Yiqi Yangjing recipe stimulates apoptosis while suppressing the energy metabolism via under-expression of PFKFB3 in A549 cells.
Lung cancer is a malignant tumor associated with high morbidity and mortality. Yiqi Yangjing recipe (YYR) is a formula of traditional Chinese medicine (TCM) that is commonly used for the treatment of lung cancer with good clinical efficacy. The specific anti-cancer mechanism of YYR is still unknown. We need to embark on a more in-depth pharmacological study of YYR to determine the complex compound ingredients, which could be promoted in clinical practice to achieve efficacy in prolonging recurrent metastasis of lung cancer. The cytotoxic effects of YYR on A549 cells were evaluated by Cell Counting Kit-8 (CCK-8) assay. The PFKFB3-under-expressed and overexpressed A549 cell lines were constructed via PFK15 treatment and transfection, respectively. The effects of YYR on PFKFB3 messenger RNA (mRNA) and protein expression were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. The pro-apoptotic and anti-glycolytic abilities of YYR were measured using flow cytometry assay and hippocampal XF96 extracellular flux analyzer. An in vivo tumorigenicity assay was performed on nude mice to confirm the anti-cancer effects of YYR. YYR has a noticeable cytotoxic activity on A549 cells, with the treatment with both YYR and PFK15 significantly inducing apoptosis. YYR and PFK15 treatment reduced the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in A549 cells. Similar to PFK15, YYR can down-regulate PFKFB3 expression, and PFKFB3 overexpression suppressed the apoptosis, which was reversed by YYR. Animal experiments confirmed that YYR was able to inhibit tumor growth, induce tumor cell apoptosis, and down-regulate PFKFB3 in tumor tissues. This study demonstrated that YYR promoted lung cancer cell apoptosis and inhibited energy metabolism by targeting PFKFB3. Furthermore, we believe that YYR may be a suitable supplement or alternative drug for lung cancer treatment.


The impact of hospital-based post-discharge pharmacist medication review on patient clinical outcomes: A systematic review.
Clinical pharmacists have been shown to identify and resolve medication related problems post-discharge, however the impact on patient clinical outcomes is unclear. To undertake a systematic review to identify, critically appraise and present the evidence on post-discharge hospital clinics that provide clinical pharmacist medication review; report the patient clinical outcomes measured; and describe the activities of the clinical pharmacist. Published studies evaluating a patient clinical outcome following a post-discharge hospital clinic pharmacy service were included. All studies needed a comparative design (intervention vs control or comparator). Pubmed, Embase, CINAHL, PsycnINFO, Web of Science, IPA and APAIS-Health databases were searched to identify studies. The type of clinic and the clinical pharmacist activities were linked to patient clinical outcomes. Fifty-seven studies were included in the final analysis, 14 randomised controlled trials and 43 non-randomised studies. Three key clinic types were identified: post-discharge pharmacist review alone, inpatient care plus post-discharge review and post-discharge collaborative clinics. The three main outcome metrics identified were hospital readmission and/or representation, adverse events and improved disease state metrics. There was often a mix of these outcomes reported as primary and secondary outcomes. High heterogeneity of interventions and clinical pharmacist activities reported meant it was difficult to link clinical pharmacist activities with the outcomes reported. A post-discharge clinic pharmacist may improve patient clinical outcomes such as hospital readmission and representation rates. Future research needs to provide a clearer description of the clinical pharmacist activities provided in both arms of comparative studies.


[A statistical genetic analysis of the calving traits of cows of a Ukrainian beef breed].
The results of investigation of calving features in 371 cows of Ukrainian beef cattle were summarized. Variance and correlation analyses of factors affecting calving in cows were used. Breeds, pedigrees of parents and progeny, assessment of complicated and lethal calvings, duration of pregnancies and mass of newborns were registered. The influence of selection type on the normal calving was shown.


A photodetoxification mechanism of the cyanobacterial hepatotoxin microcystin-LR by ultraviolet irradiation.
When microcystin-LR was exposed to UV, three major nontoxic compounds were formed. These compounds were identified as [4(E),6(Z)-Adda5]- and [4(Z),6(E)-Adda5]microcystin-LR, which are geometrical isomers of the Adda [3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-4(E),6(E)-decadienoic acid] moiety of microcystin-LR, and a novel compound, tricyclo-Adda [(2S,3S,1'R,3'S,4'S,5'R,6'R,7'R)-3-amino-5-(4',6'-dimethyl-3'-methoxy tricyclo[220.127.116.11(1',5')]undeca-8',10'-dien-6'-yl)-2-methy l-4(E)-pentenoic acid]-containing microcystin-LR ([tricyclo-Adda5]microcystin-LR), which was formed by [2 + 2] addition between the benzene ring and the double bond at position 6-7 of the Adda moiety of the microcystin. The geometrical isomers were formed reversibly, and their equilibrium constants were almost the same. [Tricyclo-Adda5]microcystin-LR was also formed reversibly and was decomposed under UV light. These results suggest that the breakdown of microcystin-LR by UV irradiation proceeds via [tricyclo-Adda5]microcystin-LR.


Aggressive gastric peripheral T-cell lymphoma of CD8+ type associated with lymphomatous meningitis.
Most gastric lymphomas are of B-cell origin, and many are either low-grade or high-grade B-cell lymphomas of mucosa-associated lymphoid tissue type. Gastric T-cell lymphomas are very rare, usually of CD4+ type, and few have had genotypic studies. We report the case of a gastric peripheral T-cell lymphoma of CD8+ type. Genotypic studies demonstrated partial deletion with rearrangement of the T-cell receptor beta-chain gene. Lymphomatous meningitis developed, and the patient died after only 2 months despite chemotherapy. The case is compared with the other gastric T-cell lymphomas that have been reported.


Investigation of the predictors of temporomandibular disorders in engineers across different variables: sociodemographic characteristics, neck pain and neck awareness.
This study aimed to investigate the predictors of temporomandibular disorders (TMD) in desk-bound engineers. The Fonseca Anamnestic Index (FAI), The Visual Analogue Scale (VAS), The Neck Pain and Disability Scale (NPDS), Neck Bournemouth Questionnaire (NBQ) and The Fremantle Neck Awareness Questionnaire-Turkish (FreNAQ-T) were used for TMD severity, pain, disability, neck awareness. The study was conducted with 208 desk-bound engineers. Mild-to-severe TMD was detected in 78.9% of the subjects. Intensity of pain at rest and during activity was higher in female engineers compared to male engineers (p = 0.002 and <0.01, respectively) and mean FAI, NBQ, NPDS and FreNAQ-T scores were also higher than that of male engineers (p = 0.005, 0.005, 0.006 and 0.016, respectively). FAI, VAS, NPDS, NBQ and FreNAQ-T were found to be correlated with each other (p < 0.05). A statistically significant contribution to the regression model was observed for the variables gender, daily duration of computer use, neck pain at rest, and NBQ (p = 0.043, p = 0.043, p = 0.031 and p = 0.003, respectively). NBQ was identified as the most influential variable in this model, followed by neck pain at rest. Temporomandibular disorders are common among desk-bound engineers and are associated with neck pain, disability, and neck awareness. For this reason, it is important to take preventive and protective ergonomic approaches at the personal and institutional levels in desk-bound engineers.


Response of aldosterone and blood pressure to angiotensin II infusion in anephric man. Effect of sodium deprivation.
Angiotensin II, infused intravenously, increased plasma aldosterone concentration in two of six anephric subjects taking their usual dietary quantities of sodium. After 3 days of dietary sodium restriction and weight-reducing hemodialysis, the aldosterone response to infused angiotensin II in the two previously reactive subjects was enhanced, while the four previously unreactive subjects also showed a rise in plasma aldosterone. Before and after sodium depletion the anephric subjects were less responsive than normal subjects. Even when sodium-depleted, the anephrics showed no further rise in plasma aldosterone when arterial plasma angiotensin II was increased by infusion to concentrations greater than 50-199pg/ml, in contrast to sodium-depleted normals who show progressive aldosterone responses with plasma angiotensin II concentrations up to at least 370pg/ml. Before the infusion of angiotensin II, arterial plasma renin, angiotensin II, and aldosterone were detectable in the anephrics, but were unchanged by dietary sodium restriction or weight-reducting hemodialysis. Sodium depletion caused significant falls in weight, plasma sodium, and blood pressure, but no changes in plasma potassium or cortisol. Increases in blood pressure in relation to increments of arterial plasma angiotensin II were unaffected by sodium depletion, as might be expected in the absence of a rise in endogenous angiotensin II.


Postoperative thrombotic thrombocytopenic purpura after aortofemoral bypass.
Thrombotic thrombocytopenic purpura (TTP) is uncommon in the postoperative setting, even more so after vascular surgery. We present a case of thrombocytopenia after aortofemoral bypass, which highlights the importance of a high index of suspicion for postoperative TTP to avoid life-threatening consequences.


In Utero Exposure to Bisphenol a Promotes Mammary Tumor Risk in MMTV-Erbb2 Transgenic Mice Through the Induction of ER-erbB2 Crosstalk.
Bisphenol A (BPA) is the most common environmental endocrine disrupting chemical. Studies suggest a link between perinatal BPA exposure and increased breast cancer risk, but the underlying mechanisms remain unclear. This study aims to investigate the effects of in utero BPA exposure on mammary tumorigenesis in MMTV-erbB2 transgenic mice. Pregnant mice were subcutaneously injected with BPA (0, 50, 500 ng/kg and 250 µg/kg BW) daily between gestational days 11-19. Female offspring were examined for mammary tumorigenesis, puberty onset, mammary morphogenesis, and signaling in ER and erbB2 pathways. In utero exposure to low dose BPA (500 ng/kg) induced mammary tumorigenesis, earlier puberty onset, increased terminal end buds, and prolonged estrus phase, which was accompanied by proliferative mammary morphogenesis. CD24/49f-based FACS analysis showed that in utero exposure to 500 ng/kg BPA induced expansion of luminal and basal/myoepithelial cell subpopulations at PND 35. Molecular analysis of mammary tissues at PND 70 showed that in utero exposure to low doses of BPA induced upregulation of ERα, p-ERα, cyclin D1, and c-myc, concurrent activation of erbB2, EGFR, erbB-3, Erk1/2, and Akt, and upregulation of growth factors/ligands. Our results demonstrate that in utero exposure to low dose BPA promotes mammary tumorigenesis in MMTV-erbB2 mice through induction of ER-erbB2 crosstalk and mammary epithelial reprogramming, which advance our understanding of the mechanism associated with in utero exposure to BPA-induced breast cancer risk. The studies also support using MMTV-erbB2 mouse model for relevant studies.


