 of them responded to our questionnaire. The majority of respondents is young adults and adults (82.8%), male (67.5%) and married (66.9%). Seventy one percent of respondents assured that community pharmacist is available in the working while only 37.3% of respondents perceived the pharmacist as a mere vendor. About 38% assured sou moto counseling by the pharmacist, 35% reported pharmacist plays an active role in their compliances to treatments, 43% acknowledged the role of pharmacist in solving medication related problems, 34% considered the pharmacist as a health awareness provider and 44.6% felt that pharmacist is indispensable and an effective part of the health care system. The image and professional performance of community pharmacist are improving in Saudi Arabia. The Saudi patients show better satisfaction, perception and appreciation of the pharmacists' role in the health care team. However, extra efforts should be paid to improve the clinical skills of the community pharmacists. Community pharmacists need to be able to reach out to patient, assess their hesitations and promptly offer solution which was appreciated by the patients as the survey indicates. They should play a pro-active role in becoming an effective and indispensable part of health care. Furthermore, they should be able to advice, guide, direct and persuade the patient to comply correct usage of drugs. Finally, community pharmacists should equip themselves with appropriate knowledge and competencies in order to tender efficient and outstanding pharmaceutical health care.


Role of glutathione S-transferases in melanoma susceptibility: association with GSTP1 rs1695 polymorphism.
Glutathione S-transferases (GSTs) GSTM1, GSTT1 and GSTP1 are multifunctional enzymes involved in the detoxification of a wide range of reactive oxygen species produced during melanin synthesis and oxidative stress processes. Single nucleotide polymorphisms (SNPs) in GSTP1 and copy number variants in GSTM1 and GSTT1 may be candidate low-penetrance variants with a role in susceptibility to malignant melanoma (MM). In this case-control study, 562 Spanish patients with sporadic MM and 338 cancer-free control subjects were included, and the role of polymorphisms in these GST genes was investigated. Genotypes were established by quantitative real-time polymerase chain reaction for GSTM1 and GSTT1 while TaqMan probes were used to genotype GSTP1 SNPs. The GSTP1 polymorphism rs1695, which encodes the amino acid change p.Ile105Val, was individually associated with MM [odds ratio (OR): 1·32, 95% confidence interval (CI): 1·06-1·63]. Furthermore, individuals carrying one or two MC1R nonsynonymous changes and GSTP1 rs1695 rare allele had an increased risk of developing MM (OR: 3·34, 95% CI: 1·42-8·09 and OR: 20·42, 95% CI: 2·80-417·42, respectively). This is the first time that the GSTP1 rs1695 polymorphism is reported to be associated with MM. In addition, this study is one of the largest GST polymorphism studies undertaken in the Spanish population and the first time that copy number variants have been scrutinized in relation to MM.


Validity evidence and psychometric evaluation of a socially accountable health index for health professions schools.
There is an expectation that health professions schools respond to priority societal health needs. This expectation is largely based on the underlying assumption that schools are aware of the priority needs in their communities. This paper demonstrates how open-access, pan-national health data can be used to create a reliable health index to assist schools in identifying societal needs and advance social accountability in health professions education. Using open-access data, a psychometric evaluation was conducted to examine the reliability and validity of the Canadian Health Indicators Framework (CHIF) conceptual model. A non-linear confirmatory factor analysis (CFA) on 67 health indicators, at the health-region level (n = 97) was used to assess the model fit of the hypothesized 10-factor model. Reliability analysis using McDonald's Omega were conducted, followed by Pearson's correlation coefficients. Findings from the non-linear CFA rejected the original conceptual model structure of the CHIF. Exploratory post hoc analyses were conducted using modification indices and parameter constraints to improve model fit. A final 5-factor multidimensional model demonstrated superior fit, reducing the number of indicators from 67 to 32. The 5-factors included: Health Conditions (8-indicators); Health Functions (6-indicators); Deaths (5-indicators); Non-Medical Health Determinants (7-indicators); and Community & Health System Characteristics (6-indicators). All factor loadings were statistically significant (p < 0.001) and demonstrated excellent internal consistency ([Formula: see text] >0.95). Many schools struggle to identify and measure socially accountable outcomes. The process highlighted in this paper and the indices developed serve as starting points to allow schools to leverage open-access data as an initial step in identifying societal needs.


Music perception in cochlear implant users: an event-related potential study.
Compare the processing of music-syntactic irregularities and physical oddballs between cochlear implant (CI) users and matched controls. Musical chord sequences were presented, some of which contained functionally irregular chords, or a chord with an instrumental timbre that deviated from the standard timbre. In both controls and CI users, functionally irregular chords elicited early (around 200 ms) and late (around 500 ms) negative electric brain responses (early right anterior negativity,ERAN and N5). Amplitudes of effects depended on the degree of music-syntactic irregularity in both groups; effects elicited in CI users were distinctly smaller than in controls. Physically deviant chords elicited a timbre-mismatch negativity (MMN) and a P3 in both groups, again with smaller amplitudes in CI users. ERAN and N5 (as well as timbre-MMN and P3), can be elicited in CI users. Although amplitudes of effects were considerably smaller in the CI group, the presence of MMN and ERAN indicates that neural mechanisms of both physical and music-syntactic irregularity-detection were active in this group.


Postpartum uterine disease and dairy herd reproductive performance: a review.
This paper reviews the causes, impact, treatment, and prevention of retained placenta (RP), metritis, and endometritis in dairy cows. The occurrence of each of these diseases largely depends on immune function in the transition period. Retained placenta affects 5-10% of calvings and greatly increases the risk of metritis and endometritis. More field studies are needed to validate criteria for treatment of metritis, but cows with at least two of RP, fever, dullness, and fetid uterine discharge appear to merit treatment with systemic antibiotics. Clinical endometritis affects 15-20% of cows at 4-6 weeks postpartum; an additional 30-35% have subclinical endometritis between 4 and 9 weeks postpartum. Under specific conditions, treatment of cows with endometritis improved pregnancy rate. Systematic use of prostaglandin F(2alpha) at 5 and 7 weeks postpartum may improve pregnancy rate. The economic benefit of efforts to identify and treat endometritis is herd-specific.


Fluoxetine induced insulin-like growth factor II (IGF-II) changes in hypothalami of normal, exercised and food restricted rats.
Hypothalamic and pituitary insulin-like growth factor II (IGF-II) peptide concentrations are differentially regulated by factors associated with metabolism such as insulin and glucoprivation. However, the effects of other metabolic stressors such as food restriction or exercise on hypothalamic IGF-II concentrations remain largely to be explored. In order to assess whether metabolic stress alters central nervous system IGF-II secretion, peptide analysis was conducted in rats exhibiting activity-based anorexia (ABA) compared to exercised-matched, body weight-matched or ad libitum fed controls. Further, the possibility of serotonergic control of IGF-II secretion was examined by determining IGF-II response to fluoxetine (FLX) injections (15 mg/kg body wt., i.p.). While ABA and body weight loss altered peripheral IGF-II concentrations compared to ad libitum fed or exercised controls, these treatments had no effect on hypothalamic or posterior pituitary IGF-II content. However, FLX administration increased IGF-II concentrations in the ventromedial hypothalamus and decreased IGF-II content in the lateral hypothalamus compared to vehicle injected. Anterior pituitary levels of IGF-II were also decreased by FLX. These data suggest that a serotonergic influence on CNS IGF-II exists and that IGF-II secretion may be altered by factors affecting serotonin metabolism or efficacy.


