The fecal occult blood test as a tool for improved outpatient qualification for colonoscopy. A single-center experience and 10-year follow-up survey.
Colonoscopy is not widely and easily available in all countries, even for symptomatic patients. This is one of the causes of tumors not being diagnosed until an advanced stage. The aim of this study was to estimate the efficacy of the fecal occult blood test (FOBT) in the diagnostic work-up of outpatients referred to a colorectal unit due to indistinct abdominal symptoms. Among 10418 consecutive symptomatic individuals referred to the outpatient clinic, an immunochemical FOBT (Hem-Check 1®) was recommended for 9432 patients with indistinct symptoms as a tool for qualifying them for colonoscopy. All the subjects were treated according to their diagnosis and followed-up for the next 10 years. Colorectal cancer (CRC) was diagnosed in 535 individuals: 393/986 (39.9%) among patients with red-flag symptoms, and 142/951 (14.9%) of individuals with indistinct symptoms and a positive FOBT. In the latter group, less-advanced tumors, classed as such using Dukes' classification, were twice as common and more advanced CRC occurred twice as seldom than in the former. Cancer recurrence-free and overall survival periods after surgical treatment for CRC were significantly longer in patients with indistinct symptoms who qualified for diagnostic procedures on the basis of a positive FOBT. Patients with symptoms suggesting organic colon disease had a worse prognosis compared to individuals with non-specific symptoms. If bowel endoscopy is not widely and easily available, qualification for colonoscopy on the basis of alarm symptoms and a positive FOBT seems to be an effective strategy in early CRC diagnosis.


Comparative analysis of human mitochondrial DNA from World War I bone samples by DNA sequencing and ESI-TOF mass spectrometry.
Mitochondrial DNA is commonly used in identity testing for the analysis of old or degraded samples or to give evidence of familial links. The Abbott T5000 mass spectrometry platform provides an alternative to the more commonly used Sanger sequencing for the analysis of human mitochondrial DNA. The robustness of the T5000 system has previously been demonstrated using DNA extracted from volunteer buccal swabs but the system has not been tested using more challenging sample types. For mass spectrometry to be considered as a valid alternative to Sanger sequencing it must also be demonstrated to be suitable for use with more limiting sample types such as old teeth, bone fragments, and hair shafts. In 2009 the Commonwealth War Graves Commission launched a project to identify the remains of 250 World War I soldiers discovered in a mass grave in Fromelles, France. This study characterises the performance of both Sanger sequencing and the T5000 platform for the analysis of the mitochondrial DNA extracted from 225 of these remains, both in terms of the ability to amplify and characterise DNA regions of interest and the relative information content and ease-of-use associated with each method.


OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN CHOROIDAL MELANOMA-ASSOCIATED SUBRETINAL FLUID.
To report optical coherence tomography findings of choroidal melanoma with subretinal fluid (SRF). Single-center, retrospective review of spectral-domain optical coherence tomography in treatment-naive choroidal melanoma with associated SRF presenting between July 2009 and August 2021. Of 236 included patients, choroidal melanoma was small (n = 98, 41.5%), medium (n = 99, 41.9%), or large (n = 39, 16.5%). The most common optical coherence tomography feature was ellipsoid zone loss/disruption (n = 174, 73.7%), with unique features of bacillary layer detachment (n = 67, 28.4%), and heterogenous (n = 72, 30.5%) or homogenous (n = 48, 20.3%) subretinal hyperreflective material. Comparison (small vs. medium vs. large) revealed greater SRF extent with increasing tumor size (SRF ≥2 quadrants: 6.1% vs. 27.2% vs. 67.7%, P < 0.001). Ellipsoid zone disruption was less common in small tumors (52.0% vs. 86.9% vs. 94.9%, P < 0.001). Bacillary layer detachment was more common in medium tumors (16.3% vs. 40.4% vs. 28.2%, P < 0.001) and, compared with eyes without bacillary layer detachment, was associated with more SRF (minimal SRF vs. SRF ≥1 quadrant: likelihood ratio 18.8, P < 0.001) and more frequent heterogenous subretinal hyperreflective material (58.2% vs. 19.5%, P < 0.001). Optical coherence tomography features of choroidal melanoma-associated SRF vary by tumor size, with greater SRF extent in larger tumors, less ellipsoid zone disruption in small tumors, and more bacillary layer detachment in medium tumors.


Nasal loop myopexy as a primary procedure to correct exotropia hypotropia complex in high myopia.
To evaluate success of nasal loop myopexy as a primary procedure in correcting the ocular deviation in primary position when combined with recession and resection procedure (R&R) in exotropia hypotropia complex in high myopia and to explore the probable cause for deviation. We present a case series of three adult males with exotropia hypotropia complex and high myopia with large angle exotropia and hypotropia, with deflection of the courses of superior and medial recti seen intraoperatively. We performed a conventional recession and resection procedure, which was combined with a nasal loop myopexy between the superior rectus (SR) and medial rectus (MR) in the same session, under local anesthesia, to correct the deflected course of SR and MR; with the aim of correcting the deviation in primary position and improving ocular motility, mainly elevation in abduction. We present a case series of three adult males with exotropia hypotropia complex, who were operated between March 2017 and October 2017. In all the three cases described above, it was noted that the preoperative exotropia and hypotropia improved following the combination of nasal loop myopexy with a conventional recession and resection procedure, as shown by improvement in ocular deviation in the primary position (measured by prism bar cover test, PBCT). First patient improved from 50 prism exotropia with 16 prism hypotropia to 5 prisms exophoria and 6 prisms hypotropia in left eye. Second patient improved from 45 prism right exotropia and 10 prism hypotropia to 10 prisms exotropia and 6 prism hypotropia. Third patient improved from 40 prism left exotropia and 20 prisms hypotropia to 10 prism esotropia and 5 prisms hypotropia. Ocular motility showed no restriction following surgery in any of the gazes. Limitation of elevation in abduction, caused due to SR deflection, improved due to repositioning of SR and MR in their anatomical positions in all the cases. In the first patient elevation in abduction improved from -4 to -1; in the second and third patients, it improved from -2 to 0. None of the three adult patients experienced any side effects following the procedure. The combination of recession and resection procedures with nasal loop myopexy was found to be effective in correcting the ocular deviation and limitation to elevation in abduction by correcting the deflected course of superior rectus and medial rectus to result in an effective improvement of elevation in abduction. One case had an overcorrection of exotropia. There were no other major complications.


