Dendrimer-Enabled Therapeutic Antisense Delivery Systems as Innovation in Medicine.
Antisense oligonucleotide (AON)-based therapies concern the treatment for genetic disorders or infections such as a range of neurodegenerative and neuromuscular diseases and have shown benefits in animal models and patients. Nevertheless, successes in the clinic are still strongly limited by unfavorable biodistribution and poor cellular uptake of AONs. Dendrimer macromolecules are synthetically accessible and consist of a core with repeated iterations (named branches) surrounding this core, and on the periphery functional groups which can be modified for ligand attachment. The generations of these branched nanoparticles are based on the number of branches emanating from the core with layered architectures. Dendrimers show promise in several biomedical applications based on their tunable surface modifications allowing the adjustment of their in vivo behavior related to biocompatibility and pharmacokinetic parameters. Dendrimers can be used as nanocarriers of various types of drugs including AONs or nanodrugs. As nanocarriers, polycationic dendrimers can complex multiple negatively charged DNA oligonucleotides on their surface and form stable complexes to promote internalization into the cells based on a good cell membrane affinity. These nanocarriers complexing antisense oligonucleotides must be stable enough to reach the cellular target, but with adequate in vivo global clearance, and have good pharmacokinetic (PK) and pharmacodynamic (PD) profiles. This Review was designed to analyze the development of AONs carried by polycationic and polyanionic (few example) dendrimers. This Review strongly supports the idea that dendrimers, with adequate modulation of their terminal groups, could be used to carry AONs in cells.


Novel Anti-LY6G6D/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Colorectal Cancer.
New therapeutics and combination regimens have led to marked clinical improvements for the treatment of a subset of colorectal cancer. Immune checkpoint inhibitors have shown clinical efficacy in patients with mismatch-repair-deficient or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). However, patients with microsatellite-stable (MSS) or low levels of microsatellite instable (MSI-L) colorectal cancer have not benefited from these immune modulators, and the survival outcome remains poor for the majority of patients diagnosed with mCRC. In this article, we describe the discovery of a novel T-cell-dependent bispecific antibody (TDB) targeting tumor-associated antigen LY6G6D, LY6G6D-TDB, for the treatment of colorectal cancer. RNAseq analysis showed that LY6G6D was differentially expressed in colorectal cancer with high prevalence in MSS and MSI-L subsets, whereas LY6G6D expression in normal tissues was limited. IHC confirmed the elevated expression of LY6G6D in primary and metastatic colorectal tumors, whereas minimal or no expression was observed in most normal tissue samples. The optimized LY6G6D-TDB, which targets a membrane-proximal epitope of LY6G6D and binds to CD3 with high affinity, exhibits potent antitumor activity both in vitro and in vivo. In vitro functional assays show that LY6G6D-TDB-mediated T-cell activation and cytotoxicity are conditional and target dependent. In mouse xenograft tumor models, LY6G6D-TDB demonstrates antitumor efficacy as a single agent against established colorectal tumors, and enhanced efficacy can be achieved when LY6G6D-TDB is combined with PD-1 blockade. Our studies provide evidence for the therapeutic potential of LY6G6D-TDB as an effective treatment option for patients with colorectal cancer.


Mercury species induced frequency-shift of molecular orientational transformation based on SERS.
We proposed a novel readout method based on a peculiar phenomenon in which the vibrational frequencies of a SERS-active probe (dimethyldithiocarbamic acid sodium salt, DASS) can be affected when there is mercury species. Compared to the SERS intensity-dependent quantitative determination method, SERS frequency-shift-based methods have several advantages: smaller standard deviation, perfect linear relationship, and higher accuracy and sensitivity. In addition, the SERS frequency-shift-based method was not affected by irreproducible aggregation of the SERS substrate and instrumental factors, which greatly improved the application prospect of SERS-based detection. The DASS-modified silver nanoparticles produced a highly sensitive sensor specific to mercury species. Upon the addition of a solution of mercury species to the chip, the mercury species specifically binds to the sulfur atoms, which induces a frequency shift of the band at 1374 cm(-1). The detection limit of the proposed method for Hg(2+) is as low as 10(-8) M. In addition, the proposed method exhibited the same phenomenon for organic mercury. Moreover, these results suggest that the proposed platform possesses the potential for sensitive, selective, and high-throughput on-site mercury pollution monitoring in resource-constrained settings.


Reverse Arene Sandwich Structures Based upon π-Hole⋅⋅⋅[MII ] (d8 M=Pt, Pd) Interactions, where Positively Charged Metal Centers Play the Role of a Nucleophile.
The complexes [Pt(tpp)] (H2 tpp=tetraphenylporphyrin), [M(acac)2 ] (M=Pd, Pt, Hacac=acetylacetone), and [Pd(ba)2 ] (Hba=benzoylacetone) were co-crystallized with highly electron-deficient arene systems to form reverse arene sandwich structures built by π-hole⋅⋅⋅[MII ] (d8 M=Pt, Pd) interactions. The adduct [Pt(tpp)]⋅2 C6 F6 is monomeric, whereas the diketonate 1:1 adducts form columnar infinity 1D-stack assembled by simultaneous action of both π-hole⋅⋅⋅[MII ] and C⋅⋅⋅F interactions. The reverse sandwiches are based on noncovalent interactions and calculated ESP distributions indicate that in π-hole⋅⋅⋅[MII ] contacts, [MII ] plays the role of a nucleophile.


The application of machine learning in early diagnosis of osteoarthritis: a narrative review.
Osteoarthritis (OA) is the commonest musculoskeletal disease worldwide, with an increasing prevalence due to aging. It causes joint pain and disability, decreased quality of life, and a huge burden on healthcare services for society. However, the current main diagnostic methods are not suitable for early diagnosing patients of OA. The use of machine learning (ML) in OA diagnosis has increased dramatically in the past few years. Hence, in this review article, we describe the research progress in the application of ML in the early diagnosis of OA, discuss the current trends and limitations of ML approaches, and propose future research priorities to apply the tools in the field of OA. Accurate ML-based predictive models with imaging techniques that are sensitive to early changes in OA ahead of the emergence of clinical features are expected to address the current dilemma. The diagnostic ability of the fusion model that combines multidimensional information makes patient-specific early diagnosis and prognosis estimation of OA possible in the future.


The loss of hemoglobin and myoglobin does not minimize oxidative stress in Antarctic icefishes.
The unusual pattern of expression of hemoglobin (Hb) and myoglobin (Mb) among Antarctic notothenioid fishes provides an exceptional model system for assessing the impact of these proteins on oxidative stress. We tested the hypothesis that the lack of oxygen-binding proteins may reduce oxidative stress. Levels and activity of pro-oxidants and small-molecule and enzymatic antioxidants, and levels of oxidized lipids and proteins in the liver, oxidative skeletal muscle and heart ventricle were quantified in five species of notothenioid fishes differing in the expression of Hb and Mb. Levels of ubiquitinated proteins and rates of protein degradation by the 20S proteasome were also quantified. Although levels of oxidized proteins and lipids, ubiquitinated proteins, and antioxidants were higher in red-blooded fishes than in Hb-less icefishes in some tissues, this pattern did not persist across all tissues. Expression of Mb was not associated with oxidative damage in the heart ventricle, whereas the activity of citrate synthase and the contents of heme were positively correlated with oxidative damage in most tissues. Despite some tissue differences in levels of protein carbonyls among species, rates of degradation by the 20S proteasome were not markedly different, suggesting either alternative pathways for eliminating oxidized proteins or that redox tone varies among species. Together, our data indicate that the loss of Hb and Mb does not correspond with a clear pattern of either reduced oxidative defense or oxidative damage.


Anesthesia Management in an Adult Patient with Sleep-Disordered Breathing and Difficult Intubation: A Case Report.
Obstructive sleep apnea may be associated with numerous comorbidities and perioperative complications. Poor laryngeal anatomy visualization can be a cause of failed tracheal intubation after multiple attempts in patients with sleep-disordered breathing due to the underlying adenoid enlargement. We present a case of difficult endotracheal intubation in a 52-year-old menopausal female patient posted for tonsillectomy with adenoid resection with a history of snoring and difficulty in breathing while asleep. A thorough preoperative assessment focusing on history and investigating obstructive sleep apnea, and preparing and planning for difficult tracheal intubation in such patients can lead to successful endotracheal intubation inside the operation theater.


Early Vaccination of Chickens Induces Suboptimal Immunity Against Infectious Bronchitis Virus.
Infectious bronchitis virus (IBV) is highly prevalent in broiler chickens despite extensive vaccination commonly conducted early after hatch. The effects of early vaccination on immune responses were further investigated in chickens primed at increasing ages, followed by booster vaccination with an attenuated Arkansas (Ark) Delmarva Poultry Industry-type vaccine. Results show that vaccination on day 1 of age elicits significantly lower systemic and mucosal antibody responses compared with vaccination at later time points in the life of the chicken. The increase of IBV antibodies in serum from secondary responses after booster vaccination was more dramatic and significantly higher when measured by an Ark spike subunit 1 protein ELISA compared with measuring by non-Ark serotype whole-virus ELISA, which underlines the immunogenic importance of the virus spike at inducing antibodies. However, the levels achieved following boosting did not differ significantly between ages of priming. Thus, it seems that the booster vaccination mitigated the differences detected after prime immunization. In contrast to the continued rise of systemic antibodies after booster vaccination, the levels of mucosal IBV-specific immunoglobulin A decreased after booster vaccination. The recruitment or expansion of cluster of differentiation (CD)4+, CD8+, and CD4+/CD8+ T-cell populations in different immune effector sites was increased with age, but remained unaltered by IBV vaccination. In contrast, peripheral blood CD4+ cells showed a significant increase in IBV-vaccinated chickens compared with nonvaccinated age-matched controls both after primary and booster immunization. The results of the current study confirm that IBV vaccination on the day of hatch induces suboptimal IBV immune responses both in the systemic and mucosal compartments. This routine practice may be contributing to the immunologic escape of the virus and increased persistence of vaccine virus in vaccinated chickens. However, booster vaccination seems to overcome poor initial responses.


Attention Deficit Hyperactivity Disorder: scaling and standard setting using Rasch measurement.
This paper explores the dimensionality of responses to the Adult Behavior Checklist Revised, a screening assessment for Attention Deficit Hyperactivity Disorder (ADHD) in college students, and demonstrates a standard setting process for diagnostic rating scales. Responses from 317 undergraduate college students were used to investigate dimensionality; 8 judges were used for the standard setting procedure. A series of Rasch rating scale analyses support the interpretation of Inattention and Impulsivity/Hyperactivity variables. Principal component analyses of residuals identified the existence of secondary variables that may have clinical implications for the evaluation and treatment of ADHD. For the standard setting process, judges generally displayed less variability than expected by the model. Several judges were in disagreement as to the level of symptomatology needed to indicate potential ADHD. The derived standard for Inattention was found to be more stringent than a previously suggested standard while the derived standard for Hyperactive/Impulsive more lenient. Prevalence rates found a diagnosis of Hyperactive/Impulsive to be more common than a diagnosis of Inattention. Efficient screening assessments for ADHD in college students are needed in order to determine who may qualify for further evaluation and special services. The standard setting process attempts to identify judge disagreement regarding the level of symptomatology (the standard) needed to qualify for additional evaluation and identify judge response strings not consistent with the item difficulties. Recommendations suggesting additional work on the screening assessment and standard setting process are outlined.