Rapid characterization of chemical constituents and metabolites of Qi-Jing-Sheng-Bai granule by using UHPLC-Q-TOF-MS.
Qi-Jing-Sheng-Bai granule is an effective traditional Chinese medicine formula that has been widely used for the treatment of leukopenia post radiotherapy or chemotherapy. However, its chemical constituents were still unclear, which hindered interpreting bioactive constituents and studying integrative mechanisms. In this study, we developed a three-step strategy to characterize the chemical constituents and metabolites of Qi-Jing-Sheng-Bai by using ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. As a result, a total of 143 compounds, including 56 flavonoids, 51 saponins, and 36 other compounds, of which contained six pairs of isomers, were tentatively identified and characterized via reference standards and by comparing mass spectrometry data with literature. After oral administration of 15 g/kg Qi-Jing-Sheng-Bai, a number of 42 compounds including 24 prototype compounds and 18 metabolites have been detected in the serum of rats. This work serves as the first reference for Qi-Jing-Sheng-Bai chemical components and metabolites. Moreover, it provided a rapid and valid analytical strategy for characterization of the chemical compounds and metabolites of traditional Chinese medicine formula.


Influence of activity and dietary energy on broiler performance, carcase yield and sensory quality.
1. A total of 2560 male and female Ross broilers were raised to 42 days of age in a 2 X 2 treatment factorial arrangement experiment to investigate the influence of different degrees of physical activity and dietary energy on broiler performance, abdominal fat content, carcase yield and sensory quality. 2. Vertical fans were used to force the treatment birds to walk 3 to 4 times as far as the normal activity birds: birds were fed a normal and a high energy diet (12.55 compared with 13.81 MJ ME/kg) with the same energy/protein, energy/lysine and energy/methionine + cystine ratios. 3. High activity birds had greater body weight (+4.1%), food intake (+5.1%) and ME intake (+5.1%) than normal activity birds. Birds receiving high energy diet had a lower food conversion and food intake than birds receiving normal energy diet. There were no significant differences in body weight or ME intake between birds with different diets. 4. Slaughter yields, both absolute and relative to live body weight, were affected by activity or dietary energy to varying degrees. Breast meat was increased with more activity. The absolute weight of abdominal fat was independent of activity and in males the relative weight of abdominal fat was decreased in high activity birds. 5. Different degrees of activity and dietary energy had only minor influences on broilers sensory quality.


Clinical Significance of Histone Demethylase NO66 in Invasive Colorectal Cancer.
Targeting epigenetic regulators is a promising therapeutic strategy against cancer. However, because of the broad spectrum of targets, selective inhibition of cancer-associated genes remains a major challenge. To address this issue, we focused on the oncogene-regulated histone demethylase, nucleolar protein 66 (NO66 [C14orf169/MAPJD]), which is known to work coordinately with the well-characterized oncogene, c-MYC. To investigate expression patterns and clinical significance of NO66 in colorectal cancer (CRC), we performed immunohistochemical staining in 114 CRC cases. We performed functional analysis of NO66 to evaluate its contribution to proliferation and migration ability in CRC cells in vitro. NO66 was selectively expressed in CRC tissues. Furthermore, high expression levels of NO66 were associated with cancer metastatic potential, including lymphatic duct invasion (p = 0.047), venous invasion (p = 0.033), and lymph node metastasis (p = 0.015). Multivariate analysis indicated that NO66 was an independent prognostic factor for overall survival. In vitro assays revealed that NO66 expression is closely associated with malignant potential, including proliferation, migration and anti-apoptotic activity. NO66 is an independent prognostic factor in CRC. The cancer-selective expression patterns and its involvement in metastatic phenotypes suggest that NO66 is not only a crucial biomarker but is also a promising therapeutic target in CRC.


Severe obesity is associated with increased migraine severity and frequency: A retrospective cohort study.
Migraine headaches and obesity are both prevalent disorders, resulting in a high socioeconomic burden. To better understand the relationship between obesity and migraine, the aim of this study was to investigate the association between migraine severity, metabolic syndrome and estrogen-associated variables. A retrospective analysis of adult patients with refractory migraine seen by our senior author (J.E.J.) was performed. Patient demographics and migraine characteristics, including migraine intensity, duration, and number of headaches per month were collected from medical records. Migraine headache index (MHI) was calculated by multiplying frequency, intensity and duration of headaches. Weight and height were used to calculate body mass index (BMI) and these were divided per Center for Disease Control (CDC) classifications. Univariate linear regression models were used to evaluate associations. Patients (n = 223) were predominantly female (78%) with a mean age of 44 years at presentation. Patients with a BMI higher than 40 (class 3 obesity) had a higher MHI (p = 0.01) and experienced a higher number of migraines per month (p = 0.007), compared to patients with a healthy BMI, respectively. Migraine frequency was found to be significantly higher in post-menopausal women compared to pre-menopausal women (p = 0.02). No other significant associations were found. This study found that severe obesity (BMI > 40) is associated with increased migraine severity and frequency. Post-menopausal patients are also found to have increased migraine frequency, which could be explained by the estrogen-withdrawal hypothesis. Future studies are needed to evaluate the outcomes of individuals with obesity after nerve deactivation surgery.


Targeting MYC-driven lymphoma: lessons learned and future directions.
MYC plays a central role in tumorigenesis by orchestrating cell proliferation, growth and survival, among other transformation mechanisms. In particular, MYC has often been associated with lymphomagenesis. In fact, MYC overexpressing lymphomas such as high-grade B-cell lymphoma (HGBL) and double expressor diffuse large B-cell lymphomas (DLBCL), are considered addicted to MYC. In such a context, MYC targeting therapies are of special interest, as MYC withdrawal is expected to result in tumor regression. However, whether high MYC levels are always predictive of increased sensitivity to these approaches is not clear yet. Even though no MYC inhibitor has received regulatory approval to date, substantial efforts have been made to investigate avenues to render MYC a druggable target. Here, we summarize the different classes of molecules currently under development, which mostly target MYC indirectly in aggressive B-cell lymphomas, paying special attention to subtypes with MYC/BCL2 or BCL6 translocations or overexpression.


Isolation of bovine cardiomyocytes for reprogramming studies based on nuclear transfer.
The goal of this study was to establish and validate a protocol for preparing bovine cardiomyocytes from slaughterhouse material for nuclear transfer experiments. The cardiomyocyte was selected because it is a terminally differentiated cell and strongly expresses a unique subset of genes which can be monitored during the reprogramming period. A total of 39 trials were conducted, and an optimized protocol was developed yielding individual contractile cardiomyocytes from 3-5-month-old bovine fetuses The basic protocol involves stabilization of bovine heart tissue for transportation from the slaughterhouse to the laboratory by perfusion with Custodiol. This was followed by an enzymatic dissociation with collagenase in calcium-free medium and yielded individual contractile rod-shaped cardiomyocytes. Subsequent addition of Ca2+ caused the cardiomyocytes to round up which was an essential pre-condition for drawing them into glass transfer pipettes for delivery into the perivitelline space and for efficient electrofusion with cytoplasts derived from in vitro matured bovine oocytes. The use of cardiomyocytes maintained at 37 degrees C in nuclear transfer, resulted in a significantly reduced proportion of blastocysts compared to adult fibroblasts (14.0% versus 32.7%). Storage of cardiomyocytes at 4 degrees C prior to nuclear transfer was not compatible with blastocyst development. It is expected that this system will be valuable for investigating the reprogramming of gene expression which occurs after somatic cell nuclear transfer.


Frequency-scanning interferometry for dynamic absolute distance measurement using Kalman filter.
We propose a frequency-scanning interferometry using the Kalman filtering technique for dynamic absolute distance measurement. Frequency-scanning interferometry only uses a single tunable laser driven by a triangle waveform signal for forward and backward optical frequency scanning. The absolute distance and moving speed of a target can be estimated by the present input measurement of frequency-scanning interferometry and the previously calculated state based on the Kalman filter algorithm. This method not only compensates for movement errors in conventional frequency-scanning interferometry, but also achieves high-precision and low-complexity dynamic measurements. Experimental results of dynamic measurements under static state, vibration and one-dimensional movement are presented.


Repellency of a kaolin particle film, Surround, and a mineral oil, Sunspray oil, to silverleaf whitefly (Homoptera: Aleyrodidae) on melon in the laboratory.
Surround, a kaolin-based particle film formulation, and Sunspray oil, a mineral oil, were evaluated alone or in combination in choice and no-choice laboratory assays on melon leaves for repellency to adults of the silverleaf whitefly, Bemisia argentifolii Bellows & Perring. In no-choice tests, the number of adults and eggs on leaves did not significantly differ among the three treatments and the water control when materials were applied to either the tipper or lower leaf surface. Significantly fewer adults and eggs were found on treated leaves compared with water when materials were applied to both leaf surfaces. Application of Surround did not affect the oviposition pattern, with 80.2-88.5% eggs oviposited on lower surface. However, whiteflies oviposited more eggs (53.1-63.8%) on the upper compared with the lower surface when Sunspray oil or Surround + Sunspray oil was applied on the lower leaf surface and both leaf surfaces. When whiteflies were allowed to choose among leaves treated with different materials on the same leaf surface(s), significantly fewer adults and eggs were found on treated leaves compared with water-treated leaves, and more adults and eggs were found on leaves when the materials were applied to tipper versus lower or both surfaces. Leaves treated with materials on both leaf surfaces had fewer whiteflies compared with leaves treated on the upper or lower surface. When whiteflies were allowed to choose among leaves treated with materials versus water-treated leaves in a 6:3 or an 8:1 ratio, significantly fewer adults and eggs were found on leaves treated with treatment materials compared with water, regardless of which leaf surface(s) were treated. No significant synergistic or additive effect was detected in Surround + Sunspray oil compared with either material used separately.


Health-related quality of life during the last three months of life in patients with advanced cancer.
The aim of the study was to explore the development of functioning impairments and symptom occurrence during the last months of life of advanced cancer patients. Self-reported data from 116 patients who all completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) at 3, 2 and 1 month before death were analysed. All functioning aspects deteriorated. For physical, cognitive and social function, the most marked changes occurred between 2 and 1 month before death. The proportion reporting serious difficulties with self-care activities increased from 14% to 43%. The most seriously affected activity could not be distinguished from the EORTC QLQ-C30 scores. Levels of fatigue, dyspnoea and appetite loss increased significantly. More than 50% of the patients had severe pain at all assessments, and only a minor number (8%) reported any improvement. The findings have implications for the planning of care and indicate that further research is required to improve assessment, treatment and follow-up procedures. Adequate pain treatment seems still to be a challenge. Anorexia, fatigue as well as dyspnoea are all symptoms that need further focus.