[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience].
Objective: To explore the safety and short-term efficacy of venetoclax combined with azacitidine (Ven+AZA) in previously untreated patients unfit for standard chemotherapy and patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) in China. Methods: A retrospective study was conducted in 60 previously untreated patients unfit for standard chemotherapy and patients with R/R AML who received Ven+ AZA (venetoclax, 100 mg D1, 200 mg D2, 400 mg D3-28; azacitidine, 75 mg/m(2) D1- 7) at the Peking University Institute of Hematology from June 1, 2019 to May 31, 2021. The incidence of adverse events, complete remission (CR) /CR with incomplete hematological recovery (CRi) rate, objective remission rate (ORR) , and minimal residual disease (MRD) status in patients with different risk stratification and gene subtypes were analyzed. Results: The median age of the patients was 54 (18-77) years, 33 (55.0%) were males, and the median follow-up time was 4.8 (1.4-26.3) months. Among the 60 patients, 24 (40.0%) were previously untreated patients unfit for standard chemotherapy, and 36 (60.0%) were R/R patients. The median mumber cycles of Ven+AZA in the two groups were both 1 (1-5) . According to the prognostic risk stratification of the National Comprehensive Cancer Network, it was divided into 8 cases of favorable-risk, 2 cases of intermediate risk, and 14 cases of poor-risk. In previously untreated patients unfit for standard chemotherapy, after the first cycle of Ven+AZA, 17/24 (70.8%) cases achieved CR/CRi, 3/24 (12.5%) achieved partial remission (PR) , and the ORR was 83.3%. Among them, nine patients received a second cycle chemotherapy and two received a third cycle. Among CR/CRi patients, 8/17 (47.1%) achieved MRD negativity after two cycles of therapy. In the R/R group, after the first cycle of Ven+AZA, 21/36 (58.3%) cases achieved CR/CRi (7/21 achieved MRD negativity) , 3 achieved PR, and the ORR was 66.7%. Among R/R patients, 12 were treated for more than two cycles. There were no new CR/CRi patients after the second treatment cycle, and 14 cases (66.7%) achieved MRD negativity. According to the time from CR to hematological recurrence, the R/R group was divided into 12 cases in the favorable-risk group (CR to hematological recurrence ≥18 months) and 24 in the poor-risk group (CR to hematological recurrence<18 months, no remission after one cycle of therapy, and no remission after two or more cycles of therapy) . Eleven of 24 (45.8%) cases achieved CR/CRi after one cycle of Ven+AZA in the poor-risk R/R group, and 10 of 12 (83.3%) achieved CR/CRi in the favorable-risk R/R group, which was significantly superior to the poor-risk group (P=0.031) . After one cycle of treatment, 13 patients with IDH1/2 mutations and 4 that were TP53-positive all achieved CR/CRi. The CR/CRi rate of 18 patients with NPM1 mutations was 77.8%. Five patients with RUNX1-RUNX1T1 combined with KIT D816 mutation (two initial diagnoses and three recurrences) had no remission. Ven+ AZA was tolerable for AML patients. Conclusion: Ven+AZA has acceptable safety in previously untreated patients unfit for standard chemotherapy, patients with R/R AML can achieve a high response rate, and some patients can achieve MRD negativity. It is also effective in NPM1-, IDH1/IDH2-, and TP53-positive patients. The long-term efficacy remains to be observed.


The effect of environmental uncertainty on morphological design and fluid balance in Sarracenia purpurea L.
To explore principles of organismic design in fluctuating environments, morphological design of the leaf of the pitcher-plant, Sarracenia purpurea, was studied for a population in northern Michigan. The design criterion focused upon the leaf shape and minimum size which effectively avoids leaf desiccation (complete loss of fluid from the leaf cavity) in the face of fluctuating rainfall and meteorological conditions. Bowl- and pitcher-shaped leaves were considered. Simulations show that the pitcher geometry experiences less frequent desiccation than bowls of the same size. Desiccation frequency is inversely related to leaf size; the size distribution of pitcher leaves in the field shows that the majority of pitchers desiccate only 1-3 times per season on average, while smaller pitchers may average up to 8 times per season. A linear filter model of an organism in a fluctuating environment is presented, in which the organism selectively filters the temporal patterns of environmental input. General measures of rainfall predictability based upon information theory and spectral analysis are consistent with the model of a pitcher leaf as a low-pass (frequency) filter which avoids desiccation by eliminating high-frequency rainfall variability.


Teledentistry adoption and applications: An American Dental Association Clinical Evaluators Panel survey.
The rise of teleworking technologies has affected various industries, including dentistry. Although some dentists have used it for some time, many are discovering the benefits of incorporating this technology to complement their existing patient care capabilities. To assess how clinicians are using teledentistry in their practices, an electronic survey was developed and deployed to the American Dental Association Clinical Evaluators (ACE) Panel on February 27, 2023. The survey link remained open for 2 weeks. Nonrespondents received reminders after 1 week. Of the 244 respondents (24% response rate), 30% use teledentistry in their practices, with more than one-half of those using synchronous (53%) or asynchronous teledentistry (63%). The most common reasons for incorporating teledentistry were increased convenience for patients (53%), COVID-19 (50%), and increased accessibility to providers (39%). Teledentistry can help serve patients of all ages (the lowest represented age group [0-5 years] had 42% of dentists treating them) and distances, with 63% of teledentistry patients fewer than 20 miles away. Most users adopted teledentistry within the past 3 years and use it fewer than 5 hours per month. Benefits cited include a reduced number of in-person patient visits (63%) and increased access and quality of care (57%). Among nonusers, 60% felt there was no need, and 39% had concerns with reimbursement. Teledentistry has gained popularity in since the onset of the COVID-19 pandemic but may be underused, despite its potential to benefit a wider range of patients and applications than many believe. Education on the capabilities and benefits of teledentistry may help increase adoption and improve patient care.


Living donor liver transplantation for patients with HCC exceeding the Milan criteria: a proposal of expanded criteria.
Optimal indications for living donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC) have yet not been established. The aim of the present study was to determine optimal criteria including categories outside the Milan criteria (MC) and still with a predictably good outcome. Between February 1999 and December 2007, 136 patients with HCC underwent LDLT. Based on preoperative imaging studies, 74 patients met the MC and 62 did not. Overall patient survival rate at 5 years was 70%. Patients who exceeded MC but presented with <or=10 tumors and all <or=5 cm in diameter (n = 33) displayed similar 5-year recurrence rate to those within MC (7 vs. 10%). Based on the results of multivariate analysis of risk factors for recurrence, we defined new criteria as n <or=10 and all <or=5 cm and PIVKA-II <or=400 mAU/ml. The 5-year recurrence rate for the 83 patients who met the new criteria was significantly lower than for the 44 patients who exceeded them (5 vs. 61%, p < 0.0001). Similarly, patients who met the new criteria showed a significantly better 5-year survival rate (87 vs. 37%, p < 0.0001). The selection criteria may be safely extended up to n <or=10 and all <or=5 cm in diameter and PIVKA-II <or=400 mAU/ml with acceptable outcomes.