Projections of multi-morbidity in the older population in England to 2035: estimates from the Population Ageing and Care Simulation (PACSim) model.
models projecting future disease burden have focussed on one or two diseases. Little is known on how risk factors of younger cohorts will play out in the future burden of multi-morbidity (two or more concurrent long-term conditions). a dynamic microsimulation model, the Population Ageing and Care Simulation (PACSim) model, simulates the characteristics (sociodemographic factors, health behaviours, chronic diseases and geriatric conditions) of individuals over the period 2014-2040. about 303,589 individuals aged 35 years and over (a 1% random sample of the 2014 England population) created from Understanding Society, the English Longitudinal Study of Ageing, and the Cognitive Function and Ageing Study II. the prevalence of, numbers with, and years lived with, chronic diseases, geriatric conditions and multi-morbidity. between 2015 and 2035, multi-morbidity prevalence is estimated to increase, the proportion with 4+ diseases almost doubling (2015:9.8%; 2035:17.0%) and two-thirds of those with 4+ diseases will have mental ill-health (dementia, depression, cognitive impairment no dementia). Multi-morbidity prevalence in incoming cohorts aged 65-74 years will rise (2015:45.7%; 2035:52.8%). Life expectancy gains (men 3.6 years, women: 2.9 years) will be spent mostly with 4+ diseases (men: 2.4 years, 65.9%; women: 2.5 years, 85.2%), resulting from increased prevalence of rather than longer survival with multi-morbidity. our findings indicate that over the next 20 years there will be an expansion of morbidity, particularly complex multi-morbidity (4+ diseases). We advocate for a new focus on prevention of, and appropriate and efficient service provision for those with, complex multi-morbidity.


Adenosine deaminase complexing protein (ADCP) expression and metastatic potential in prostatic adenocarcinomas.
The expression of the adenosine deaminase complexing protein (ADCP) was investigated by immunohistochemistry in the normal and hyperplastic human prostate, in 30 prostatic adenocarcinomas, and in seven human prostatic adenocarcinoma cell lines grown as xenografts in athymic nude mice. In the normal and hyperplastic prostate, ADCP was localized exclusively in the apical membrane and the apical cytoplasm of the glandular epithelial cells. In prostatic adenocarcinomas, four distinct ADCP expression patterns were observed: diffuse cytoplasmic, membranous, both cytoplasmic and membranous, and no ADCP expression. The expression patterns were compared with the presence of metastases. We found an inverse correlation between membranous ADCP immunoreactivity and metastatic propensity. Exclusively membranous ADCP immunoreactivity occurred only in non-metastatic tumours. In contrast, the metastatic tumours showed no or diffuse cytoplasmic ADCP immunoreactivity. This suggests that immunohistochemical detection of ADCP might predict the biological behaviour of prostatic cancer. However, the occurrence of membranous ADCP immunoreactivity in the xenograft of a cell line (PC-EW), derived from a prostatic carcinoma metastasis, indicates that not only the tendency to metastasize modulates ADCP expression.


Genetics of polycystic liver diseases.
This review provides an outline of the most recent insights and significant discoveries regarding the genetic mechanisms involved in polycystic liver disease. Polycystic liver disease includes a heterogeneous group of genetic disorders characterized by multiple hepatic cysts. Isolated liver cysts are caused by mutations in Protein Kinase C Substrate 80K-H (PRKCSH), SEC63, and LDL Receptor Related Protein 5 (LRP5), whereas Polycystic Kidney Disease (PKD)1, PKD2, and PKHD1 mutations cause kidney cysts often accompanied by liver cysts. Glucosidase II Alpha Subunit (GANAB) has been reported to cause both phenotypes. These mutations, together with the newly identified ones in SEC61B and Alpha-1,3-Glucosyltransferase (ALG8), can be found in ∼50% of patients with isolated polycystic liver disease. Somatic second hit-mutations are hypothesized as driving force leading to cystogenesis. Subsequently, loss of heterozygosity in the cystic tissue aggravates disease progression. All genetic mutations lead to reduced levels of functional polycystin-1. This ciliary protein is therefore considered to be the central factor in the development and severity of liver cysts. Recent advances of the genetic complexity leading to hepatic cystogenesis provide novel candidate genes and important mechanistic insights with polycystin-1 as a common denominator.


[Making repeated clinical trials aiming at finding specific indications is the way for improving clinical efficacy of traditional Chinese medicine].
The modern clinical evaluation methods and index system are the tools for clinical evaluation in traditional Chinese medical trial, and more importantly the prerequisite for approbation of their outcomes. From the view of syndrome differentiation theory of traditional Chinese medicine, the previous therapeutic process is also a diagnostic process for the following therapeutic course, so to make repeated clinical trials aiming at finding specific indications would be one of the important ways to improve the clinical efficacy of traditional Chinese medicine.


The co-application of sprayed cultured autologous keratinocytes and autologous fibrin sealant in a porcine wound model.
We have explored the potential for cultured autologous keratinocytes to form an epidermis when delivered as a spray intermixed with autologous fibrin sealant. Twelve full-thickness wounds in Large White pigs (six wounds in each of two pigs) were isolated from the surrounding skin by 4 cm diameter polytetrafluoroethylene chambers, and grafted with Integra artificial skin (Ethicon). Autologous fibrin sealant was produced 10 days later, using an automated processor unit (Vivostat System, ConvaTec, Bristol Myers Squibb), from 120 ml of autologous citrated blood taken 30 min before keratinocyte application. Nine wounds were sprayed, using a Vivostat System automated applicator unit, with a mixture of the sealant preparation and freshly trypsinised cultured autologous keratinocytes in growth medium, at a density of 1-3 x 10(5) cm(-2). Three control wounds were sprayed with the same mixture without cells. The sealant-cell mixture polymerised and adhered to the wound surface immediately. Histological analysis of biopsies taken following sealant-cell application showed that isolated spherical keratinocytes were distributed throughout the sealant at between 3.1 x 10(4) cm(-2) and 7.6 x 10(4) cm(-2). After 4 days discreet colonies of keratinocytes were observed on the wound bed. At 14 days a multi-layered undulating epidermis was formed, punctuated by sporadic epidermal cysts; the mean area of epithelium was 50.1% (s.d. = 19.7%, n = 9). There was no epithelium in the controls (s.d. = 0, n = 3). The difference was statistically significant (P=0.016). This study suggests that co-sprayed cultured keratinocytes and autologous fibrin sealant may be an effective means of delivering epithelial cells to assist wound healing.


[Diagnostic value of platelet associated biomarkers in chronic periprosthetic joint infection].
Objective: To evaluate the diagnostic value of platelet count(PC),PC to mean platelet volume(MPV) ratio(PC/MPV) and plateletcrit(PCT) in chronic periprosthetic joint infection(PJI). Method: The medical records of 159 patients who underwent hip or knee revisions at Department of Joint Surgery,Affiliated Hospital of Qingdao University from August 2013 to June 2019 were retrospectively reviewed. There were 51 patients(26 knees and 25 hips) in the PJI group,which included 28 males and 23 females,aged (68.0±11.8)years (range:32 to 84 years)with a body mass index(BMI)of (26.1±3.6) kg/m².There were 116 patients(19 knees and 97 hips) in the aseptic loosening(AL) group,including 67 males and 49 females,aged (70.3±8.9)years(range:49 to 89 years)with a BMI of (25.0±3.6)kg/m².The plasma C-reactive protein(CRP),erythrocyte sedimentation rate(ESR),PC,MPV,PC/MPV and PCT levels of the two groups were recorded and analyzed. Receiver operating characteristic curve was used to calculate the sensitivity and specificity of each biomarker,expect for MPV,and the diagnostic value of each biomarker was compared according to the area under the curve(AUC).Independent-sample t test or Mann-Whitney U test were used for comparison between groups. Result: Compared with AL group,AJI group had significantly higher levels of CRP,ESR,PC,PC/MPV and PCT(all P<0.05),but lower level of MPV (P<0.05).The AUCs for CRP,ESR,PC,PC/MPV and PCT were 0.820, 0.829, 0.689, 0.668 and 0.676,respectively. Based on the Youden index,the optimal predictive cutoff for CRP was 11.12 mg/L,with a sensitivity of 74.4% and a specificity of 87.1%.The optimal predictive cutoff for ESR was 17.60 mm/1 h,with a sensitivity of 81.4% and a specificity of 75.3%.The optimal predictive cutoff for PC was 243.00×109/L,with a sensitivity of 60.6% and a specificity of 71.8%.The optimal predictive cutoff for PC/MPV was 24.95,the sensitivity was 58.1% and the specificity was 74.1%.And the optimal predictive cutoff for PCT was 0.24%,with a sensitivity of 69.8% and a specificity of 63.5%. Conclusion: PC,PC to MPV ratio and PCT were of limited value to diagnose PJI.


Neokestose suppresses the growth of human melanoma A2058 cells via inhibition of the nuclear factor‑κB signaling pathway.
Neokestose has superior prebiotic effects compared with the commercial fructooligosaccharides (FOS). In addition, the branched structure of neokestose, a type of neo‑FOS, confers improved chemical stability compared with conventional FOS; therefore, the investigation of the branched structure by the present study may be of high biomedical value. The present study aimed to determine whether neokestose may suppress growth of the A2058 melanoma cell line. The cells were initially treated with neokestose; subsequently, in vitro cytotoxicity was assessed using MTT, and cell cycle progression and apoptosis were detected using flow cytometry. The protein expression levels of cyclin D1, phosphorylated (p)‑inhibitor of κB (IκB) and nuclear factor‑κB (NF‑κB) were determined using western blotting. Treatment with neokestose led to a dose‑dependent inhibition of cell viability. Flow cytometry data indicated that neokestose increased the sub‑G1 cell population, and induced early and late apoptosis. Western blot analysis revealed that neokestose treatment reduced the expression levels of p‑IκB and cyclin D1. These findings suggest that neokestose treatment may induce suppression of A2058 melanoma cell viability via inhibition of the NF‑κB pathway. The present findings support the requirement for further investigation into the potential use of neokestose as an additional or chemopreventive therapeutic agent for the treatment of melanoma.