Quantitative Assessment of Response to Long-Term Treatment with Intravenous Immunoglobulin in Patients with Stiff Person Syndrome.
Stiff person syndrome (SPS) is an autoimmune condition involving antibodies against several components of the inhibitory synapse in the spinal cord, with glutamic acid decarboxylase antibodies being the predominant immune marker. SPS affects approximately 1 patient per million population per year. The effect of intravenous immunoglobulin (IVIG) has been established, but studies on the long-term efficacy of regular IVIG are limited. To review clinical details and long-term treatment response using a patient-reported questionnaire in SPS and related syndromes. Patients were identified from a tertiary neuroimmunology clinic based on classical clinical symptoms, autoimmune profiles, and neurophysiological changes (Dalakas criteria). They were followed up after treatment to assess the response to IVIG. A total of 23 patients fulfilled the selection criteria. Patients' demographic profiles and clinical presentations were akin to that reported in literature. There was significant improvement in the functional ability (assessed by the modified Rankin scale [mRS]) and quality of life (QoL) following treatment with IVIG within 4 to 10 weeks (pre-mRS vs. post-mRS, P < 0.0001; pre-QoL vs. post-QoL, P = 0.0003) and sustained after 5 years of treatment (pre-mRS vs. present mRS, P = 0.0003; pre-QoL vs. present QoL, P = 0.0002). This article describes one of the largest single-center experiences of 23 patients with SPS and related syndromes and is the first to establish the long-term efficacy of regular IVIG using a patient-reported scoring system (Birmingham Response to Immunomodulatory Therapy [BRIT]). Consistent improvement in QoL and functional scores were seen over nearly 5 years after regular use of IVIG. It is recommended to use BRIT scores to assess the initial response as well as to monitor continued improvement to immunomodulation in SPS.


Diffusing capacity for carbon monoxide correlates best with tissue volume from quantitative CT scanning analysis.
Quantitative analysis of high-resolution chest CT scan (QCT) is an established method for determining the severity and distribution of lung parenchymal destruction inpatients with emphysema. Diffusing capacity of the lung for carbon monoxide (D(LCO)) is a traditional physiologic measure of emphysema severity and is probably influenced more by destruction of the alveolar capillary bed than by membrane diffusion per se. We reasoned that D(LCO) should correlate with tissue volume from QCT. A total of 460 patients with upper-lobe-predominant emphysema were enrolled in the study. Th e mean (SD) of percent predicted values for FEV 1 , total lung capacity, and D(LCO) were 30.6% (8.0%), 129.5% (18.1%), and 6.7% (13.1%), respectively. QCT was performed using custom soft ware; the relationship between D(LCO) and various metrics from QCT were evaluated using Pearson correlation coefficients. On average, whole-body plethysmography volumes were higher by 841 mL compared with QCT-calculated total lung volume. However, there was a strong correlation between these measurements (r=0.824, P < .0001). D(LCO) correlated with total lung volume (r=0.314, P<.0001), total tissue volume (r=0.498, P<.0001), and percentage of lung with low density (-950 Hounsfield units) (r=-0.337, P<.0001). In patients with severe emphysema, D(LCO) correlates best with total tissue volume,supporting the hypothesis that pulmonary capillary blood volume is the main determinant of D(LCO) in the human lung. Th e relationships between D(LCO) and various anatomic metrics of lung parenchymal destruction from QCT inform our understanding of the relationship between structure and function of the human lung.


MyD88 plays a unique role in host defense but not arthritis development in Lyme disease.
To assess the contribution of TLR signaling in the host response to Borrelia burgdorferi, mice deficient in the common TLR adaptor protein, myeloid differentiation factor 88 (MyD88), were infected with B. burgdorferi. MyD88-deficient mice harbored extremely high levels of B. burgdorferi in tissues when compared with wild-type littermates and greater amounts of spirochetes in tissues than TLR2-deficient mice. These findings suggest that, in addition to TLR2, other MyD88-dependent pathways play a significant role in the host defense to B. burgdorferi. MyD88(-/-) mice maintained the ability to produce Abs directed against B. burgdorferi. Partial clearance of spirochetes was evident in long term infection studies and immune sera from MyD88-deficient mice were able to protect naive mice from infection with B. burgdorferi. Thus, the acquired immune response appeared to be functional in MyD88(-/-) mice, and the inability to control spirochete numbers was due to a failure of cells involved in innate defenses. Although macrophages from MyD88(-/-) mice responded poorly to Borrelia sonicate in vitro, MyD88(-/-) mice still developed an inflammatory arthritis after infection with B. burgdorferi characterized by an influx of neutrophils and mononuclear cells. The findings presented here point to a dichotomy between the recruitment of inflammatory cells to tissue and an inability of these cells to kill localized spirochetes.


Systematic Review of Molecular Targeted Therapies for Adult-Type Diffuse Glioma: An Analysis of Clinical and Laboratory Studies.
Gliomas are the most common brain tumor in adults, and molecularly targeted therapies to treat gliomas are becoming a frequent topic of investigation. The current state of molecular targeted therapy research for adult-type diffuse gliomas has yet to be characterized, particularly following the 2021 WHO guideline changes for classifying gliomas using molecular subtypes. This systematic review sought to characterize the current state of molecular target therapy research for adult-type diffuse glioma to better inform scientific progress and guide next steps in this field of study. A systematic review was conducted in accordance with PRISMA guidelines. Studies meeting inclusion criteria were queried for study design, subject (patients, human cell lines, mice, etc.), type of tumor studied, molecular target, respective molecular pathway, and details pertaining to the molecular targeted therapy-namely the modality, dose, and duration of treatment. A total of 350 studies met the inclusion criteria. A total of 52 of these were clinical studies, 190 were laboratory studies investigating existing molecular therapies, and 108 were laboratory studies investigating new molecular targets. Further, a total of 119 ongoing clinical trials are also underway, per a detailed query on clinicaltrials.gov. GBM was the predominant tumor studied in both ongoing and published clinical studies as well as in laboratory analyses. A few studies mentioned IDH-mutant astrocytomas or oligodendrogliomas. The most common molecular targets in published clinical studies and clinical trials were protein kinase pathways, followed by microenvironmental targets, immunotherapy, and cell cycle/apoptosis pathways. The most common molecular targets in laboratory studies were also protein kinase pathways; however, cell cycle/apoptosis pathways were the next most frequent target, followed by microenvironmental targets, then immunotherapy pathways, with the wnt/β-catenin pathway arising in the cohort of novel targets. In this systematic review, we examined the current evidence on molecular targeted therapy for adult-type diffuse glioma and discussed its implications for clinical practice and future research. Ultimately, published research falls broadly into three categories-clinical studies, laboratory testing of existing therapies, and laboratory identification of novel targets-and heavily centers on GBM rather than IDH-mutant astrocytoma or oligodendroglioma. Ongoing clinical trials are numerous in this area of research as well and follow a similar pattern in tumor type and targeted pathways as published clinical studies. The most common molecular targets in all study types were protein kinase pathways. Microenvironmental targets were more numerous in clinical studies, whereas cell cycle/apoptosis were more numerous in laboratory studies. Immunotherapy pathways are on the rise in all study types, and the wnt/β-catenin pathway is increasingly identified as a novel target.


Investigating the retention and time course of phonotactic constraint learning from production experience.
Adults can rapidly learn artificial phonotactic constraints such as /f/ occurs only at the beginning of syllables by producing syllables that contain those constraints. This implicit learning is then reflected in their speech errors. However, second-order constraints in which the placement of a phoneme depends on another characteristic of the syllable (e.g., if the vowel is /æ/, /f/ occurs at the beginning of syllables and /s/ occurs at the end of syllables, but if the vowel is /I/, the reverse is true) require a longer learning period. Two experiments investigated the transience of second-order learning and whether consolidation plays a role in learning phonological dependencies, with speech errors used as a measure of learning. Experiment 1 tested the durability of learning and found that learning was still present in speech errors a week later. Experiment 2 looked at whether more time in the form of a consolidation period or more experience in the form of more trials was necessary for learning to be revealed in speech errors. Both consolidation and more trials led to learning; however, consolidation provided a more substantial benefit.


Porphyromonas gingivalis infection accelerates intimal thickening in iliac arteries in a balloon-injured rabbit model.
Current epidemiologic data suggest that a localized infection (periodontitis) can disseminate into the distant tissues, and subgingival bacteria can migrate in the bloodstream, thereby contributing to independent systemic disease processes. To test this hypothesis, we investigated the effect of repeated systemic inoculations with Porphyromonas gingivalis (Pg) on intimal hyperplasia in iliac arteries in a rabbit model of balloon injury. One week after single balloon injury to the iliac artery, 30 male New Zealand rabbits were randomly assigned to intravenous inoculation with 100 microl live Pg (10(7) colony-forming units; n = 15) or vehicle (n = 15) once weekly for 4, 8, or 12 consecutive weeks. Arteries were fixed by perfusion and removed for analysis of neointimal lesion formation. We measured intimal and medial lesion areas in iliac artery cross-sections as well as the intimal/medial ratio (I/M). We also analyzed Pg 16S ribosomal DNA amplification with polymerase chain reaction, systemic proinflammatory mediators with enzyme-linked immunosorbent assay, and immunolocalization of macrophages in the balloon-injured arteries. At 12 weeks, iliac intimal hyperplasia was accelerated, and I/M was significantly increased in Pg-inoculated animals (I/M 3.961 +/- 0.536 in the Pg group versus 3.585 +/- 0.353 in the control animals; P <0.01). Pg-inoculated animals also had significant increases in macrophage infiltration at 12 weeks, C-reactive protein levels at all time points, and interleukin-6 levels at 12 weeks. Moreover, Pg ribosomal DNA was found in the injured arteries of Pg-inoculated animals, but only after 12 weeks. Long-term systemic challenge with Pg, an oral pathogen, may accelerate intimal hyperplasia in balloon-injured iliac arteries.


Efficacy of a Home Visiting Enhancement for High-Risk Families Attending Parent Management Programs: A Randomized Superiority Clinical Trial.
Antisocial behavior and adult criminality often have origins in childhood and are best addressed early in the child's life using evidence-based parenting programs. However, families with additional risk factors do not always make sufficient changes while attending such programs; these families may benefit from additional support. To evaluate the efficacy of adding a 10-session, structured home parent support (HPS) intervention to enhance outcomes for high-risk families attending the Incredible Years Parent (IYP) program. A randomized clinical superiority trial of 126 parents of children aged 3 to 7 years with conduct problems compared the IYP program plus HPS with treatment as usual of the IYP program alone. Child behavior measures were collected before and after treatment and at the 6-month follow-up. Recruitment from 19 IYP groups began February 13, 2013, and follow-up data collection was completed June 4, 2015. All data were analyzed using an intention-to-treat design with last observation carried forward. Statistical analysis took place from May 20, 2015, to March 31, 2016. Parents were randomly assigned to receive IYP program plus HPS or IYP alone. The primary outcome measure was the posttreatment change in Eyberg Child Behavior Inventory Total Problem Scale (ECBI-P) score. Secondary outcomes included maintenance of change on the ECBI-P score, ECBI Intensity Scale score, and Social Competence Scale score at the 6-month follow-up; percentage of child behavior scores in the clinical range after treatment; retention; and attendance. A total of 126 parents (112 women and 14 men; mean [SD] age, 34.7 [8.4] years) were included; 63 parents were randomly assigned to each intervention group. Analysis of variance using intention to treat showed no significant difference between groups after treatment (P = .62). At follow-up, there was a medium effect (d = 0.63) showing a significant benefit from IYP plus HPS of 3.6 (95% CI, 0.8-6.5) on the ECBI-P score (F1,124 = 6.3; P = .01). Families receiving the IYP plus HPS intervention had significantly fewer children with child behavior scores in the clinical range after treatment (9 of 51 [17.6%]) compared with families receiving the IYP program alone (18 of 45 [40.0%]), and this status was maintained at follow-up. The HPS intervention had better retention than the IYP program (dropout, 7 [5.6%] vs 16 [12.7%]) as well as better attendance. In this trial, the IYP plus HPS intervention significantly improved outcomes for the most vulnerable families at 6 months. This study demonstrated that the HPS intervention is an effective addition to the IYP program to improve engagement and implementation of IYP program strategies and enhance child behavior outcomes for the most vulnerable families. http://anzctr.org.au Identifier: ACTRN12612000878875.