Micronucleus assay in the exfoliated cells of buccal mucosa of gasoline station workers in Tehran.
One of the most critical landmarks of DNA damage is the micronucleus assay. Enumeration of micronuclei contributes to the early diagnosis of precancerous lesions and cancers; however, there are few studies on the frequency of micronucleus in gasoline station workers. To the best of our knowledge, no study has addressed this issue in Iran. The present study aimed to determine the role of working in the gasoline stations of Tehran city on micronucleus frequency in buccal mucosa. In this historical cohort study, buccal mucosa samples were collected from 110 individuals working at gasoline stations and 100 unemployed persons using wet tongue depressors. After Papanicolaou staining, the percentage of cells containing micronucleus as well as the mean number of micronucleus in the micronucleated cells was reported. Student's t-test, Mann-Whitney test, and regression analyses were used to specify the effect of other variables on the frequency and mean number of micronucleus per cell. The mean frequency of micronucleus in the case and control group was 29.8 ± 8.2 and 9.3 ± 3.2, respectively, which was statistically significant (P = 0.0001). Furthermore, the mean number of micronucleus in the micronucleated cells of buccal mucosa was significantly higher in individuals who were exposed to gasoline than the control group (P = 0.0001). The results indicated that exposure to gasoline could increase the frequency of micronucleus. It was also revealed that cigarette and hookah smoking and alcohol consumption, together with working in gasoline stations, increase micronucleus abundance, implying the cumulative carcinogenic effect of these factors.


Perceived risks of produced water management and naturally occurring radioactive material content in North Dakota.
Unconventional oil and gas development using hydraulic fracturing has caused conflict and controversy across the globe including the U.S. where some States banned the practice. Nevertheless, North Dakota (ND) has supported the practice because the State perceives the risks to be acceptable and because it has brought growth and opportunities to small communities. However, social acceptance of new technology is based on a number of factors and not contingent on economic benefits. To date, no research has been conducted to understand public risk perception of hazards associated with produced water from hydraulic fracturing in ND. This study focuses on understanding the risk perception of select ND stakeholder groups regarding produced water management and naturally occurring radioactive material. The software Qualtrics was used to create an online survey, collect data, and perform statistical analysis. The most important variables that seem to influence risk perception are the images and thoughts associated with produced water, level of knowledge about produced water handling and content, and knowing how to proceed in case of a spill of produced water. Overall, social risk perception could be in alignment with actual technical risk if availability of objective information is improved.


Immune cell residency in the nasal mucosa may partially explain respiratory disease severity across the age range.
Previous studies focusing on the age disparity in COVID-19 severity have suggested that younger individuals mount a more robust innate immune response in the nasal mucosa after infection with SARS-CoV-2. However, it is unclear if this reflects increased immune activation or increased immune residence in the nasal mucosa. We hypothesized that immune residency in the nasal mucosa of healthy individuals may differ across the age range. We applied single-cell RNA-sequencing and measured the cellular composition and transcriptional profile of the nasal mucosa in 35 SARS-CoV-2 negative children and adults, ranging in age from 4 months to 65 years. We analyzed in total of ~ 30,000 immune and epithelial cells and found that age and immune cell proportion in the nasal mucosa are inversely correlated, with little evidence for structural changes in the transcriptional state of a given cell type across the age range. Orthogonal validation by epigenome sequencing indicate that it is especially cells of the innate immune system that underlie the age-association. Additionally, we characterize the predominate immune cell type in the nasal mucosa: a resident T cell like population with potent antiviral properties. These results demonstrate fundamental changes in the immune cell makeup of the uninfected nasal mucosa over the lifespan. The resource we generate here is an asset for future studies focusing on respiratory infection and immunization strategies.


Molecular mechanism underlying modulation of TRPV1 heat activation by polyols.
Sensing noxiously high temperatures is crucial for living organisms to avoid heat-induced injury. The TRPV1 channel has long been known as a sensor for noxious heat. However, the mechanism of how this channel is activated by heat remains elusive. Here we found that a series of polyols including sucrose, sorbitol, and hyaluronan significantly elevate the heat activation threshold temperature of TRPV1. The modulatory effects of these polyols were only observed when they were perfused extracellularly. Interestingly, mutation of residues E601 and E649 in the outer pore region of TRPV1 largely abolished the effects of these polyols. We further observed that intraplantar injection of polyols into the hind paws of rats reduced their heat-induced pain response. Our observations not only suggest that the extracellular regions of TRPV1 are critical for the modulation of heat activation by polyols, but also indicate a potential role of polyols in reducing heat-induced pain sensation.


Crystal structure of the EnvZ periplasmic domain with CHAPS.
Bacteria sense and respond to osmolarity through the EnvZ-OmpR two-component system. The structure of the periplasmic sensor domain of EnvZ (EnvZ-PD) is not available yet. Here, we present the crystal structure of EnvZ-PD in the presence of CHAPS detergent. The structure of EnvZ-PD shows similar folding topology to the PDC domains of PhoQ, DcuS, and CitA, but distinct orientations of helices and β-hairpin structures. The CD and NMR spectra of EnvZ-PD in the presence of cholate, a major component of bile salts, are similar to those with CHAPS. Chemical cross-linking shows that the dimerization of EnvZ-PD is significantly inhibited by the CHAPS and cholate. Together with β-galactosidase assay, these results suggest that bile salts may affect the EnvZ structure and function in Escherichia coli.


