Results following implementation of a cardiac surgery ERAS protocol.
Adequate peri-operative care is essential to ensuring a satisfactory outcome in cardiac surgery. In this study, we look at the impact of evidence-based protocols implemented at Stanford Hospital. This study is a single-center, retrospective analysis. Enhanced recovery after surgery (ERAS) protocols were implemented for CABG/Valve and open Aortic operations on 11/1/2017 and 6/1/2018, respectively. Propensity-score matched analysis was used to compare 30-day mortality and morbidity of patients from the pre- and post-implementation cohorts. Secondary endpoints included the following: total hospital length of stay (LOS), ICU LOS, time until extubation, and time until urinary catheter removal. After the implementation of the ERAS protocols for CABG/Valve operations, the median post-op LOS decreased from 7.0 days to 6.1 days (p<0.001), and median ICU LOS decreased from 69.9 hours to 54.0 (p = 0.098). There was no significant decrease in 30-day mortality (4% to 3.3%, p = 0.47). However, the incidence of post-op ventilator associated pneumonia (VAP) decreased from 5.0% to 2.1% (p = 0.003) and post-op urinary tract infections (UTIs) from 8.3% to 3.6% (p<0.001). Patients who underwent open aortic procedures experienced an improvement in 30-day mortality (7% to 3.5%, p = 0.012), decrease in median ICU LOS (91.7 hours to 69.6 hours, p<0.001), and a decrease in duration of mechanical ventilation (79.3 hours to 46.3 hours, p = 0.003). There was a decrease in post-op LOS, post-op VAP, and post-op UTI, although statistical significance was not attained. At Stanford Hospital, ERAS pathways have led to decreased morbidity and LOS while simultaneously improving mortality amongst our critically ill patient population.


Temperature and humidity of expired air of sheep.
The temperature and humidity of expired air from three adult Merino sheep were measured at air temperatures of 20, 30 and 40 degrees C before and after the animals were shorn. Expired air was apparently always saturated with water vapour. At the higher air temperatures the temperature of expired air was close to deep body temperature; at lower air temperatures, expired air had been significantly cooled, e.g. to 32.3 degrees C in shorn sheep at 20 degrees C air temperature. Expired air was cooler from shorn than from unshorn animals at 20 and 30 degrees C air temperature, possibly due to thermally induced vasomotor changes in the upper respiratory tract. Cooling of expired air would be expected to lead to recovery of some of the water evaporated during inspiration; at 20 degrees C air temperature, this fraction was estimated to be 25% in unshorn sheep and 36% in shorn sheep.


Targeted epigenetic repression of a lymphoma oncogene by sequence-specific histone modifiers induces apoptosis in DLBCL.
Alterations to the epigenetic landscape of diffuse large B-cell lymphoma (DLBCL) play a fundamental role in deregulating genes involved in normal lymphocyte differentiation. To determine whether targeted epigenetic therapy could reverse these pathogenic chromatin changes and suppress the expression of a lymphoma oncogene, we focused on BCL6, a transcriptional repressor whose aberrant expression is tightly linked to DLBCL proliferation and survival. We fused zinc-finger (ZF) domains specific for regulatory regions in the BCL6 locus to a repressive epigenetic modifier, the Kruppel-associated box (KRAB) repressor domain. Distinct ZF-KRAB fusions repressed the local chromatin landscape, suppressed BCL6 expression, significantly impaired DLBCL growth, and caused widespread cell death in a BCL6-dependent manner. Importantly, expression of ectopic BCL6 protein rescued ZF-KRAB-induced cell death, demonstrating the modifiers' specificity. We show that sequence-specific epigenetic modifiers can alter oncogene expression and induce apoptosis in cancer cells, underscoring their potential for future development as targeted epigenetic protein therapies.


Unveiling the molecular crosstalk in a human induced pluripotent stem cell-derived cardiac model.
In vitro cell-based models that better mimic the human heart tissue are of utmost importance for drug development and cardiotoxicity testing but also as tools to understand mechanisms related with heart disease at cellular and molecular level. Besides, the implementation of analytical tools that allow the depiction and comprehensive understanding of the molecular mechanisms of the crosstalk between the different cell types is also relevant. In this work, we implemented a human cardiac tissue-like in vitro model, derived from human-induced pluripotent stem cell (hiPSC), and evaluated the relevance of the cell-cell communication between the two of the most representative cell populations of the human heart: cardiomyocytes (hiPSC-CM) and endothelial cells (hiPSC-EC). We observed that heterotypic cell communication promotes: (a) structural maturation of hiPSC-CM and (b) deposition of several extracellular matrix components (such as collagens and fibronectin). Overall, the toolbox of analytical techniques used in our study not only enabled us to validate previous reports from the literature on the importance of the presence of hiPSC-EC on hiPSC-CM maturation, but also bring new insights on the molecular mechanisms involved in the communication between these two cell types when cocultured in vitro.


Accuracy in Blood Pressure Monitoring: The Effect of Noninvasive Blood Pressure Cuff Inflation on Intra-arterial Blood Pressure Values.
Both invasive and noninvasive blood pressure (invasive arterial blood pressure [IABP] and noninvasive BP [NIBP]) monitors are used perioperatively; however, they often produce different values. The reason for this discrepancy is not clear, and it is possible that the act of cuff inflation itself might affect the IABP values, especially with the recurrent cycling of NIBP cuff. The aim of this study was to determine the effect of ipsilateral NIBP cuff inflation on the contralateral IABP values. Prospective, observational study. One hundred consecutive patients were studied. The NIBP device was set to cycle every 5 min for a total of 6 times. During each cuff inflation cycle, changes in IABP values from the arterial line in the contralateral arm were recorded. A total of 582 measurements were included for data analysis. Chi-square, paired t-test, analysis of variance. Mean (± standard deviation) changes in systolic BP (SBP), diastolic BP, and mean BP with cuff inflation were 6.7 ± 5.9, 2.6 ± 4.0, and 4.0 ± 3.9 mmHg, respectively. We observed an increase of 0-10 mmHg in SBP in majority (73.4%) of cuff inflations. The changes in IABP did not differ between the patients with or without hypertension or with the baseline SBP. This study showed that there is a transient reactive rise in IABP values with NIBP cuff inflation. This is important information in the perioperative and intensive care settings, where both these measurement techniques are routinely used. The exact mechanism for this effect is not known but may be attributed to the pain and discomfort from cuff inflation.


Suppression of sleep bruxism: effect of electrical stimulation of the masseter muscle triggered by heart rate elevation.
To examine whether electrical stimulation of the masseter muscle triggered by heart rate elevation preceding sleep bruxism (SB) can actively suppress SB. Ten volunteers who were aware of their SB habits participated in the study. Baseline electromyogram (EMG) activity of the unilateral masseter muscle and electrocardiogram (ECG) signal were recorded on the first night. The individual mean sensation and pain thresholds to electrical stimulation of the unilateral masseter muscle were determined in awake subjects before the experiment. On the second night, electrical stimulations at either of the two threshold intensities were automatically generated and delivered to the masseter muscle on the opposite side from where electrodes were placed immediately after the heart rate exceeded 110%. On the third night, electrical stimulations at the other threshold intensity were delivered. The numbers of SB events per night and per hour, the number of EMG bursts per SB event, and the duration of SB events decreased significantly on the nights when stimulation was applied compared with the baseline data. There were no significant differences between cases where the sensation threshold was used as the stimulation intensity and those in which the pain threshold was used as the stimulation intensity. The results suggest that electrical stimulation of the masseter muscle triggered by heart rate elevation can significantly suppress SB.


Early growth response 4 is involved in cell proliferation of small cell lung cancer through transcriptional activation of its downstream genes.
Small cell lung cancer (SCLC) is aggressive, with rapid growth and frequent bone metastasis; however, its detailed molecular mechanism remains poorly understood. Here, we report the critical role of early growth factor 4 (EGR4), a DNA-binding, zinc-finger transcription factor, in cell proliferation of SCLC. EGR4 overexpression in HEK293T cells conferred significant upregulation of specific splice variants of the parathyroid hormone-related protein (PTHrP) gene, resulting in enhancement of the secretion of PTHrP protein, a known mediator of osteolytic bone metastasis. More importantly, depletion of EGR4 expression by siRNA significantly suppressed growth of the SCLC cell lines, SBC-5, SBC-3 and NCI-H1048. On the other hand, introduction of EGR4 into NIH3T3 cells significantly enhanced cell growth. We identified four EGR4 target genes, SAMD5, RAB15, SYNPO and DLX5, which were the most significantly downregulated genes upon depletion of EGR4 expression in all of the SCLC cells examined, and demonstrated the direct recruitment of EGR4 to their promoters by ChIP and luciferase reporter analysis. Notably, knockdown of the expression of these genes by siRNA remarkably suppressed the growth of all the SCLC cells. Taken together, our findings suggest that EGR4 likely regulates the bone metastasis and proliferation of SCLC cells via transcriptional regulation of several target genes, and may therefore be a promising target for the development of anticancer drugs for SCLC patients.


An approach to contrast enhancement in computed tomography of the brain.
A total of 450 brain examinations were performed using computed tomography before and after intravenous infusion of methylglucamine diatrizoate 30%. In 110 cases involving a documented intracranial lesion, the scans were analyzed to determine the degree and usefulness of contrast enhancement. Enhancement was achieved in a wide variety of neoplastic and non-neoplastic lesions and was found to be of considerable help in detection of abnormality as well as in defining tumor morphology.


Cytotoxic triterpenoid saponins from the roots of Cephalaria gigantea.
Three new oleanane-type saponins, giganteosides L (1), M (2) and N (3) along with eight known ones were isolated from the roots of Cephalaria gigantea. Their structures were established as 3-O-[beta-D-galactopyranosyl-(1-->2)-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]-oleanolic acid, 3-O-[beta-D-galactopyranosyl-(1-->2)-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]-hederagenin, 3-O-[alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl]-hederagenin, respectively, by means of spectroscopic methods (1D and 2D NMR, HR-ESI-MS). Cytotoxic activity of monodesmosides was investigated in vitro using three cancer cell lines, namely, human non pigmented melanoma MEL-5 and human leukemia HL-60. Giganteosides D (4) and E (5) showed antiproliferative effect on human cell lines with IC(50) values in the range 3.15-7.5 microM.