Dual Transcriptomic Analyses Unveil Host-Pathogen Interactions Between Salmonella enterica Serovar Enteritidis and Laying Ducks (Anas platyrhynchos).
Salmonella enteritidis (SE) is a pathogen that can readily infect ovarian tissues and colonize the granulosa cell layer such that it can be transmitted via eggs from infected poultry to humans in whom it can cause food poisoning. Ducks are an important egg-laying species that are susceptible to SE infection, yet the host-pathogen interactions between SE and ducks have not been thoroughly studied to date. Herein, we performed dual RNA-sequencing analyses of these two organisms in a time-resolved infection model of duck granulosa cells (dGCs) by SE. In total, 10,510 genes were significantly differentially expressed in host dGCs, and 265 genes were differentially expressed in SE over the course of infection. These differentially expressed genes (DEGs) of dGCs were enriched in the cytokine-cytokine receptor interaction pathway via KEGG analyses, and the DEGs in SE were enriched in the two-component system, bacterial secretion system, and metabolism of pathogen factors pathways as determined. A subsequent weighted gene co-expression network analysis revealed that the cytokine-cytokine receptor interaction pathway is mostly enriched at 6 h post-infection (hpi). Moreover, a number of pathogenic factors identified in the pathogen-host interaction database (PHI-base) are upregulated in SE, including genes encoding the pathogenicity island/component, type III secretion, and regulators of systemic infection. Furthermore, an intracellular network associated with the regulation of SE infection in ducks was constructed, and 16 cytokine response-related dGCs DEGs (including IL15, CD40, and CCR7) and 17 pathogenesis-related factors (including sseL, ompR, and fliC) were identified, respectively. Overall, these results not only offer new insights into the mechanisms underlying host-pathogen interactions between SE and ducks, but they may also aid in the selection of potential targets for antimicrobial drug development.


In vivo xenoestrogenic actions of cadmium and arsenic in anterior pituitary and uterus.
Cadmium (Cd) and arsenic (iAs) are toxic metals ubiquitously present in the environment. Both pollutants exert nonmonotonic dose responses, being mostly cytotoxic at high concentrations but mimicking estrogen (E2) effects at low doses. Xenoestrogenic activity of Cd and iAs has been demonstrated in different hormone-dependent tumor cell lines; however, their actions in vivo remain largely unknown. Here, we investigated whether in vivo administration of low doses of Cd and iAs through drinking water would display xenoestrogenic effects in the anterior pituitary gland and uterus of ovariectomized rats. Cd (1ppm) and iAs (0.1ppm) exposure increased the wet weight of anterior pituitary gland and uterus and induced proestrus- and estrus-like vaginal smears. Both metals stimulate cell proliferation of these tissues as they increased the expression of proliferation markers. More importantly, they augmented soluble guanylyl cyclase α1 subunit expression, which has been linked to hormone-dependent tumor progression. Also, Cd and iAs modified protein levels of full-length estrogen receptor α and its truncated variants in an E2-like manner. Anterior pituitary hormone secretion was differentially affected by both metals. Luteinizing hormone synthesis and release were strongly diminished after Cd exposure and only mildly reduced by iAs. Both metals were able to increase prolactin synthesis, although only iAs augmented serum prolactin levels. This study shows for the first time that Cd and iAs exert strong xenoestrogenic effects on anterior pituitary gland at low doses. The differences between Cd and iAs E2-like behavior indicate that other Cd- and iAs-specific mechanisms could be involved. Altogether, these results contribute to the knowledge of reproductive disorders associated with Cd and iAs environmental contamination.


The role of alpha 1-adrenoceptor subtypes in the phasic and tonic responses to phenylephrine in the longitudinal smooth muscle of the rat portal vein.
The purpose of this investigation was to determine whether alpha 1-adrenoceptor subtypes (co)exist in the rat portal vein and, if so, whether they could be functionally associated with the phasic and tonic types of contraction as a response to alpha 1-adrenoceptor stimulation by phenylephrine. A low Ca2+ concentration (0.9 mmol/l) in the Tyrode solution enabled us to quantify changes both in the phasic myogenic activity and in the basal tone of the rat portal vein preparation very precisely. We used both competitive and non-competitive alpha-adrenoceptor antagonists which have been employed successfully by other investigators to discriminate between alpha 1-adrenoceptor subtypes in vascular and other tissues. Schild analysis showed that the competitive alpha-adrenoceptor antagonists prazosin, phentolamine, yohimbine, corynanthine, idazoxan, rauwolscine and 5-methyl-urapidil could not distinguish between the phasic and tonic responses to phenylephrine and/or different alpha 1-adrenoceptor subtypes in the rat portal vein. However, when we compared our pA2 values with those found to be representative indicators according to subclassifications based on the use of selective antagonists in different tissues, the alpha 1-adrenoceptors in the rat portal vein appeared to belong to the alpha 1L- or alpha 1a-subtype. This subclassification was not in accordance with the data obtained with the irreversible alpha-adrenoceptor antagonist chloroethylclonidine. However, the validity of this alkylating agent as a tool for receptor classification was restricted, at least in the rat portal vein, by its effects on receptor reserve.(ABSTRACT TRUNCATED AT 250 WORDS)


Hydrogen peroxide supports human and rat cytochrome P450 1A2-catalyzed 2-amino-3-methylimidazo[4,5-f]quinoline bioactivation to mutagenic metabolites: significance of cytochrome P450 peroxygenase.
We show that the naturally occurring hydroperoxide hydrogen peroxide is highly effective in supporting the cytochrome P450 1A2 peroxygenase-catalyzed metabolic activation of the heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) to genotoxic metabolites. Mutagenicity was assessed by the Ames assay with Salmonella typhimurium strain YG1012 and an activation system consisting of hydroperoxides plus either 3-methylcholanthrene-induced rat liver microsomes (rP4501A) or human P450 1A2-containing microsomes (hP4501A2). The mutagenic response was dependent on the concentration of microsomal protein, IQ, and hydroperoxides. The addition of hydrogen peroxide or tert-butyl hydroperoxide to rP4501A greatly enhanced the yield of histidine prototrophic (His+) revertants. This increase was inhibited, in a concentration-dependent manner, by alpha-naphthoflavone, a P450 1A inhibitor. Hydrogen peroxide was the most effective peroxygenase cofactor, particularly with hP4501A2 (K(m) = 0.1 mM). The hydroperoxide-supported activation of IQ produced reactive intermediates which bound to 2'-deoxyguanosine; LC/MS analysis of the adducts revealed the same major (protonated) adduct at m/z = 464.4 as previously reported for the DNA adduct formed (in vivo or in vitro) by the mixed function-catalyzed bioactivation system. None of the peroxidase-catalyzed IQ metabolites (nitro-, azo-, or azoxy-IQ) were detected. In conclusion, hydrogen peroxide in the physiological/pathological concentration range may be able to support the metabolic activation of arylamines to genotoxic products through the cytochrome P450 peroxygenase pathway.


Prognosis of primary rhegmatogenous retinal detachments. 2. Accounting for and predicting final visual acuity in surgically reattached cases.
Multiple linear regression-analysis of variance was used to define relationships between final visual acuity and several parameters in 31 patients with reattached primary rhegmatogenous retinal detachments. Older patient age, preoperative macular detachment, clinically visible macular lesions, greater detachment duration and extent, and higher subretinal fluid butyrylcholinesterase activity were all inversely related to final acuity. The relationship of each parameter to final acuity, in conjunction with and apart from all the other parameters, was defined. Collectively the parameters accounted for 85% of the variation about the mean of the clinically observed finally acuities. The parameters could be weighted to give a generally, reasonably accurate prediction of final acuity at the time of surgery. The findings are consistent with a pathophysiological sequence involving alterations in the choroidal circulation and the blood-ocular barrier of the posterior segment.


JAK/STAT of all trades: linking inflammation with cancer development, tumor progression and therapy resistance.
Inflammation is at the forefront of carcinogenesis, tumor progression and resistance to therapy. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling axis is a central pathway that mediates the cellular response to inflammation and contributes to carcinogenesis. The JAK/STAT pathway coordinates intercellular communication between tumor cells and their immune microenvironment, and JAK/STAT activation leads to the expression of a variety of proteins involved in cell proliferation, cell survival, stemness, self-renewal, evasion of immunosurveillance mechanisms and overall tumor progression. Activation of JAK/STAT signaling also mediates resistance to radiation therapy or cytotoxic agents and modulates tumor cell responses to molecularly targeted and immune modulating drugs. Despite extensive research focused on understanding its signaling mechanisms and downstream phenotypic and functional consequences in hematological disorders, the importance of JAK/STAT signaling in solid tumor initiation and progression has been underappreciated. We highlight the role of chronic inflammation in cancer, the epidemiological evidence for contribution of JAK/STAT to carcinogenesis, the current cancer prevention measures involving JAK/STAT inhibition and the impact of JAK/STAT signaling activity on cancer development, progression and treatment resistance. We also discuss recent therapeutic advances in targeting key factors within the JAK/STAT pathway with single agents and the use of these agents in combination with other targeted therapies and immune checkpoint inhibitors.


Biologic therapy for brain cancers--based on cellular and immunobiology.
The overall goal of our research projects is to develop effective immunotherapeutic regimens, particularly combining vaccine and gene therapy/ cell therapy strategies. For the development of clinically effective immunotherapy for brain cancers, the following issues are considered to be particularly important: 1) Induction of effective immune responses against tumors (afferent arm of the immune response), 2) Delivery of immune effector cells to the target tumor sites and maintaining the activity of the effector cells (efferent arm), 3) For specific and safe immunotherapy, specific brain tumor rejection antigens have to be identified, 4) Feasibility, safety and efficacy need to be tested in a series of clinical trials. The following presentation summarizes my research projects and demonstrates how each plan will fit in the whole schema of designing successful immunotherapeutic strategies for brain cancers. In this presentation, I would like to focus on our clinical and basic studies related to the vaccine strategies for patients with glioma, and modulation of tumor-microenvironment using bone-marrow derived stroma cells as vehicles for cytokine- gene delivery.