Physical and stressful psychological impacts of prolonged personal protective equipment use during the COVID-19 pandemic: A cross-sectional survey study.
Healthcare workers (HCWs) caring for COVID-19 infected patients are exposed to stressful and traumatic events with potential for severe and sustained adverse mental and physical health consequences. Our aim was to assess the magnitude of physical and mental health outcomes of HCWs due to the prolonged use of personal protective equipment (PPE) treating COVID-19 patients. This cross-sectional study assessed the symptoms of stress, anxiety, insomnia, and psychological resilience using the Stress and Anxiety to Viral Epidemics (SAVE) scale, Insomnia Severity Index (ISI), and Resilience Scale (RS), respectively, in Italy between 1st February and 31st March 2022. The physical outcomes reported included vertigo, dyspnea, nausea, micturition desire, retroauricular pain, thirst, discomfort at work, physical fatigue, and thermal stress. The relationships between prolonged PPE use and psychological outcomes and physical discomforts were analyzed using Generalized Linear Models (GLMs). We calculated the factor mean scores and a binary outcome to measure study outcomes. We found that 23% of the respondents reported stress related symptoms, 33% anxiety, 43% moderate to severe insomnia, and 67% reported moderate to very low resilience. The GLMs suggested that older people (>55 years old) are less likely to suffer from stress compared to younger people (<35 y.o); conversely, HCW aged more than 35 years are more inclined to suffer from insomnia than younger people (<35 y.o). Female HCW reported a lower probability of resilience than males. University employed HCWs were less likely to report anxiety than those who worked in a community hospital. The odds of suffering from insomnia for social workers was significantly higher than for other HCWs. Female HCW>3 years old, enrolled in training programs for nursing, social work, technical training and other healthcare professionals increased the probability of reported physical discomforts. HCW that worked on non COVID-19 wards and used PPE for low-medium exposure level, were at lower risks for lasting physical side effects as compared to the HCW who worked in high-risk PPE intense, COVID-19 environments. The study suggests that frontline HCWs who had extensive PPE exposure while directly engaged in the diagnosis, treatment, and care for patients with COVID-19 are at significant risks for lasting physical and psychological harm and distress.


FBXL6 governs c-MYC to promote hepatocellular carcinoma through ubiquitination and stabilization of HSP90AA1.
Heat shot protein 90 (HSP90) AA1 functions as an onco-protein to regulate the assembly, manipulation, folding and degradation of its client proteins, including c-MYC. However, little is known about the mechanism of HSP90AA1 regulation. Transcriptome RNA-sequencing data of hepatocellular carcinoma (HCC) samples were used to detect the mRNA expression of FBXL6. Immunoprecipitation/Mass Spectrum (IP/MS) method was used to identify the interacting proteins of FBXL6. The co-immunoprecipitation assay was used to determine the interaction between FBXL6 and HSP90AA1. The in vivo ubiquitination assay was performed to determine the regulation of HSP90AA1 by FBXL6. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to determine the transcriptional regulation of FBXL6 by c-MYC. Immunohistochemical (IHC) staining was performed to study the correlation of FBXL6 and HSP90AA1 protein expression in 87 HCC samples. Cell counting and colony formation assays were implemented to detect the biological effects of FBXL6 on the growth of HCC cells in vitro. The effect of FBXL6 on HCC tumor growth in vivo was studied in a tumor xenograft model in mice. Here, we identified the orphan F-box protein FBXL6, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the ubiquitin ligase for HSP90AA1. FBXL6 promoted K63-dependent ubiquitination of HSP90AA1 to stabilize it. Through analysis of the TCGA dataset, we found that FBXL6 was significantly increased in HCC tissues and positively correlated with c-MYC pathway. FBXL6 accumulation in HCC causes the stabilization and activation of c-MYC by preventing HSP90AA1 degradation. The activated c-MYC directly binds to the promoter region of FBXL6 to induce its mRNA expression. Collectively, our data revealed an unknown FBXL6-HSP90AA1-c-MYC axis which might contribute to the oncogenesis of HCC, and we propose that inhibition of FBXL6 might represent an effective therapeutic strategy for HCC treatment. Video abstract.


Role of cyclin-dependent kinase 5 in the neurodegenerative process triggered by amyloid-Beta and prion peptides: implications for Alzheimer's disease and prion-related encephalopathies.
Tau hyperphosphorylation, amyloid plaques, and neuronal death are major neuropathological features of Alzheimer's disease (AD) and Prion-related encephalopathies (PRE). Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase, active in post-mitotic neurons, where it regulates survival and death pathways. Overactivation of Cdk5 is conferred by p25, a truncated fragment of the p35 activator formed upon calpain activation. Cdk5 deregulation causes abnormal phosphorylation of microtubule-associated protein tau, leading to neurodegeneration. In this work we investigated the involvement of Cdk5 in the neurodegeneration triggered by amyloid-beta (Abeta) and prion (PrP) peptides, the culprit agents of AD and PRE. As a work model, we used cultured rat cortical neurons treated with Abeta 1-40 and PrP 106-126 synthetic peptides. The obtained data show that apoptotic neuronal death caused by both the peptides was in part due to Cdk5 deregulation. After peptide treatment, p25 levels were significantly enhanced in a pattern consistent with the augment in calpain activity. Moreover, Abeta 1-40 and PrP 106-126 increased the levels of tau protein phosphorylated at Ser202/Thr205. Cdk5 (roscovitine) and calpain (MDL28170) inhibitors reverted tau hyperphosphorylation and prevented neuronal death caused by Abeta 1-40 and PrP 106-126. This study demonstrates, for the first time, that Cdk5 is involved in PrP-neurotoxicity. Altogether, our data suggests that Cdk5 plays an active role in the pathogenesis of AD and PRE.


Shorter duration of first-line chemotherapy reflects poorer outcomes in patients with HER2-negative advanced breast cancer: a multicenter retrospective study.
Post-progression survival affects overall survival (OS) in patients with HER2-negative advanced breast cancer (HER2-ABC); thus, the optimal choice of first-line chemotherapy (1LCT) remains controversial. We investigated patients with HER2-ABC focusing on their sensitivity to 1LCT. We retrospectively analyzed patients with HER2-ABC who received 1LCT between January 2011 and December 2016 in three participating institutions. We identified 149 patients in the shorter and 152 patients in the longer time to treatment failure (TTF) groups. The median OS was significantly longer in the longer TTF group (hazard ratio [HR] 0.44, P < 0.001, log-rank). In the shorter TTF group, OS of patients who received paclitaxel plus bevacizumab (PB) therapy was significantly inferior to that of those who received chemotherapy other than PB (HR 2.57, P < 0.001, log-rank), and subsequent eribulin therapy significantly improved OS from 1LCT initiation (Wilcoxon P < 0.001); multivariate analyses showed that 1LCT PB therapy was an independent risk factor for poorer OS (HR 2.05, P = 0.003), while subsequent eribulin therapy was an independent prognostic factor for better OS (HR 0.56, P = 0.004). OS was significantly poorer in patients with HER2-ABC with a shorter duration of 1LCT, including PB therapy, while subsequent eribulin therapy improved OS.


High-dose radiotherapy (60 Gy) with oral UFT/folinic acid and escalating doses of oxaliplatin in patients with non-resectable locally advanced rectal cancer (LARC): a phase I trial.
Consensus is that patients with locally advanced rectal cancer (LARC) should receive long-term chemoradiotherapy (CRT) before surgery. With the intent to offer the patients intensified concomitant chemotherapy (CT) to improve outcome and to assess tolerability and toxicity of oxaliplatin (Ox) a phase I trial of high dose pelvic radiotherapy (RT), fixed dose of oral UFT/l-leucovorin and increasing doses of weekly Ox were performed. Pelvic RT with 48.6 Gy/27 fractions was given to the primary tumour and the regional lymph nodes and a concurrent boost of 5.4 Gy/27 fractions with a final boost of 6 Gy/3 fractions was given to the gross tumour volume (GTV) (60 Gy/30 fractions). Concurrent with RT patients received a daily dose of UFT 300 mg/m(2) plus fixed dose l-leucovorin 22.5 mg 5/7 days and increasing weekly doses of Ox with 10 mg/m(2)/week from a start dose of 30 mg/m(2)/week to a maximum of 60 mg/m(2)/week. In addition, before and after CRT the patients received one course of TEGAFOX (UFT 300 mg/m(2) with l/leucovorin 22.5 mg Days 1-14 and Ox 130 mg/m(2) given on Day 1). Surgery was planned at least six weeks after the completion of the CRT. From May 2005 to March 2009, 18 patients with LARC (16 primary, two recurrent) were included in this phase I trial. Toxicity was low with only 5-17% grade 3-4 toxicity. Fifteen patients (83%) were operated (14 R0 resection and 1 R1 resection) after completion of CRT. Five (33%) patients had a pathological complete response (ypCR). When ypCR was combined with yp few residual cells, the rate was 60%. Thirteen patients are still alive December 2011. Preoperative high-dose RT and concomitant UFT with increasing doses of Ox up to 60 mg/m(2)/week was feasible with low toxicity, high ypCR rates and promising OS in patients with non-resectable LARC.