Impact of hemicellulose pre-extraction for bioconversion on birch Kraft pulp properties.
The combination of hemicellulose extraction with chemical pulping processes is one approach to generate a sugar feedstock amenable to biochemical transformation to fuels and chemicals. Extractions of hemicellulose from silver birch (Betula pendula) wood chips using either water or Kraft white liquor (NaOH, Na(2)S, and Na(2)CO(3)) were performed under conditions compatible with Kraft pulping, using times ranging between 20 and 90 min, temperatures of 130-160 degrees C, and effective alkali (EA) charges of 0-7%. The chips from select extractions were subjected to subsequent Kraft pulping and the refined pulps were made into handsheets. Several metrics for handsheet strength properties were compared with a reference pulp made without an extraction step. This study demonstrated that white liquor can be utilized to extract xylan from birch wood chips prior to Kraft cooking without decreasing the pulp yield and paper strength properties, while simultaneously impregnating cooking alkali into the wood chips. However, for the alkaline conditions tested extractions above pH 10 resulted in low concentrations of xylan. Water extractions resulted in the highest final concentrations of xylan; yielding a liquor without the presence of toxic or inhibitory inorganics and minimal soluble aromatics that we demonstrate can be successfully enzymatically hydrolyzed to monomeric xylose and fermented to succinic acid. However, water extractions were found to negatively impact some pulp properties including decreases in compression strength, bursting strength, tensile strength, and tensile stiffness while exhibiting minimal impact on elongation and slight improvement in tearing strength index.


Biosynthetic Potential of a Novel Antarctic Actinobacterium Marisediminicola antarctica ZS314T Revealed by Genomic Data Mining and Pigment Characterization.
Rare actinobacterial species are considered as potential resources of new natural products. Marisediminicola antarctica ZS314T is the only type strain of the novel actinobacterial genus Marisediminicola isolated from intertidal sediments in East Antarctica. The strain ZS314T was able to produce reddish orange pigments at low temperatures, showing characteristics of carotenoids. To understand the biosynthetic potential of this strain, the genome was completely sequenced for data mining. The complete genome had 3,352,609 base pairs (bp), much smaller than most genomes of actinomycetes. Five biosynthetic gene clusters (BGCs) were predicted in the genome, including a gene cluster responsible for the biosynthesis of C50 carotenoid, and four additional BGCs of unknown oligosaccharide, salinixanthin, alkylresorcinol derivatives, and NRPS (non-ribosomal peptide synthetase) or amino acid-derived compounds. Further experimental characterization indicated that the strain may produce C.p.450-like carotenoids, supporting the genomic data analysis. A new xanthorhodopsin gene was discovered along with the analysis of the salinixanthin biosynthetic gene cluster. Since little is known about this genus, this work improves our understanding of its biosynthetic potential and provides opportunities for further investigation of natural products and strategies for adaptation to the extreme Antarctic environment.


Gastroesophageal reflux disease: alexithymia and attachment style.
Alexithymia and its relation with attachment style were evaluated in a group of 69 patients (men, M age = 46.4 yr., SD = 12.6; women, M age = 44.2 yr., SD = 14.4) affected by Gastroesophageal Reflux Disease. Two self-evaluation questionnaires were used for psychological evaluation, the 20 item Toronto Alexithymia Scale (TAS-20) and the Attachment Style Questionnaire (ASQ). The TAS-20 analysis showed that the clinical sample taken as a whole did not score in the alexithymic range. The inverse correlations between the Confidence ASQ subscale and the Difficulty Communicating Feelings TAS-20 subscale showed that communication of emotions could develop more easily within the framework of a relational context characterized by safety and confidence. In this group of patients this was represented by the referent caregiver.


High pressure rheology of gas hydrate formed from multiphase systems using modified Couette rheometer.
Conventional rheometers with concentric cylinder geometries do not enhance mixing in situ and thus are not suitable for rheological studies of multiphase systems under high pressure such as gas hydrates. In this study, we demonstrate the use of modified Couette concentric cylinder geometries for high pressure rheological studies during the formation and dissociation of methane hydrate formed from pure water and water-decane systems. Conventional concentric cylinder Couette geometry did not produce any hydrates in situ and thus failed to measure rheological properties during hydrate formation. The modified Couette geometries proposed in this work observed to provide enhanced mixing in situ, thus forming gas hydrate from the gas-water-decane system. This study also nullifies the use of separate external high pressure cell for such measurements. The modified geometry was observed to measure gas hydrate viscosity from an initial condition of 0.001 Pa s to about 25 Pa s. The proposed geometries also possess the capability to measure dynamic viscoelastic properties of hydrate slurries at the end of experiments. The modified geometries could also capture and mimic the viscosity profile during the hydrate dissociation as reported in the literature. The present study acts as a precursor for enhancing our understanding on the rheology of gas hydrate formed from various systems containing promoters and inhibitors in the context of flow assurance.


Evaluation of the functional capacity, respiratory functions and musculoskeletal systems of the children with chest pain for non-cardiac reasons.
Daşkapan A, Şanlı C, Aydoğan-Arslan S, Çiledağ-Özdemir F, Korkem D, Kara U. Evaluation of the functional capacity, respiratory functions and musculoskeletal systems of the children with chest pain for non-cardiac reasons. Turk J Pediatr 2017; 59: 295-303. Chronic chest pain in healthy children and adolescents generally arises from non-cardiac factors. The purpose of our study was to compare the evaluation results of effort test, respiratory function and musculoskeletal system in children and adolescents with chest pain for non-cardiac reasons with healthy children and adolescents. Physical activity level was determined by the International Physical Activity Questionnaire. The respiratory function test was performed using a spirometer. The posture analysis was performed to determine the upper body deformities. The effort test was performed on a treadmill. The two groups were similar in terms of the physical activity levels, respiratory function and effort test results (p > 0.05). The rate of the rounded shoulder, kyphosis was significantly higher in the patient group with chest pain (p < 0.005). Consequently, the musculoskeletal system findings including the pectoralis minor shortness, rounded shoulder, and thoracic kyphosis could have a role in non-cardiac chest pain.


Prospective pilot study on combined use of pulsed dye laser and 1% topical rapamycin for treatment of nonfacial cutaneous capillary malformation.
The regeneration or revascularization of blood vessels after pulsed dye laser (PDL) treatment is one of the causes of treatment failures of cutaneous capillary malformations (CM). Recently, topical administration of rapamycin was introduced as a possible adjunctive therapeutic option to minimize postlaser revascularization in facial CM. We evaluated the effect of combined use of 1% topical rapamycin with PDL compared to PDL alone in cutaneous CM of trunk or extremities and tried to identify the optimal duration of topical rapamycin application. Three adjacent areas of cutaneous CM that had never been treated before were selected in each patient and underwent the following regimens: (A) PDL + vehicle for 8 weeks post-PDL; (B) PDL + topical rapamycin for 1-week post-PDL and (C) PDL + topical rapamycin for 8 weeks post-PDL. Each test site was treated by PDL for two sessions with 8 weeks interval. Only one of six patients showed clinical improvement with combined rapamycin treatment. Overall, there was no statistically significant difference in erythema and blanching rate among PDL alone and combined rapamycin regimens. One percent topical rapamycin does not seem to be effective as a treatment modality for cutaneous CM of trunk or extremities.


Effects of Osmolytes on Ligand Binding to Dihydropteroate Synthase from Bacillus anthracis.
Osmolyte interactions with ligands can affect their affinity for proteins and are dependent upon the cosolute and the functional groups of the ligand. Here, we explored ligand binding to Bacillus anthracis dihydropteroate synthase (BaDHPS) under osmotic stress conditions. Osmolyte effects were specific to the cosolute and ligand, suggesting interaction of the osmolytes with the free ligands in solution. The association rates of pterin pyrophosphate were mostly unaffected by the osmolytes, except for a 2-fold decrease in the presence of 1 M trehalose, while the dissociation rates decreased in most osmolyte solutions. The viscosity and dielectric constant of the solution did not correlate with the effects of the osmolytes. Experimental results were compared with predicted preferential interaction coefficients (Δμ23/RT) between the osmolytes and ligands. The Δμ23/RT were able to predict the experimental data for most of the osmolytes. Trehalose and proline effects did not correlate with the predicted values, indicating that these two osmolytes may affect binding in more complex ways than simple preferential interactions. Additionally, osmolytes weakly interacted with the sulfa drug sulfathiazole, which altered its affinity for BaDHPS, suggesting that these types of weak interactions can also impact drug binding. As osmolytes affect ligands binding to two different folate cycle enzymes (DHFRs and DHPS), we predicted how ligand binding to other folate cycle enzymes will be altered by the presence of osmolytes.


Racial and ethnic disparities in hematologic malignancies.
Racial and ethnic disparities in patients with solid malignancies have been well documented. Less is known about these disparities in patients with hematologic malignancies. With the advent of novel chemotherapeutics and targeted molecular, cellular, and immunologic therapies, it is important to identify differences in care that may lead to disparate outcomes. This review provides a critical appraisal of the empirical research on racial and ethnic disparities in incidence, survival, and outcomes in patients with hematologic malignancies. The review focuses on patients with acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, myeloproliferative neoplasms, and myelodysplastic syndrome. The review discusses possible causes of racial and ethnic disparities and also considers future directions for studies to help decrease disparities.


Improving Optical Measurements: Non-Linearity Compensation of Compact Charge-Coupled Device (CCD) Spectrometers.
Charge-coupled device (CCD) spectrometers are widely used as detectors in analytical laboratory instruments and as sensors for in situ optical measurements. However, as the applications become more complex, the physical and electronic limits of the CCD spectrometers may restrict their applicability. The errors due to dark currents, temperature variations, and blooming can be readily corrected. However, a correction for uncertainty of integration time and wavelength calibration is typically lacking in most devices, and detector non-linearity may distort the signal by up to 5% for some measurements. Here, we propose a simple correction method to compensate for non-linearity errors in optical measurements where compact CCD spectrometers are used. The results indicate that the error due to the non-linearity of a spectrometer can be reduced from several hundred counts to about 40 counts if the proposed correction function is applied.