Rotationally Selected and Resolved State-to-State Photoelectron Study of Vanadium Monoxide Cation VO(+)(X(3)Σ(-); v(+) = 0-3).
Vanadium monoxide cation VO(+)(X(3)Σ(-)) has been investigated by two-color visible (VIS)-ultraviolet (UV) pulsed field ionization-photoelectron (PFI-PE) methods. The unambiguous rotational assignment of rotationally selected and resolved VIS-UV-PFI-PE spectra thus obtained confirms the ground state term symmetry of VO(+) to be X(3)Σ(-). The rotational analysis also yields the rotational constants Be(+) = 0.5716 ± 0.0012 cm(-1) and αe(+) = 0.0027 ± 0.0005 cm(-1) for VO(+)(X(3)Σ(-)), from which the equilibrium bond distance of VO(+)(X(3)Σ(-)) is determined to be re(+) = 1.557 ± 0.002 Å. This PFI-PE study covers the vibrational bands, VO(+)(X(3)Σ(-); v(+) = 0, 1, 2, and 3) ← VO(X(4)Σ(-); v″ = 0), which has made possible the determination of the vibrational constants for VO(+)(X(3)Σ(-)) to be ωe(+) = 1068.0 ± 0.7 cm(-1) and ωe(+)xe(+) = 5.5 ± 0.7 cm(-1). The present state-to-state measurement also yields a more precise value (58 380.0 ± 0.7 cm(-1) or 7.238 20 ± 0.000 09 eV) for the ionization energy of VO [IE(VO)]. This value along with the known IE(V) has allowed the determination of the difference between the 0 K bond dissociation energy (D0) of VO(+)(X(3)Σ(-)) and that of VO(X(4)Σ(-)) to be D0(V(+)-O) - D0(V-O) = IE(V) - IE(VO) = -3967 ± 1 cm(-1).


Five-year follow-up after transcatheter aortic valve implantation for symptomatic aortic stenosis.
Transcatheter aortic valve implantation (TAVI) has been implemented into the care of elderly patients suffering from severe symptomatic aortic stenosis. However, data on long-term follow-up are sparse and predictors of long-term mortality need to be evaluated to better select patients. Therefore, we aimed to analyse predictors of 5-year mortality after TAVI. We analysed data from the German Transcatheter Aortic Valve Interventions-Registry. Each of the 27 participating hospitals agreed to include all consecutive TAVI patients at their institution. Out of 1444 patients treated with TAVI, 1378 patients had a follow-up of at least 4.5 years (completeness 95.4%). Endpoint for this analysis was 5-year survival. Cox regression analysis was used to determine risk factors associated with this endpoint. Patients who died were compared with survivors. The two groups showed multiple differences in patient characteristics, indications for interventions, preinterventional, as well as interventional characteristics and postinterventional events. Calculated 1-year mortality was 21.8% and 5-year mortality 59.1%. A higher logistic EuroScore was associated with a lower 5-year survival, being 45.5% in patients with a logistic EuroScore of <20%, 34.5% in those with 20% to 40% and 28.4% in patients with a logistic EuroScore >40%. Cox proportional hazard analysis revealed the following independent predictors of 5-year mortality: female gender (HR =0.66, 95% CI 0.56 to 0.77, p<0.0001), renal failure (HR=1.43, 95% CI 1.22 to 1.69, p<0.0001), prior mitral regurgitation ≥II° (HR=1.42, 95% CI 1.21 to 1.65, p<0.0001), residual aortic regurgitation ≥II° (HR=1.52, 95% CI 1.24 to 1.85, p<0.0001), atrial fibrillation (HR=1.38, 95% CI 1.18 to 1.64, p=0.0001), low gradient aortic stenosis (HR=1.48, 95% CI 1.19 to 1.84, p=0.0004), prior decompensation (HR=1.32, 95% CI 1.13 to 1.54, p=0.0006), frailty (HR=1.31, 95% CI 1.09 to 1.58, p=0.004), surgical TAVI (HR=1.42, 95% CI 1.12 to 1.80, p=0.004), age (by year) (HR=1.02, 95% CI 1.01 to 1.03, p=0.006), prior myocardial infarction (HR=1.29, 95% CI 1.07 to 1.57, p=0.009), urgent TAVI (HR=1.25, 95% CI 1.04 to 51, p=0.020) and diabetes mellitus (HR=1.20, 95% CI 1.02 to 1.40, p=0.024). These data from the early TAVI experience show a 5-year mortality of 59.1%. Some of the predictors of 5-year mortality seem to be modifiable, such as residual aortic regurgitation, type of TAVI access route and concomitant mitral regurgitation.


A small survey of introduced Zaprionus indianus (Diptera: Drosophilidae) in orchards of the eastern United States.
The African fig fly, Zaprionus indianus (Gupta), is a generalist fruit fly that typically breeds in decaying fruits from over 70 plant species. The species has spread globally from its native range in tropical Africa, becoming an invasive pest on ripening figs in Brazil. First reported in the United States in 2005 in Florida, Z. indianus has since been documented as far north as Canada and is hypothesized to recolonize northwards from southern refugia each year. We sampled drosophilid communities over the growing season at 2 orchards in Virginia from 2020 to 2022 and 11 orchards along the East Coast during the fall of 2022 to quantify the abundance of Z. indianus relative to other drosophilids across locations, seasons, and fruit crops. Massachusetts had the northernmost population, with no Z. indianus detected in Maine and no correlation between latitude and relative abundance. Variation in Z. indianus relative abundance was high between nearby orchards and abundance was higher on peaches relative to apples within orchards. Comparisons of seasonal abundance curves between 2 Virginia orchards showed similar dynamics across years with individuals first detected around July and becoming absent around December, with peaks in late summer and mid-fall. The variation in seasonal and latitudinal abundance shown here highlights a need for broader sampling to accurately characterize the range, spread, and environmental tolerances of Z. indianus in North America.


Characterization of Kinetic Binding Properties of Unlabeled Ligands via a Preincubation Endpoint Binding Approach.
The dissociation rates of unlabeled drugs have been well studied by kinetic binding analyses. Since kinetic assays are laborious, we developed a simple method to determine the kinetic binding parameters of unlabeled competitors by a preincubation endpoint assay. The probe binding after preincubation of a competitor can be described by a single equation as a function of time. Simulations using the equation revealed the degree of IC50 change induced by preincubation of a competitor depended on the dissociation rate koff of the competitor but not on the association rate kon To validate the model, an in vitro binding assay was performed using a smoothened receptor (SMO) and [(3)H]TAK-441, a SMO antagonist. The equilibrium dissociation constants (KI) and koff of SMO antagonists determined by globally fitting the model to the concentration-response curves obtained with and without 24 h preincubation correlated well with those determined by other methods. This approach could be useful for early-stage optimization of drug candidates by enabling determination of binding kinetics in a high-throughput manner because it does not require kinetic measurements, an intermediate washout step during the reaction, or prior determination of competitors' KI values.


Eight-Hour Continuous Normothermic Ex Vivo Kidney Perfusion Is a Safe Preservation Technique for Kidney Transplantation: A New Opportunity for the Storage, Assessment, and Repair of Kidney Grafts.
Hypothermic kidney storage causes preservation injury and is poorly tolerated by renal grafts. We investigated whether static cold storage (SCS) can be safely replaced with a novel technique of pressure-controlled normothermic ex vivo kidney perfusion (NEVKP) in heart-beating donor kidney transplantation. Right kidneys were removed from 30 kg Yorkshire pigs in a model of heart-beating donation and either preserved in cold histidine-tryptophan-ketoglutarate solution for 8 hours (n = 5), or subjected to 8 hours of pressure-controlled NEVKP (n = 5) followed by renal heterotopic autotransplantation. During NEVKP, physiologic perfusion conditions were maintained with low intrarenal resistance and normal electrolyte and pH parameters. Aspartate aminotransferase and lactate dehydrogenase as injury markers were below the detectable analyzer range (<4 and <100 U/L, respectively). Perfusate lactate concentration decreased from baseline until the end of perfusion (10.38 ± 0.76 mmol/L vs 1.22 ± 0.26 mmol/L; P < 0.001). Posttransplantation, animals transplanted with NEVKP versus SCS grafts demonstrated similar serum creatinine peak levels (NEVKP, 2.0 ± 0.5 vs SCS 2.7 ± 0.7 mg/dL; P = 0.11) and creatinine clearance on day 10 (NEVKP, 65.9 ± 18.8 mL/min vs SCS 61.2 ± 15.6 mL/min; P = 0.74). After 10 days of follow-up, animals transplanted with NEVKP grafts had serum creatinine and blood urea nitrogen values comparable to their basal levels (P = 0.49 and P = 0.59), whereas animals transplanted with SCS grafts had persistently elevated serum creatinine and blood urea nitrogen when compared with basal levels (P = 0.01 and P = 0.03). Continuous pressure-controlled NEVKP is feasible and safe in good quality heart-beating donor kidney grafts. It maintains a physiologic environment and excellent graft function ex vivo during preservation without causing graft injury.


Improved Infrared Spectra Prediction by DFT from a New Experimental Database.
This work aims to improve the computation of infrared spectra of gas-phase cations using DFT methods. Experimental infrared multiple photon dissociation (IRMPD) spectra for ten Zn and Ru organometallic complexes have been used to provide reference data for 64 vibrational modes in the 900-2000 cm-1 range. The accuracy of the IR vibrational frequencies predicted for these bands has been assessed over five DFT functionals and three basis sets. The functionals include the popular B3LYP and M06-2X hybrids and the range-separated hybrids (RSH) CAM-B3LYP, LC-BLYP, and ωB97X-D. B3LYP gives the best mean absolute error (MAE) and root-mean-square error (RMSE) values of 7.1 and 9.6 cm-1 , whilst the best RSH functional, ωB97X-D, gives 12.8 and 16.6 cm-1 , respectively. Using linear correlations instead of scaling factors improves the prediction accuracy significantly for all functionals. Experimental and computed spectra for a single complex can show significant differences even when the molecular structure is calculated correctly, and a means of defining confidence limits for any given computed structure is also provided.