Outcomes of the roll-in cohort of the Amulet IDE trial of left atrial appendage occlusion.
Left atrial appendage (LAA) occlusion is an alternative therapy to oral anticoagulants to reduce stroke risk in patients with nonvalvular atrial fibrillation (NVAF). The Amulet IDE trial compared the Amplatzer™ Amulet™ occluder (Abbott) with the Watchman™ 2.5 device (Boston Scientific) for LAA occlusion in patients with NVAF. The purpose of this study was to describe outcomes of the Amulet IDE trial roll-in cohort. At US sites up to 3 patients per implanter could be implanted with the Amulet occluder in the roll-in phase. The primary Endpoints in the Amulet IDE trial included safety (composite of procedure-related complications, all-cause death, or major bleeding at 12 months), effectiveness (composite of ischemic stroke or systemic embolism at 18 months), and rate of LAA occlusion at 45 days. A total of 201 roll-in patients were enrolled. Device success occurred in 99% of patients, and device closure (residual jet ≤5 mm) was observed in 98.9% of patients at 45 days. The safety endpoint rate was numerically higher (worse) in the roll-in cohort compared to the randomized Amulet occluder cohort (18.4% vs 14.5%). Six patients (3.1%) experienced an ischemic stroke and 0 patients with a systemic embolism within 18 months, which was similar to the primary effectiveness endpoint rate in the randomized Amulet occluder cohort (2.8%). Despite lack of experience of the operators with the Amulet occluder in the roll-in phase, device implant success was high, a high rate of device closure was achieved, and low stroke rates were observed in patients with NVAF.


Neurocognitive functioning in antiretroviral therapy-naïve youth with behaviorally acquired human immunodeficiency virus.
Youth living with human immunodeficiency virus (HIV) account for over one third of new HIV infections and are at high risk of adverse psychosocial, everyday living, and health outcomes. Human immunodeficiency virus-associated neurocognitive disorders (HAND) are known to affect health outcomes of HIV-infected adults even in the era of combination antiretroviral therapy. Thus, the current study aimed to characterize the prevalence and clinical correlates of HAND in youth living with HIV. Here, we report baseline neurocognitive data for behaviorally HIV-infected youth enrolled in a prospective study evaluating strategies of antiretroviral treatment initiation and use. A total of 220 participants, age 18-24 years, who were naive to treatment (except for prevention of mother-to-child HIV transmission; n = 3), completed a comprehensive neurocognitive, substance use, and behavioral health assessment battery. Sixty-seven percent of youth met criteria for HAND (96.4% were asymptomatic and 3.5% were syndromic); deficits in episodic memory and fine-motor skills emerged as the most commonly affected ability areas. Multivariable models showed that lower CD4 count, longer time since HIV diagnosis, and high-risk alcohol use were uniquely associated with neurocognitive deficits. Over two thirds of youth with behaviorally acquired HIV evidence neurocognitive deficits, which have modest associations with more advanced HIV disease as well as other factors. Research is needed to determine the impact of such neuropsychiatric morbidity on mental health and HIV disease treatment outcomes (e.g., nonadherence) and transition to independent living responsibilities in HIV-infected youth, as well as its long-term trajectory and possible responsiveness to cognitive rehabilitation and pharmacotherapy.


Diagnostic and therapeutic stereotactic cerebral endoscopy.
Modern neuro-imaging caused a renewed interest in endoscopic techniques. Several indications for stereotactic endoscopy are illustrated. A prototype of a new four channel endoscope is used. Lesions in the posterior part of the third ventricle an even the fourth ventricle are reachable for biopsy. Cystic intra- or paraventricular lesions can be approached stereotactically and treated. Continuous rinsing is mandatory to preserve a clear vision.


Direct Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation and Low Body Weight.
It is unclear whether the overall effectiveness and safety of direct oral anticoagulants (DOACs) are consistent in patients with nonvalvular atrial fibrillation (AF) and extremely low body weight (<50 kg). This study compared DOACs with warfarin in AF patients with low body weight. Using data from the Korean National Health Insurance Service database from January 2014 to December 2016, AF patients with body weight ≤60 kg and who were treated with oral anticoagulants (n = 14,013 taking DOACs and n = 7,576 taking warfarin) were included and examined for ischemic stroke, intracranial hemorrhage (ICH), gastrointestinal bleeding, major bleeding, all-cause death, and composite outcome. The propensity score weighting was used to balance the 2 groups. Baseline characteristics were well balanced between the 2 groups (mean age 73 years, mean CHA2DS2-VASc score 4, and 28% of patients weighed <50 kg). DOACs were associated with lower risks of ischemic stroke (hazard ratio [HR]: 0.591; 95% confidence interval [CI]: 0.510 to 0.686) and major bleeding (HR: 0.705; 95%: CI 0.601 to 0.825), which were caused by a reduction in ICH (HR: 0.554; 95% CI: 0.429 to 0.713) compared with warfarin. DOAC improved the net clinical benefit compared with warfarin (HR for composite outcome: 0.660; 95% CI: 0.606 to 0.717), and this was consistent in patients who weighed <50 kg (HR for composite outcome: 0.665; 95% CI: 0.581 to 0.762). In this real-world Asian AF population with low body weight, DOACs showed better effectiveness and safety than warfarin. These results were consistent in patients with extremely low body weight. Regular dosages of DOACs showed comparable results as reduced dosages of DOACs in both effectiveness and safety.


Establishment and characterization of cisplatin-resistant sublines of human lung cancer cell lines.
Human lung cancer sublines resistant to cisplatin (CDDP) have been developed by continuously exposing cells to gradually increasing doses of CDDP and use of the limiting dilution technique. The cell lines used were PC-7, PC-9 and PC-14 (pulmonary adenocarcinoma) and H69 and N231 (small-cell lung cancer). The resistant phenotype of the resistant sublines was stable for more than 2 months in the absence of drug. PC-7/1.2 (i.e., PC-7 cells growing stably in medium containing 1.2 micrograms/ml of CDDP), PC-9/0.5, PC-14/1.5, H69/0.4, and N231/0.2 have been developed, which are 22.9, 7.1, 3.1, 25.6, and 8.4 times more resistant to CDDP than the respective parent cell line in terms of IC50 in the soft agar colony assay with continuous drug exposure. Cloning efficiency decreased significantly in N231/0.2. The doubling times increased significantly in most of the resistant sublines. Cellular DNA contents increased in all resistant sublines, but statistical significance was observed only in H69/0.4 (p less than 0.05). Cells of the resistant sublines of PC-7, PC-9, PC-14 and H69 were larger than cells of the parent lines, but the differences were not significant. The growth morphologies of all resistant sublines in the drug-free medium were similar to those of parent cell lines. All resistant sublines tested were significantly cross-resistant to carboplatin. The patterns of cross-resistance, cross-sensitivity and collateral sensitivity to adriamycin, mitomycin-C, 5-fluorouracil, vindesine, etoposide, aclacinomycin and vincristine were different in each resistant subline. Verapamil (3.3 micrograms/ml) showed little modifying effect on CDDP resistance in 5 CDDP-resistant sublines tested except N231/0.2 (Modification Index: 0.49). Cyclosporin A (5.0 micrograms/ml) modified CDDP resistance in CDDP-resistant small-cell lung cancer sublines (H69/0.4 and N231/0.2) (Modification Index: 0.45 and 0.07, respectively), while in CDDP-resistant NSCLC sublines (PC-7/1.0 and PC-9/0.5), cyclosporin A reduced the sensitivity to CDDP.