Effect of ethanol and fructose on liver metabolism: a dynamic 31Phosphorus magnetic resonance spectroscopy study in normal volunteers.
In vivo 31Phosphorus magnetic resonance spectroscopy (31P-MRS) permits evaluation of dynamic changes of individual phosphorus-containing metabolites in the liver parenchyma, such as phosphomonoester (PME), adenosine triphosphate, and inorganic phosphate (Pi). Intravenous fructose load alters phosphorus metabolites and allows assessment of liver function by 31P-MRS. 31P-MRS data obtained in alcoholic liver disease are however inconclusive. To study the hypothesis that fructose load can be used to investigate metabolic effects of ethanol ingestion, the interaction of different metabolites--i.e., fructose and ethanol--were followed in vivo. Using a 1.5 Tesla magnetic resonance system, six healthy volunteers were examined in three sessions each: a session after administration of (a) fructose only (250 mg/kg) was compared with (b) fructose load after ethanol ingestion (0.8 g/kg). A control experiment (c) was done after ethanol only. Spectra were acquired using one-dimensional chemical shift imaging with a temporal resolution of 5 min. Following a fructose load, the concomitant uptake of ethanol showed drastic changes of individual metabolic steps of the hepatic metabolism (averages +/- standard deviation). While the velocity of the net formation of PME (relative increase 0.46 +/- 0.11 without ethanol vs. 0.61 +/- 0.25 with ethanol) and the use of adenosine triphosphate (-0.13 +/- 0.03 vs. -0.16 +/- 0.03) and Pi (-0.022 +/- 0.009 vs. -0.021 +/- 0.004) were not significantly affected by ethanol uptake, a significant (p < 0.01) reduction of PME degradation (31.3 +/- 9.4 vs. 61.9 +/- 16.9 relative total area) and absence of an overshoot for Pi (10.5 +/- 4.9 vs. -7.1 +/- 5.3 relative area 13 min to 43 min) was observed after ethanol administration. Dynamic 31P-MRS allows the observation of individual steps of hepatic metabolism in situ; fructose metabolism in the human liver is slowed down by concomitant ethanol ingestion after the phosphorylation step of fructose. This could be explained by inhibition of aldolase rather than ethanol-induced changes of the hepatic redox state. Fructose load can be used to study effects of alcohol ingestion and might therefore be useful in patients with alcoholic liver disease.


Characterization of a GSK-3 inhibitor in culture of human cord blood primitive hematopoietic cells.
Wnt signaling pathway plays important roles in the biology of stem cells in maintaining their self-renewal property. Glycogen synthase kinase-3 (GSK-3) inhibitors, the Wnt signaling agonists, maintain the pluripotency of embryonic stem cells. We report here that a synthetic GSK-3 inhibitor, 6-bromoindirubin-3'-oxime (BIO), showed opposite effects on the expansion of human primitive hematopoietic cells isolated from umbilical cord blood (UCB). In combination with human c-kit ligand (KL), BIO at low concentration (0.2 μM) enhanced the expansion of UCB CD34+ cells, which was BIO structure and exposure time dependent; however, at high concentration (2 μM) it inhibited the expansion of the cells. Furthermore, hematopoietic stem cells (HSCs) were exhausted when the UCB CD34+ cells were exposed to 0.2 μM BIO and KL longer than 2 days. In conclusion, the use of BIO in expansion of UCB HSCs remains a significant challenge.


Refining the role for adult stem cells as cancer cells of origin.
Significant progress has been made to identify the cells at the foundation of tumorigenesis, the cancer cell of origin (CCO). The majority of data points towards resident adult stem cells (ASCs) or primitive progenitors as the CCO for those cancers studied, highlighting the importance of stem cells not only as propagators but also as initiators of cancer. Recent data suggest tumor initiation at the CCOs can be regulated through both intrinsic and extrinsic signals and that the identity of the CCOs and their propensity to initiate tumorigenesis is context dependent. In this review, we summarize some of the recent findings regarding CCOs and solid tumor initiation and highlight its relation with bona fide human cancer.


Modeling the photoperiodic entrainment of the plant circadian clock.
The circadian clock is an endogenous 24 hour rhythm that helps organisms anticipate and adapt to daily and seasonal variations in environment, such as the day/night cycle or changing temperatures. The plant clock is a complex network of transcription factors that regulate each other, forming interlocked feedback loops. Most of its components are light-regulated in some way, making the system highly sensitive to changes in light conditions. Here, we explore the mechanisms by which the plant clock adapts to changing day length. We first present some experimental data illustrating the variety of behaviors found in seedlings exposed to external day/night cycles different from 24h. We then use a mathematical model to characterize the response of the clock to a wide range of external cycle lengths and photoperiods. We show the existence of several domains of periodic entrainment with different ratios between the external cycle length and the period of the clock, and the presence of quasiperiodic and chaotic behaviors outside of the entrainment range. We simulate knockout mutants with impaired clock function and theoretical variants with diminished light sensitivity to highlight the role of a complex network and multiple light inputs in keeping the clock entrained over a wide range of conditions.