Incidence, clinical features, and treatment of familial moyamoya in pediatric patients: a single-institution series.
OBJECTIVE Limited data exist on familial moyamoya in children. The purpose of this study was to characterize presentation and outcomes of pediatric moyamoya patients who have relatives diagnosed with moyamoya. METHODS The authors performed a single-institution retrospective analysis of a case series including all surgically treated children with moyamoya with first- or second-degree relatives with moyamoya. Clinical and radiographic characteristics were analyzed, along with surgical outcomes. RESULTS A total of 537 patients underwent surgery for moyamoya during the study period. Eighteen of those patients (3.4% of the total series) had moyamoya and a family history of moyamoya and were included in this study. Of these 18 patients, 14 were non-twin siblings, and the remaining 4 represented 2 pairs of identical (affected) twins. The presentation was predominantly ischemic (72%), but 4 patients (33%) were asymptomatic when they were found to have moyamoya. Bilateral disease was present in 13 patients (72%). Radiographic stroke prevalence (67%), Suzuki grade (3.3), and angiographic findings were comparable to findings in nonfamilial moyamoya patients. Thirty revascularization procedures were performed, with a 3.3% operative stroke rate per hemisphere and no new strokes in an average follow-up period of 4.5 years. CONCLUSIONS In a North American surgical series, familial moyamoya existed in 3.4% of cases, and was distinguished by manifesting in a broad range of ethnic groups, with a higher proportion of male patients and increased rates of asymptomatic and unilateral disease in comparison to nonfamilial moyamoya. Screening indications remain controversial and the current data are used to suggest guidelines. Surgical therapy is warranted, effective, and durable in these patients, but patients should be carefully selected.


SERPINA3K Ameliorates the Corneal Oxidative Injury Induced by 4-Hydroxynonenal.
We previously demonstrated that SERPINA3K has anti-inflammatory, antiangiogenic, and antioxidant effects in corneas. Here we further investigated the effects of SERPINA3K on the corneal oxidant injury setting recently developed and induced by 4-hydroxynonenal (4-HNE). We applied the 4-HNE-induced corneal oxidant stress in cultured human corneal epithelial (HCE) cells in vitro and to the cornea of rats in vivo. The following experiments were conducted: cell counting kit 8 assay to detect cell viability; quantitative real-time PCR assay; Western blotting and immunofluorescent staining to measure gene expressions or protein levels of key reactive oxygen species (ROS)-associated factors (3-nitrotyrosine [3-NT]; nicotinamide adenine dinucleotide phosphate [NADPH]-oxidase 4 [NOX4]; superoxide dismutase [SOD]); catalase and nuclear factor [erythroid-derived 2]-like 2 [NRF2]); as well as main factors of the Wnt/β-catenin signaling pathway (p-LRP6, β-catenin and transcription factor 4 [TCF4]); histologic staining; and TUNEL staining to examine sections of rat corneas. We found that SERPINA3K concentration dependently protected cell viability, decreased levels of ROS marker 3-NT, suppressed NOX4, and upregulated SOD and catalase. Furthermore, SERPINA3K inhibited the activation of the ROS pathway NRF2 and its downstream factors, NAD(P)H dehydrogenase (quinone) 1 (NQO1) and heme oxygenase 1 (HO1), and also suppressed the activation of the Wnt signaling pathway p-LRP6, β-catenin, and TCF4 in HCE cells treated with 4-HNE. Meanwhile, SERPINA3K ameliorated the oxidant injury of rat corneas induced by 4-HNE and downregulated ROS systems and the Wnt/β-catenin pathway. Our findings show that SERPINA3K protected the oxidant damage induced by 4-HNE in the cornea and its underlying mechanism was through suppression of the ROS system and inhibition of the activated Wnt/β-catenin signaling pathway.


A Group of ent-Kaurane Diterpenoids Inhibit Hedgehog Signaling and Induce Cilia Elongation.
The Hedgehog (Hh) signaling pathway plays important roles in the tumorigenesis of multiple cancers and is a key target for drug discovery. In a screen of natural products extracted from Chinese herbs, we identified eight ent-Kaurane diterpenoids and two triterpene dilactones as novel Hh pathway antagonists. Epistatic analyses suggest that these compounds likely act at the level or downstream of Smoothened (Smo) and upstream of Suppressor of Fused (Sufu). The ent-Kauranoid-treated cells showed elongated cilia, suppressed Smo trafficking to cilia, and mitotic defects, while the triterpene dilactones had no effect on the cilia and ciliary Smo. These ent-Kaurane diterpenoids provide new prototypes of Hh inhibitors, and are valuable probes for deciphering the mechanisms of Smo ciliary transport and ciliogenesis.


Parametric acoustic array lensed by a gradient-index phononic crystal.
This work presents a theoretical study of a parametric transmitter employing a small ultrasonic transducer and an acoustic lens for the collimation of the non-directional primary ultrasonic waves into a highly-directional beam. The acoustic lens is represented by a gradient-index phononic crystal (GRIN PC) composed of an array of toroidal scatterers. Parameters of the GRIN PC lens are determined employing an optimization procedure that maximizes the minimum value of the primary-wave amplitude over a wide frequency range at a distant point in front of the transducer-lens system. The Westervelt equation is used as a wave equation taking into account diffraction, nonlinearity, and thermoviscous attenuation. The wave equation is solved numerically in the quasi-linear approximation in the frequency domain employing the finite element method. The numerical results show that employing a simple GRIN PC lens, a highly-directional low-frequency beam can be parametrically radiated from a small ultrasonic transducer.


Bioinformatics Analysis of Prognostic Value of SPC24 in ccRCC and Pan-Cancer.
Clear cell renal cell carcinoma (ccRCC) is one of the most common diseases in the world, with high morbidity and mortality. Recent studies have revealed the important role of SPC24, a subunit of the Ndc80 complex, in the occurrence and development of carcinoma. However, the latent effect of SPC24 in the progress of ccRCC remains to be further explored. The intent of this research is to investigate whether SPC24 can be used as an index to predict the progression of ccRCC and to explore its relationship with the immune microenvironment and pan-cancer. Based on data from public databases, we determined the expression level and clinical value of SPC24 in ccRCC and human pan-cancer. RT-qPCR analysis was carried out to detect the expression level of SPC24 in the OSRC/786O (human ccRCC cells) cell lines and HK2 (human normal kidney cells) cell line. The signal transduction pathways activated by different levels of SPC24 expression were explored by Gene Set Enrichment Analysis (GSEA), and the CIBERSORT algorithm was applied to analyze the relationship between infiltrating immune cells and SPC24 expression in ccRCC and pan-cancer tissues. SPC24 is overexpressed in ccRCC and several types of tumors, which is associated with poor prognosis. GSEA and CIBERSORT algorithms suggested that the high expression group of SPC24 enriched various pathways including immune-related pathways, and the several infiltrated immunocytes were related to the expression of SPC24. Our study revealed that SPC24 is a prognostic factor in ccRCC related to immunomodulation and has generalized value in pan-cancer.


Prevalence of Extended-Spectrum Beta-Lactamases-Producing Microorganisms in Patients Admitted at KRRH, Southwestern Uganda.
The emergence of extended-spectrum beta-lactamase- (ESBL-) producing pathogenic bacteria at Kabale Regional Referral Hospital (KRRH), located in southwestern Uganda, is of great concern: a phenomenon that worries clinicians and other healthcare workers due to the serious threat they pose to patients. This current study aimed at determining the phenotypic detection of ESBL-producing strains of E. coli, Klebsiella sp., and Proteus sp. isolated from clinical specimens and their prevalence in patients admitted at KRRH. We used combined disc diffusion technique to detect and establish the presence of ESBLs-producing bacteria. Of the 100 tested bacterial isolates, 89 (89%) were identified as ESBL-producing bacteria. Klebsiella sp. predominated in the samples (46 (52%)), presenting the highest frequency of ESBLs producing followed by E. coli (39 (44%)) and Proteus mirabilis (4 (4.5%)) from the combined disk diffusion.


Smith-Magenis Syndrome Patients Often Display Antibody Deficiency but Not Other Immune Pathologies.
Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder associated with recurrent otitis. Most SMS cases result from heterozygous interstitial chromosome 17p11.2 deletions that encompass not only the intellectual disability gene retinoic acid-induced 1 but also other genes associated with immunodeficiency, autoimmunity, and/or malignancy. The goals of this study were to describe the immunological consequence of 17p11.2 deletions by determining the prevalence of immunological diseases in subjects with SMS and by assessing their immune systems via laboratory methods. We assessed clinical histories of 76 subjects with SMS with heterozygous 17p11.2 deletions and performed in-depth immunological testing on 25 representative cohort members. Laboratory testing included determination of serum antibody concentrations, vaccine titers, and lymphocyte subset frequencies. Detailed reactivity profiles of SMS serum antibodies were performed using custom-made antigen microarrays. Of 76 subjects with SMS, 74 reported recurrent infections including otitis (88%), pneumonia (47%), sinusitis (42%), and gastroenteritis (34%). Infections were associated with worsening SMS-related neurobehavioral symptoms. The prevalence of autoimmune and atopic diseases was not increased. Malignancy was not reported. Laboratory evaluation revealed most subjects with SMS to be deficient of isotype-switched memory B cells and many to lack protective antipneumococcal antibodies. SMS antibodies were not more reactive than control antibodies to self-antigens. Patients with SMS with heterozygous 17p.11.2 deletions display an increased susceptibility to sinopulmonary infections, but not to autoimmune, allergic, or malignant diseases. SMS sera display an antibody reactivity profile favoring neither recognition of pathogen-associated antigens nor self-antigens. Prophylactic strategies to prevent infections may also provide neurobehavioral benefits to selected patients with SMS.


Pharmacokinetic model for serum concentrations of ampicillin in the newborn infant.
The time course of ampicillin concentrations in the sera of three newborn infants during and upon termination of intravenous infusion at a constant rate can be described by a two-compartment pharmacokinetic model. The parameters of the model were determined by simultaneously fitting the serum concentration data obtained during and after the infusion by means of a nonlinear regression program with the aid of a digital computer. The half-life of ampicillin in the infants ranged from 2.1 to 2.9 hr; these values are more than twice those observed in adults with normal renal function.


[Clinical research of vestibular autorotation test for patients with vertebrobasilar insufficiency].
To explore the diagnostic values of vestibular autorotation test (VAT) for patients with vertebrobasilar insufficiency (VBI). VAT and videonystagmography ( VNG) were performed on 73 patients with VBI and 48 patients with peripheral vestibular lesions (contrast group). Parameters analyzed included Gain, phase and asymmetry of VAT, as well as the canal paresis (CP) of caloric test and results of optokinetic-pursuit tests in VNG. Positive result of the test could be defined if anyone of the parameters was abnormal. For VAT test, Gain was enhanced in VBI group and was reduced in contrast group. In VBI group and contrast group, Gain enhanced showed in 47 (64.4%) cases and 5 (10.4%) cases, respectively (chi2 = 31.19, P < 0.01). Simultaneity, Gain reduced in 11 cases (15.5%) and 22 cases (45.8%), respectively (chi2 = 13.82, P < 0.01). But there was no statistics significant for results of the parameters of phase, asymmetry and integration between two groups. For VNG test, results with optokinetic-pursuit tests were more abnormal in VBI group than that in contrast group, which showed central lesions characteristics. Forty-four cases (60.3%) in VBI group and 10 cases (20.8%) in control group showed central lesions results with optokinetic-pursuit tests and visual fixation test (chi2 = 15.89, P < 0.01). Unilateral or bilateral CP showed in 33 cases (68.6%) in control group and 51 cases (69.9%) in VBI group with caloric test. Gain of VAT is mostly enhanced in VBI group, and Gain as a main characteristic is reduced in patients with peripheral vestibular lesions. The Gain parameter is availability for assessing characteristics of vestibular lesions. Phase and asymmetry can be used to assess the vestibular function but can not indicate the characteristics of vestibular lesions.