Expression pattern of the activin receptor type IIA gene during differentiation of chick neural tissues, muscle and skin.
To elucidate target cells of activins during embryogenesis we isolated cDNAs of chick activin receptor type II (cActR-II) and studied expression patterns of the cActR-II gene by in situ hybridization. Transcripts of cActR-II were observed in neuroectoderm developing to spinal cord, brain and eyes, in surface ectoderm differentiating to epidermis, and in myotomes differentiating to muscles. The expression patterns of cActR-II suggest that activin and its receptor are involved in differentiation of chick neural tissues, muscle and skin after inducing the dorsal mesoderm.


Genome of the Psychrophilic Bacterium Bacillus psychrosaccharolyticus, a Potential Source of 2'-Deoxyribosyltransferase for Industrial Nucleoside Synthesis.
Here we report the draft genome sequence of Bacillus psychrosaccharolyticus, a cold-adapted bacterium with biotechnological interest. The genome contains genes related to the ability of this microorganism to grow at low temperatures and includes a nucleoside 2'-deoxyribosyltransferase, which can be used in the industrial synthesis of modified nucleosides with therapeutic activity.


Prolonged survival in rat liver transplantation with mouse monoclonal antibody against an inducible costimulator (ICOS).
An inducible costimulator (ICOS), a recently identified costimulatory receptor with a close structural homology to CD28 and CTLA4, is expressed on activated T cells. Interaction with its ligand on antigen-presenting cells stimulates T-cell proliferation to produce a different spectrum of cytokine. The inhibition of ICOS-mediated signal transduction by an anti-ICOS antibody is considered to be capable of protecting against graft rejection in organ transplantation. An anti-rat ICOS antibody was intravenously administered into recipients of dark Agouti-to-Lewis liver transplantations. The recipient lymphocytes from mesenteric lymph nodes were harvested on day 7 after transplantation for fluorescence-activated cell sorting analysis, and tissue specimens from the grafts were removed for histologic evaluation. Antigen-specific T-cell proliferation responses were assessed in vitro with anti-ICOS antibody. Monotherapy with the antibody significantly prolonged the graft survival time by inhibiting T-cell activation and its proliferation response. The graft-infiltrating cells, both CD4 and CD8 T cells, were not completely reduced even when rats were administered the antibody, whereas the expression of ICOS almost completely disappeared in these cells. T-cell activation through the ICOS costimulatory pathway plays an important role in graft rejection, and manipulating its pathway is an effective method for modulating transplantation immunity.


In vivo evaluation of whey protein-based biofilms as scaffolds for cutaneous cell cultures and biomedical applications.
This study evaluated the toxicity, biodegradability and immunogenicity of newly developed whey protein-based biofilms for possible use as biomaterials for medical applications. Biofilms were prepared using (A) a whey protein isolate plasticized with either diethylene glycol (DEG) or glycerol (GLY), and (B) beta-lactoglobulin (betaLGA) plasticized with DEG. The biofilms were implanted subcutaneously into Balb/c mice. Analyses were performed at various time points. At 15, 30 and 60 days post-implantation, no necrotic zones or exudates were present at the recipient sites. The biofilms began to degrade as early as 15 days post-implantation, as evidenced by erosion and crumbling. The macroscopic observations were supported by tissue analyses revealing no tissue necrosis or degradation and confirming that the biodegradation of the biofilms began as early as 15 days post-implantation and was almost complete after 60 days. The biodegradation was accompanied by significant leukocyte infiltration at 15 days which significantly decreased at 60 days. The absence of splenomagaly in the implanted mice confirms that these biofilms were not immunogenic. Whey protein-based biofilms are biocompatible and biodegradable and may be of interest for medical applications such as scaffolds for cutaneous cell cultures and skin recovery in burn patients.


The light aging behavior of daylight fluorescent paints: a colorimetric, photographic, Raman spectroscopic and fluorescence spectroscopic study.
Daylight fluorescent pigments with their intense color effects have attracted great interest among artists since their market launch in the mid-twentieth century. Since then they have been widely used in the visual arts. The pigments are mainly compositions of organic fluorescent dyes and optical brighteners diluted in an insoluble resin. Due to the susceptibility of the dyes to visible and UV radiation, their lightfastness is comparatively low. This paper presents a comprehensive study of the color and fluorescence changes of daylight fluorescent paints upon exposure in visible light and ultraviolet radiation conducted on mock-ups of commercial daylight fluorescent pigments. The different aging characteristics of the pigments depend on the color tone. They were recorded by means of photographic and colorimetric documentation. In addition, Raman spectroscopy was used to identify the main dyes of the various pigments, even in the complex system of paints, consisting of primer, binder, resin and dyes, and to determine their degradation during aging. Fluorescence spectroscopy revealed that the change in fluorescent color may not only be due to the decrease in dye concentration, but also to the transformation of the original dyes into other fluorescent compounds during light aging. Finally, this paper provides recommendations for the presentation of artworks containing daylight fluorescent pigments. The online version contains supplementary material available at 10.1186/s40494-022-00812-4.


H2 generated by fermentation in the human gut microbiome influences metabolism and competitive fitness of gut butyrate producers.
Hydrogen gas (H2) is a common product of carbohydrate fermentation in the human gut microbiome and its accumulation can modulate fermentation. Concentrations of colonic H2 vary between individuals, raising the possibility that H2 concentration may be an important factor differentiating individual microbiomes and their metabolites. Butyrate-producing bacteria (butyrogens) in the human gut usually produce some combination of butyrate, lactate, formate, acetate, and H2 in branched fermentation pathways to manage reducing power generated during the oxidation of glucose to acetate and carbon dioxide. We predicted that a high concentration of intestinal H2 would favor the production of butyrate, lactate, and formate by the butyrogens at the expense of acetate, H2, and CO2. Regulation of butyrate production in the human gut is of particular interest due to its role as a mediator of colonic health through anti-inflammatory and anti-carcinogenic properties. For butyrogens that contained a hydrogenase, growth under a high H2 atmosphere or in the presence of the hydrogenase inhibitor CO stimulated production of organic fermentation products that accommodate reducing power generated during glycolysis, specifically butyrate, lactate, and formate. Also as expected, production of fermentation products in cultures of Faecalibacterium prausnitzii strain A2-165, which does not contain a hydrogenase, was unaffected by H2 or CO. In a synthetic gut microbial community, addition of the H2-consuming human gut methanogen Methanobrevibacter smithii decreased butyrate production alongside H2 concentration. Consistent with this observation, M. smithii metabolic activity in a large human cohort was associated with decreased fecal butyrate, but only during consumption of a resistant starch dietary supplement, suggesting the effect may be most prominent when H2 production in the gut is especially high. Addition of M. smithii to the synthetic communities also facilitated the growth of E. rectale, resulting in decreased relative competitive fitness of F. prausnitzii. H2 is a regulator of fermentation in the human gut microbiome. In particular, high H2 concentration stimulates production of the anti-inflammatory metabolite butyrate. By consuming H2, gut methanogenesis can decrease butyrate production. These shifts in butyrate production may also impact the competitive fitness of butyrate producers in the gut microbiome. Video Abstract.