NMR-based metabolomics Reveals Alterations of Electro-acupuncture Stimulations on Chronic Atrophic Gastritis Rats.
Chronic atrophic gastritis (CAG) is a common gastrointestinal disease which has been considered as precancerous lesions of gastric carcinoma. Previously, electro-acupuncture stimulation has been shown to be effective in ameliorating symptoms of CAG. However the underlying mechanism of this beneficial treatment is yet to be established. In the present study, an integrated histopathological examination along with molecular biological assay, as well as 1H NMR analysis of multiple biological samples (urine, serum, stomach, cortex and medulla) were employed to systematically assess the pathology of CAG and therapeutic effect of electro-acupuncture stimulation at Sibai (ST 2), Liangmen (ST 21), and Zusanli (ST 36) acupoints located in the stomach meridian using a rat model of CAG. The current results showed that CAG caused comprehensive metabolic alterations including the TCA cycle, glycolysis, membrane metabolism and catabolism, gut microbiota-related metabolism. On the other hand, electro-acupuncture treatment was found able to normalize a number of CAG-induced metabolomics changes by alleviating membrane catabolism, restoring function of neurotransmitter in brain and partially reverse the CAG-induced perturbation in gut microbiota metabolism. These findings provided new insights into the biochemistry of CAG and mechanism of the therapeutic effect of electro-acupuncture stimulations.


A protease additive increases fermentation of alfalfa diets by mixed ruminal microorganisms in vitro.
In vitro experiments were conducted to examine the characteristics and mode of action of a protease that increased the ruminal fiber digestibility of alfalfa hay. A commercial source of protease (Protex 6L, Genencor Int., Rochester, NY), already characterized for its main activities, was further analyzed to determine protease activity in response to pH, molecular size by SDS-PAGE, specificity to degrade model or feed substrates, response to autoclaving, and action of specific protease inhibitors in the absence or presence of ruminal fluid. In addition, batch culture in vitro incubations in buffered ruminal fluid were conducted to compare the enzyme product with purified protease sources, and dose-response studies (0 to 10 microL/g of forage DM) were carried out using alfalfa hay as a substrate. The enzyme product was shown to be an alkaline protease (optimum pH >8.5) of approximately 30 kDa. Specificity in the absence of ruminal fluid showed that the enzyme was active against gelatin and casein to the same extent, whereas it had limited (21% of the total) activity on BSA. In the presence of ruminal fluid and with the use of feed substrates, the protease increased (P < 0.05) 22-h IVDMD (%) of alfalfa hay, fresh corn silage, dry-rolled corn, and a total mixed ration composed of the 3 ingredients (39.5 vs. 44.7; 50.3 vs. 54.5; 63.8 vs. 68.4; and 55.4 vs. 56.4 for control vs. protease for each feed, respectively). Inhibitor studies in the absence of ruminal fluid indicated that the enzyme was inhibited most by a serine protease inhibitor but not by cysteine- or metalloprotease inhibitors (10 vs. 1.9 and 0.1%, respectively). In the presence of ruminal fluid, the serine protease inhibitor reversed (P < 0.05) the increase in alfalfa IVDMD achieved by the enzyme product, such that IVDMD was similar to that of the control treatment. Comparisons among different proteases revealed that only pure subtilisin achieved increases in IVDMD that were similar to those with protease, suggesting the serine protease was subtilisin-like (EC 188.8.131.52). Dose-response studies using alfalfa hay as substrate showed quadratic responses in IVDMD, NDF digestion, and hemicellulose and protein disappearance. It is postulated that this enzyme acts by removing structural proteins in the cell wall, allowing ruminal microbes to gain faster access to digestible substrates.


Utility of routine urinalysis and urine culture testing in an ambulatory urology clinic: a quality improvement initiative in a Veterans healthcare facility.
Urinalysis (UA) and urine culture (UCx) are commonly performed tests in the urology clinic. Many of these urine studies are performed prior to the patient visit may not always be indicated, thus contributing to unintended consequences such as antibiotic use and costs without enhancing patient care. Our objective was to perform a quality improvement initiative aimed to assess the utility of routine UA/UCx. The practice pattern at our site's Veteran Affairs (VA) urology clinic prior to 2014 was to obtain routine UA/UCx on most clinic visits prior to patient evaluation. Starting in 2014, we designed an intervention whereby our nurse practitioner triaged all new patient referrals and selectively ordered UA/UCx. We performed multivariable logistic regression to assess for predictors of obtaining UA or UCx. A total of 1308 patients were seen in January-March 2013 and 1456 in June-August 2014 and were included in this analysis. Fewer patients in 2014 received UA (59.8% versus 70.0%, p < 0.001) and UCx (49.6% versus 64.2%, p < 0.001). There was a decreased odds of obtaining UA in 2014 (OR 0.52, p < 0.001) as well as a decreased odds of obtaining UCx in 2014 (OR0.38, p < 0.001) on multivariable logistic regression. The results of UA/UCx only rarely resulted in change of management in either cohort (3%). Selective ordering resulted in an estimated cost savings of $4915.08/month in UCx costs alone. Our quality improvement initiatives reduced rates of UA/UCx testing when providers assess patients prior to ordering these tests. The implication of this initiative is significant cost savings for the healthcare system.


[Molecular characterization of a mitogen-activated protein kinase gene DoMPK1 in Dendrobium officinale].
The mitogen-activated protein kinase (MAPK) cascade, composed of MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K), and MAPK, is abundantly conserved in all eukaryotes. MAPK along with MAPK cascade plays a vital regulatory role in the plant-arbuscular mycorrhiza/rhizobium nodule symbioses. However, the biological function of MAPK in orchid mycorrhiza (OM) symbiosis remains elusive. In the present study, a MAPK gene, designated as DoMPK1 (GenBank accession No. JX297594), was identified from D. officinale roots infected by an OM fungus-Mycena sp. using the reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) methods. The full length cDNA of DoMPK1 was 1 263 bp and encoded a 372 aa protein with a molecular weight of 42.61 kD and an isoelectric point (pI) of 6.07. The deduced DoMPK1 protein contained the conserved serine/threonine-protein kinase catalytic domain (39-325) and MAP kinase signature (77-177). Multiple sequence alignment and phylogenetic analysis demonstrated that DoMPK1 was highly homologous (71%-85%) to MAPK genes from various plant species and was closely related to those from monocots. Real time quantitative PCR (qPCR) analysis revealed that DoMPK1 was constitutively expressed in leaves, stems, roots and seeds, and the transcript abundance was not significantly different in the four included tissues. Furthermore, DoMPK1 transcript was markedly induced in roots at 30 d after fungal infection, with 7.91 fold compared to that of the mock inoculated roots, suggesting implication of DoMPK1 in the early D. officinale and Mycena sp. interaction and an essential role in the symbiosis. Our study characterized a MAPK gene associated with OM symbiosis for the first time, and will be helpful for further functional elucidation of DoMPK1 involving in D. officinale and Mycena sp. symbiotic interaction.


A novel technique in the use of fractional flow reserve in coronary artery bifurcation lesions.
The side branch (SB) in bifurcation lesions is a frequently encountered challenge that interventional cardiologists must face. There is great interest in determining fractional flow reserve (FFR) in the SB to help guide treatment decisions; however, difficulty with the pressure guidewire limits its widespread use. We propose a novel technique that will ease the incorporation of FFR in routine evaluation of bifurcation lesions, and allow better assessment of provisional stenting and need for SB intervention. Conventionally, to measure SB FFR, the jailed SB is re-crossed through the stent strut using a pressure wire. Our technique involves the use of a microcatheter and wire exchange within the SB, thereby alleviating some of the technical difficulties associated with the FFR wire. In light of the difficulties and clinical concerns associated with bifurcation lesions, we propose an innovative method to ease the incorporation of FFR to allow better assessment of provisional stenting and need for SB intervention.


Clinical effect of aerobic exercise training in chronic obstructive pulmonary disease: A retrospective study.
Aerobic exercise training is a kind of pulmonary rehabilitation for lung diseases. This was a retrospective study to assess the efficacy of aerobic exercise training in chronic obstructive pulmonary disease (COPD) at a stable stage. A total of one hundred and fifty-six stable COPD patients who had accepted self-education only or self-education combined with an aerobic exercise training between January 2017 to January 2019 were reviewed retrospectively. A total of 79 patients who had received self-education combined with an aerobic exercise training schedule comprised the aerobic exercise training group (AET group) and 77 patients who had received self-education only were regarded as the education group (EDU group). The acute incidence rate in AET group was 7.6% better than that in EDU group 20.7% (P < .05). The AET group patients expressed higher levels of 6 minutes walking distance (6MWD) (P < .05) and better evaluations of both lung function (P < .05) and T lymphocyte immune response (P < .05), as well as significantly decreased chronic obstructive pulmonary disease assessment test (CAT) scores and modified British medical research council (mMRC) grades (P < .05). Patients in EDU group did not report any changes in any of these characteristics. The aerobic exercise training intervention contributed to an increasing in 6MWD and decrease in CAT scores and mMRC grades, as well as improving the T lymphocyte immune response in stable COPD patients.


Use of prediction markets to forecast infectious disease activity.
Prediction markets have accurately forecasted the outcomes of a wide range of future events, including sales of computer printers, elections, and the Federal Reserve's decisions about interest rates. We propose that prediction markets may be useful for tracking and forecasting emerging infectious diseases, such as severe acute respiratory syndrome and avian influenza, by aggregating expert opinion quickly, accurately, and inexpensively. Data from a pilot study in the state of Iowa suggest that these markets can accurately predict statewide seasonal influenza activity 2-4 weeks in advance by using clinical data volunteered from participating health care workers. Information revealed by prediction markets may help to inform treatment, prevention, and policy decisions. Also, these markets could help to refine existing surveillance systems.


The Difference in Performance and Compatibility between Crystalline and Amorphous Fillers in Mixed Matrix Membranes for Gas Separation (MMMs).
An increasing number of high-performing gas separation membranes is reported almost on a daily basis, yet only a few of them have reached commercialisation while the rest are still considered pure research outcomes. This is often attributable to a rapid change in the performance of these separation systems over a relatively short time. A common approach to address this issue is the development of mixed matrix membranes (MMMs). These hybrid systems typically utilise either crystalline or amorphous additives, so-called fillers, which are incorporated into polymeric membranes at different loadings, with the aim to improve and stabilise the final gas separation performance. After a general introduction to the most relevant models to describe the transport properties in MMMs, this review intends to investigate and discuss the main advantages and disadvantages derived from the inclusion of fillers of different morphologies. Particular emphasis will be given to the study of the compatibility at the interface between the filler and the matrix created by the two different classes of additives, the inorganic and crystalline fillers vs. their organic and amorphous counterparts. It will conclude with a brief summary of the main findings.