JACIE accreditation for blood and marrow transplantation: past, present and future directions of an international model for healthcare quality improvement.
Blood and marrow transplantation (BMT) is a complex and evolving medical speciality that makes substantial demands on healthcare resources. To meet a professional responsibility to both patients and public health services, the European Society for Blood and Marrow Transplantation (EBMT) initiated and developed the Joint Accreditation Committee of the International Society for Cellular Therapy and EBMT-better known by the acronym, JACIE. Since its inception, JACIE has performed over 530 voluntary accreditation inspections (62% first time; 38% reaccreditation) in 25 countries, representing 40% of transplant centres in Europe. As well as widespread professional acceptance, JACIE has become incorporated into the regulatory framework for delivery of BMT and other haematopoietic cellular therapies in several countries. In recent years, JACIE has been validated using the EBMT registry as an effective means of quality improvement with a substantial positive impact on survival outcomes. Future directions include development of Europe-wide risk-adjusted outcome benchmarking through the EBMT registry and further extension beyond Europe, including goals to faciliate access for BMT programmes in in low- and middle-income economies (LMIEs) via a 'first-step' process.


What was the ancestral sex-determining mechanism in amniote vertebrates?
Amniote vertebrates, the group consisting of mammals and reptiles including birds, possess various mechanisms of sex determination. Under environmental sex determination (ESD), the sex of individuals depends on the environmental conditions occurring during their development and therefore there are no sexual differences present in their genotypes. Alternatively, through the mode of genotypic sex determination (GSD), sex is determined by a sex-specific genotype, i.e. by the combination of sex chromosomes at various stages of differentiation at conception. As well as influencing sex determination, sex-specific parts of genomes may, and often do, develop specific reproductive or ecological roles in their bearers. Accordingly, an individual with a mismatch between phenotypic (gonadal) and genotypic sex, for example an individual sex-reversed by environmental effects, should have a lower fitness due to the lack of specialized, sex-specific parts of their genome. In this case, evolutionary transitions from GSD to ESD should be less likely than transitions in the opposite direction. This prediction contrasts with the view that GSD was the ancestral sex-determining mechanism for amniote vertebrates. Ancestral GSD would require several transitions from GSD to ESD associated with an independent dedifferentiation of sex chromosomes, at least in the ancestors of crocodiles, turtles, and lepidosaurs (tuataras and squamate reptiles). In this review, we argue that the alternative theory postulating ESD as ancestral in amniotes is more parsimonious and is largely concordant with the theoretical expectations and current knowledge of the phylogenetic distribution and homology of sex-determining mechanisms.


[Acute leukemia in the terminal phase of Hodgkin's disease: a consequence of the depressed immune function?].
A 52 year old patient suffering from Hodgkin's disease received ionizing radiation and chemotherapy. 7 years after the diagnosis was made he died of acute leukemia. In the recent past similar cases were reported in the literature. There it was suggested that the leukemogenic effect of treatment may be an etiological factor for the development of leukemia. The clinical and experimental data show that the immune function of thymus-dependent lymphocytes is depressed in patients with Hodgkin's disease. According to the Burnet's immune surveillance theory the T-lymphocytes eliminate malignant cells in an early stage. If this T-dependent immune function is depressed - as in Hodgkin's disease - further malignancies may develop.


[Doctor Westerlund's letters to Augusta Jansson].
Dr Ernst Westerlund--in Sweden called the Enköping-doctor--had his practice in the town of Enköping. Dr. Westerlund was known to be an excellent diagnostician; he had a very good reputation in Sweden and even abroad. He had a very personal and individual relation with his patients and the article describes a correspondence between him and one of his patients, Miss Augusta Jansson and is based on 150 letters from 1879 to 1923.


Oxidative stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin is mediated by the aryl hydrocarbon (Ah) receptor complex.
The toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its bioisosteres involves binding to a specific TCDD (Aryl hydrocarbon (Ah)) receptor, interaction of this complex with chromatin, and the ultimate production of a pleiotropic response. The mechanism whereby toxic effects are produced following interaction of TCDD with the receptor complex is not known. Oxidative stress (OS) may play an important role in expression of the toxic manifestations of TCDD. TCDD has been shown to produce a dose- and time-dependent increase in superoxide anion from peritoneal lavage cells (PLC) (primarily macrophage). Therefore, to determine if TCDD-induced production of superoxide anion by PLC is mediated through the Ah receptor, congenic mice were used which differ at the Ah locus. One day after the administration of 5, 25, 50 or 125 micrograms TCDD/kg p.o. as a single dose, 1.4-, 1.7-, 4.3- and 3.5-fold increases, respectively, occurred in superoxide anion production by PLC from the TCDD-responsive C57BL/6J (bb) mice relative to control cells. However, only 125 micrograms TCDD/kg produced a significant increase in superoxide anion formation with PLC from the non-responsive C57BL/6J (dd) strain of mice (1.7-fold increase). The role of the Ah receptor was further evaluated by utilizing the TCDD-resistant DBA/2 strain of mice, two TCDD congeners and in vitro studies. The combined results indicate that TCDD produces an oxidative stress in mice as measured by production of superoxide anion, and this effect is controlled in part by the Ah receptor complex.


Germ line transmission of an inactive N-myc allele generated by homologous recombination in mouse embryonic stem cells.
We have disrupted one allele of the N-myc locus in mouse embryonic stem (ES) cells by using homologous recombination techniques and have obtained germ line transmission of null N-myc ES cell lines with transmission of the null N-myc allele to the offspring. The creation of mice with a deficient N-myc allele will allow the generation of offspring bearing null N-myc alleles in both chromosomes and permit study of the role that this proto-oncogene plays in embryonic development.


Dynamic transcriptional and chromatin accessibility landscape of medaka embryogenesis.
Medaka (Oryzias latipes) has become an important vertebrate model widely used in genetics, developmental biology, environmental sciences, and many other fields. A high-quality genome sequence and a variety of genetic tools are available for this model organism. However, existing genome annotation is still rudimentary, as it was mainly based on computational prediction and short-read RNA-seq data. Here we report a dynamic transcriptome landscape of medaka embryogenesis profiled by long-read RNA-seq, short-read RNA-seq, and ATAC-seq. By integrating these data sets, we constructed a much-improved gene model set including about 17,000 novel isoforms and identified 1600 transcription factors, 1100 long noncoding RNAs, and 150,000 potential cis-regulatory elements as well. Time-series data sets provided another dimension of information. With the expression dynamics of genes and accessibility dynamics of cis-regulatory elements, we investigated isoform switching, as well as regulatory logic between accessible elements and genes, during embryogenesis. We built a user-friendly medaka omics data portal to present these data sets. This resource provides the first comprehensive omics data sets of medaka embryogenesis. Ultimately, we term these three assays as the minimum ENCODE toolbox and propose the use of it as the initial and essential profiling genomic assays for model organisms that have limited data available. This work will be of great value for the research community using medaka as the model organism and many others as well.


The role of infectious agents in the spondylarthropathies.
The clinical similarities of the spondylarthropathies and their frequent association with both HLA B27 and microbial infections suggest common pathogenetic mechanisms. The latter may include deposition of immune complexes containing bacterial antigens. or cross-reactivity of such antigens with host target tissue or responding cell antigens. Enteric bacteria, chlamydia and mycoplasma are all candidate etiologic agents, but proof is difficult because they are often found as normal flora, although only genetically susceptible individuals may acquire disease, and many patients have been treated with antibiotics before they can be studied. Nonetheless, a role for endogenous bacteria in reactive arthritis at least seems certain, and should stimulate further investigation into similar pathogenetic mechanisms in other chronic arthritides.


Uncontrolled Hemorrhagic Shock Modeled via Liver Laceration in Mice with Real Time Hemodynamic Monitoring.
Uncontrolled hemorrhage is an important cause of preventable deaths among trauma patients. We have developed a murine model of uncontrolled hemorrhage via a liver laceration that results in consistent blood loss, hemodynamic alterations, and survival. Mice undergo a standardized resection of the left-middle lobe of the liver. They are allowed to bleed without mechanical intervention. Hemostatic agents can be administered as pre-treatment or rescue therapy depending on the interest of the investigator. During the time of hemorrhage, real-time hemodynamic monitoring via a left femoral arterial line is performed. Mice are then sacrificed, blood loss is quantified, blood is collected for further analysis, and organs are harvested for analysis of injury. Experimental design is described to allow for simultaneous testing of multiple animals. Liver hemorrhage as a model of uncontrolled hemorrhage exists in the literature, primarily in rat and porcine models. Some of these models utilize hemodynamic monitoring or quantify blood loss but lack consistency. The present model incorporates quantification of blood loss, real-time hemodynamic monitoring in a murine model that offers the advantage of using transgenic lines and a high-throughput mechanism to further investigate the pathophysiologic mechanisms in uncontrolled hemorrhage.


Orthopaedic Trends in the 1990s An introduction.
Recent advances in orthopaedic technology have been among the most exciting medical developments of the past decade. More than 90 percent of the procedures and implants in use today did not exist a decade ago. The development of new prostheses and implants, the modifications of existing ones, and the development of new surgical techniques have allowed orthopaedic surgeons to treat and rehabilitate patients with diseases and deformities that were previously unmanageable. Furthermore, the newer and less invasive procedures have decreased the cost of treatment and recovery time for many patients. Prosthetic joint replacement is now capable of relieving arthritic pain in a predictable fashion, and spinal deformities of any magnitude can be treated in patients of any age with a high probability of success. The reattachment of amputated parts has become commonplace, and techniques of tissue transfer have enabled the salvage and reconstruction of cancerous or traumatised limbs that previously would have been lost to amputation.