A chalcone derivative, 1m-6, exhibits atheroprotective effects by increasing cholesterol efflux and reducing inflammation-induced endothelial dysfunction.
Atherosclerosis, resulting from lipid dysregulation and vascular inflammation, causes atherosclerotic cardiovascular disease (ASCVD), which contributes to morbidity and mortality worldwide. Chalcone and its derivatives possess beneficial properties, including anti-inflammatory, antioxidant and antitumour activity with unknown cardioprotective effects. We aimed to develop an effective chalcone derivative with antiatherogenic potential. Human THP-1 cells and HUVECs were used as in vitro models. Western blots and real-time PCRs were performed to quantify protein, mRNA and miRNA expressions. The cholesterol efflux capacity was assayed by 3 H labelling of cholesterol. LDL receptor knockout (Ldlr-/- ) mice fed a high-fat diet were used as an in vivo atherogenesis model. Haematoxylin and eosin and oil red O staining were used to analyse plaque formation. Using ATP-binding cassette transporter A1 (ABCA1) expression we identified the chalcone derivative, 1m-6, which enhances ABCA1 expression and promotes cholesterol efflux in THP-1 macrophages. Moreover, 1m-6 stabilizes ABCA1 mRNA and suppresses the expression of potential ABCA1-regulating miRNAs through nuclear factor erythroid 2-related factor 2 (Nrf2)/haem oxygenase-1 (HO-1) signalling. Additionally, 1m-6 significantly inhibits TNF-α-induced expression of adhesion molecules, vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), plus production of proinflammatory cytokines via inhibition of JAK/STAT3 activation and the modulation of Nrf2/HO-1 signalling in HUVECs. In atherosclerosis-prone mice, 1m-6 significantly reduces lipid accumulation and atherosclerotic plaque formation. Our study demonstrates that 1m-6 produces promising atheroprotective effects by enhancing cholesterol efflux and suppressing inflammation-induced endothelial dysfunction, which opens a new avenue for treating ASCVD. This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.


Inpatient healthcare trends among adult cystic fibrosis patients in the U.S.
Adult cystic fibrosis (CF) patients are an expanding cohort that is taken care of in a variety of hospital settings including adult centers located within pediatric institutions. This study compared costs and discharge rates among adult CF patient hospitalizations in terms of location of hospitalization. The 2007 Nationwide Inpatient Sample was utilized to identify adult CF patient admission data on patients aged 18-44. Data were separated into pediatric and adult facilities based on percentage discharge rate for patients >18. Primary outcomes measures were length of stay (LOS) and total hospital charges. Secondary predictors were geographic, primary payer, and co-morbidity effects on LOS and total hospital charges. LOS was higher for adult CF patient admissions in pediatric facilities compared to adult facilities by a mean of 2.5 days. Mean total hospital charges were not significantly different. Adult hospitals in the Western U.S. had a mean total charge more than $50,000 greater than any region in the U.S. Self-pay patients had significantly fewer hospital days and charges across all hospital types. Adult facilities had 7% more CF patients discharged home with home healthcare use. Depressed CF patients had longer LOS by 1.5 days regardless of facility type. LOS for adult CF inpatient admissions was significantly lower in adult facilities compared to pediatric facilities without a significant difference in hospital charges and is influenced by geographic hospital location. Depressed patients had longer lengths of stay regardless of facility type. Self-insured adult CF patients have a significant reduction in LOS and hospital charges when compared to all other payers regardless of hospital type.


Coagulation in pediatric extracorporeal membrane oxygenation: A systematic review of studies shows lack of standardized reporting.
Extracorporeal membrane oxygenation (ECMO) involves complex coagulation management and frequent hemostatic complications. ECMO practice between centers is variable. To compare results between coagulation studies, standardized definitions and clear documentation of ECMO practice is essential. We assessed how study population, outcome definitions, and ECMO-, coagulation-, and transfusion-related parameters were described in pediatric ECMO studies. Embase, Medline, Web of Science, Cochrane Library and Google Scholar. English original studies of pediatric ECMO patients describing hemostatic tests or outcome. Eligibility was assessed following PRISMA guidelines. Study population, outcome and ECMO-, coagulation, and transfusion parameters were summarized. A total of 107 of 1312 records were included. Study population parameters most frequently included (gestational) age (79%), gender (60%), and (birth) weight (59%). Outcomes, including definitions of bleeding (29%), thrombosis (15%), and survival (43%), were described using various definitions. Description of pump type, oxygenator and cannulation mode occurred in 49%, 45%, and 36% of studies, respectively. The main coagulation test (53%), its reference ranges (49%), and frequency of testing (24%) were the most prevalent reported coagulation parameters. The transfusion thresholds for platelets, red blood cells, and fibrinogen were described in 27%, 18%, and 18% of studies, respectively. This systematic review demonstrates a widespread lack of detail or standardization of several parameters in coagulation research of pediatric ECMO patients. We suggest several parameters that might be included in future coagulation studies. We encourage the ECMO community to adopt and refine this list of parameters and to use standardized definitions in future research.


A randomized controlled trial of the effect of rosiglitazone and clomiphene citrate versus clomiphene citrate alone in overweight/obese women with polycystic ovary syndrome.
In women suffering from polycystic ovary syndrome, correction of hyperinsulinemia results in enhanced responsiveness to ovulation induction agents. The effect of rosiglitazone was investigated on ovulation induction in obese women with PCOS. A randomized controlled trial was set up. One hundred women were randomly assigned. Group A (n = 46) received rosiglitazone 4 mg b.i.d. plus clomiphene citrate (CC) 100 mg on cycle days 3-7. Group B (n = 45) received CC only. Primary outcome was ovulation. Secondary outcomes included pregnancy as well as changes in fasting glucose and insulin. Both groups were similar with respect to background and hormonal characteristics (age, duration of infertility, BMI, WHR, FSH, LH, E2, testosterone, fasting glucose and insulin). The cumulative ovulation rate over 12 weeks was significantly higher in group A (81.8%) than in group B (55.2%) (p < 0.001), whereas the difference in cumulative pregnancy rate was not statistically significant (30.4% versus 28.8%, respectively) in groups A and B (p = 0.946). Fasting insulin levels significantly declined after rosiglitazone therapy (p < 0.001) without change in glucose levels this resulted in normalization of the mean glucose to insulin ratio. Short term administration of rosiglitazone to overweight and obese PCOS women results in enhancement of CC induced ovulation as well as improvement of insulin sensitivity.


Low muscle mass and Charlson comorbidity index are risk factors for short-term postoperative prognosis of elderly patients with gastrointestinal tumor: a cross-sectional study.
Sarcopenia is one of the most frequent syndromes in older adults and one of its main characteristics is low muscle mass. Gastrointestinal tumor is a malignant disease with high incidence. This study aimed to investigate the risk factors of low muscle mass in older adults with gastrointestinal tumor, the prognostic indicators of and short-term outcomes after resection for gastrointestinal tumor, and to explore the relationship between low muscle mass and short-term postoperative prognosis. A total of 247 older patients with gastrointestinal tumors who underwent radical resection in 2019 were included in this study. Relevant indexes were calculated using L3 slice image of computed tomography (CT) to evaluate low muscle mass. Short-term postoperative complications and length of stay were considered as short-term outcomes of this study. Advanced age, lower higher body mass index (BMI), lower hemoglobin, having history of abdominal surgery and higher visceral fat index (VFI) were risk factors of low muscle mass, while higher BMI and lower subcutaneous fat index (SFI) were protective factors of low muscle mass. Further multivariate logistic regression analysis showed that having history of abdominal surgery, advanced age and lower BMI were independent risk factors. Low muscle mass and higher Charlson comorbidity index were independent risk factors of short-term postoperative complications in older adults with gastrointestinal tumor. Higher Charlson comorbidity index gave rise to longer length of stay. Low muscle mass and higher Charlson comorbidity index predict poor short-term prognosis of older patients undergoing gastrointestinal tumor resection.


Implication of activation of intraperitoneal macrophages with bio-degradable microspheres.
To estimate the possibility that biological degradable starch microspheres (DMS) activate abdominal or intraperitoneal macrophages (IMP), two sizes of DMS (Spherex, Pharmacia, Sweden) were injected into the peritoneum of the ICR mice of 4 to 8 weeks of age. Three days after the injection, peritoneal fluid was collected and incubated for one hour at 37 degrees C under 5% CO2. The cells which adhered to the petri dish were IMP, to which DMS was added for 18 hrs. The cultured IMP were observed by scanning electron microscope (SEM) and the ratio of the active type to the total number of IMP was counted as an index of the effect of DMS to IMP. The activation effect of DMS on the incubated IMP was significant in the group which was cultured with 2 microns DMS after the 45 microns DMS injection. That indicated the possible DMS function as a potential IMP activating factor (MAF).