Bile salt metabolism. I. The physiology of bile salts.
Bile salts are synthesized in the liver from cholesterol, conjugated with glycine or taurine and secreted in bile with cholesterol and lecithin. The molar concentrations of these three lipids determine solubility of cholesterol in bile. Within the gastrointestinal lumen bile salts play an essential role in lipid absorption and faty transport. An efficienct entero-hepatic circulation maintains hepatic bile salt secretion and provides a "feed-back" control of the bile salt and cholesterol metabolism. Potentially hepatotoxic lithocholic acid formed in the intestinal lumen by bacterial action on chenodeoxycholic acid is sulphated in the liver thus decreasing intestinal reabsorption. The total faecal excretion of bile salts balances hepatic synthesis and represents a major catabolic path in cholesterol metabolism.


[Effect of Different Stimulating Strength of Electroacupuncture on Gastrointestinal Motility and RhoA/ROCK Signaling in Gastric Antral Smooth Muscle in Diabetic Gastroparesis Rats].
To observe the effect of different strength of electroacupuncture (EA) stimulation on gastrointestinal motility and Ras homolog gene family member (RhoA)/Rho associated coiled-coil forming protein kinase (ROCK) signaling in diabetic gastroparesis (DGP) rats, so as to reveal the underlying mechanisms of EA for improving DGP. Sixty SD rats were randomly and equally divided into blank control, DGP model, weak EA, medium EA, and strong EA groups (n=12 rats in each). The DGP model was established by intraperitoneal injection of streptozotocin (STZ, 55 mmol/kg, 2%) and high-sugar and high-fat fodder feeding for 8 weeks. EA (0.12, 0.24, 0.36 mA, 20 Hz/100 Hz) was applied to "Zusanli" (ST 36), "Sanyinjiao" (SP 6) and "Liangmen" (ST 21) for 20 min, once daily for 15 successive days. Blood glucose levels were measured weekly with blood glucose meter and blood glucose test paper. Fecal phenol red excretion method was used to display gastric emptying and small intestinal propulsion function. The expression of RhoA protein in the gastric antral smooth muscle tissue was detected by immunohistochemistry and Western blot (WB), separately, and that of ROCK, myosin phosphatase target subunit 1 (MYPT 1) and phosphorylated (p)-MYPT 1 proteins in gastric antrum detected by WB. Compared with the blank control group, the gastric emptying rate and small intestine propulsion rate of the model group were significantly decreased (P<0.05), and the blood glucose level was remarkably increased (P<0.05). Moreover, the expression levels of RhoA, ROCK, MYPT 1 and p-MYPT 1 proteins in the gastric antrum were significantly down-regulated relevant to the control group (P<0.05). After administration of EA, the decreased gastric emptying rate and intestinal propulsion rate, and the down-regulated expression of RhoA, ROCK, MYPT 1 and p-MYPT 1 proteins were significantly increased in the strong, medium and weak EA stimulation groups (P<0.05). Comparison among the 3 EA groups showed that the strong stimulation was significantly superior to weak stimulation in up-regulating the expression of RhoA, ROCK, MYPT 1 and p-MYPT 1 proteins, and obviously superior to the medium stimulation in up-regulating RhoA and MYPT 1 protein levels (P<0.05), while the medium stimulation was significantly stronger than the weak stimulation in up-regulating the expression of ROCK, MYPT 1 and p-MYPT 1 proteins (P<0.05). There were no significant differences among the 3 EA groups in up-regulating the gastric emptying rate and small intestinal propulsion rate, and between the strong stimulation and medium stimulation in the expression levels of ROCK and p-MYPT 1 proteins (P>0.05). Electroacupuncture stimulation of ST 36-SP 6-ST 21 at 0.12, 0.24 and 0.36 mA can promote the gastrointestinal motility in DGP rats, which may be associated with its effects in enhancing RhoA/ROCK signaling in the gastric antral smooth muscle at different degrees.


Artificial Saliva: Challenges and Future Perspectives for the Treatment of Xerostomia.
The chronic sensation of a dry mouth is a disease condition called xerostomia and affects a large part of the population. Xerostomia is associated with decreased secretion, or more often, qualitative changes in saliva proteins and immunoglobulin concentrations that develop as a result of salivary gland dysfunction. Several reasons causing dry mouth were described, and usually, they include taking medications, diseases or radiotherapy. In some situations, when it is difficult to use salivary stimulants or salivary gland damage is irreversible, the only option might seem to be saliva substitutes. The paper presents the most important aspects considering saliva preparations. The rheological and lubricating properties and the reconstruction of the complex saliva structure has been the main purpose of research. The biological properties of saliva preparations were also widely discussed. As part of the work, the antimicrobial effect of three commercial saliva preparations was tested. Finally, inadequate antimicrobial properties against the strains isolated from the oral cavity were demonstrated. The development of salivary substitutes, in particular, the improvement of antimicrobial properties, can be achieved using nanotechnology, including drug delivery systems containing nanocarriers.


Merkel cell carcinoma: a case report.
Merkel cell carcinoma is an uncommon, highly malignant, primary cutaneous neuroendocrine tumour mostly occurring as a solitary nodule on the head or on the extremities. It has high recurrence rate. We hereby report a case of Merkel cell carcinoma in a young woman.


Autoimmune Cytopenia in CLL: Prognosis and Management in the Era of Targeted Therapies.
Chronic lymphocytic leukemia (CLL) is frequently associated with autoimmune hemolytic anemia and immune thrombocytopenia and, less frequently, with pure red cell aplasia and immune neutropenia. The emergence of these complications is related to an intertwined and complex relationship between patient, disease, and treatment characteristics. The prognostic repercussion of autoimmune cytopenia (AIC) in patients with CLL mainly depends on its response to therapy. For patients with AIC and nonactive CLL, treatment is as in primary, uncomplicated AIC, keeping in mind that no response is an indication for CLL therapy. The success of treating active CLL-related AIC widely relies on a flexible strategy that should include initial therapy with corticosteroids and a rapid shift to effective CLL therapy in nonresponding patients. Targeted therapies (e.g., ibrutinib) that have already demonstrated to be effective in CLL-related AIC will likely offer a unique possibility of treating both AIC and CLL as a single target.


Water-soluble ionic benzoporphyrins.
Novel ionic water-soluble tetrabenzoporphyrins have been successfully synthesized via a cascade reaction based on the Heck reaction. The UV-Vis spectra of these porphyrins displayed red-shifted and broadened Soret bands, and significantly enhanced Q bands. These porphyrins are highly water soluble.


Catalyst-Free Insertion of Sulfoxonium Ylides into Aryl Thiols. A Direct Preparation of β-Keto Thioethers.
Insertion of sulfoxonium ylides into the S-H bond of aryl thiols without the need for a catalyst is demonstrated, furnishing β-keto thioethers in excellent yield in most cases. The method overcomes traditional syntheses that employ metal catalysts in combination with diazo compounds or toxic and hard-prepared haloketones. The experimental setup consists of mixing the reagents in acetonitrile at room temperature. Additional experimental as well as kinetic isotopic effect studies give some insight into the mechanism of this reaction.


Potential loss of muscle function during dynamic actions caused by significantly decreased muscle strength in older women with hip osteoarthritis.
The aim of the study was to analyze the results of the hip joint torques within the patients with osteoarthritis (OA). A total of 119 women were divided into 3 groups performing 3 dimensional strength tests. For the measurements a new apparatus was invented and used. Specially designed position was safety and comfortable during testing OA and elderly women. Significant differences (p≤0.05) in strength tests were found both between body side and muscle groups in most of the performed tests. The biggest unilateral deficit in OA group was found in muscles most important for gait and weight bearing − 0.55 for both flexors and extensors. Surprisingly no lateral difference was found for the hip joint adductors. Analysis of the correlation coefficient between the hip joint muscles proved that complex movements needed well-developed coordination between the muscle groups. The most important agonist muscle coordination occurs between hip extensors and abductors − 0.68 to 0.80. Unilateral hip OA affecting older women is directly responsible for significantly lower muscle strength when compared with both control groups. Lost of balance and coordination needed for dynamic actions like gait is caused by strength asymmetry of crucial hip muscles as well as near zero correlation between important agonist muscles.


Dihydroartemisinin ameliorates the liver steatosis in metabolic associated fatty liver disease mice by attenuating the inflammation and oxidative stress and promoting autophagy.
To explore the effect and potential mechanism of dihydroartemisinin (DHA) on metabolism-related fatty liver disease. A metabolic associated fatty liver disease (MAFLD) mice model was induced with continuous supplies of high-fat diet. DHA was intraperitoneally injected into mice. The weight of mice was monitored. The concentrations of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in serum were detected by an automatic biochemical analyzer. The liver tissues were stained by hematoxylin and eosin and oil red O. The level of inflammation, oxidative stress, and autophagy was assessed by reverse transcription polymerase chain reaction, biochemical examination, Western blot and transmission electron microscope assays. DHA treatment reduced theMAFLD-enhanced the level of weight gain, the concentrations of TC, TG, LDL and malonaldehyde, while increasedthe MAFLD-decreased the concentrations of HDL and superoxide dismutase. DHA ameliorated the MAFLD-aggravated pathological changes and the number of lipid droplets. Low dose of DHA declined the MAFLD-induced the enhancement of the expression of inflammatory factor. DHA treatment increased the MAFLD-enhanced the level of autophagy related protein, while decreased the MAFLD-reduced the protein level of p62. The increased level of autophagy was confirmed by transmission electron microscope. DHA can improve liver steatosis in MAFLD mice by inhibiting inflammation and oxidative stress and promoting autophagy.


Monoclonal antibodies produced against antigenic determinants present in complex mixtures of proteins.
This overview provides information concerning the production of monoclonal antibodies (MAbs) against specific antigenic determinants present in complex mixtures of proteins. We review five specific techniques for the production of these antibodies (Abs): (a) So-called "shotgun," non-selective approach; (b) cascade procedure; (c) lymphocyte "panning"; (d) cyclophosphamide elimination of unwanted Ab producers; and finally (e) use of polyclonal antisera to extinguish unwanted antibody production. We discuss the relative advantages and disadvantages of these various procedures, and suggest alternative strategies by which specific MAbs might be generated.