Noninvasive Bioluminescence Imaging of AKT Kinase Activity in Subcutaneous and Orthotopic NSCLC Xenografts: Correlation of AKT Activity with Tumor Growth Kinetics.
Aberrant signaling through the AKT kinase mediates oncogenic phenotypes including cell proliferation, survival, and therapeutic resistance. Here, we utilize a bioluminescence reporter for AKT kinase activity (BAR) to noninvasively assess the therapeutic efficacy of the EGFR inhibitor erlotinib in KRAS-mutated lung cancer therapy. A549 non-small cell lung cancer cell line, engineered to express BAR, enabled the evaluation of compounds targeting the EGFR/PI3K/AKT pathway in vitro as well as in mouse models. We found that erlotinib treatment of resistant A549 subcutaneous and orthotopic xenografts resulted in significant AKT inhibition as determined by an 8- to 13-fold (P < .0001) increase in reporter activity 3 hours after erlotinib (100 mg/kg) administration compared to the control. This was confirmed by a 25% (P < .0001) decrease in pAKT ex vivo and a decrease in tumor growth. Treatment of the orthotopic xenograft with varying doses of erlotinib (25, 50, and 100 mg/kg) revealed a dose- and time-dependent increase in reporter activity (10-, 12-, and 23-fold). Correspondingly, a decrease in phospho-AKT levels (0%, 16%, and 28%, respectively) and a decrease in the AKT dependent proliferation marker PCNA (0%, 50%, and 50%) were observed. We applied μ-CT imaging for noninvasive longitudinal quantification of lung tumor load which revealed a corresponding decrease in tumor growth in a dose-dependent manner. These findings demonstrate the utility of BAR to noninvasively monitor AKT activity in preclinical studies in response to AKT modulating agents. These results also demonstrate that BAR can be applied to study drug dosing, drug combinations, and treatment efficacy in orthotopic mouse lung tumor models.


Mechanism underlying the block of human Cav3.2 T-type Ca2+ channels by benidipine, a dihydropyridine Ca2+ channel blocker.
Benidipine, a dihydropyridine Ca(2+) channel blocker, has been reported to block T-type Ca(2+) channels; however, the mechanism underlying this effect was unclear. In this study, we characterized the mechanism responsible for this blocking activity. Furthermore, the blocking activity was compared between two enantiomers of benidipine, (S, S)- and (R, R)-benidipine. Human Ca(v)3.2 (hCa(v)3.2) T-type Ca(2+) channels stably expressed in the human embryonic kidney cell line, HEK-293, were studied in whole-cell patch-clamp recordings and Ca(2+) mobilization assay. In whole-cell patch-clamp recordings, benidipine blocked hCa(v)3.2 T-type Ca(2+) currents elicited by depolarization to a comparable extent as efonidipine. The block was dependent on stimulation frequency and holding potential, but not test potential. Benidipine significantly shifted the steady-state inactivation curve to the hyperpolarizing direction, but had no effect on the activation curve. Benidipine prolonged the recovery from inactivation of hCa(v)3.2 T-type Ca(2+) channels without any effect on the kinetics of activation, inactivation, or deactivation. In the Ca(2+) mobilization assay, benidipine was more potent than efonidipine in blocking Ca(2+) influx through hCa(v)3.2 T-type Ca(2+) channels. (S, S)-Benidipine was more potent than (R, R)-benidipine in blocking hCa(v)3.2 T-type Ca(2+) currents, but there was no difference in blocking the Ca(2+) influx. We have characterized the blocking activity of benidipine against hCa(v)3.2 Ca(2+) channels and revealed the difference between the two enantiomers of benidipine. The blocking action of benidipine could be mediated by stabilizing hCa(v)3.2 Ca(2+) channels in an inactivated state.


[Change in phagocytic activity toward the agent of tularemia in highly sensitive animals with mixed infections].
An increase of the ingestive and digestive capacity of neutrophils to the homologous causative agent and tularemia microbe was revealed by the opsonophagocytic test in Microtus arvalis, albino mice and guinea pigs infected with sublethal Yersinia pseudotuberculosis and Salmonella typhimurium doses. In subsequent tularemia infection some of the animals displayed a reduction of the septicemia intensity, prolongation of the disease and elevation of the susceptibility threshold. Period of manifestation of the inhibitory action on tularemia coincided with that of the increase in phagocytic activity


Single methyl group determines prion propagation and protein degradation activities of yeast heat shock protein (Hsp)-70 chaperones Ssa1p and Ssa2p.
Organisms encode multiple homologous heat shock protein (Hsp)-70s, which are essential protein chaperones that play the major role in cellular protein "quality control." Although Hsp70s are functionally redundant and highly homologous, many possess distinct functions. A regulatory motif underlying such distinctions, however, is unknown. The 98% identical cytoplasmic Hsp70s Ssa1p and Ssa2p function differently with regard to propagation of yeast [URE3] prions and in the vacuolar-mediated degradation of gluconeogenesis enzymes, such as FBPase. Here, we show that the Hsp70 nucleotide binding domain (NBD) regulates these functional specificities. We find little difference in ATPase, protein refolding, and amyloid inhibiting activities of purified Ssa1p and Ssa2p, but show that interchanging NBD residue alanine 83 (Ssa1p) and glycine 83 (Ssa2p) switched functions of Ssa1p and Ssa2p in [URE3] propagation and FBPase degradation. Disrupting the degradation pathway did not affect prion propagation, however, indicating these are two distinct processes where Ssa1/2p chaperones function differently. Our results suggest that the primary evolutionary pressure for Hsp70 functional distinctions is not to specify interactions of Hsp70 with substrate, but to specify the regulation of this activity. Our data suggest a rationale for maintaining multiple Hsp70s and suggest that subtle differences among Hsp70s evolved to provide functional specificity without affecting overall enzymatic activity.


Resting heart rate variability and the startle reflex to briefly presented affective pictures.
We have previously shown that persons with low HRV showed potentiated startle responses to neutral stimuli. In the present study we replicated our prior findings and extended them to examine the effects of HRV on the startle magnitude to pictures that were presented outside of conscious awareness. A total of 85 male and female students were stratified via median split on their resting HRV. They were presented pictures for 6 s or for 30 ms. Results indicated that the high HRV group showed the context appropriate startle magnitude increase to unpleasant foreground. The low HRV group showed startle magnitude increase from pleasant to neutral pictures but no difference between the neutral and unpleasant pictures. This pattern of results was similar for the 30 ms and the 6 s conditions. These results suggest that having high HRV may allow persons to more efficiently process emotional stimuli and to better recognize threat and safety signals.