Why creating standardized core outcome sets for chronic kidney disease will improve clinical practice.
Chronic kidney disease (CKD) is common and is associated with increased mortality, morbidity and cost. However, insufficient high-quality trial data are available to answer many relevant clinical questions in this field. In addition, a wide range of variable outcomes are used in studies, and often they are incompletely reported. Furthermore, there is a lack of patient-relevant outcomes, such as mortality, morbidity, quality of life, pain, need for dialysis or costs. Common problems with outcome reporting are as follows: choosing the wrong domains to measure; within domains, choosing the wrong measures (invalid surrogates, composite, non-patient relevant); within measures, choosing the wrong/variable metrics; and within metrics, choosing variable presentation methods. With this article, we aim to underline why standardized outcome reporting is key to achieving evidence-based guidance and improving clinical care for patients; highlight the frameworks available for achieving core outcome sets; and starting from these frameworks, we propose steps needed to develop a core outcome set in the field of CKD. We hope that standardized core outcome sets for nephrology will lead to the most important outcome of guideline production, improving outcomes for our patients.


Phase I trial of a personalized peptide vaccine for patients positive for human leukocyte antigen--A24 with recurrent or progressive glioblastoma multiforme.
Personalized selection of suitable peptides for patients could offer a novel approach to developing cancer vaccines that boost anticancer immunity. We present the results of a phase I trial of 14 kinds of vaccine candidates (ITK-1) in patients with recurrent or progressive glioblastoma multiforme (GBM). From January 2006 to January 2008, 12 patients from eight Japanese hospitals who were positive for human leukocyte antigen-A24, including 10 patients refractory to temozolomide (TMZ), were enrolled. The dose escalation trial included three dose groups (1, 3, and 5 mg) to determine the safety and tolerability of ITK-1 peptides. Immunologic response was monitored by measuring levels of cytotoxic T-lymphocyte precursors and peptide-specific immunoglobulin G. In another ITK-1 phase I trial for advanced prostate cancer, the vaccination schedule was skipped or discontinued in all three patients receiving the highest dose (5 mg/peptide) because of injection site reactions. This trial was therefore ended without enrollment for the highest dose, and data were analyzed by intention to treat. No serious adverse drug reactions were encountered, and treatment was well tolerated. The vaccine induced dose-dependent immune boosting. The recommended dose of ITK-1 peptides is 3 mg/peptide. Personalized vaccination with ITK-1 peptides could be recommended in further stages of clinical trials. The safety and increased frequency of immune boosting offers potential clinical benefits in cases of recurrent or progressive GBM, even in TMZ-refractory settings.


[Emodin combined gemcitabine inhibited the growth of pancreatic cancer in vitro and in vivo and its mechanisms study].
To study the effect of emodin combined gemcitabine on the growth of pancreatic cancer in vivo and in vitro as well as its mechanisms. After human pancreatic cancer cell line SW1990 was treated with emodin (40 micromol/L), gemcitabine (20 micromol/L), and emodin combined gemcitabine, the cell proliferation was detected by cell counting kit-8 (CCK-8) assay. The apoptosis of pancreatic cancer cells was detected using the flow cytometry (FCM). The protein expressions of Bax and Bcl-2 were detected using Western blot. SW1990 cells were injected subcutaneously into nude mice to establish pancreatic xenograft tumors. The mice were then treated by emodin, gemcitabine, and emodin combined gemcitabine, respectively. The changes of tumor volume were monitored. The positive expressions of Ki-67, Bax, and Bcl-2 in the xenograft tumors were detected using immunohistochemical method. Emodin combined with gemcitabine induced a higher percentage of growth inhibition and apoptosis in pancreatic cancer cell line SW1990 than that of gemcitabine or emodin alone (P < 0.05). The protein expression of Bax was up-regulated and that of Bcl-2 down-regulated in the emodin group and the emodin combined gemcitabine group when compared with the control group (P < 0.05). Emodin combined with gemcitabine could significantly inhibit the growth of pancreatic xenograft tumors, increase the positive expression of Bax in tumor tissues, obviously decrease the positive expressions of Ki-67 and Bcl-2 (P < 0.05). The optimal effects were obtained in the emodin combined gemcitabine group (P < 0.05). Emodin could potentiate the inhibition of pancreatic cancer growth induced by gemcitabine both in vitro and in vivo, which might be achieved by up-regulating the expression of Bax and down-regulating the expression of Bcl-2.


High-affinity ligands of Siglec receptors and their therapeutic potentials.
Sialic acids are one of the important constituents of glycoconjugates in the deuterostome lineage of animals and microorganisms. Siglecs (Sialic acid-binding immunoglobulin like lectins) are a family of cell-surface receptor proteins that recognize sialylated glycoconjugates as ligands. To date, 15 Siglecs have been described in humans and are mainly known as regulators of the immune system. Several of the Siglecs are emerging as potential targets for the treatment of some inflammatory, autoimmune, allergic, neurodegenerative and infectious diseases. In addition to antibody mediated therapy, high-affinity ligand-based probes of Siglec receptors would represent invaluable tools to effectively address therapeutic opportunities of Sialic acid-mediated Siglec recognition. This review discusses some aspects of structure and function of Siglec receptors, and concisely summarizes up-to-date progress on the identification of sialic acid based high-affinity ligands of certain well explored Siglec receptors.


[Severe hyperkalemia associated to the use of losartan and spironolactone: case report].
Hyperkalemia is a complications of the use of angiotensin converting enzyme inhibitors, angiotensin receptor antagonists and aldosterone antagonists. These drugs are commonly used for the treatment of hypertension and cardiac failure. We report a 84 year-old female treated with losartan 50 mg/day and spironolactone 25 mg/day that presented with a hyperkalemia of 8.4 mEq/l and bradicardia, drowsiness and respiratory depression. She required hemodialysis and ventilatory assistance. She was discharged in good conditions five days after admission.


Organic-inorganic hybrid compounds containing polyhedral oligomeric silsesquioxane for conservation of stone heritage.
Alkoxysilane solutions based on tetraethoxysilane (TEOS) have been widely used for the consolidation of decaying heritage stone surfaces. TEOS-based products polymerize within the porous structure of the decaying stone, significantly increasing the cohesion of the grains of stone components. However, they suffer from practical drawbacks, such as crack formation of the gel during the drying phase due to the developing capillary force and dense gel fractures left inside of the stone. In this study, a TEOS-based stone consolidant containing functional (3-glycidoxypropyl)trimethoxysilane (GPTMS) and polyhedral oligomeric silsesquioxane (POSS) has been prepared in order to reduce gel crack formation during the drying phase. The addition of nanometer-sized POSS and/or GPTMS having a flexible segment reduces the capillary force developed during solvent evaporation. The properties of the TEOS/GPTMS/POSS composite solutions were compared with those of commercial products (Wacker OH and Unil sandsteinfestiger OH 1:1). The gelation time was similar to that of commercial consolidants, and the TEOS/GPTMS/POSS solution was stable over a period of up to 6 months. The addition of POSS and GPTMS provided a crack-free gel, while the gel from the commercial consolidants exhibited cracks after drying. The surface hydrophobicity of the treated decayed granite increased with the addition of POSS and GPTMS, and it was higher than that of the commercial product, implying the possibility of POSS and GPTMS as barriers to the penetration of water. This result implies that the TEOS/GPTMS/POSS solution showed a high suitability for the consolidation of granite heritage.


A coaching program to improve quality of life in older people in Japan: a randomised controlled trial.
As the world's population ages, efforts to improve quality of life (QOL) in old age are gaining public attention. In this study, a programme was conducted for older people with the aim of clarifying their life goals related to QOL and the meaning of their existence, and the effect of the programme in improving QOL was evaluated. Participants were randomly assigned to the intervention or control group after registration. The program consisted of four 90-minute classes. The primary outcome was the Philadelphia Geriatric Center Morale Scale score (PGC), and changes in outcomes were compared between groups. The intervention group had significantly improved PGC scores (P<0.003). Further, the scores of PGC subscales 'Acceptance of one's own ageing' and 'Lonely dissatisfaction' showed significant improvements after the intervention (P<0.001). The findings suggest the effectiveness of the developed program in improving QOL in people aged ≥65 years.


Escherichia coli-Derived γ-Lactams and Structurally Related Metabolites Are Produced at the Intersection of Colibactin and Fatty Acid Biosynthesis.
Colibactin is a genotoxic hybrid polyketide-nonribosomal peptide that drives colorectal cancer initiation. While clinical data suggest colibactin genotoxicity in vivo is largely caused by the major DNA-cross-linking metabolite, the colibactin locus produces a diverse collection of metabolites with mostly unknown biological activities. Here, we describe 10 new colibactin pathway metabolites (1-10) that are dependent on its α-aminomalonyl-carrier protein. The most abundant metabolites, 1 and 2, were isolated and structurally characterized mainly by nuclear magnetic resonance spectroscopy to be γ-lactam derivatives, and the remaining related structures were inferred via shared biosynthetic logic. Our proposed formation of 1-10, which is supported by stereochemical analysis, invokes cross-talk between colibactin and fatty acid biosynthesis, illuminating further the complexity of this diversity-oriented pathway.


[Neurologic diseases in a rural tropical area: experience at a primary health care center in the Boeny region of Madagascar].
There is, to our knowledge, no study reporting the demand for health care related to neurological diseases in rural tropical areas of developing countries. Neurology is nonetheless more or less closely related to the priority health issues in these countries. Over a 6-week period, 626 patients were seen at the primary health center in the town of Madirovalo, Madagascar. Neurological disorders accounted for 11.1% of the consultations. The neurological disorders most frequently leading to consultations were headaches (42.7%), with primary headaches accounting for 16%; next came leprosy neuropathy (14.7%), with a worrisome total of 8 new cases; other peripheral neuropathies (13.3%), and epilepsy (12%). The relatively low share of the latter seems likely related to families' frequent use of traditional healers rather than Western medicine. Neurological diseases appears to represent a significant part of the health-care demand of people living in rural tropical areas of developing countries, and specific support in this specialization is essential.


Psychological status before and after surgery for breast cancer.
A psychological study of 80 patients undergoing mastectomy showed that the preoperative period is more affected with anxiety, that the patients need communication to remove the anxious state, and that disclosure of the diagnosis should always be accompanied by an understanding interview that includes a clear and moderately optimistic evaluation of the consequences, plans for the future, involvement of the partner and other relatives. Physician and psychologist should share this task to inform the patient and help the patient's psychological reaction towards a constructive cooperation for treatment and rehabilitation.