PD-1 Blockade Promotes Emerging Checkpoint Inhibitors in Enhancing T Cell Responses to Allogeneic Dendritic Cells.
Immune checkpoint inhibitors, which target coinhibitory T cell molecules to promote anticancer immune responses, are on the rise to become a new pillar of cancer therapy. However, current immune checkpoint-based therapies are successful only in a subset of patients and acquired resistances pose additional challenges. Finding new targets and combining checkpoint inhibitors might help to overcome these limitations. In this study, human T cells stimulated with allogeneic dendritic cells (DCs) were used to compare immune checkpoint inhibitors targeting TIM-3, BTLA, LAG-3, CTLA-4, and TIGIT alone or in combination with a PD-1 antibody. We found that PD-1 blockade bears a unique potency to enhance T cell proliferation and cytokine production. Other checkpoint inhibitors failed to significantly augment T cell responses when used alone. However, antibodies to TIM-3, BTLA, LAG-3, and CTLA-4 enhanced T cell proliferation in presence of a PD-1 antibody. Upregulation of coinhibitory T cell receptors upon PD-1 blockade was identified as a potential mechanism for synergistic effects between checkpoint inhibitors. Donor-specific variation in response to immune checkpoint inhibitors was attributed to the T cells rather than DCs. Additionally, we analyzed the regulation of checkpoint molecules and their ligands on T cells and allogeneic DCs in coculture, which suggested a PD-1 blockade-dependent crosstalk between T cells and APC. Our results indicate that several immune checkpoint inhibitors have the capacity to enhance T cell responses when combined with PD-1 blockade. Additional in vitro studies on human T cells will be useful to identify antibody combinations with the potential to augment T cell responses in cancer patients.


Effect of Hip Prosthesis on Photon Beam Characteristics in Radiological Physics.
Aim of study is to investigate the effect of hip prosthesis on 6 and 15 MV photon beam energies. Prosthesis was kept at the level of tray position. The measurements were done on Varian Clinac-iX linac. Customized prosthesis, termed as Prosthetic Metal Implant (PMI) was made up of wrought austenitic stainless steel rod and covered with paraffin-wax. 'Standard prosthesis' was made up of wrought titanium alloy. The dose profiles were measured for three field sizes i.e. 5, 10 and 20 cm at 100 cm SSD for 6 and 15 MV energies. The perturbation index (PI) was also calculated. Perturbation caused by standard prosthesis was approximately 50% higher than that of PMI. This result may be due to difference in dimension and not because of material composition. Variation of central axis dose might be due to the dimensions of PMI used for experiment which gave intermediate response (e.g. 102.1%, 141.0% and 117.7% for Open, Standard and PMI respectively for 10x10 cm2 field size, 10 cm depth and 15MV photon beam setup )as compared to the 'open' and 'standard' prosthesis. Percentage dose at 10 cm for 6MV photon increased rapidly with field-size for PMI. But, for 15MV photon, difference was not significant. Surface dose (Ds) for PMI remains significantly higher for smaller field. The perturbation index varied from 0.05 to 0.22 for the measured energies and gave an idea to the planner to assess the behavior of the prosthesis. This range is applicable for both type of implants and for all clinical field-sizes. The attenuation caused by the prosthesis was significant and this effect should be considered in the treatment planning calculations.


Monolayer Borophene Formation on Cu(111) Surface Triggered by ⟨ 1 1 ¯ 0 ⟩ $\langle {1\bar{1}0} \rangle $ Step Edge.
Borophene, a promising material with potential applications in electronics, energy storage, and sensors, is successfully grown as a monolayer on Ag(111), Cu(111), and Au(111) surfaces using molecular beam epitaxy. The growth of two-dimensional borophene on Ag(111) and Au(111) is proposed to occur via surface adsorption and boron segregation, respectively. However, the growth mode of borophene on Cu(111) remains unclear. To elucidate this, scanning tunneling microscopy in conjunction with theoretical calculations is used to study the phase transformation of boron nanostructures under post-annealing treatments. Results show that by elevating the substrate temperature, boron nanostructures undergo an evolution from amorphous boron to striped-phase borophene (η = 1/6) adhering to the Cu ⟨ 1 1 ¯ 0 ⟩ $\langle {1\bar{1}0} \rangle $ step edge, and finally to irregularly shaped β-type borophene (η = 5/36) either on the substrate surface or embedded in the topmost Cu layer. dI/dV spectra recorded near the borophene/Cu lateral interfaces indicate that the striped-phase borophene is a metastable phase, requiring more buckling and electron transfer to stabilize the crystal structure. These findings offer not only an in-depth comprehension of the β-type borophene formation on Cu(111), but also hold potential for enabling borophene synthesis on weakly-binding semiconducting or insulating substrates with 1D active defects.


Dose-related inhibition of gastric secretion by intraduodenal trypsinogen in dogs.
It has been shown previously that trypsinogen and its activation peptide but not trypsin decreased gastric secretion. The purpose of this work was to study the dose-action relation between the intraduodenal infusion of trypsinogen and gastric secretion. Three dogs provided with gastric and duodenal Thomas fistulae were stimulated by continuous i.v. perfusion of porcine gastrin I-II (6 microgram kg-1 h-1). Pancreatic juice was diverted to the exterior and gastric secretion was collected. Upon reaching a gastric secretory plateau, porcine trypsinogen was infused intraduodenally at doses of 5, 10, 20, 40, 80 and 160 mg. Each test was continued for a further 60 min. Control was made with isotonic saline. There was a dose-related inhibition of the gastrin-stimulated gastric acid output. This inhibition reached a maximum of 50% with 40 mg of intraduodenal trypsinogen, showing no increase with higher doses.


Aloe spp.--plants with vertebrate-like telomeric sequences.
Chromosome termini of most eukaryotes end in tracks of short tandemly repeated GC-rich sequences, the composition of which varies among different groups of organisms. Plant species predominantly contain (TTTAGGG)n repeats at their telomeres. However, a few plant species, including members of Alliaceae and Aloe spp. (Asphodelaceae) were found to lack such Arabidopsis-type (T3AG3)n telomeric repeats. Recently, it has been proposed that the lack of T3AG3 telomeric repeat sequences extends to all species forming the Asparagales clade. Here, we analysed the composition of Aloe telomeres by single-primer PCR and fluorescence in-situ hybridization (FISH) with directly labelled Arabidopsis-type (TTTAGGG)28-43 DNA probe, and with vertebrate-type (TTAGGG)33-50 DNA and a (C3TA2)3 peptide nucleic acid (PNA) probe. It was found that Nicotiana tabacum contained Arabidopsis-type telomeric repeats, while Aloe telomeres lacked the corresponding FISH signals. Surprisingly, FISH with the highly specific vertebrate-type (C3TA2)3 PNA probe resulted in strong T2AG3-specific FISH signals at the ends of chromosomes of both Aloe and Nicotiana tabacum, suggesting the presence of T2AG3 telomeric repeats in these species. FISH with a long (TTAGGG)33-50 DNA probe also highlighted Aloe chromosome ends, while this probe failed to reveal FISH signals on tobacco chromosomes. These results indicate the presence of vertebrate-like telomeric sequences at the telomeres of Aloe spp. chromosomes. However, single-primer PCR with (TAG3)5 primers failed to amplify such sequences in Aloe, which could indicate a low copy number of T2AG3 repeats at the chromosome ends and/or their co-orientation and interspersion with other repeat types. Our results suggest that telomeres of plant species, which were thought to lack GC-rich repeats, may in fact contain variant repeat types.


Design and Construction of a Smart Targeting Drug Delivery System Based on Phototriggered Competition of Host-Guest Interaction.
A smart targeting drug delivery nanocarrier is successfully constructed based on phototriggered competition of host-guest interaction. The targeting motif, i.e., biotin is first concealed by β-cyclodextrin (β-CD) via host-guest interaction. When the nanoparticles are exposed to UV light, the cleavage of photosensitive groups results in the exposure of adamantane (Ad) groups initially located in the interior of nanoassemblies, and β-CDs capped on biotin ligands can be replaced by Ad because of the higher binding constant between Ad and β-CD than that between biotin and β-CD. The competition of host-guest interaction leads to the recovery of targeting capacity of biotin ligands on the nanocarriers. By virtue of photoregulation, the nanocarriers exhibit controllable ligand-receptor recognition, which is proved by flow cytometry, laser confocal microscopy, and cytotoxicity assay. This strategy has a potential to improve the selectivity and safety of targeting drug delivery systems.


67Cu-Radiolabeling of a multimeric RGD peptide for αVβ3 integrin-targeted radionuclide therapy: stability, therapeutic efficacy, and safety studies in mice.
Copper-67 (Cu) is one of the most promising radionuclides for internal radiation therapy. Globally, several projects have recently been initiated for developing innovative approaches for the large-scale production of Cu. Encouraged by these, we performed Cu-radiolabeling of a tetrameric cyclic Arg-Gly-Asp (cRGD) peptide conjugate, cyclam-RAFT-c(-RGDfK-)4, which selectively targets αVβ3 integrin (αVβ3), the transmembrane receptor involved in tumor invasion, angiogenesis, and metastasis. We also evaluated the therapeutic potential and safety of this radiocompound. Cu, produced through the Ni(α, p)Cu reaction, was used for the radiolabeling of cyclam-RAFT-c(-RGDfK-)4 at 70°C for 10 min. The radiolabeling efficiency and product stability were assessed using reversed-phase high-performance liquid chromatography and/or thin-layer chromatography. Mice with subcutaneous αVβ3-positive U87MG-glioblastoma xenografts received a single intravenous injection of one of the following: Cu-cyclam-RAFT-c(-RGDfK-)4 (11.1 MBq), peptide control, or vehicle solution. The tumor volumes were measured, side effects were assessed in terms of body weight, routine hematology, and hepatic and renal functions, and the mouse radiation dosimetry was estimated. Cu-cyclam-RAFT-c(-RGDfK-)4 was produced with a radiochemical purity of 97.9±2.4% and a specific activity of 2.7±0.6 MBq/nmol and showed high in-vitro and in-vivo plasma stability. The administration of a single dose of Cu-cyclam-RAFT-c(-RGDfK-)4 resulted in significant tumor growth delay in comparison with that observed upon vehicle or peptide control administration, with an estimated tumor-absorbed dose of 0.712 Gy. No significant toxicity was observed in Cu-cyclam-RAFT-c(-RGDfK-)4-treated mice. Cu-cyclam-RAFT-c(-RGDfK-)4 would be a promising therapeutic agent for αVβ3 integrin-targeted internal radiotherapy.