Immunohistochemical localization of porcine diazepam-binding inhibitor (DBI) to rat endocrine pancreas.
The occurrence of diazepam-binding inhibitor (DBI), isolated and characterized from porcine upper intestine, was examined in the pancreas of Sprague-Dawley albino rats using indirect immunofluorescence. The polypeptide was found in the endocrine Langerhans islets and, utilizing double-labelling controls, it was shown to be present within the peripherally located glucagon-containing cells. Regulation of islet hormone production may therefore be under DBI control.


Inhibition of HMGB1 alleviates myocardial ischemia/reperfusion injury in diabetic mice via suppressing autophagy.
Diabetes aggravates myocardial ischemia/reperfusion (I/R) injury (MI/RI). The association between high mobility group box 1 protein (HMGB1) and autophagy in diabetic MI/RI remains unknown. Therefore, we investigated whether inhibiting HMGB1 can regulate autophagy in diabetic mice (DM) after I/R injury. I/R models of C57BL/KsJ mice and db/db mice were established. Histological changes, infarct size (IS), HMGB1 protein, and autophagy-related proteins were detected after 24h of reperfusion. In DM treatment groups, anti-HMGB1 antibody (H-Ig) was injected via tail vein after reperfusion for 15min, and the above-mentioned experimental methods were performed at the end of reperfusion. Compared with the I/R group, the pathological myocardial damage and IS were significantly increased in the I/R (DM) group. Additionally, the levels of HMGB1, Beclin1, and LC3II/LC3I ratio were remarkably higher in the I/R (DM) group than those in the I/R group, while p62 level was lower. In the H-Ig (DM) group, injection of H-Ig significantly reduced the IS, as well as alleviated pathological myocardial damage. Moreover, Beclin1, LC3II/LC3I ratio, and p62 levels were notably reversed after this treatment. I/R-induced myocardium was aggravated by diabetes, which may be related to increased release of HMGB1 and activated autophagy. Inhibition of HMGB1 alleviates diabetic MIRI which was associated with reduced autophagy.


Racial/ethnic differences in health-related quality of life among female breast cancer survivors: cross-sectional findings from the Medical Expenditure Panel Survey.
Breast cancer survivors have reported worse health-related quality of life (HRQoL) outcomes on some subscales when compared with members of the general population. However, the increased attention to breast cancer survivorship should have improved the HRQoL of these survivors. Our aim was to examine whether physical and mental component scores (PCS-12 and MCS-12) using the Short Form (SF-12) questionnaire were different for racial/ethnic minorities, specifically for Black and Hispanic women relative to White women. Furthermore, we stratified the data by age group to evaluate these racial/ethnic differences in HRQoL of breast cancer survivors. Cross-sectional study. Pooled cross-sectional analyses using data from the Medical Expenditure Panel Survey between 2008 and 2016 were conducted. Pooled ordinary least squares (OLS) regression was used to examine the racial/ethnic differences in PCS-12 and MCS-12 scores of breast cancer survivors. Furthermore, stratified analyses by age group were conducted to evaluate racial/ethnic differences in HRQoL by the age of breast cancer survivors. After adjusting for confounders, there was no association between race/ethnicity and PCS-12 scores. However, Hispanic breast cancer survivors had statistically significantly lower MCS-12 scores (by 1.9 points [95% confidence interval {CI}: -3.53 to -0.37]) when compared with White breast cancer survivors. For PCS-12, after stratifying by age, the adjusted analyses showed no significant differences in PCS-12 scores when White female breast cancer survivors were compared with the other racial/ethnic categories. On the other hand, Black female survivors aged <50 years had 4.3 points (95% CI: 0.46-8.13) higher MCS-12 scores when compared with their White counterparts, while Hispanic breast cancer survivors aged <50 years had 3.1 points (95% CI: -0.40-6.69) higher MCS-12 scores relative to White women. Furthermore, among female breast cancer survivors aged ≥50 years, Hispanic women had 3.2 points (95% CI: -4.98 to -1.40) lower MCS-12 scores than White women. Our study generated findings showing the racial/ethnic differences in HRQoL of breast cancer survivors and presented results stratified by age group. These findings provide the much-needed rationale for targeted and racial/ethnic-specific HRQoL improvement strategies among breast cancer survivors.


Quantal secretion and response lag demonstrated in single rat neutrophils.
The release of 9-aminoacridine loaded into neutrophil granules has been monitored using quantitative fluorescence microscopy of individual rat neutrophils. Within the granule, the fluorescence of the dye was substantially quenched, but release into the surrounding medium restored fluorescence. From kinetic analysis of the increase in fluorescence it was shown that secretion from a single neutrophil in response to a low concentration of chemotactic peptide occurred in 'bursts'. Each 'burst' of secretion was of equal size and kinetics, which were equal to the size and kinetics of the smallest evoked response possible. A significant time-lag of 5-10 s between the arrival of the stimulus at the cell and the onset of secretion was recorded. It was therefore concluded that secretion from neutrophils was the result of release of quantal amounts of dye following a delay period.


Treatment results of radiation therapy for muscle-invasive bladder cancer.
To assess local control and survival rates in patients with muscle-invasive bladder cancer treated with external-beam radiotherapy and to investigate prognostic factors. Between 1997 and 2007, 75 patients (male, n = 58; female, n = 17, median age, 74.2 years) with localized transitional cell carcinoma of the bladder (T2, n = 34; T3, n = 32; T4, n = 9) not suitable for radical surgery due to advanced age, comorbidity or inoperability underwent external-beam radiotherapy without simultaneous chemotherapy at the University Clinic of Therapeutic Radiology and Oncology, Medical University of Graz, Austria. A conformal four-field technique was used in all patients to treat the tumor and regional lymph nodes with single daily fractions of 1.8-2 Gy to a total dose of 50-50.4 Gy, followed by a cone-down to encompass the empty bladder which was boosted to 70-70.4 Gy. All patients had undergone transurethral tumor resection prior to radiotherapy which was macroscopically incomplete in 62 patients. Complete response was achieved in 65% of patients. Actuarial 3-year local control and metastases-free survival rates were 52.5% and 63.7%, 3-year local recurrence-free survival rate in complete responders was 71%. In univariate analysis, hydronephrosis, lymph vessel invasion, and macroscopic residual tumor were significantly predictive of disease progression. Hydronephrosis and lymph vessel invasion were also associated with a higher risk of local recurrence. The actuarial 3-year progression-free and overall survival rates were 40.1% and 56.9%, respectively. Radiotherapy is an effective treatment option in terms of local control and survival even in elderly patients with locally advanced bladder cancer not suitable for cystectomy.