Effect of Salinity on Ionic Shifts in Mesohaline Scyphomedusae, Chrysaora quinquecirrha.
Mesohaline populations of the scyphomedusae Chrysaora quinquecirrha are found in salinities ranging from 5{permill} to 25{permill}. Osmotic and ionic adjustments within this salinity range were investigated using C. quinquecirrha ephyrae budded from polyps in the laboratory and young medusae collected from the mid-salinity region of the Patuxent River, Maryland. When medusae were transferred from 20{permill} salinity to lower salinities (8{permill}, 12{permill}), concentrations of sodium and magnesium in tissue and mesogleal fluid fell rapidly and approached those of dilute seawater within 6 hours. There was some recovery of these levels relative to the 8{permill} medium, and they were significantly higher than the dilute seawater concentration after 1 week. Tissue concentrations of calcium showed no evidence of being regulated, whereas potassium was strongly regulated such that levels did not fall significantly following transfer of medusae to lower salinities. However, after 1 week, the concentration of potassium in mesogleal fluid approached that of the dilute medium. Extracellular space measured by direct blotting and weighing or using 35S was about 40%. As a result, estimates for intracellular potassium were revised to 17 mM1-1. The concentration of potassium in tissue remained stable following transfer to lower salinity, despite a substantial osmotic influx of water. This influx was measured as a >20% gain in body weight over 24 h following transfer of medusae from 16{permill} to 8{permill}. Mesogleal fluid was slightly hypo-osmolar to the medium at 15% and 20{permill} and slightly hyperosmolar to the medium at 5{permill} and 12{permill}. Sulfate concentrations in mesogleal fluid were 66%-70% those of the external medium. Medusae died or were unable to achieve positive buoyancy at 5%{permill}, which is probably very close to a lower salinity limit for C. quinquecirrha in the mesohaline Chesapeake Bay.


Preoperative bi-fractionated accelerated radiation therapy for combined treatment of locally advanced rectal cancer in a consectutive series of unselected patients.
although preoperative RT (Radiation Therapy) is becoming the preferred approach for combined treatment of locally advanced rectal adenocarcinoma, no regimen can be now considered as a standard. Since the toxicity of preoperative RT isn't yet completely known, and the advantages of preoperative RT could be counterbalanced by increased postoperative morbidity and mortality, a monocentre series of preoperative bifractionated accelerated RT was retrospectively reviewed to clarify toxicity and outcomes after a prolonged follow up. patients were screened following these eligibility criteria: histology-proven adenocarcinoma of the rectum; distal tumour extent at 12 cm or less from the anal verge; clinical stage T3-4/anyN, or anyT/N1-2; ECOG Performance Status 0-2. A total dose of 41.6 Gy (26 twice daily fractions of 1.6 Gy) was delivered. Surgery was carried out 17 +/- 2 days after RT completion, adopting the total mesorectal excision technique. 24 men and 23 women were enrolled; median age was 55 years (r.: 39-77). Twenty-eight patients were stage II and 19 stage III. 9 patients suffered from a recurrent tumour. 2 patients experienced a severe grade 4 gastrointestinal toxicity (a colo-vaginal fistula and an intestinal obstruction, both successfully treated). Operative mortality was nil; postoperative early complications occurred in 13 cases; mean length of hospital stay was 15 days. After a mean follow up of 44 months (r.: 18-84) 8 patients had deceased for recurrent disease, 15 were alive with a disease progression (2 pelvic recurrences and 13 pure distant deposits) and 24 were alive, without disease. The 5-year actuarial overall survival was 74.2%, the disease-free survival 62.9% and the regional control rate 84.7%. Long-term complications included 1 case of radiation enteritis requiring surgery, 2 cases of anastomotic stricture and 3 cases of bladder incontinence. bifractionated accelerated RT administered in the preoperative setting to patients bearing locally advanced rectal cancer is reliable and safe, as its immediate and late toxicity (mainly infectious) is acceptably low and long-term survivals are achievable. These findings support the increasing use of preoperative RT for treatment of this malignancy in experienced centres. Ongoing multicentric trials are expected to address still unsolved issues, including the benefit of CT adjunct to preoperative RT.


Donor corneoscleral rim contamination by gentamicin-resistant organisms.
Gentamicin is the most widely used antibiotic in the decontamination of donor cornea for penetrating keratoplasty. However, the incidence of resistance to gentamicin is on the rise. Bacterial isolates from 178 donor corneal rims were studied for gentamicin sensitivity. The overall rate of gentamicin resistance was 63.4%. At 86.2% the Pseudomonas. species had the highest rate of resistance, followed by Streptococci at 84.6%. The high rate of gentamicin resistance encountered by us and others suggest that either addition of a second antibiotic to corneal storage media or replacement of gentamicin by an antibiotic with a broader spectrum of activity may help reduce the risk of endophthalmitis following penetrating keratoplasty.


Atorvastatin treatment does not affect gonadal and adrenal hormones in type 2 diabetes patients with mild to moderate hypercholesterolemia.
Atorvastatin, a second generation synthetic 3-hydroxy 3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitor used in the treatment of hypercholesterolemia, reduces both intracellular cholesterol synthesis and serum cholesterol levels, and this could have a potential negative impact on gonadal and adrenal steroidogenesis. Hypercholesterolemia in type 2 diabetes, even when mild, must be treated in an aggressive way, due to the more strict therapeutic goals than in the non diabetic population. Since the wide use of 3-hydroxy 3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitor (statins) in type 2 diabetes, the main aim of our study was to evaluate the effects of "therapeutic" doses of atorvastatin on gonadal and adrenal hormones in 24 type 2 diabetic patients (16 males and 8 postmenopausal females), with mild to moderate hypercholesterolemia (LDL-cholesterol = 150.1 +/- 32.0 and 189.9 +/- 32.9 mg/dl, respectively) studied before and after a 3 months treatment with atorvastatin (20 mg/day). In all patients, lipids and serum cortisol, dehydroepiandrosterone sulphate (DHEA-S), androstendione and sex hormone binding globulin (SHBG) were measured, with the addition, only in males, of testosterone and free testosterone index. After atorvastatin treatment a significant decrease in total and LDL cholesterol was observed (p < 0.05), while HDL-cholesterol did not significantly change ( p = N.S.), as no significant difference was found between steroid hormones measured before and after atorvastatin either in male and females. In conclusion, our data suggest that, in type 2 diabetic patients, the use of atorvastatin has no clinically important effects on either gonadal or adrenal steroid hormones.


Beyond postprandial hyperglycaemia: metabolic factors associated with cardiovascular disease.
Type II (non-insulin-dependent) diabetes mellitus is associated with a considerably enhanced risk of cardiovascular disease morbidity and mortality. Several epidemiological studies have shown an association between the 2-h glucose value after a 75 gm glucose load (2hPG) and mortality from all causes and from cardiovascular disease. The key question is whether postprandial glucose is related causally to the adverse outcomes (risk factors) or just a marker of risk. Since insulin resistance is one of the determinants of the 2hPG, factors associated with the insulin resistance syndrome, in particular postprandial hypertriglyceridaemia, also need to be considered. Glycaemic excursions could contribute to oxidative stress, endothelial dysfunction, formation of advanced glycation end-products and prolongation of the QTc interval. However, high postprandial concentrations of triglyceride rich lipoproteins, which can be partly attributed to obesity and insulin resistance, have now been recognised to affect endothelial function, to promote atherogenesis, and to be associated with coronary artery disease. On the basis of present evidence Type II diabetic patients require good overall glycaemic control, as reflected by target values of HbA(1 c). However, postprandial hyperglycaemia should be considered as a marker of underlying metabolic abnormalities. Therefore, at present there is no evidence to support the recommendation to consider postprandial hyperglycaemia as a treatment target in itself and would thus require intervention studies showing added benefit of selectively targeting at meal-related glucose excursions in patients with an adequate HbA(1 c). Drugs aiming at improving only postprandial glucose values are not likely to lower the excess mortality associated with Type II diabetes.


SMMB: a stochastic Markov blanket framework strategy for epistasis detection in GWAS.
Large scale genome-wide association studies (GWAS) are tools of choice for discovering associations between genotypes and phenotypes. To date, many studies rely on univariate statistical tests for association between the phenotype and each assayed single nucleotide polymorphism (SNP). However, interaction between SNPs, namely epistasis, must be considered when tackling the complexity of underlying biological mechanisms. Epistasis analysis at large scale entails a prohibitive computational burden when addressing the detection of more than two interacting SNPs. In this paper, we introduce a stochastic causal graph-based method, SMMB, to analyze epistatic patterns in GWAS data. We present Stochastic Multiple Markov Blanket algorithm (SMMB), which combines both ensemble stochastic strategy inspired from random forests and Bayesian Markov blanket-based methods. We compared SMMB with three other recent algorithms using both simulated and real datasets. Our method outperforms the other compared methods for a majority of simulated cases of 2-way and 3-way epistasis patterns (especially in scenarii where minor allele frequencies of causal SNPs are low). Our approach performs similarly as two other compared methods for large real datasets, in terms of power, and runs faster. Parallel version available on https://ls2n.fr/listelogicielsequipe/DUKe/128/. Supplementary data are available at Bioinformatics online.


Hereditary breast and ovarian cancer: from genes to molecular targeted therapies.
Hereditary familial tumors constitute 10-15% of all malignancies and present opportunities for the identification of therapeutic approaches against specific germline genetic defects. Hereditary breast and ovarian cancer (HBOC) syndrome, which is linked to the pathogenic mutations of the breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes, is an important research model for personalized therapeutic approaches for specific germline mutations. HBOC is characterized by multiple cases of breast and ovarian carcinoma in association with other tumors (prostate, pancreas and stomach carcinoma) within the same family branch, a young age of onset (<36 years), bilaterality and an autosomal dominant pattern of inheritance. Counseling, evaluation of the clinical criteria for the diagnosis of HBOC, and the performance of genetic testing allow for the identification of subjects with BRCA1/2 mutations and provide crucial information for clinical and therapeutic management. The identification of a BRCA gene mutation has therapeutic implications for women with metastatic and non-metastatic breast cancer. In the therapeutic setting of BRCA+ breast cancer, treatment with poly (ADP-ribose) polymerase (PARP) inhibitors, which keep cancer cells from repairing their damaged DNA and cause cell death, is remarkable. This review summarizes the evidence demonstrating the value of BRCA1/2 status as a diagnostic and prognostic tool and as a predictive biomarker in the personalized approach to hereditary BRCA + cancers.


Reinterpreting the results of the LHC with MadAnalysis 5: uncertainties and higher-luminosity estimates.
The MadAnalysis 5 framework can be used to assess the potential of various LHC analyses for unraveling any specific new physics signal. We present an extension of the LHC reinterpretation capabilities of the programme allowing for the inclusion of theoretical and systematical uncertainties on the signal in the reinterpretation procedure. We have implemented extra methods dedicated to the extrapolation of the impact of a given analysis to higher luminosities, including various options for the treatment of the errors. As an application, we study three classes of new physics models. We first focus on a simplified model in which the Standard Model is supplemented by a gluino and a neutralino. We show that uncertainties could in particular degrade the bounds by several hundreds of GeV when considering 3000/fb of future LHC data. We next investigate another supersymmetry-inspired simplified model, in which the Standard Model is extended by a first generation squark species and a neutralino. We reach similar conclusions. Finally, we study a class of s-channel dark matter setups and compare the expectation for two types of scenarios differing in the details of the implementation of the mediation between the dark and Standard Model sectors.