Effect of pulsed light on curcumin chemical stability and antioxidant capacity.
Curcumin is the major bioactive component in turmeric with potent antioxidant activity. Little is known about how pulsed light (PL) technology (an emerging non-thermal food processing technology relying on high intensity short duration flashes of light) can affect the chemical stability and antioxidant capacity of curcumin. This study found that PL treatment of fluence levels from 0 to 12.75 J/cm2 produced a fluence-dependent reduction in curcumin content. These results paralleled the production of a tentative curcumin dimer, identified as a potential photochemical transformation product. PL-treated curcumin at relatively higher fluence levels decreased chemical-based ORAC and ABTS antioxidant capacity, relative to control (P < 0.05). This contrasted the effect observed to increase coincidently both intracellular antioxidant capacity (e.g., DCFH-DA (P < 0.05)) and GSH/GSSG ratio (P < 0.05), respectively, in cultured differentiated Caco-2 cells. In conclusion, the application of PL on curcumin results in photochemical transformation reactions, such as dimerization, which in turn, can enhance biological antioxidant capacity in differentiated Caco-2 cells.


Identification of a new Schistosoma mansoni membrane-bound protein through bioinformatic analysis.
Progress in schistosome genome research has enabled investigators to move rapidly from genome sequences to vaccine development. Proteins bound to the surface of parasites are potential vaccine candidates, or they can be used for diagnosis. We analyzed 4342 proteins deduced from the Schistosoma mansoni transcriptome with bioinformatic computer programs. Thirty-four proteins had membrane-bound motifs. Within this group, we selected the Sm29 protein to be further characterized by in silico analysis. Sm29 was found to have a signal peptide made up of 26 amino acids, with a cleavage site between Ser26 and Val27. The glycosylation site search revealed three threonines (39, 132 and 133) with high probability of O-glycosylation and two asparagines (58 and 115) with high probability of N-glycosylation. Only one transmembrane helix was found in the C-terminal region of the protein from Leu169 to Lis191. The search for similarities and conserved motifs show that Sm29 is a protein with high identity to proteins present in S. japonicum (53, 52, 49, and 37% of identity) and it possesses disulfide-rich conserved domains. Apparently, Sm29 is a membrane bound protein, and it may be an important molecule in host-parasite interactions.


High-precision camera calibration based on a 1D target.
In this paper, the problem of camera 1D calibration is well solved by our proposed high-precision algorithm, which can satisfy actual requirements. We present a viewpoint that the closed-form solution can simply achieve high calibration accuracy in the absence of distortion. So, we abandon the habitual strategy of global nonlinear optimization for all intrinsic and extrinsic parameters. The innovations of the proposed algorithm are three-fold: firstly, cyclic distortion correction method is introduced to ensure that the estimated distortion parameters gradually approach the exact values; secondly, a new criterion for the nonlinear optimization of distortion correction is developed; thirdly, we enhance the anti-noise ability of the closed-form solution by optimally weighting the constraint equations. Extensive experiments prove that the proposed algorithm provides the highest calibration accuracy and robustness, which is comparable to 2D calibration. In addition, our proposed algorithm provides a new approach for desirable distortion correction and an idea for 2D calibration of large field of view.


Interdisciplinary shared decision-making: taking shared governance to the next level.
Healthcare organizations have been challenged to make high-quality, safe, and reliable care more affordable, portable, transparent, and efficient. Skillful leadership and contributions from all members of the organization are needed to accomplish these changes. This article describes how one organization, driven by a vision for finding better ways, embarked on a journey to design, implement, and refine their model for interdisciplinary shared decision-making (SDM). The model was based on the principles of accountability, equity, ownership, and partnership, and designed to support staff members in right decision-making at the point of service. The success of SDM depends on leaders who believe in the process and demonstrate their commitment by holding front-line managers accountable for allocating resources and coaching staff. Point-of-service staff, in turn, must accept ownership and accountability for the content of their work and be willing to develop their SDM knowledge, comfort, and skills over time. Preliminary outcomes indicate that these new processes have had a positive effect in helping the organization find better ways to innovate and improve patient care.


Euglenophycin is produced in at least six species of euglenoid algae and six of seven strains of Euglena sanguinea.
Euglena sanguinea is known to produce the alkaloid toxin euglenophycin and is known to cause fish kills and inhibit mammalian tissue and microalgal culture growth. An analysis of over 30 species of euglenoids for accumulation of euglenophycin identified six additional species producing the toxin; and six of the seven E. sanguinea strains produced the toxin. A phylogenetic assessment of these species confirmed most taxa were in the Euglenaceae, whereas synthesis capability apparently has been lost in the Phacus, Eutreptiella, and Discoplastis branches.


The metastasis suppressor, NDRG1, inhibits "stemness" of colorectal cancer via down-regulation of nuclear β-catenin and CD44.
N-myc downstream-regulated gene 1 (NDRG1), has been identified as an important metastasis suppressor for colorectal cancer (CRC). In this study, we investigated: (1) the effects of NDRG1 on CRC stemness and tumorigenesis; (2) the molecular mechanisms involved; and (3) the relationship between NDRG1 expression and colorectal cancer prognosis. Our investigation demonstrated that CRC cells with silenced NDRG1 showed more tumorigenic ability and stem cell-like properties, such as: colony and sphere formation, chemoresistance, cell invasion, high expression of CD44, and tumorigenicity in vivo. Moreover, NDRG1 silencing reduced β-catenin expression on the cell membrane, while increasing its nuclear expression. The anti-tumor activity of NDRG1 was demonstrated to be mediated by preventing β-catenin nuclear translocation, as silencing of this latter molecule could reverse the effects of silencing NDRG1 expression. NDRG1 expression was also demonstrated to be negatively correlated to CRC prognosis. In addition, there was a negative correlation between NDRG1 and nuclear β-catenin and also NDRG1 and CD44 expression in clinical CRC specimens. Taken together, our investigation demonstrates that the anti-metastatic activity of NDRG1 in CRC occurs through the down-regulation of nuclear β-catenin and suggests that NDRG1 is a significant therapeutic target.


Making the call: the diagnosis of acute community-acquired bacterial sinusitis.
Although one of the most common illnesses encountered in the primary care setting, acute community-acquired bacterial sinusitis (ACABS) can be a challenge to diagnose. Existing diagnostic modalities ranging from clinical history to imaging studies used to diagnose ACABS are discussed. Numerous methods exist but they do not distinguish well between viral and bacterial illness. Diagnosis of ACABS should primarily be made based on the clinical history. Other modalities provide useful information in select cases.


Intratumoral heterogeneity in prostate cancer demonstrated by volume-weighted mean nuclear volume.
This study was conducted to investigate the degree of heterogeneity of the volume-weighted mean nuclear volume (MNV) calculated from radical prostatectomy specimens, and to evaluate how closely the MNV calculated from transrectal biopsy specimens reflected the overall malignancy. MNV was evaluated using 77 sections of histological specimens from 9 patients who underwent radical prostatectomy at Shizuoka City Hospital between January 1990 and December 1995. The MNV values calculated from radical prostatectomy specimens were compared with those calculated from preoperative transrectal biopsy specimens. MNV was judged to be homogeneous in six cases and heterogeneous in three cases. Of the heterogeneous cases, MNV calculated from the transrectal biopsy specimens was judged to be underestimated in 2 of 3 cases. This study shows that intratumoral heterogeneity of prostate cancer may affect clinical estimates of the grade of malignancy based on the MNV, and indicates the need for a sufficient number of specimens in order to evaluate the MNV by transrectal biopsy.


Effect of copigments and grape cultivar on the color of red wines fermented after the addition of copigments.
The prefermentation addition of copigments led to significantly different red wines according to the copigment structure (flavonol or hydroxycinnamic acid) and the grape cultivar [Tempranillo (= Cencibel) or Cabernet Sauvignon]. The flavonol rutin enhanced copigmentation and anthocyanin extraction, improving the red color, but the hydroxycinnamic acids (especially caffeic acid) had converse results. The above effects were higher in Cabernet Sauvignon wines, particularly if rutin or p-coumaric acid was used. These wines showed the highest copigmentation as they contained more anthocyanins and flavonols, whereas the coumaroylated anthocyanins of Tempranillo wines could have prevented the action of the added copigments. After 21 months, the main pyranoanthocyanins found were the malvidin-3-glucoside 4-vinylphenol and the malvidin-3-glucoside 4-vinylcatechol (pinotin A) adducts. The results suggested that the former adduct was primarily generated following enzymatic decarboxylation of p-coumaric acid during fermentation, whereas pinotin A was formed through a pure chemical reaction, which depended on the concentration of free caffeic acid during aging.


Estimation of Premature Deaths From Lack of Access to Anti-HER2 Therapy for Advanced Breast Cancer in the Brazilian Public Health System.
Patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic tumors treated in the public health system in Brazil do not have access to trastuzumab. This study aimed to estimate the impact of the lack of access to anti-HER2 therapies on the mortality of these patients. On the basis of published data, the number of patients with HER2-positive advanced breast cancer in 2016 who should receive anti-HER2 targeted therapy was estimated. Three different treatment groups were considered for this hypothetical cohort: chemotherapy alone, chemotherapy plus trastuzumab, and chemotherapy plus trastuzumab and pertuzumab. The number of patients alive after 2 years of follow-up was estimated on the basis of the efficacy results of the pivotal trials considering these interventions. It was calculated that 2,008 women will be diagnosed with advanced HER2-positive breast cancer in Brazil in 2016. It was estimated that only 808 women would be alive in 2018 if they receive only chemotherapy (which is the treatment offered by the public health system). On the other hand, the bar rises to 1,408 women alive in 2018 if they receive chemotherapy plus trastuzumab and 1,576 women alive in 2018 if they receive the gold standard of chemotherapy plus trastuzumab and pertuzumab. Trastuzumab is included in the WHO's list of essential medications, but the Brazilian public health system does not yet provide this treatment to its population with advanced disease. The introduction of trastuzumab and pertuzumab would have a positive effect, preventing premature deaths in women with metastatic HER2-positive breast cancer in Brazil.