Plasma cholecystokinin levels in acute pancreatitis.
Recent studies have shown that cholecystokinin (CCK) is involved in the induction and development of acute pancreatitis in experimental animals. In the present study we determined basal plasma CCK concentrations by a specific and sensitive radioimmunoassay using antiserum OAL656 in 17 patients with acute pancreatitis due to gallstone in the common bile duct (n = 7), alcoholic (n = 4), post endoscopic retrograde pancreatography (n = 1), and unknown causes (n = 4), and 37 patients with cholelithiasis (n = 18) and choledocholithiasis (n = 19). Plasma CCK concentrations in patients with gallstone pancreatitis on hospital day 1 (mean +/- SEM, 6.78 +/- 1.39 pM) were significantly higher than those in patients with other causes (1.33 +/- 0.16 pM) or in 20 healthy control subjects (1.55 +/- 0.11 pM). There was no relationship between plasma CCK and serum pancreatic enzyme levels, the severity of acute pancreatitis, or serum bilirubin concentrations. Plasma CCK levels in patients with acute symptomatic cholelithiasis (n = 7; 4.35 +/- 0.90 pM) and choledocholithiasis (n = 8; 4.52 +/- 1.17 pM) were significantly higher than those in patients without symptoms (cholelithiasis, n = 11, 1.40 +/- 0.17 pM; choledocholithiasis, n = 11, 1.88 +/- 0.49 pM) but tended to be lower than those in patients with gallstone pancreatitis. These present observations suggest that the increase in plasma CCK levels in gallstone pancreatitis appears not to be the cause but to be the result of gallstone pancreatitis probably due to a transient disturbance of bile flow into the duodenum by stones or edema of the bile duct. Our present results provide some evidence for the usefulness of CCK receptor antagonists for the treatment of biliary colics and acute pancreatitis.


Division of the genera Sparna Thomson, 1864 and Carterica Pascoe, 1858 (Coleoptera, Cerambycidae, Lamiinae, Colobotheini) with description of six new genera and eight new species.
Sparna Thomson, 1864 and Carterica Pascoe, 1858 are divided into seven genera: Sparna, Carterica, Francisparna gen. nov., Batesparna gen. nov., Allocarterica gen. nov., Piriana gen. nov., Miguellus gen. nov., and Confluentia gen. nov. From the species currently placed in Sparna, only S. lycoides Thomson, 1864 is maintained in the genus, and only Carterica mucronata (Olivier, 1795) is considered a true Carterica. Sparna bosqi Gilmour, 1954 is revalidated and included in a new genus. The following new species are described: Sparna tavakiliani, from Colombia; Piriana birai, and P. nearnsi, from Brazil (Pará); P. consimilis, from Ecuador; P. svachai, from Brazil (Rio Grande do Sul); Confluentia nigra, from Colombia; and C. flavomaculata, from Peru. Miguellus monnei, sp. nov., gen. nov. is described from Ecuador. Keys to species of Piriana and Confluentia are provided, as well as a key to the genera from the division of Sparna and Carterica, including Miguellus.


Single-Incision Rotator Cuff Repair With a Needle Arthroscope.
Arthroscopy frequently has been used to treat a variety of shoulder conditions, including rotator cuff tears. Arthroscopic techniques, when compared with open techniques, are associated with less morbidity, leading to lower complication rates, easier recovery, and improved outcomes. As technology improves, we continue to develop less-invasive surgical techniques to treat rotator cuff pathology. With the development of the NanoScope (Arthrex, Naples, FL), we have the opportunity to view through a small cannula without making a standard viewing portal. This technique combines this small viewing portal with standard repair techniques through only a single lateral incision to provide a less-invasive rotator cuff repair technique.


Safety, pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir, a novel liver-targeting, anti-hepatitis B virus drug, in healthy Chinese subjects.
Pradefovir is efficiently converted to adefovir [9-(2-phosphonylmethoxyethyl) adenine (PMEA)], producing high hepatic PMEA concentration but low levels in the systemic circulation and kidney. The aim of this study is to evaluate the tolerability, adverse effect (AEs), pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir. Fifty healthy subjects were divided into five groups and randomized within each group at a ratio of 3:1:1 to receive a single ascending dose of pradefovir (10, 30, 60, 90, or 120 mg), and 10 mg adefovir dipivoxil (ADP) or placebo. Blood and urine samples were collected and analyzed. A total of 1930 polymorphic loci were analyzed in 6 blood samples collected from the 90 mg pradefovir group. The single oral dose of pradefovir up to 120 mg was well tolerated. A total of 29 dose-limited mild AEs were reported in 17 subjects. The peak plasma concentration (C max) and area under the curve (AUC)0-48 of serum pradefovir ranged from (21.41 ± 12.98) to (447.33 ± 79.34) ng/mL and (46.10 ± 29.45) to (748.18 ± 134.15) ng h/mL across the dose range, respectively. The C max and AUC0-48 of serum PMEA ranged from 18.10 ± 4.96 to 312.33 ± 114.19 ng/mL and 72.65 ± 28.25 to 1095.48 ± 248.47 ng h/mL. Generally, no kidney impairment was observed. Pharmacogenetic analysis identified three metabolism-related single nucleotide polymorphism (SNP) locis, P450 (cytochrome) oxidoreductase [POR (rs6965343)], arylamine N-acetyltransferases [NAT1 (rs4986993)] and CYP2F1 (rs305968)], and one distribution-related loci, orosomucoid 2 [ORM2 (rs12685968)]. The single oral dose of pradefovir 10-120 mg was well tolerated. SNPs may be associated with variable rates of adverse events. CTR20140341.