Comparison of direct wet mount and trichrome staining techniques for detecting Entamoeba species trophozoites in stools.
Simulated freshly passed stools containing motile Entamoeba moshkovskii trophozoites were examined by direct wet mount and permanent (Trichrome) staining techniques. The percentage of detection by direct mount was 4.8%. The percentage of detection of the trophozoites by direct mount plus permanent stain was 58.5%. Laboratorians should be cautioned not to rely solely on the direct wet mount for detection or identification of protozoan trophozoites.


Development of FE modeling for hybrid greenhouse dryer for potato chips drying.
In this communication, a combination of heat and mass transfer model was developed using finite element (FE) model to explain the drying performance of the hybrid greenhouse dryer for potato chips. The hybrid greenhouse dryer is integrated with a single-pass solar air heater (SAH). A partial differential equation for a combined set of heat and mass transfer was numerically solved by the FE method. In order to see the spatial moisture distribution within the potato sample, a 3-dimensional FE model was created, and moisture removal takes place from the surface during drying of the products. Lagrange triangle FEs of extremely small size and second-order geometry shape were employed for meshing the geometry of model. Time-dependent study was express the fluctuation in time interval of 0-5 h. The developed model showed the maximum crop and ground temperature are 67.1 and 79.1°C, respectively. Moisture ratio in dry basis is reduced from 1 to 0.005 in 03 h and remains constant at 0.005. Thus, average moisture ratio in dry basis was found as 0.18902. Drying efficiency for the hybrid greenhouse dryer found to be 20.52%, whereas thermal efficiency for SAH was found 54.53%. Relative humidity inside the drying chamber found to be 26.50% in hybrid greenhouse dryer. The predicted versus the experimental results observed that hybrid greenhouse dryer having moderate inside temperature is suitable for crop drying as well as ith sustaining the environmental balance, hybrid greenhouse proves to be most effective.


The archipelago ubiquitin ligase subunit acts in target tissue to restrict tracheal terminal cell branching and hypoxic-induced gene expression.
The Drosophila melanogaster gene archipelago (ago) encodes the F-box/WD-repeat protein substrate specificity factor for an SCF (Skp/Cullin/F-box)-type polyubiquitin ligase that inhibits tumor-like growth by targeting proteins for degradation by the proteasome. The Ago protein is expressed widely in the fly embryo and larva and promotes degradation of pro-proliferative proteins in mitotically active cells. However the requirement for Ago in post-mitotic developmental processes remains largely unexplored. Here we show that Ago is an antagonist of the physiologic response to low oxygen (hypoxia). Reducing Ago activity in larval muscle cells elicits enhanced branching of nearby tracheal terminal cells in normoxia. This tracheogenic phenotype shows a genetic dependence on sima, which encodes the HIF-1α subunit of the hypoxia-inducible transcription factor dHIF and its target the FGF ligand branchless (bnl), and is enhanced by depletion of the Drosophila Von Hippel Lindau (dVHL) factor, which is a subunit of an oxygen-dependent ubiquitin ligase that degrades Sima/HIF-1α protein in metazoan cells. Genetic reduction of ago results in constitutive expression of some hypoxia-inducible genes in normoxia, increases the sensitivity of others to mild hypoxic stimulus, and enhances the ability of adult flies to recover from hypoxic stupor. As a molecular correlate to these genetic data, we find that Ago physically associates with Sima and restricts Sima levels in vivo. Collectively, these findings identify Ago as a required element of a circuit that suppresses the tracheogenic activity of larval muscle cells by antagonizing the Sima-mediated transcriptional response to hypoxia.


Improvement of beamline 4B9A and results of an X-ray diffraction experiment.
4B9A is a focusing and monochromatic photon beam at the BSRF, which was constructed in 1990. During the second phase of the BSRF program, the surface of the cylindrical mirror has been coated with Pt, covering the original Ni, and the monochromator has been upgraded. The maximum photon energy extends to 11 keV and the intensity has increased about tenfold with respect to the previous intensity at 6 keV. Synchrotron X-ray diffraction patterns for the Hg-1223 (HgBa(2)Ca(2)Cu(3)O(8+delta)) superconducting bulk and thin film have been measured at 1.54014 A. Results indicate that the bulk and film can be indexed as possessing tetragonal symmetry; lattice parameters a = 3.856 A and c = 15.851 A for the bulk Hg-1223 compound, and a = 3.8517 A and c = 15.8511 A for the film. Their structures are similar.


Pars plana capsulectomy and vitrectomy for posterior capsular opacification in pseudophakic children.
To evaluate the safety and efficacy of pars plana capsulectomy and vitrectomy for posterior capsular opacification (PCO) in pseudophakic children. Pars plana capsulectomy and vitrectomy was performed for PCO in 63 pseudophakic eyes of 57 children with an infusion through sutureless clear cornea. The patients' ages ranged from 3 to 12 years (mean: 5.8 +/- 1.9 years). Surgical technique, intraoperative and postoperative complications, visual acuity, intraocular pressure (IOP), and corneal endothelial cell density were recorded. The surgical procedure was performed uneventfully in all patients. The mean follow-up was 2.4 +/- 1.4 years (range: 6 months to 5.2 years). During the follow-up period, no incision leakage or other complications were noted and no eye developed recurrent PCO. All eyes had an improvement of visual acuity. Mean postoperative IOP was 13.8 +/- 2.6 mm Hg (range: 8 to 19 mm Hg). Mean overall endothelial cell loss was 3.4%. Pars plana capsulectomy and vitrectomy with an infusion through sutureless clear cornea appears to be a safe and effective approach for thick PCO in pseudophakic children.


Prognostic Value of Serum Free Light Chain in Multiple Myeloma.
The measurement of serum free light chain (sFLC) has been shown to be valuable in screening for the presence of plasma cell dyscrasia as well as for baseline prognosis in newly diagnosed patients. The aim of the present work was to study the prognostic value of sFLC in multiple myeloma in relation to other serum biomarkers, response to therapy and survival. Forty five newly diagnosed patients with MM were included in the study. Patients were divided into responders and non-responders groups according to response to therapy. sFLC and serum Amyloid A (SAA) were measured by immunonephelometry. The non-responders group showed a statistically significant higher kappa/lambda or lambda/kappa ratio and higher β2 microglobulin level, but lower albumin level at presentation, as compared to the responders group (P < 0.001). However, no statistically significant difference was detected between the two groups regarding SA A or calcium levels. Comparison between sFLC ratio obtained before and after therapy revealed significant decrease after treatment in the responders group (P = 0.05). Survival was significantly inferior in patients with an FLC ratio of ≥ 2.6 or ≤ 0.56 compared with those with an FLC ratio that was between 0.56 and 2.6 (P = 0.002).


Multiphoton microscopy for label-free identification of intramural metastasis in human esophageal squamous cell carcinoma.
For complete removal of cancerous tissue in esophageal squamous cell carcinoma (ESCC), intramural metastasis (IM) should be identified preoperatively or intraoperatively. Here, multiphoton microscopy (MPM) was introduced for label-free identification of IM in the esophageal wall, by a combination of two-photon excited fluorescence (TPEF), second harmonic generation (SHG) imaging, and spectral analysis. Three-dimensional (3D) imaging of the IM region was also performed. Quantitative parameters, including 3D fiber orientation, were measured by 3D-weighted orientation vector summation. Overall, MPM showed the potential to identify IM. With the development of the advanced MPM endoscope, clinical identification of IM by MPM will be possible.


Re-expansion pulmonary oedema following removal of intrathoracic haematoma.
Acute ipsilateral pulmonary oedema is a well documented complication of the treatment of lung collapse secondary to pneumothorax, pleural effusion and atelectasis. We present a case of bilateral re-expansion pulmonary oedema following removal of an intrathoracic haematoma. High protein concentration of the oedema fluid suggests increased pulmonary vascular permeability as a cause of this pulmonary oedema.


Polo-like kinase 2-dependent phosphorylation of NPM/B23 on serine 4 triggers centriole duplication.
Duplication of the centrosome is well controlled during faithful cell division while deregulation of this process leads to supernumary centrosomes, chromosome missegregation and aneuploidy, a hallmark of many cancer cells. We previously reported that Polo-like kinase 2 (Plk2) is activated near the G1/S phase transition, and regulates the reproduction of centrosomes. In search for Plk2 interacting proteins we have identified NPM/B23 (Nucleophosmin) as a novel Plk2 binding partner. We find that Plk2 and NPM/B23 interact in vitro in a Polo-box dependent manner. An association between both proteins was also observed in vivo. Moreover, we show that Plk2 phosphorylates NPM/B23 on serine 4 in vivo in S-phase. Notably, expression of a non-phosphorylatable NPM/B23 S4A mutant interferes with centriole reduplication in S-phase arrested cells and leads to a dilution of centriole numbers in unperturbed U2OS cells. The corresponding phospho-mimicking mutants have the opposite effect and their expression leads to the accumulation of centrioles. These findings suggest that NPM/B23 is a direct target of Plk2 in the regulation of centriole duplication and that phosphorylation on serine 4 can trigger this process.


Baseline quality of life and anxiety in solid organ transplant recipients: a pilot study.
Solid organ transplant recipients on high doses of immunosuppression are at increased risk for the development of nonmelanoma skin cancer (NMSC). The objective was to assess the possible factors impacting quality of life (QOL) in solid organ transplant recipients. Patients were seen in a dermatology clinic integrated within the transplant center at a university-based hospital. One anxiety questionnaire and three QOL questionnaires were administered to each patient. A regression model was used to determine possible predictors of anxiety and lower QOL. The baseline scores on the QOL instruments and anxiety questionnaire indicate poor organ-specific and general QOL as well as high levels of anxiety. Time since transplant was predictive of lower QOL as measured by Skindex-16 (p<.01). While not significant, number of NMSCs correlated with higher anxiety as measured by the STAI (p=.055). While transplant patients enjoy longer survival, the quality of the extended life has room for improvement. Future studies will determine how QOL changes over time as these patients develop more numerous and aggressive skin cancers. Intervention with regular screening may not only lessen morbidity associated with skin cancer but may improve overall QOL in the posttransplant period.