Reproductive health of Roma women in Slovakia.
In most indicators of the way of life, the Roma community is generally different from the majority population and dominant culture. The objective of the study was to describe factors affecting the health of the Roma living in Slovakia, with an emphasis on the sexual and reproductive health of Roma women, and report on the results of analysis of high-risk pregnancies of Roma women in the district of Rimavská Sobota, Slovakia. A retrospective study of medical documentation was used. The results were analyzed using the absolute and relative frequencies. Statistical methods were used. A total of 1,256 high-risk pregnancies were analyzed, of which 622 (49.52%) were in Roma women. The average age of Roma respondents was lower by 5 years compared to non-Roma. The age of Roma women at the first pregnancy was statistically significantly lower compared to non-Roma (p < 0.001). The Roma respondents achieved statistically significantly lower levels of education than non-Roma. There was a demonstrably higher number of pregnancies as well as a higher number of artificial and spontaneous abortions per Roma woman. These results were statistically significant. For Roma women, pregnancy began to be risky demonstrably earlier than for non-Roma (p < 0.001). There was a statistically significant difference in attending prenatal counselling. Roma women attended prenatal counselling statistically significantly less frequently than non-Roma (p < 0.001). A significant statistical dependence was found between attending prenatal counselling and the onset of pregnancy problems in Roma women. There was no significant difference in the incidence of other diseases associated with high-risk pregnancy among Roma and non-Roma respondents. The findings indicate that Roma women are exposed to health problems in the area of sexual and reproductive health in Slovakia. In the approach to the Roma, it is essential to focus on improving accessibility to health care, prevention, knowledgeableness and effectively preventing, eradicating and strongly penalizing all forms of discrimination in access to health care, especially for Roma women, who are more likely to receive health care.


Genetic variation of aggrecanase-2 (ADAMTS5) in susceptibility to osteoarthritis.
Aggrecanase-2 (ADAMTS5) gene is responsible for aggrecan degradation that may contribute to cartilage destruction in a mouse osteoarthritis (OA) model. We aimed to investigate the effects of ADAMTS5 gene polymorphisms on OA risk in a Chinese population. A total of 300 OA patients and 300 controls were recruited and their genotypes for ADAMTS5 gene rs226794 and rs2830585 polymorphisms were determined using a custom-by-design 48-Plex single nucleotide polymorphism Scan™ kit. ADAMTS5-associated genes were identified by co-expression analysis and their functions were investigated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Bioinformatics analysis showed that ADAMTS5 was significantly related to the components, structural constituent, and organization of the extracellular matrix. The rs2830585 polymorphism, but not rs226794 polymorphism, was significantly associated with an increased risk of knee OA. Stratified analysis further confirmed this significant association in patients at age ≥55 years. In conclusion, the ADAMTS5 rs2830585 polymorphism may be involved in the development of knee OA by destroying the extracellular matrix, but this finding should be further confirmed by larger studies.


Treatment for amblyopia after surgery for cataract and vitreoretina in pediatric ocular trauma.
We investigated the value of occlusion therapy assisted by wearing spectacles or implanting an intraocular lens following surgeries for cataract and vitreoretina in pediatric pa-tients. Fifty-one children with ocular trauma, aged from 3 to 12 years, were enrolled in this study, including 39 cases of open global injuries and 12 ocular blunt injuries. The patients underwent a series of surgeries, including suture of the cornea or sclera wound, cataract extraction, vitrectomy, and repair of retinal detachment in some cases. Occlusion therapy was prescribed for 29 eyes wearing spectacles and 22 eyes with implanted intraocular lenses (IOLs) for 6 to 12 months. All the children were followed up for 12 to 60 months (mean 41.5 months) after the final operations. Best corrected visual acuity was improved in 32 eyes (62.7%) and not improved in 19 eyes (37.3%), including 6 eyes with a leucoma involving the central cornea, 5 eyes with a retina scar involving the macula, and 2 eyes with unsatisfactory overall patching time. Occlusion therapy assisted by wearing spectacles (65.5%) and implanting IOLs (59.1%) showed similar improvements in the visual acuity of the injured eyes. Occlusion therapy, combined with wearing spectacles and implanting IOLs, is valuable in treating deprivation amblyopia due to ocular trauma and series surgeries in pediatric patients. Spectacles may be dependable during occlusion therapy in the early post-surgery stage.


Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation.
Cancer-associated fibroblasts (CAFs) are important for tumor initiation and promotion. CSL, a transcriptional repressor and Notch mediator, suppresses CAF activation. Like CSL, ATF3, a stress-responsive transcriptional repressor, is down-modulated in skin cancer stromal cells, and Atf3 knockout mice develop aggressive chemically induced skin tumors with enhanced CAF activation. Even at low basal levels, ATF3 converges with CSL in global chromatin control, binding to few genomic sites at a large distance from target genes. Consistent with this mode of regulation, deletion of one such site 2 Mb upstream of IL6 induces expression of the gene. Observed changes are of translational significance, as bromodomain and extra-terminal (BET) inhibitors, unlinking activated chromatin from basic transcription, counteract the effects of ATF3 or CSL loss on global gene expression and suppress CAF tumor-promoting properties in an in vivo model of squamous cancer-stromal cell expansion. Thus, ATF3 converges with CSL in negative control of CAF activation with epigenetic changes amenable to cancer- and stroma-focused intervention.


Synthesis and characterization of highly ordered cobalt-magnetite nanocable arrays.
Magnetically tunable, high-density arrays of coaxial nanocables within anodic aluminum oxide (AAO) membranes have been synthesized. The nanocables consist of magnetite nanowires surrounded by cobalt nanotube sheaths and cobalt nanowires surrounded by magnetite nanotube sheaths. These materials are a combination of separate hard (Co) and soft (Fe3O4) magnetic materials in a single nanocable structure. The combination of two or more magnetic materials in such a radial structure is seen as a very powerful tool for the future fabrication of magnetoresistive, spin-valve and ultrafast spin-injection devices with nonplanar geometries. The nanocable arrays were prepared using a supercritical-fluid inclusion process, whereby the nanotube was first deposited onto the pore walls of the nanoporous membranes and subsequently filled with core material to form coaxial nanocables. In essence, this paper describes a technique for placing novel magnetic technologies into well-defined building blocks that may ultimately lead to new multifunctional devices, such as spin valves and high-density magnetic storage devices.


A risk-based approach to management of leachables utilizing statistical analysis of extractables.
To incorporate quality by design concepts into the management of leachables, an emphasis is often put on understanding the extractable profile for the materials of construction for manufacturing disposables, container-closure, or delivery systems. Component manufacturing processes may also impact the extractable profile. An approach was developed to (1) identify critical components that may be sources of leachables, (2) enable an understanding of manufacturing process factors that affect extractable profiles, (3) determine if quantitative models can be developed that predict the effect of those key factors, and (4) evaluate the practical impact of the key factors on the product. A risk evaluation for an inhalation product identified injection molding as a key process. Designed experiments were performed to evaluate the impact of molding process parameters on the extractable profile from an ABS inhaler component. Statistical analysis of the resulting GC chromatographic profiles identified processing factors that were correlated with peak levels in the extractable profiles. The combination of statistically significant molding process parameters was different for different types of extractable compounds. ANOVA models were used to obtain optimal process settings and predict extractable levels for a selected number of compounds. The proposed paradigm may be applied to evaluate the impact of material composition and processing parameters on extractable profiles and utilized to manage product leachables early in the development process and throughout the product lifecycle.


Conjugative DNA Transfer Is Enhanced by Plasmid R1 Partitioning Proteins.
Bacterial conjugation is a form of type IV secretion used to transport protein and DNA directly to recipient bacteria. The process is cell contact-dependent, yet the mechanisms enabling extracellular events to trigger plasmid transfer to begin inside the cell remain obscure. In this study of plasmid R1 we investigated the role of plasmid proteins in the initiation of gene transfer. We find that TraI, the central regulator of conjugative DNA processing, interacts physically, and functionally with the plasmid partitioning proteins ParM and ParR. These interactions stimulate TraI catalyzed relaxation of plasmid DNA in vivo and in vitro and increase ParM ATPase activity. ParM also binds the coupling protein TraD and VirB4-like channel ATPase TraC. Together, these protein-protein interactions probably act to co-localize the transfer components intracellularly and promote assembly of the conjugation machinery. Importantly these data also indicate that the continued association of ParM and ParR at the conjugative pore is necessary for plasmid transfer to start efficiently. Moreover, the conjugative pilus and underlying secretion machinery assembled in the absence of Par proteins mediate poor biofilm formation and are completely dysfunctional for pilus specific R17 bacteriophage uptake. Thus, functional integration of Par components at the interface of relaxosome, coupling protein, and channel ATPases appears important for an optimal conformation and effective activation of the transfer machinery. We conclude that low copy plasmid R1 has evolved an active segregation system that optimizes both its vertical and lateral modes of dissemination.


Breast Cancer Immunotherapy.
Although unlikely to replace current standard of care therapies, immunotherapy is emerging as a critical component of breast cancer treatment. Despite initial setbacks, clinical benefit is now evident through immunomodulation and cancer vaccines. Over the past decade, passive immunotherapeutic strategies such as anti-HER2 monoclonal antibody (mAb) therapy have significantly improved the prognosis in HER2 overexpressing breast cancers. Novel active immunotherapeutic strategies include checkpoint blockade modifiers, also a mAb therapy. Although non-specific, checkpoint blockade modifiers show great promise in clinical trials. A form of active and specific immunotherapy, cancer vaccines may be used alone or in conjunction with these aforementioned mAb therapies. While there is significant initial promise, the complexities of the host immune system-tumor interaction and the vast array of potential immune targets require the field of cancer immunotherapy to be further developed. Here, we briefly discuss the field of breast immunotherapy to date and its implications for the future of breast cancer care.


Iridoid glycosides from Globularia davisiana.
From the ethanolic extract of the aerial parts of Globularia davisiana, a new iridoid glycoside, davisioside (1), was isolated. Davisioside (1) comprises a rare iridoid aglycone structure with a saturated double bond between C-3 and C-4. Nine known iridoid glycosides, asperuloside (2), alpinoside (3), geniposide (4), globularin (5), globularicisin (6), 10-O-benzoylcatalpol (7), lytanthosalin (8), melampyroside (9), agnuside (10), and three known phenylethanoid glycosides, verbascoside, isoacteoside and leucosceptoside A were also isolated and characterized. The structures of the isolates were established by spectroscopic methods (one-dimensional (1D)- and two-dimensional (2D)-NMR, MS).