Arthroscopically assisted ankle fusion in patients with end-stage tuberculosis.
Our purpose was to evaluate the clinical outcomes of arthroscopically assisted ankle fusion in patients with end-stage tuberculosis. Ten patients, all with end-stage tuberculosis, were operated on by arthroscopically assisted ankle fusion, and a half-ring sulcated external fixator was used. Partial weight-bearing was started on the fourth day. The clinical results were assessed with the American Orthopaedic Foot & Ankle Society score. Ankle fusion was proved by radiographs. At the mean follow-up of 23 months, all fusions were healed; the mean time to radiologic healing was 14.5 weeks. The final American Orthopaedic Foot & Ankle Society score was 66 points. Arthroscopically assisted debridement and ankle arthrodesis with an external fixator provided a very satisfactory rate of ankle fusion in 10 patients who had no recurrences or other complications. Level IV, therapeutic case series.


Changes in the epidemiology of ventilator-associated events over the course of the coronavirus disease 2019 (COVID-19) pandemic.
Management of critically ill coronavirus disease 2019 (COVID-19) patients has evolved considerably during the pandemic. We investigated rates and causes of ventilator-associated events (VAEs) in COVID-19 patients in the late versus early waves in 4 Massachusetts hospitals. VAE rates per episode decreased, rates per ventilator day were stable, and most cases were caused by acute respiratory distress syndrome (ARDS).


Pollination by brood-site deception.
Pollination is often regarded as a mutualistic relationship between flowering plants and insects. In such a relationship, both partners gain a fitness benefit as a result of their interaction. The flower gets pollinated and the insect typically gets a food-related reward. However, flower-insect communication is not always a mutualistic system, as some flowers emit deceitful signals. Insects are thus fooled by irresistible stimuli and pollination is accomplished. Such deception requires very fine tuning, as insects in their typically short life span, try to find mating/feeding breeding sites as efficiently as possible, and following deceitful signals thus is both costly and time-consuming. Deceptive flowers have thus evolved the ability to emit signals that trigger obligate innate or learned responses in the targeted insects. The behavior, and thus the signals, exploited are typically involved in reproduction, from attracting pheromones to brood/food-site cues. Chemical mimicry is one of the main modalities through which flowers trick their pollen vectors, as olfaction plays a pivotal role in insect-insect and insect-plant interactions. Here we focus on floral odors that specifically mimic an oviposition substrate, i.e., brood-site mimicry. The phenomenon is wide spread across unrelated plant lineages of Angiosperm, Splachnaceae and Phallaceae. Targeted insects are mainly beetles and flies, and flowers accordingly often emit, to the human nose, highly powerful and fetid smells that are conversely extremely attractive to the duped insects. Brood-site deceptive plants often display highly elaborate flowers and have evolved a trap-release mechanism. Chemical cues often act in unison with other sensory cues to refine the imitation.


Genome-scale metabolic modelling when changes in environmental conditions affect biomass composition.
Genome-scale metabolic modeling is an important tool in the study of metabolism by enhancing the collation of knowledge, interpretation of data, and prediction of metabolic capabilities. A frequent assumption in the use of genome-scale models is that the in vivo organism is evolved for optimal growth, where growth is represented by flux through a biomass objective function (BOF). While the specific composition of the BOF is crucial, its formulation is often inherited from similar organisms due to the experimental challenges associated with its proper determination. A cell's macro-molecular composition is not fixed and it responds to changes in environmental conditions. As a consequence, initiatives for the high-fidelity determination of cellular biomass composition have been launched. Thus, there is a need for a mathematical and computational framework capable of using multiple measurements of cellular biomass composition in different environments. Here, we propose two different computational approaches for directly addressing this challenge: Biomass Trade-off Weighting (BTW) and Higher-dimensional-plane InterPolation (HIP). In lieu of experimental data on biomass composition-variation in response to changing nutrient environment, we assess the properties of BTW and HIP using three hypothetical, yet biologically plausible, BOFs for the Escherichia coli genome-scale metabolic model iML1515. We find that the BTW and HIP formulations have a significant impact on model performance and phenotypes. Furthermore, the BTW method generates larger growth rates in all environments when compared to HIP. Using acetate secretion and the respiratory quotient as proxies for phenotypic changes, we find marked differences between the methods as HIP generates BOFs more similar to a reference BOF than BTW. We conclude that the presented methods constitute a conceptual step in developing genome-scale metabolic modelling approaches capable of addressing the inherent dependence of cellular biomass composition on nutrient environments.