The role of bovine high-molecular-weight (HMW) kininogen in contact-mediated activation of bovine factor XII: interaction of HMW kininogen with kaolin and plasma prekallikrein.
Previous studies from our laboratories (Sugo et al. (1980) Biochemistry 19, 3215-3220) have shown that bovine high-molecular-weight (HMW) kininogen remarkably accelerates the kaolin-mediated activation of Factor XII in the presence of prekallikrein, and that both fragment 1.2 and the light chain regions located in the COOH terminal half of the kininogen molecule are essential for the activation. In the present study, we demonstrate that the accelerating effect of HMW kininogen is mediated through its adsorption on the kaolin surface through the fragment 1.2 region and its complex formation with prekallikrein through the light chain region. The evidence is as follows: 1. HMW kininogen radio-labeled with 125I was adsorbed on kaolin and the adsorption was inhibited by the prior treatment of kaolin with fragment 1.2, fragment 1.2-light chain, kinin-free protein or HMW kininogen, but not with kinin- and fragment 1.2-free protein, light chain or low molecular-weight (LMW) kininogen. 2. The complex formation of HMW kininogen with prekallikrein in bovine plasma or in the purified system was examined by gel-filtration on a column of Sephacryl S-200 In bovine plasma, prekallikrein was eluted in the same fraction as HMW kininogen, showing an apparent molecular weight of 250,000, whereas purified prekallikrein was eluted in the fraction corresponding to an apparent molecular weight of 100,000. When purified prekallikrein was mixed with purified HMW kininogen in a mol ratio of 1 to 2, all prekallikrein was found to be associated with HMW kininogen. Furthermore, purified prekallikrein mixed with kininogen derivatives, such as kinin- and fragment 1.2-free protein, fragment 1.2-light chain or light chain, was eluted in the higher molecular weight fraction. HMW kininogen did not form a complex with prekallikrein. Using the same technique, it was shown that kinin- and fragment 1.2-free protein forms a complex not only with prekallikrein but also with kallikrein.


Seasonal variation of admission severity and outcomes in ischemic stroke - a consecutive hospital-based stroke registry.
Different morbidities and mortalities of ischemic stroke may occur among seasons. For detecting the seasonal variations of severity after stroke onset and prognosis, we employed a retrospective analysis on a prospective regional hospital-based stroke registry and included a total of 1039 consecutive patients with onset date from January 2014 to December 2015. Patients were divided into four groups according to the onset seasons. Baseline characteristics, stroke subtypes, admission National Institute of Health Stroke Scale (NIHSS) score and modified Rankin Scale (mRS) score in 90 d were recorded and compared. Ordinal logistic regression was used to evaluate the association of seasons and severity or outcomes. Higher proportion of cardiac embolisms appeared in spring and winter (p < 0.001). The median admission NIHSS score was 5 in spring, 3 in summer, 4 in fall and 4 in winter (p = 0.036). After 90 d from onset, 40.5% of patients in spring suffered poor outcome (mRS 3-6), while 24.6% in summer, 33.9% in fall and 40.1% in winter (p < 0.001). After adjusted for age, sex, stroke subtypes and other covariates, patients in spring and winter had 1.76 times (95%CI 1.14-2.70, p = 0.010) and 1.53 times (95%CI 1.08-2.18, p = 0.017) the risk of suffering higher severity category than patients in summer, respectively. Compared with summer group, risk of worse outcomes at 90 d increased to 2.30 times in spring (95%CI 1.53-3.45, p < 0.001), 1.57 times in fall (95%CI 1.14-2.16, p = 0.006) and 2.09 times in winter (95%CI 1.50-2.91, p < 0.001), respectively. In conclusion, onset seasons were associated with severity and outcomes in ischemic stroke, and patients admitted in spring and winter had more severity and worse outcomes than patients in summer.


Taking Aim at the Cognitive Side of Learning in Sensorimotor Adaptation Tasks.
Sensorimotor adaptation tasks have been used to characterize processes responsible for calibrating the mapping between desired outcomes and motor commands. Research has focused on how this form of error-based learning takes place in an implicit and automatic manner. However, recent work has revealed the operation of multiple learning processes, even in this simple form of learning. This review focuses on the contribution of cognitive strategies and heuristics to sensorimotor learning, and how these processes enable humans to rapidly explore and evaluate novel solutions to enable flexible, goal-oriented behavior. This new work points to limitations in current computational models, and how these must be updated to describe the conjoint impact of multiple processes in sensorimotor learning.


Highly excited and exotic meson spectrum from dynamical lattice QCD.
Using a new quark-field construction algorithm and a large variational basis of operators, we extract a highly excited isovector meson spectrum on dynamical anisotropic lattices. We show how carefully constructed operators can be used to reliably identify the continuum spin of extracted states, overcoming the reduced cubic symmetry of the lattice. Using this method we extract, with confidence, excited states, states with exotic quantum numbers (0+-, 1-+, and 2+-), and states of high spin, including, for the first time in lattice QCD, spin-four states.


Calysolins V-IX, resin glycosides from Calystegia soldanella and their antiviral activity toward herpes.
Five new resin glycosides having macrolactone structures (jalapins), named calysolins V-IX (1-5), were isolated from the leaves, stems, and roots of Calystegia soldanella ROEM. et SCHULT. (Convolvulaceae). Their structures were determined on the basis of spectroscopic data as well as chemical evidence. The isolated compounds could be classified into two macrolactone types-one having a 22-membered ring (1-4) and the other with a 27-membered ring (5). The sugar moieties of 1-5 were found to exist in partially acylated forms comprising 2S-methylbutyric acid and tiglic acid. Compounds 4 and 5 are the first representatives of the calysolic acid C as the component glycosidic acid. Additionally, the antiviral activity of 1-5, together with calysolins I-IV and soldanelline B, which are previously isolated jalapins from this plant, toward herpes simplex virus type 1 was evaluated. All the compounds showed antiviral activity.


[The clinical characteristics analysis of Escherichia coli bloodstream infection].
To explore the clinical features of Escherichia coli bloodstream infection. The clinical data of underlying diseases, antimicrobial susceptibility, temperature at blood sampling, results of routine blood tests, venous catheterization, therapy and prognosis of Escherichia coli bloodstream infection in the First Affiliated Hospital of Soochow University from January 2007 to December 2014 were analyzed retrospectively. The pathogens were routinely isolated and identified. Susceptibilities against antimicrobial agents were determined by Kirby-Bauer methods. All patients had at least one underlying disease. Most of the basic diseases were hematological malignancies, malignant solid tumors, pneumonia and so on. Body temperature was normal in 40 patients (6.4%), fever in 587 patients (93.5%) and low temperature in 1 patient. There were 252 patients with leukopenia (40.1%), 237 patients with granulocytopenia (37.7%) and 216 patients with agranulocytosis. The resistance rate to imipenem was 3.3%, which was the lowest among the total antimicrobial susceptibilities of 628 Escherichia Coli. The extended-spectrum-β-lactamase (ESBL)-producing strains accounted for 53.8% among the total patients. The resistance rates of ESBLs-producing-Escherichia coli for the Sulfamethoxazole, Ampicillin, Gentamicin, Cefazolin, Cefuroxime, Cefotaxime, Ceftriaxone, Cefepime, Ceftazidime, Cefoperazone, Piperacillin and Ciprofloxacin were 80.2%, 100.0%, 62.4%, 99.1%, 99.1%, 98.8%, 98.2%, 48.5%, 50.6%, 95.0%, 98.2%, 79.6%, respectively, which were higher than that of non-ESBLs-producing-Escherichia coli (67.9%, 79.7%, 47.6%, 50.0%, 47.2%, 41.0%, 40.3%, 27.2%, 24.1%, 40.0%, 56.2%, 58.3%, respectively), the differences were significant statistically (χ(2)=12.33, 75.90, 13.92, 209.00, 224.94, 259.25, 256.59, 27.79, 46.19, 222.85, 165.08, 33.59, all P<0.05). One hundred and seventy eight patients received venous catheterization when blood culture were performed. All the patients received antimicrobial treatment, mainly including carbapenem antibiotics and beta-lactamase inhibitors combinations. Of which 533 patients were improved, the improvement rate was 84.9%. There are many risk factors in relation to Escherichia coli bloodstream infection. The antimicrobial resistance rate of ESBLs-producing-Escherichia coli is higher than that of none-ESBLs-producing-Escherichia coli. Individualized strategies should be based on antimicrobial sensitivity.


Human tissue transglutaminase enzyme linked immunosorbent assay outperforms both the guinea pig based tissue transglutaminase assay and anti-endomysium antibodies when screening for coeliac disease.
Anti-endomysium antibodies (EMA) and antigliadin antibodies (AGA) are widely used when screening for coeliac disease (CD), although their specificity and sensitivity are suboptimal. The guinea pig tissue transglutaminase (tTG) assay also did not prove to be superior. A newly developed enzyme linked immunosorbent assay (Celikey), based on human tTG, might however have a better performance. We therefore investigated the sensitivity and specificity of this human IgA tTG assay in 101 patients with aspecific gastrointestinal complaints and compared this to guinea pig IgA tTG, AGA and EMA. A total of 52 patients with CD were investigated and 49 patients without CD. All had a small bowel biopsy. Our results showed that human IgA tTG had a sensitivity of 96% and a specificity of 100%. Guinea pig IgA-tTG had a sensitivity of 96% and a specificity of 92%. EMA had a sensitivity of 92% and a specificity of 90%. Both IgA AGA and IgG AGA had a sensitivity of 83% whilst having a specificity of 86% and 80% respectively. both the human IgA tissue transglutaminase enzyme linked immunosorbent assay and the guinea pig IgA tissue transglutaminase assay could better identify patients with coeliac disease than IgA anti-endomysium antibodies. Although in a larger series of control patients the specificity for the human IgA tissue transglutaminase enzyme linked immunosorbent assay might fall below 100%, in our opinion this is currently the serological method of choice in identifying patients with coeliac disease in the absence of IgA deficiency.


Sciadopitysin suppresses RANKL-mediated osteoclastogenesis and prevents bone loss in LPS-treated mice.
Previous studies reported that sciadopitysin (Sc), a type of biflavonoids, protects reactive oxygen species (ROS)-mediated osteoblast dysfunction, but its role in osteoclastogenesis remains unclear. In this study, we observed that Sc dose-dependently suppressed RANKL-induced osteoclastogenesis and bone resorption. Our results indicated that Sc treatment strongly reduced RANKL-induced osteoclast-specific genes expression, including cathepsin K (CTSK), tartrate-resistant acid phosphatase (TRAP) and MMP-9. Furthermore, Sc apparently attenuated RANKL-increased expressions of c-Fos and NFATc1. Meanwhile, Sc also strikingly inhibited the activation of NF-κB without altering the phosphorylation of MAPKs (p38, JNK and ERK1/2). Finally, our study demonstrated that Sc administration could reverse the bone loss in LPS-induced mice model. This study suggests that Sc inhibits RANKL-induced osteoclastogenesis and bone loss by inhibiting NF-κB activation and reducing the expression of c-Fos and NFATc1. Therefore, Sc might be benefit for RANKL-mediated osteolytic bone diseases.