Diabetes mellitus associated changes in glomerular glycocompounds: a fluorescence microscopical study.
Renal biopsy specimens showing histological alterations typical of advanced diabetic glomerulopathy were studied for changes in glomerular glycoconjugates, using fluorochrome-coupled lectins as probes. All samples studied showed a marked reduction in the binding of Triticum vulgaris (WGA) lectin in the glomerular basement membranes. On the other hand, 'new' glomerular binding sites for the lectins of Dolichos biflorus (DBA), Helix pomatia (HPA) and Arachis hypogaea (PNA), recognizing galactosyl moieties of glycoconjugates and giving no reaction in normal glomeruli, were seen in all samples studied. In addition, Wistaria floribunda lectin (WFA), recognizing galactosyl and, N-acetylgalactosaminyl configurations in glycoconjugates, gave a typical linear binding along the glomerular basement membranes, differing markedly from its reaction with normal kidney. Ulex europaeus (UEA I) showed reduced binding in the glomeruli of diabetic nephropathy. The results show that changes in glomerular glycoconjugates may appear in diabetic nephropathy, suggesting a disturbance in the turnover of the non-reducing terminal saccharide residues. In addition, the results show that lectins are useful probes for studying these changes further.


Loss of Pkd1 limits susceptibility to colitis and colorectal cancer.
Colorectal cancer (CRC) is one of the most common cancers, with an annual incidence of ~135,000 in the US, associated with ~50,000 deaths. Autosomal dominant polycystic kidney disease (ADPKD), associated with mutations disabling the PKD1 gene, affects as many as 1 in 1000. Intriguingly, some studies have suggested that individuals with germline mutations in PKD1 have reduced incidence of CRC, suggesting a genetic modifier function. Using mouse models, we here establish that loss of Pkd1 greatly reduces CRC incidence and tumor growth induced by loss of the tumor suppressor Apc. Growth of Pkd1-/-;Apc-/- organoids was reduced relative to Apc-/- organoids, indicating a cancer cell-intrinsic activity, even though Pkd1 loss enhanced activity of pro-oncogenic signaling pathways. Notably, Pkd1 loss increased colon barrier function, with Pkd1-deficient animals resistant to DSS-induced colitis, associated with upregulation of claudins that decrease permeability, and reduced T cell infiltration. Notably, Pkd1 loss caused greater sensitivity to activation of CFTR, a tumor suppressor in CRC, paralleling signaling relations in ADPKD. Overall, these data and other data suggest germline and somatic mutations in PKD1 may influence incidence, presentation, and treatment response in human CRC and other pathologies involving the colon.


Atrial fibrillation in patients with an atrial septal defect in a single centre cohort during a long clinical follow-up: its association with closure and outcome of therapy.
Currently, consensus is lacking on the relation between closure of atrial septal defect (ASD) and the incidence of atrial fibrillation (AF), which is a known complication in ASD patients. More importantly, studies reporting on the treatment applied for AF in ASD patients are scarce. The aims of this study were (1) to assess the incidence of AF in ASD patients, (2) to study the relation between closure and AF and (3) to evaluate applied treatment strategies. A single-centre retrospective study in 173 patients with an ASD was performed. We analysed the incidence of AF, the relation of AF with closure, method of closure and the treatment success of therapies applied. Almost 20% of patients with an ASD developed AF, with a mean age of 59 (±14) years at first presentation of AF during a median clinical follow-up of 43 (29-59) years. Older age (OR 1.072; p<0.001) and a dilated left atrium (OR 3.727; p=0.009) were independently associated with new-onset AF. Closure itself was not independently associated with AF. First applied treatment strategy was rhythm control in 77%. Of the 18 patients treated with antiarrhythmic drugs 50% had at least 1 recurrence of AF. No clear relation between closure of the ASD and AF could be assessed. This is the first study describing applied therapy for AF in ASD patients of which medical rhythm control was the most applied strategy with a disappointing efficacy.


Intravital microscopic characterization of suramin effects in an orthotopic immunocompetent rat model of pancreatic cancer.
We investigated the effect of suramin on tumor growth and spread in an immunocompetent, orthotopic rat model of pancreatic cancer and analyzed the tumor vasculature by intravital microscopy. In vitro, rat ductal pancreatic cancer cells (DSL-6A) were incubated with suramin (10-800 microg/ml), and cell proliferation was assessed. In vivo, DSL-6A tumors were induced in the pancreas of Lewis rats. Animals received suramin (60 mg/kg, weekly i.p.) or the vehicle (controls). Treatment started after 3 days. Intravital microscopy after 1, 4, and 8 weeks quantified diameter, density, and permeability of tumor vessels. Primary tumor volume, local infiltration, and metastatic spread were determined at autopsy. Microvessel density was analyzed by immunohistochemistry. In vitro, proliferation was inhibited by suramin up to 95%. In vivo, all controls developed extensive tumor growth and spread. No tumor was detectable in half of the suramin-treated animals after 8 weeks; tumor dissemination was almost completely depressed. Suramin therapy resulted in a complete regression of tumor macrovessels and a significant reduction of microvessel density. Suramin significantly reduces primary tumor growth and dissemination in a clinically relevant rat model of pancreatic cancer and seems to play an important role for the inhibition of tumor angiogenesis.


Cookies enriched with psyllium or oat bran lower plasma LDL cholesterol in normal and hypercholesterolemic men from Northern Mexico.
Psyllium and oat bran have been shown to lower plasma LDL cholesterol levels in different populations. Hypercholesterolemia is prevalent in the Northern part of Mexico and might be associated to dietary habits and sedentary lifestyle. Sedentary normal (cholesterol<200 mg/dL) (n=36) and hypercholesterolemic (cholesterol>220 mg/dL) (n=30) men from the Northern part of Mexico aged 20 to 45 years of age participated in an 8-week study to determine the effects of dietary soluble fiber, either psyllium or oat bran, in lowering plasma LDL cholesterol in this population. Fiber was administered by feeding the subjects an amount of cookies (100 g) equivalent to 1.3 or 2.6 g/day of soluble fiber from psyllium or oat bran, respectively. Subjects were randomly allocated to three groups: a control group consuming cookies with wheat bran, a known source of fiber with no cholesterol lowering effects, psyllium, or oat bran. Food frequency questionnaires indicated that subjects from the three groups had similar intakes of foods classified as hypercholesterolemic (p>0.05). Plasma LDL cholesterol concentrations were reduced by an average of 22.6 and 26% in the psyllium and oat bran groups (p<0.001) while a non-significant reduction of 8.4% was observed in the hypercholesterolemic individuals from the control group. No effects on plasma HDL or triglycerides levels were observed among the three dietary treatments except for hypercholesterolemic individuals supplemented with oat bran where a 28% reduction in plasma triglycerides was observed after 8 weeks (p<0.01). These results indicate that psyllium and oat bran are efficacious in lowering plasma LDL cholesterol in both normal and hypercholesterolemic individuals from this population.


Acute ST-elevation myocardial infarction secondary to paradoxical embolism.
Acute ST-elevation myocardial infarction (STEMI) is a life threatening condition usually caused by rupture of an atheromatous plaque in the coronary arteries. Other causes, such as septic emboli, cholesterol emboli and cocaine abuse have been reported. We report a case of acute STEMI in a young female without any vascular risk factors due to a presumptive paradoxical embolism via a secundum atrial septal defect (ASD). Young patients without vascular risk factors presenting with acute myocardial infarction should be investigated to exclude an underlying cause of their myocardial infarction, such as a paradoxical embolus.