The therapeutic release of anger: Helen Watkins's silent abreaction and subsequent elaborations of the anger rock.
This paper summarizes Helen Watkins's (1980) silent abreaction technique for releasing anger and the subsequent elaborations it has inspired. Discussion of Watkins's seminal article incorporates her verbatim account of the technique, 2 clinical applications, and her encouragement of further adaptations. Other scholars' subsequent contributions include an adaptation for dissociative identity disorder, brief treatment of constant pain syndrome, and inpatient treatment of a suicidally depressed, dissociative survivor of sexual abuse. Commonalities and distinctions among Watkins's work and these modifications are discussed. New case material from the author's practice illustrate further elaborations, with emphasis on the role of releasing anger in the resolution of dissociative defenses and internal fragmentation in dissociative clients. To enhance the clinical utility of this paper, verbatim passages are included for all case illustrations in H. H. Watkins (1980), the 3 published elaborations, and the new case material.


Current Sample Preparation Methods and Determination Techniques for the Determination of Phthalic Acid Ester Plasticizers in Edible Oils.
In the process of production, processing, transportation, and storage of edible oils, the oils inevitably come into contact with plastic products. As a result, plasticizers migrate into edible oils, are harmful to human health, and can exhibit reproductive toxicity. Therefore, the determination of plasticizers in edible oils is very important, and a series of sample preparation methods and determination techniques have been developed for the determination of plasticizers in edible oils. Phthalic acid ester (PAE) plasticizers are the most widely used among all plasticizers. This review aims to provide a comprehensive overview of the sample preparation methods and detection techniques reported for the determination of PAEs in edible oils since 2010, focusing on sample preparation methods of edible oils combined with various separation-based analytical techniques, such as gas chromatography (GC) and liquid chromatography (LC) with different detectors. Furthermore, the advantages, disadvantages, and limitations of these techniques as well as the prospective future developments are also discussed.


Neurodegeneration in ataxia-telangiectasia: Multiple roles of ATM kinase in cellular homeostasis.
Ataxia-telangiectasia (A-T) is characterized by neuronal degeneration, cancer, diabetes, immune deficiency, and increased sensitivity to ionizing radiation. A-T is attributed to the deficiency of the protein kinase coded by the ATM (ataxia-telangiectasia mutated) gene. ATM is a sensor of DNA double-strand breaks (DSBs) and signals to cell cycle checkpoints and the DNA repair machinery. ATM phosphorylates numerous substrates and activates many cell-signaling pathways. There has been considerable debate about whether a defective DNA damage response is causative of the neurological aspects of the disease. In proliferating cells, ATM is localized mainly in the nucleus; however, in postmitotic cells such as neurons, ATM is mostly cytoplasmic. Recent studies reveal an increasing number of roles for ATM in the cytoplasm, including activation by oxidative stress. ATM associates with organelles including mitochondria and peroxisomes, both sources of reactive oxygen species (ROS), which have been implicated in neurodegenerative diseases and aging. ATM is also associated with synaptic vesicles and has a role in regulating cellular homeostasis and autophagy. The cytoplasmic roles of ATM provide a new perspective on the neurodegenerative process in A-T. This review will examine the expanding roles of ATM in cellular homeostasis and relate these functions to the complex A-T phenotype. Developmental Dynamics 247:33-46, 2018. © 2017 Wiley Periodicals, Inc.


Shape control of Au nanostructures using peptides for biotechnological applications.
Metallic gold (Au) nanostructures have attracted attentions in various fields of materials science and electrical science in terms of catalysts, sensing systems, photonic devices, and drug delivery systems because of their characteristic physical, chemical, and biocompatible properties. Recently, Au nanostructures with near-infrared light absorbing properties have shown potential for applications such as biological imaging and thermotherapy in biotechnological fields. However, fabrication of Au nanostructures with complex shapes often requires the use of highly biotoxic substances such as surfactants and reducing agents. Peptides are promising compounds for controlling the shape of Au nanostructures by mineralization with several advantages for this purpose. In this highlight, we focus on the shapes with respect to the fabrication of Au nanostructures using biocompatible peptides. We classify the peptides that form Au nanostructures into three broad categories: those that bind Au ions, those that reduce Au ions, and those that control the direction of Au crystal growth. Then, we briefly summarize the correlations between peptide sequences and their roles, and propose future strategies for fabricating Au nanostructures using peptides for biotechnological applications.


Hereditary hemochromatosis of a young girl: detection of early iron deposition in liver cell lysosomes using transmission electron microscopy and electron energy loss spectroscopy.
A 14-year-old girl demonstrated increased iron concentration and transferrin saturation, suggesting iron overload of unknown origin. Liver biopsy showed no fibrosis or hepatocytic atrophia. Nevertheless, Prussian blue reaction for histochemical detection of iron demonstrated very weak positive granules in a few hepatocytes on the periphery of hepatic lobules in close connection to bile capillaries. This very early stage of hemochromatosis was confirmed by TEM and EELS for iron accumulation inside hepatocytic lysosomes and residual bodies. Such siderosomes were scarce in number and iron content, compared to a case of manifested hemochromatosis and liver cirrhosis (Jonas L, Fulda G, Salemeh T, et al. Ultrastruct Pathol. 2001; 25: 111-118.). Liver iron concentration as measured by inductively coupled plasma-mass spectrometry (ICP-MS) and atomic absorption spectrometry (AAS) yielded 2.005 mg/g tissue dry weight, which was considered not significantly increased. In the absence of known causes for secondary iron overload, the early diagnosis was evidenced by genotyping, revealed homozygosity for the HFE gene C282Y mutation, demonstrating the presence of hereditary hemochromatosis.


Dinuclear Coordination Compounds Based on a 5-Nitropicolinic Carboxylate Ligand with Single-Molecule Magnet Behavior.
Isostructural dinuclear dysprosium and yttrium coordination compounds based on the 5-nitropicolinic carboxylate ligand were synthesized and characterized. The formation of these air-stable complexes is achieved via solvothermal routes employing water as the reaction solvent. The dysprosium-based complex exhibits single-molecule magnet behavior with frequency dependence of the out-of-phase susceptibility at zero direct-current field. High-resolution mass spectrometry (electrospray ionization) experiments and advanced NMR methods including diffusion NMR techniques were applied on the diamagnetic yttrium analogue and established that these species retained their solid-state structure in solution with hydrodynamic radii of 6.5 Å. Full 1H, 13C, 15N, 89Y, Δ1Hcoord, Δ13Ccoord, and Δ15Ncoord NMR data are given, and through the analysis of the Ramsey equation, the first electronic insights of these derivatives are provided.


Ethylenediamine-N,N'-Disuccinic Acid (EDDS)-Enhanced Flushing Optimization for Contaminated Agricultural Soil Remediation and Assessment of Prospective Cu and Zn Transport.
This paper presents the results of an experimental study aimed at investigating the effect of operative parameters on the efficiency of a soil flushing process, conducted on real contaminated soil containing high amounts of Cu and Zn. Soil flushing tests were carried out with Ethylenediamine-N,N'-disuccinic acid (EDDS) as a flushing agent due to its high biodegradability and environmentally friendly characteristics. Process parameters such as Empty-Bed Contact Time (EBCT) and EDDS solution molarity were varied from 21-33 h and from 0.36-3.6 mM, respectively. Effects on the mobility of cations such as Fe and Mn were also investigated. Results showed that very high performances can be obtained at [EDDS] = 3.6 mM and EBCT = 33 h. In these conditions, in fact, the amount of removed Cu was 53%, and the amount of removed Zn was 46%. Metal distribution at different depths from the top surface revealed that Cu has higher mobility than Zn. The process results were strongly dependent on the exchange of metals due to the different stability constants of the EDDS complexes. Finally, results from a comparative study showed that soil washing treatment reached the same removal efficiency of the flushing process in a shorter time but required a larger amount of the EDDS solution.


Survey of health and use characterization of pesticide appliers in Minnesota.
We surveyed 1,000 randomly selected state-licensed pesticide appliers to improve our understanding of pesticide use and its potential health effects. Participants were stratified by pesticide class (herbicides, insecticides, fungicides, fumigants) to determine potential differences in health characteristics among different pesticide groups. A subset of 60 applicators, divided by pesticide class used, were studied for exposure-related cholinesterase (ChE) depression. ChE depression in excess of 20% was most frequent in fumigant applicators who did enclosed-space application, in addition to other pesticide application procedures (p < .05). Survey data demonstrated that the prevalence of all common chronic diseases considered together was significantly increased (p = .015) in fumigant appliers, compared with all other pesticide use groups. The frequency of chronic lung disease was also significantly increased in the fumigant applier group (p = .027). Curiously, two cases of a rare hematopoietic neoplasm--hairy cell leukemia--were identified in our study group (annual incidence 0.67/100,000 in Minnesota). Whether there is an association between this unique tumor and agricultural work is uncertain, and further study is needed in this regard.


Transient depletion of innate immunity in varicella infections in otherwise healthy children.
Varicella is a common childhood infection and has a number of complications in the unvaccinated population. Perforin, found in natural killer cells, is important for the killing of virally infected cells. For this reason, the aim of this study was to determine natural killer cell count and activity, perforin expression, and Fas and soluble Fas ligand (sFas-L) levels in immunocompetent children with varicella infection and define any possible relations between the levels and varicella complications. Forty children were analyzed at diagnosis and on the 15th day of varicella infection. There was a significant difference in hemoglobin levels and leukocyte and platelet counts between days 0 and 15. Thirteen (32%) patients were found to be lymphopenic. Natural killer cell count and activity were significantly higher on day 15 when compared to values at diagnosis. The Fas-mediated apoptotic pathway was found to be active in acute varicella infection because Fas and sFas-L levels at diagnosis were higher than values on day 15. These findings suggest that the Fas and Fas-L apoptotic pathway is active during the acute phase of the viral infection and that it becomes inactive by day 15, paralleling the hematologic recovery.