Composites of plasma surface functionalized barium titanate nanoparticles covalently attached to epoxide matrices: synthesis and evaluation.
Inorganic/organic nanocomposites consisting of surface functionalized barium titanate (BTO) nanoparticles covalently bonded to epoxy polymeric matrices are described. A plasma-enhanced CVD process was employed to functionalize the particle surfaces with reactive amine groups. Subsequently, these modified particles were reacted with an epoxide monomer to synthesize the final nanocomposites, containing particle loadings ranging from 1 to 5 weight percent. Control samples, containing unmodified BTO, were also synthesized under identical reaction conditions and particle loading. The resultant nanocomposites were characterized spectroscopically and microscopically, and their physical and thermal properties were evaluated. The results obtained reveal a more uniform distribution of the surface modified BTO in the composites relative to that observed with the unmodified particles. Additionally, the physical and thermal properties of the nanocomposites containing the plasma modified particles were determined to be significantly improved over that of the pure polymer or the composites containing the unmodified particles, for each level of loading employed in this study. In light of these improved properties, it appears that the surface modifications employed significantly improve the interfacial interactions between the inorganic particles and the organic matrices in these nanocomposites.


Trichoderma harzianum metabolites pre-adapt mushrooms to Trichoderma aggressivum antagonism.
Trichoderma spp. is the cause of green mold, a disorder that affects cultivated mushrooms. The aims of the study were to establish whether improvement of mushroom resistance to Trichoderma aggressivum could be obtained by inducing reaction mechanisms before contact with the pathogen and whether this ability was species or strain dependent. Twenty nine isolates of Agaricus bisporus, 29 isolates of Lentinula edodes and 18 isolates of Pleurotus spp. were studied. The effect of T. harzianum metabolites on mycelial growth of these isolates was evaluated on YMEA (yeast, malt extract and agar), supplemented or not with Lysing Enzymes from T. harzianum (Sigma®, L1412). Mycelial growth generally was affected by Lysing Enzymes, but some L. edodes and Pleurotus spp. adapted to Lysing Enzymes. When mycelium was taken from a first culture with Lysing Enzymes and placed on YMEA with Lysing Enzymes for a second culture, their growth rate was not different from those of the controls. In the case of A. bisporus, only partial adaptation was obtained with a few isolates. The effect of adaptation to Lysing Enzymes on resistance to T. aggressivum was assayed for one strain of each group. Trichoderma aggressivum was exposed to the margin of 5- to 9-day-old mushroom colonies. Agaricus bisporus produced brown droplets, and T. aggressivum overgrew its mycelium. Lentinula edodes and P. ostreatus produced brown lines blocking the progression of T. harzianum, both on YMEA and YMEA plus Lysing Enzymes. The line was visible after 3 d on YMEA and after only 2 d on YMEA plus Lysing Enzymes. Improvement in the resistance to antagonists by introduction of some of their metabolites to the culture medium is a method for mushroom protection.


Eruptive milia and comedones during treatment with dovitinib.
Dovitinib (TKI258) is a multi-targeted receptor tyrosine kinase inhibitor currently under clinical trials for a wide variety of cancers. Well-known side effects include nausea, vomiting, diarrhea, and fatigue. To date, there have only been only two reported cases with skin manifestations as a side effect. We report a case of eruptive facial milia and comedones in the setting of dovitinib treatment for metastatic gastrointestinal cancer. This case is unique as the clinical presentation was more rapid in onset and showed an absence of inflammatory lesions. Although the pathogenesis for skin manifestations is presently unknown, we present this case to increase awareness of potentially under-reported cutaneous side effects.


Pesticide Residues in Table Grapes and Exposure Assessment.
This report describes levels of 172 pesticide residues in table grapes in Turkey. A total of 280 samples of table grapes were collected from supermarkets, bazaar, and greengrocer shops located in four provinces of Turkey from August to October 2016. The samples were analyzed by liquid chromatography coupled to tandem mass spectrometry. The limit of quantification ranged from 0.002 to 0.010 mg kg-1. The validation data revealed good recoveries and good repeatability and reproducibility and fulfilled the other requirements of the European SANTE/11945/2015 Guideline. One or more pesticide residues were detected in 59.6% of the table grapes. The residues above the EU maximum residue levels were 20.4% of the samples. The most prevalent pesticide residues were azoxystrobin, chlorpyrifos, boscalid, and cyprodinil. Left-censored results (40.4% of the results) were substituted by lower bound , middle bound, and upper bound values. In the worst-case scenario, the hazard index (HI) was 3.37% for adults and 9.42% for children. Chlorpyrifos was the major contributor (65%) to HI.


Comparison of Apixaban and Low Molecular Weight Heparin in Preventing Deep Venous Thrombosis after Total Knee Arthroplasty in Older Adults.
To compare the effect of apixaban and low molecular weight heparin (LMWH) in the prevention and treatment of deep venous thrombosis (DVT) after total knee arthroplasty in older adult patients. A total of 220 patients (average age of 67.8±6.4 years) undergoing total knee arthroplasty were randomly selected as research subjects and were divided into apixaban and LMWH groups (110 in each group). The incidence of DVT was lower in the apixaban group than in the LMWH group (5.5% vs. 20.0%, p=0.001). Activated partial thromboplastin times (35.2±3.6 sec vs. 33.7±2.2 sec, p=0.010; 37.8±4.6 sec vs. 34.1±3.2 sec, p<0.001; 39.6±5.1 sec vs. 35.7±3.0 sec, p=0.032) and prothrombin times (14.0±1.0 sec vs. 12.8±0.9 sec, p<0.001; 14.5±1.2 sec vs. 13.0±1.1 sec, p<0.001; 15.3±1.4 sec vs. 13.2±1.3 sec, p=0.009) in the apixaban group at 1 week after surgery, 3 weeks after surgery, and the end of treatment were higher than those in the LMWH group. Platelet and fibrinogen levels in the apixaban group were lower than those of the LMWH group. Also, capillary plasma viscosity and erythrocyte aggregation in the apixaban group at 1 week after surgery, 3 weeks after surgery, and the end of treatment were lower than those in the LMWH group. Apixaban, which elicits fewer adverse reactions and is safer than LMWH, exhibited better effects in the prevention and treatment of DVT after total knee arthroplasty in older adults.


Virus-encoded TLR ligands reveal divergent functional responses of mononuclear phagocytes in pathogenic simian immunodeficiency virus infection.
The role of mononuclear phagocytes in the pathogenesis or control of HIV infection is unclear. In this study, we monitored the dynamics and function of dendritic cells (DC) and monocytes/macrophages in rhesus macaques acutely infected with pathogenic SIVmac251 with and without antiretroviral therapy (ART). SIV infection was associated with monocyte mobilization and recruitment of plasmacytoid DC (pDC) and macrophages to lymph nodes, which did not occur with ART treatment. SIVmac251 single-stranded RNA encoded several uridine-rich sequences that were potent TLR7/8 ligands in mononuclear phagocytes of naive animals, stimulating myeloid DC (mDC) and monocytes to produce TNF-α and pDC and macrophages to produce both TNF-α and IFN-α. Following SIV infection, pDC and monocytes/macrophages rapidly became hyporesponsive to stimulation with SIV-encoded TLR ligands and influenza virus, a condition that was reversed by ART. The loss of pDC and macrophage function was associated with a profound but transient block in the capacity of lymph node cells to secrete IFN-α upon stimulation. In contrast to pDC and monocytes/macrophages, mDC increased TNF-α production in response to stimulation following acute infection. Moreover, SIV-infected rhesus macaques with stable infection had increased mDC responsiveness to SIV-encoded TLR ligands and influenza virus at set point, whereas animals that progressed rapidly to AIDS had reduced mDC responsiveness. These findings indicate that SIV encodes immunostimulatory TLR ligands and that pDC, mDC, and monocytes/macrophages respond to these ligands differently as a function of SIV infection. The data also suggest that increased responsiveness of mDC to stimulation following SIV infection may be beneficial to the host.


A camera-phone based study reveals erratic eating pattern and disrupted daily eating-fasting cycle among adults in India.
The daily rhythm of feeding-fasting and meal-timing are emerging as important determinants of health. Circadian rhythm research in animal models and retrospective analyses of human nutrition data have shown that reduced length of overnight fasting or increased late night eating increases risk for metabolic diseases including obesity and diabetes. However, the daily rhythm in eating pattern in humans is rarely measured. Traditional methods to collect nutrition information through food diary and food log pay little attention to the timing of eating which may also change from day to day. We adopted a novel cell-phone based approach to longitudinally record all events of food and beverage intake in adults. In a feasibility study daily food-eating patterns of 93 healthy individuals were recorded for 21 days using camera phones. Analysis of the daily eating patterns of these individuals indicates deviation from conventional assumption that people eat three meals-a-day within a 12 h interval. We found that eating events are widespread throughout the day, with <30% of calories consumed before noon and >30% consumed in evening and late night hours. There was little difference in eating pattern between weekdays and weekends. In this cohort more than 50% of people spread their caloric intake events over 15 h or longer. One decile of the cohort who were spouses of shift-workers or had flexible work schedule spread their caloric intake over 20 h. Although the nutrition quality and diversity of food consumed is different between South-East Asian and Western countries, such overall disruption of daily eating-fasting rhythm is similar. Therefore, in view of hypothesis that disrupted daily eating pattern may contribute to the global increase in metabolic diseases and modification of daily eating pattern is a potential modifiable behavior to contain these diseases, monitoring eating pattern is an important aspect of lifestyle.


Monte Carlo calculated TG-43 dosimetry parameters for the SeedLink 125Iodine brachytherapy system.
The SeedLink brachytherapy system is comprised from an assembly of I-Plant 3500 interstitial brachytherapy seeds and bioresorbable spacers joined together by a 6-mm-long titanium sleeve centered over each seed. This device is designed to maintain specified spacing between seeds during treatment thereby decreasing implant preparation time and reducing radionuclide migration within the prostate and periprostatic region. Reliable clinical treatment and planning applications necessitate accurate dosimetric data for source evaluation, therefore the authors report the results of a Monte Carlo study designed to calculate the AAPM Task Group Report No. 43 dosimetric parameters for the SeedLink brachytherapy source and compare these values against previously published Monte Carlo study results of the I-Plant 3500 brachytherapy seed. For this investigation, a total of 1 x 10(9) source photon histories were processed for each set of in-water and in-air calculations using the MCNP4C2 Monte Carlo radiation transport code (RSICC). Statistically, the radial dose function, g(r), and the dose-rate constant, lambda, were identical to the values calculated previously for the Model 3500 with the dose-rate constant evaluated to be lambda = 1.000+/-0.026 cGyh(-1) U(-1). The titanium sleeve used in SeedLink to bind together Model 3500 seeds and spacers resulted in slightly greater dosimetric anisotropy as exhibited in the anisotropy function, F(r, theta), the anisotropy factor, phi(an) (r), and the anisotropy constant, phi(an), which was calculated to be phi(an) = 0.91 +/- 0.01, or roughly 2% lower than the value calculated previously for the Model 3500. These results indicate that the radiological characteristics of the SeedLink dosimetry system are comparable to those obtained for previously characterized single seeds such as the Implant Sciences Model 3500 I-Plant seed.