Individual repeatability of avian migration phenology: A systematic review and meta-analysis.
Changes in phenology and distribution are being widely reported for many migratory species in response to shifting environmental conditions. Understanding these changes and the situations in which they occur can be aided by understanding consistent individual differences in phenology and distribution and the situations in which consistency varies in strength or detectability. Studies tracking the same individuals over consecutive years are increasingly reporting migratory timings to be a repeatable trait, suggesting that flexible individual responses to environmental conditions may contribute little to population-level changes in phenology and distribution. However, how this varies across species and sexes, across the annual cycle and in relation to study (tracking method, study design) and/or ecosystem characteristics is not yet clear. Here, we take advantage of the growing number of publications in movement ecology to perform a phylogenetic multilevel meta-analysis of repeatability estimates for avian migratory timings to investigate these questions. Of 2,433 reviewed studies, 54 contained suitable information for meta-analysis, resulting in 177 effect sizes from 47 species. Individual repeatability of avian migratory timings averaged 0.414 (95% confidence interval: 0.3-0.5) across landbirds, waterbirds and seabirds, suggesting consistent individual differences in migratory timings is a common feature of migratory systems. Timing of departure from the non-breeding grounds was more repeatable than timings of arrival at or departure from breeding grounds, suggesting that conditions encountered on migratory journeys and outcome of breeding attempts can influence individual variation. Population-level shifts in phenology could arise through individual timings changing with environmental conditions and/or through shifts in the numbers of individuals with different timings. Our findings suggest that, in addition to identifying the conditions associated with individual variation in phenology, exploring the causes of between-individual variation will be key in predicting future rates and directions of changes in migratory timings. We therefore encourage researchers to report the within- and between- individual variance components underpinning the reported repeatability estimates to aid interpretation of migration behaviour. In addition, the lack of studies in the tropics means that levels of repeatability in less strongly seasonal environments are not yet clear.


Natural infection of land-snails by protostrongylids on a pasture grazed by sheep in the Rabat area of Morocco.
The output by sheep of first-stage protostrongylid larvae, and the population density and level of infection of terrestrial molluscs were assessed monthly during a 1-year study. Limax maximus was the most infected mollusc. Juveniles were less infected than adults, for Cernuella virgata and Theba pisana; the reverse was observed for Otala lactea. Banded individuals had a lower intensity of infection than the non-banded ones for C. virgata and T. pisana. Sixty-one percent of protostrongylid larvae in molluscs on the pastures studied were found in C. virgata, and 25% in O. lactea. The infectivity of the pasture for sheep was related to rainfall.


TRAIL protein expression in breast cancer cells correlates with nuclear grade.
TRAIL protein may serve as an escape mechanism for cancer cells from the immune response. The aim of the study was to assess whether the presence of TRAIL protein correlates with unfavourable prognostic factors in breast carcinoma. The study group was composed of breast cancer patients treated surgically in the Department of Surgical Oncology, Medical University of Lodz, Poland, from January to December 2003. Inclusion criteria for the study were fulfilled by 117 women. The immunohistochemical study of TRAIL protein expression was performed in 118 breast carcinomas diagnosed in the study group. TRAIL protein expression was correlated with other variables: tumour size, lymph node status, grade, histological type of carcinoma, oestrogen and progesterone receptor status, HER2 expression, presence of lymphovascular invasion and age of the patient. Expression of TRAIL protein was present in 73% of breast carcinomas. The percentage of TRAIL-expressing breast carcinoma cells correlated with the nuclear grade (τ = 0.26, p < 0.05; Tau Kendall test). The intensity of TRAIL expression (intensity of staining) in breast carcinoma cells correlated with the nuclear grade (τ = 0.15, p < 0.05; Tau Kendall test). TRAIL expression in breast carcinoma did not correlate with other studied variables. Our analysis revealed that expression of TRAIL protein in breast carcinoma cells correlates with nuclear grade of carcinoma.


Conservative management of renal carbuncles in children.
Renal carbuncles have traditionally been treated with surgical drainage and appropriate antibiotic therapy. Recently, 2 pediatric patients with well-documented renal carbuncles were treated with antibiotic therapy alone. Close follow-up documented complete resolution in both cases. Late studies showed no evidence of renal scarring or functional compromise.


In Vivo Safety and Regeneration of Long-Term Transported Amniotic Fluid Stem Cells for Renal Regeneration.
Despite major progress in stem cell therapy, our knowledge of the characteristics and tissue regeneration potency of long-term transported cells is insufficient. In a previous in vitro study, we established the optimal cell transport conditions for amniotic fluid stem cells (AFSCs). In the present study, the target tissue regeneration of long-term transported cells was validated in vivo. For renal regeneration, transported AFSCs were seeded on a poly(lactide-co-glycolide) scaffold and implanted in a partially resected kidney. The target tissue regeneration of the transported cells was compared with that of freshly harvested cells in terms of morphological reconstruction, histological microstructure reformation, immune cell infiltration, presence of induced cells, migration into remote organs, expression of inflammation/fibrosis/renal differentiation-related factors, and functional recovery. The kidney implanted with transported cells showed recovery of total kidney volume, regeneration of glomerular/renal tubules, low CD4/CD8 infiltration, and no occurrence of cancer during 40 weeks of observation. The AFSCs gradually disappeared and did not migrate into the liver, lung, or spleen. We observed low expression levels of pro-inflammatory cytokines and fibrotic factors; enhanced expression of the genes Wnt4, Pax2, Wt1, and Emx2; and significantly reduced blood urea nitrogen and creatinine values. There were no statistical differences between the performance of freshly harvested cells and that of the transported cells. This study demonstrates that long-term transported cells under optimized conditions can be used for cell therapy without adverse effects on stem cell characteristics, in vivo safety, and tissue regeneration potency.


New studies on papillary calculi.
Five hundred spontaneously passed stones were collected during a three-year period in an outpatient clinic. They were studied under a stereoscopical optical microscope. Complementary analyses were performed with infrared spectroscopy, scanning electron microscopy and EDAX. There were 142 true papillary stones (28.4%). The rest (71.6%) showed different non-papillary patterns. Papillary stones, type 1 (61 calculi), had an apatite plaque of intrapapillary origin of which 14 showed calcified tubules. Type 2 showed other substances, presumably due to crystalluria but not to an interstitial papillary process (28 stones). Type 3 showed no plaques in their concave faces (53 stones). In types 1 and 2 whewellite is a secondary growth, the plaque acting as a trigger for the development of calcium oxalate. The possibility of hidden Randall's plaques is discussed. Stones with papillary patterns are not as rare as hitherto considered and merit microscopical study.


EBV-associated diffuse large B-cell lymphoma in a psoriatic treated with methotrexate.
Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a lymphoid proliferation or lymphoma in a patient immunosuppressed with MTX, which is usually administered for treating autoimmune diseases. The majority of MTX-LPD cases develop in patients with rheumatoid arthritis and occasionally with psoriasis who had been treated with MTX. Here, we report on a 50-year-old Taiwanese male with severe psoriasis, who received high doses of MTX. The patient developed EBV-positive MTX-LPD at nodal and extranodal sites. The diffuse and polymorphic lymphoid infiltrate consisted predominantly of immunoblasts and plasmablasts expressing B-cell markers, CD138, Epstein-Barr virus (EBV)-LMP1, and EBNA2, and these were monotypic for kappa light chain. The tumor cells were also positive for EBV by in situ hybridization. These findings indicated a type III latency infection of EBV. The patient died of progressive disease after 19 months. A review of the previously reported cases shows that MTX-LPD, in association with psoriasis, occurs in middle-aged males. The tumors are diffuse large B-cell lymphomas with immunoblastic morphology, and frequently show plasmacytic differentiation.