Does Hunger Contribute to Socioeconomic Gradients in Behavior?
Recent research has uncovered many examples of socioeconomic gradients in behavior and psychological states. As yet there is no theoretical consensus on the nature of the causal processes that produce these gradients. Here, I present the hunger hypothesis, namely the claim that part of the reason that people of lower socioeconomic position behave and feel as they do is that they are relatively often hungry. The hunger hypothesis applies in particular to impulsivity-hyperactivity, irritability-aggression, anxiety, and persistent narcotic use, all of which have been found to show socioeconomic gradients. I review multiple lines of evidence showing that hunger produces strong increases in these outcomes. I also review the literatures on food insufficiency and food insecurity to show that, within affluent societies, the poor experience a substantial burden of hunger, despite obtaining sufficient or excess calories on average. This leads to the distinctive prediction that hunger is an important mediator of the relationships between socioeconomic variables and the behavioral/psychological outcomes. This approach has a number of far-reaching implications, not least that some behavioral and psychological differences between social groups, though persistent under current economic arrangements, are potentially highly reversible with changes to the distribution of financial resources and food.


Detecting reactive islands using Lagrangian descriptors and the relevance to transition path sampling.
It has been known for sometime now that isomerization reactions, classically, are mediated by phase space structures called reactive islands (RI). RIs provide one possible route to correct for the nonstatistical effects in the reaction dynamics. In this work, we map out the reactive islands for the two dimensional Müller-Brown model potential and show that the reactive islands are intimately linked to the issue of rare event sampling. In particular, we establish the sensitivity of the so called committor probabilities, useful quantities in the transition path sampling technique, to the hierarchical RI structures. Mapping out the RI structure for high dimensional systems, however, is a challenging task. Here, we show that the technique of Lagrangian descriptors is able to effectively identify the RI hierarchy in the model system. Based on our results, we suggest that the Lagrangian descriptors can be useful for detecting RIs in high dimensional systems.


Characterization of metallization and amorphization for GaP under different hydrostatic environments in diamond anvil cell up to 40.0 GPa.
High-pressure phase stability of gallium phosphide was explored under different hydrostatic environments up to 40.0 GPa in a diamond anvil cell. Two irreversible phase transitions from the semiconductor to metal to an amorphous state appear at 19.8 and 31.5 GPa and as well as 22.6 and 35.3 GPa under nonhydrostatic and hydrostatic environments, respectively. Furthermore, the hysteresis effect of the high-pressure phase transition of a sphalerite-structure compound under a hydrostatic environment was disclosed. All of the obtained results can provide new insight into the underlying structural evolution and electrical transport characteristics for the semiconducting compound at different hydrostatic environments.


Gender differences in the prevalence and determinants of tobacco use among school-aged adolescents (11-17 years) in Sudan and South Sudan.
Tobacco use is one of the leading and preventable causes of global morbidities and premature mortalities. The study explores gender differences in the prevalence and determinants of tobacco use among school-aged adolescents (11-17 years) in Sudan and South Sudan. The study utilized the national Global Youth Tobacco Survey (GYTS) data collected in 2005 for Sudan (4,277 unweighted; 131,631 weighted). Univariate and bivariate analyses were conducted to examine the associations between the dependent (tobacco use status) and independent variables. Logistic regression analyses were performed to identify the key factors which influence tobacco consumption among adolescents in the 2 Sudans for ever cigarette users, current cigarette users, and users of noncigarette tobacco products. There were significant gender differences in the prevalence of ever cigarette users (21.8%; male=13.1%, female=6.5%, p<0.05) and current cigarette users (6.9%; male=4.9%, female = 1.3%, p<0.05) but not among users of noncigarette tobacco products (14.7%; male=6.8%, female=6.1%). Adolescent tobacco use was significantly associated with availability of monthly income or allowance, exposure to tobacco industry promotions, and tobacco-use behavior of familial relations. Knowledge about the harmful effects of secondhand smoke was related with decreased likelihood of tobacco use. School programs that focus on health messages alone may not work for the adolescent population. Legislations that ban all types of tobacco advertisements, promotions, and sponsorships among adolescents are needed in the 2 countries.


A small interfering ABCE1-targeting RNA inhibits the proliferation and invasiveness of small cell lung cancer.
Small cell lung cancer (SCLC) is a highly aggressive lung neoplasm. To study the pathogenesis of SCLC, we investigated roles of ABCE1, a member of the ATP-binding cassette (ABC) superfamily, in the development of small cell lung cancer. RNA interference was used to knock down ABCE1 expression in human small cell lung cancer cell lines (NCI-H446). Then we examined the effects of ABCE1 knockdown in cancer cells, including proliferation, invasiveness, apoptosis, and gene expression. We found that ABCE1 could be efficiently knocked down by siRNA, and the ABCE1 silence inhibited the proliferation, invasiveness of small cell lung cancer cell lines NCI-H446. In conclusion, our results suggest that ABCE1 play an important role in the pathogenesis of human small cell lung cancer cell. ABCE1 may be used as a potential target of gene therapy for small cell lung cancer in future.


Distribution of Seven N-Nitrosamines in Food.
N-nitrosamines, which are classified as carcinogens by IARC and US EPA, can be easily found in various foods. They are reaction products between nitrogen oxide and secondary amines, but can also be generated during fermentation. Ever since the 1960s, when nitrite, used as a preservative in processed meats, was suspected to generate N-nitrosamines, the usage of the food additive has been debated. However, the benefit of nitrite in food supply could not be ignored and the risk-benefit analysis has become a key issue in the use of the additive. For a risk analysis, an accurate estimation of the hazardous material is necessary; therefore, analytical methods for nitrosamines have continuously evolved from the 1950s. Solid supported liquid-liquid extraction and solid phase extractions have replaced the distillation for the clean-up steps, and tandem mass spectrometry is employed for higher selectivity and sensitivity. In the present study, for a better estimation of N-nitrosamine intake, the total diet study samples were prepared for the N-nitrosamines analysis. In order to obtain the most sensitive results, a partial preparation procedure was developed and modified for different food matrices. Among seven N-nitrosamines (N-nitrosodimethylamine, N-nitrosomethylethylamine, N-nitrosodiethylamine, N-nitrosodibutylamine, N-nitrosopiperidine, N-nitrosopyrrolidine, and N-nitrosomorpholine) analyzed in the present study, N-nitrosodiethylamine has shown the highest detection rate in agricultural foods, while N-nitrosodimethylamine has appeared most frequently in livestock and fishery food products. The concentration of N-nitrosodimethylamine was the highest in seasoning.


Diagnostic challenges with intraoral myeloid sarcoma: report of two cases & review of world literature.
Myeloid sarcomas (MS) are rare extramedullary tumors composed of blasts of myeloid lineage that either precede, follow or present concomitantly with acute myeloid leukaemia (AML) or myeloproliferative neoplasms. The diagnosis of MS is especially challenging in patients without an antecedent history of leukemia. We present 2 cases of intraoral MS that presented as de novo lesions. A detailed review of cases of intraoral MS that either preceded or presented along with leukemia has been done with emphasis on diagnostic criteria used. Two male patients aged 28 and 5 years presented with MS with one patient presenting with concomitant AML. A combination of morphological and immunohistochemical methods was used for diagnosis. A thorough review of world literature revealed 44 cases of intraoral MS that presented as de novo lesions. Intraoral MS is a rare tumor with poor prognosis. It may be diagnostically challenging due to its protean clinical manifestations and histological overlap with other tumors.


An unusual cause of suicidal ideations.
While the differential for suicidal ideations is broad, it is known that pathologic brain issues are a cause. Here, a case is presented of a gentleman who had an unusual growth into his frontal lobe leading to the suicidal ideations. The fact that he is chronically immunosuppressed likely led to this unique situation.


Endovascular treatment of distal medium vessel occlusions using microcatheter aspiration thrombectomy.
Recent studies suggest that endovascular treatment (EVT) in distal medium vessel occlusion (DMVO) stroke is beneficial even beyond middle cerebral artery (MCA) - M2 segment. However, data about aspiration thrombectomy of DMVOs is scarce since common state-of-the-art aspiration catheters are usually too large for small distal intracranial arteries. We report our initial experiences using the microcatheter aspiration thrombectomy (MAT) technique as frontline therapy for acute DMVOs in the MCA territory. We retrospectively analyzed all acute ischemic stroke (AIS) patients that underwent MAT of a primary or secondary DMVO in the M3 or M4 segment between January 2019 and October 2021. Recanalization rates, procedural safety and outcome data were recorded. MAT of acute M3 and M4 occlusions was performed in 19 patients with AIS. Six had isolated DMVO strokes, 13 had secondary DMVOs during EVT of a proximal large vessel occlusion. Successful revascularization to DMVO TICI ≥ 2b was achieved in 58% (11/19) with a single pass in all of them. The median National Institutes of Health Strokes Scale (NIHSS) score at admission and discharge was 12 and 3, respectively. 68% (13/19) of the patients had a good clinical outcome at discharge (modified Rankin Scale 0-2). No symptomatic complications related to MAT occurred. MAT of DMVOs in the MCA territory is technically feasible and effective. Compared to stent retriever-based thrombectomy in DMVOs the hemorrhagic complication rate appears notably lower. Further studies are needed to validate the benefit of mechanical thrombectomy in the distal intracranial vasculature.


Chicken granulosa cell proliferation and progesterone production in culture: effects of EGF and theca secretions.
Paracrine/autocrine factors like epidermal growth factor (EGF) and transforming growth factor (TGF alpha) produced in the mammalian ovary modulate ovarian functions such as cell proliferation, differentiation, and steroidogenesis. To study similar activities in the avian ovary, we have developed a culture system for chicken granulosa cells using either serum containing or serum-free media. In the defined medium, granulosa cells for the F1, F2, and F3 follicles of the chicken ovary proliferated as indicated by enhanced levels of DNA, synthesised progesterone in similar amounts to those observed in acute experiments, and responded to luteinizing hormone (LH) during and after the culture period. The morphology of the cells and profile of growth in both media (although better in serum than in serum-free medium) are similar to those reported for mammalian cells. EGF stimulated granulosa cell proliferation over 72 hr in culture while inhibiting basal and LH-stimulated progesterone production; these effects were greatest in the less mature cells taken from the F3 follicles. Theca-conditioned medium (TCM) from chicken ovarian theca cell cultures mimicked the effects of EGF when cultured with granulosa cells. Taken together, these results suggest that EGF/TGF alpha-like peptides have a role in avian ovarian function. Moreover, the effects observed for TCM suggest that these peptides may be present in the theca layer with a paracrine function in the adjacent granulosa.