Semantic knowledge constrains the processing of serial order information in working memory.
Long-term memory knowledge is considered to impact short-term maintenance of item information in working memory, as opposed to short-term maintenance of serial order information. Evidence supporting an impact of semantic knowledge on serial order maintenance remains weak. In the present study, we demonstrate that semantic knowledge can impact the processing of serial order information in a robust manner. Experiment 1 manipulated semantic relatedness effect by using semantic categories presented in subgroups of items (leaf-tree-branch-cloud-sky-rain). This semantic grouping manipulation was compared to a temporal grouping manipulation whose impact on the processing of serial order information is well-established. Both the semantic and temporal grouping manipulations constrained the occurrence of serial order errors in a robust manner: when migrating to a nontarget serial position, items tended to do so most of the time toward the position of a semantically related item or within the same temporal group. Critically, this impact of semantic knowledge on the pattern of migration errors was not observed anymore in Experiment 2, in which we broke-up the semantic groups, by presenting the semantically related items an interleaved fashion (leaf-cloud-tree-sky-branch-rain). Both semantic and temporal grouping factors may reflect a general mechanism through which information is represented hierarchically. Alternatively, both factors could result from the syntactic and/or semantic regularities that naturally structures linguistic information. These results support models considering direct interactions between serial order and linguistic components of WM. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Atypical processing in domain III of 23S rRNA of Rhizobium leguminosarum ATCC 10004(T) at a position homologous to an rRNA fragmentation site in protozoa.
For still unknown reasons, the 23S rRNA of many alpha-Proteobacteria shows a unique fragmentation pattern compared to other bacteria. The 23S rRNA processing involves RNase III and additional, yet unidentified enzymes. The alpha-proteobacterium Rhizobium leguminosarum ATCC 10004(T) possesses two fragmentation sites in its 23S rRNA. The first one harbors an intervening sequence in helix 9 which is cleaved by RNase III. We demonstrate that the mature 5' end of the resulting 2.6-kb rRNA fragment is generated by additional removal of helix 10. A fraction of the 2.6-kb rRNA is further processed in domain III, giving rise to two 1.3-kb rRNA fragments. We mapped the domain III fragmentation site and found it to be at a position which has only been reported for trypanosomatid protozoa. This fragmentation site is also unique in that it lacks an intervening sequence. We found that the simultaneous occurrence of 2.6-kb and 1.3-kb rRNA fragments is not due to interoperonal sequence differences but rather reflects slow processing. The different characteristics of the two fragmentation sites in the 23S rRNA suggest that they are processed by different mechanisms. Interestingly, the amount of 2.6-kb rRNA varies during culture growth. We observed a transient increase in the relative amount of 2.6-kb rRNA fragments during the first hours after inoculation, which points to changes in the ratio of rRNA synthesis rate to domain III processing rate during the growth of a culture.


Human kidney glomerulus proteome and biomarker discovery of kidney diseases.
The kidney glomerulus is the site of plasma filtration and production of primary urine in the kidney. The structure not only plays a pivotal role in ultrafiltration of plasma into urine but also is the locus of kidney diseases progressing to chronic renal failure. Patients afflicted with these glomerular diseases frequently progress to irreversible loss of renal function and inevitably require replacement therapies. The diagnosis and treatment of glomerular diseases are now based on clinical manifestations, urinary protein excretion level, and renal pathology of needle biopsy specimens. The molecular mechanisms underlying the progression of glomerular diseases are still obscure despite a great number of clinical and experimental studies. Proteomics is a particularly promising approach for the discovery of proteins relevant to physiological and pathophysiological processes, and has been recently employed in nephrology. Although until now most efforts of proteomic analysis have been conducted with urine, the biological fluid that is easily collected without invasive procedures, proteomic analysis of the glomerulus, the tissue most proximal to the disease loci, is the most straightforward approach. In this review, we attempt to outline the current status of clinical proteomics of the glomerulus and provide a perspective of protein biomarker discovery of glomerular diseases.


Process Evaluation of a Clinical Trial to Test School Support as HIV Prevention Among Orphaned Adolescents in Western Kenya.
Orphaned adolescents are a large and vulnerable population in sub-Saharan Africa, at higher risk for HIV than non-orphans. Yet prevention of new infection is critical for adolescents since they are less likely than adults to enter and remain in treatment and are the only age group with rising AIDS death rates. We report process evaluation for a randomized controlled trial (RCT) testing support to stay in school (tuition, uniform, nurse visits) as an HIV prevention strategy for orphaned Kenyan adolescents. The RCT found no intervention effect on HIV/HSV-2 biomarker outcomes. With process evaluation, we examined the extent to which intervention elements were implemented as intended among the intervention group (N = 412) over the 3-year study period (2012-2014), the implementation effects on school enrollment (0-9 terms), and whether more time in school impacted HIV/HSV-2. All analyses examined differences as a whole, and by gender. Findings indicate that school fees and uniforms were fully implemented in 94 and 96% of cases, respectively. On average, participants received 79% of the required nurse visits. Although better implementation of nurse visits predicted more terms in school, a number of terms did not predict the likelihood of HIV/HSV-2 infection. Attending boarding school also increased number of school terms, but reduced the odds of infection for boys only. Four previous RCTs have been conducted in sub-Saharan Africa, and only one found limited evidence of school impact on adolescent HIV/HSV-2 infection. Our findings add further indication that the association between school support and HIV/HSV-2 prevention appears to be weak or under-specified.


Interleukin-6 enhances growth factor-dependent proliferation of the blast cells of acute myeloblastic leukemia.
The effects of recombinant interleukin-6 (IL-6) on the proliferation of blast precursors present in the peripheral blood of patients with acute myeloblastic leukemia (AML) was investigated. IL-6 had little effect by itself; however, it synergized with granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) in the stimulation of AML blast colony formation. Responsiveness of blast progenitors to IL-6 was heterogeneous. On normal bone marrow cells the same synergy was observed on granulocyte and monocyte precursors (GM-CFC), while there was no significant effect on erythroid and multipotential precursors.


Predicting worker exposure--the effect of ventilation velocity, free-stream turbulence and thermal condition.
Three-dimensional computational fluid dynamics (CFD) simulations were used to predict the flow field and resulting worker exposures when toxic airborne contaminants were released into the wake region of a mannequin that had its back to the airflow while holding the source of airborne contaminants. The effects of ventilation velocity, free-stream turbulence, and various thermal conditions on fluid flow and exposure levels were evaluated. The results showed good agreement between predicted and experimental concentrations at the mouth at a broad range of airflow velocities when the mannequin was both heated and unheated. When the mannequin was unheated, the exposure level decreased as the ventilation velocity increased. The expectation that buoyancy provided by the heat from the mannequin would be most important at very low velocities and decreasingly important at high velocities was proved true for both the predicted and observed exposures. The result was that when the mannequin was heated to normal human body temperatures, exposure levels had an inverted V relationship with velocity. These findings are important, since they call into question the common practice of modeling human exposures with mannequins at ambient temperatures. In addition, free-stream turbulence could be used to reduce worker exposure to airborne pollutants as suggested by the simulations. CFD enabled a detailed investigation of the effect of particular factors for exposure predictions in a cost-effective way.


An Extensive Meta-Metagenomic Search Identifies SARS-CoV-2-Homologous Sequences in Pangolin Lung Viromes.
In numerous instances, tracking the biological significance of a nucleic acid sequence can be augmented through the identification of environmental niches in which the sequence of interest is present. Many metagenomic data sets are now available, with deep sequencing of samples from diverse biological niches. While any individual metagenomic data set can be readily queried using web-based tools, meta-searches through all such data sets are less accessible. In this brief communication, we demonstrate such a meta-metagenomic approach, examining close matches to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in all high-throughput sequencing data sets in the NCBI Sequence Read Archive accessible with the "virome" keyword. In addition to the homology to bat coronaviruses observed in descriptions of the SARS-CoV-2 sequence (F. Wu, S. Zhao, B. Yu, Y. M. Chen, et al., Nature 579:265-269, 2020, https://doi.org/10.1038/s41586-020-2008-3; P. Zhou, X. L. Yang, X. G. Wang, B. Hu, et al., Nature 579:270-273, 2020, https://doi.org/10.1038/s41586-020-2012-7), we note a strong homology to numerous sequence reads in metavirome data sets generated from the lungs of deceased pangolins reported by Liu et al. (P. Liu, W. Chen, and J. P. Chen, Viruses 11:979, 2019, https://doi.org/10.3390/v11110979). While analysis of these reads indicates the presence of a similar viral sequence in pangolin lung, the similarity is not sufficient to either confirm or rule out a role for pangolins as an intermediate host in the recent emergence of SARS-CoV-2. In addition to the implications for SARS-CoV-2 emergence, this study illustrates the utility and limitations of meta-metagenomic search tools in effective and rapid characterization of potentially significant nucleic acid sequences.IMPORTANCE Meta-metagenomic searches allow for high-speed, low-cost identification of potentially significant biological niches for sequences of interest.


A chitosan-based coating with or without clove oil extends the shelf life of cooked pork sausages in refrigerated storage.
Chitosan coatings, with and without clove oil, were investigated for effects on quality and shelf life of cooked pork sausages stored at a refrigerated temperature (4±2°C). The various treatments of cooked pork sausages were: untreated (control), coating with 2% chitosan (CS), and coating with a mixture having 2% chitosan and 1.5% clove oil (CS+CO). Various microbiological, physical, chemical and sensory properties were monitored over 25 days of storage. The total viable count, the psychrotrophic bacteria count, the L* value, peroxide value and the thiobarbituric acid reactive substances increased, while the a* value, the b* value, the pH and the sensory scores decreased with storage time, across all treatments. However, these changes were slowest with the CS+CO treatment. Based on sensory evaluation and microbiological quality, the shelf lives were 14 days for control, 20 days for CS, and 20 days for CS+CO treated samples, under refrigerated storage.


Structural damage to Schiotz tonometers after disinfection with solutions.
Although Schiotz tonometry has been long ago replaced by Goldmann applanation tonometry measurement of intraocular pressure, it remains a viable clinical technique in nursing homes and other "out of office" settings. Because Schiotz tonometers come into contact with the cornea and tear film, they must be properly disinfected to prevent cross-infection with HIV and other infectious pathogens. The Centers for Disease Control and Prevention (CDC) recommends that all eye contact devices be disinfected by a 5- to 10-min soak in one of following disinfectants: 3% hydrogen peroxide, 1:10 sodium hypochlorite (household bleach), or 70% isopropyl alcohol. The effects of these disinfectants on Schiotz tonometers have not been previously investigated. This study investigated the effects of CDC-recommended disinfectants on the structural integrity of Schiotz tonometers. The results of the study indicated that soaking in 1:10 sodium hypochlorite and 3% hydrogen peroxide damaged Schiotz tonometers and rendered them inoperable. Alcohol caused minor damage to the tonometer and was the safest of the CDC disinfectants. This study showed there is limited application of CDC infection control criteria to Schiotz tonometers due to the extensive corrosion and damage caused by hydrogen peroxide and bleach.