Preoperative patient factors associated with blood product use in cardiac surgery, a retrospective cohort study.
Cardiac surgery is associated with a high rate of blood use. The aim of this study is to identify preoperative patient factors associated with allogeneic Red Blood Cell (RBC) or non-Red Blood Cell (NRBC) use in cardiac surgery. All adult cardiac surgical procedures conducted at a single Western Australian institution were retrospectively analysed. Data was collected from the Australia and New Zealand Cardiac Surgery Database from 2015 to 2018. A number of preoperative factors were identified, relating to past medical history or preoperative cardiac status. Outcome 1 was defined as the use of one or more RBC products intra or post-operatively. Outcome 2 was defined as the use of one or more NRBC products intra or post-operatively. Multivariate logistical regression analysis was done to assess for the association between preoperative factors and allogeneic blood product use. A total of 1595 patients were included in this study, of which 1488 underwent a Coronary Artery Bypass Graft, Valve or a combined procedure. Patients on dialysis preoperatively and those who had preoperative cardiogenic shock demonstrated the greatest risk of requiring RBC transfusion with an odds ratio of 5.643 (95% CI 1.305-24.40) and 3.257 (95% 1.801-5.882) respectively. Patients who had preoperative cardiogenic shock demonstrated the greatest risk of requiring NRBC transfusion with an odds ratio of 3.473 (95% CI 1.970-6.135). Patients who have had a previous cardiothoracic intervention are at increased risk of both RBC and NRBC transfusion, with adjusted odds ratios of 1.774 (95% CI 1.353-2.325) and 2.370 (95% CI 1.748-3.215) respectively. A number of factors relating to past medical history or preoperative cardiac status are implicated with increased allogeneic blood product use in cardiac surgery. Identifying high-risk patients in a preoperative setting can enable us enrol them in a blood conservation program, therefore minimizing the risk of exposure to blood transfusion.


Patterns of regional gray matter and white matter atrophy in cortical multiple sclerosis.
We investigated the patterns of regional distribution of focal lesions, white matter (WM) and gray matter (GM) atrophy in patients with cortical (cort) MS in comparison to classical (c) MS patients. Nine cort-MS, nine c-MS and nine age-matched healthy controls (HC) underwent a brain MRI exam, including FLAIR and high-resolution T1-weighted scans. MS patients underwent neurological and neuropsychological assessment. Between-group differences of GM and WM volumes and their correlations with neuropsychological performances were assessed with voxel-based morphometry. FLAIR and T1 lesion probability maps (LPMs) were also obtained. Performance at neuropsychological tests was worse in cort-MS than in c-MS patients. Compared to HC, MS patients had a distributed pattern of GM and WM atrophy. No GM/WM area was more atrophic in c-MS vs cort-MS patients. Compared to c-MS, cort-MS patients experienced GM atrophy of frontal-temporal-parietal areas and cingulate cortex and WM atrophy of the cingulum bundle, bilateral cerebral peduncles, right inferior longitudinal fasciculus and left superior longitudinal fasciculus. FLAIR and T1 LPMs did not differ between c-MS vs cort-MS patients. A higher susceptibility to neurodegenerative processes in key brain regions known to be related to cognitive functions is likely to underlie the clinical manifestations of cort-MS.


Mouse mammary tumor virus DNA in infected rat cells: characterization of unintegrated forms.
Mouse mammary tumor virus (MMTV) DNA in chronically infected rat hepatoma cells is maintained in both the integrated and unintegrated state. Fractionation of DNA by the procedure of Hirt (1967) as well as by sedimentation through alkaline sucrose suggests that about two thirds of the viral DNA is associated with high molecular weight cell DNA. The remainder of the viral DNA is unintegrated and is present primarily as linear or open circular duplexes consisting of a genome-length strand complementary to the viral RNA ("minus" strand) and "plus" strands of subgenomic length. Approximately 20% of the unintegrated MMTV DNA is present as double-stranded, covently closed circles (form I) with a molecular weight of 6 X 10(6) daltons. Form I viral DNA is found primarily in the nucleus, whereas the open forms are both nuclear and cytoplasmic.


Characteristics of bacterial community and ARGs profile in engineered goldfish tanks with stresses of sulfanilamide and copper.
Abuse of antibiotics in aquaculture have been alarming and might aggravate spread of resistance genes in the environment. Holistic ARGs proliferation checks require deeper analyses of coupled absolute abundances in 16S rRNA bacteria communities at the phylum level to detect biomarkers. Sulfanilamide (sul) and copper II sulfate (CuSO4 II) were, therefore, designed and added as separate or combined treatments in 9 replicate engineered goldfish tanks comprising 3 individual sul, 3 CuSO4 II, 3 (sul + CuSO4 II) combinations, and 3 controls within 180 days. The DNA from water and fish guts was sequenced under qPCR to determine 16S rRNA bacteria biomarkers co-occurring with the correspondent ARGs. Combined chemical addition at 0.8-1.5 mg sul + 0.5-1.0 mg CuSO4 II/3 L of tank waters reduced sequenced 16S rRNA bacteria absolute abundances in fish gut and water samples while portraying the biomarkers. Absolute abundances of the entire 16S rRNA bacteria was higher in fish guts (3.4 × 1014-4.9 × 108 copies/g) than water samples (1.5 × 109-2.6 × 1015 copies/L), respectively. Much as sul 1(log) were dominant over intl 1(log) genes, and their fundamental profiles were also higher in the fish guts than water samples; the Spearman's correlation analyses revealed positive relationship (p < 0.01 and r = 0.873) among the biomarkers of both ARG pairs at the phylum level and the physicochemical parameters. In the fish gut and water samples ratios, Bacteroidetes (10-85:12-85%) > Proteobacteria (10-50:15-65%) > Planktomycetes (10-52:8-25%) featured prominently based on LEfSe use as the hot-spotted biomarkers, hence justifying its higher prospects towards innovative environmental microbiological and biotechnological studies.


Incidence and cost of treatment-emergent comorbid events in insured patients with chronic hepatitis C virus infection: a retrospective cohort study.
Treatment-emergent comorbid events (TECs) are common In patients initiating treatment with pegylated interferon alpha (PEG-IFN-alfa) and ribavirin for chronic hepatitis C virus (HCV) infection. The purpose of this study was to estimate the incidence and incremental cost of these events. In a retrospective cohort analysis of healthcare claims, we studied patients with HCV who were newly treated with PEG-IFN-alfa/ribavirin between 2006 and 2008. TECs were defined by new medical/pharmacy claims for predefined conditions in the 12 months after treatment initiation. The net incremental cost of the TECs was the difference between baseline and follow-up costs for these comorbidities and their treatment, excluding PEG-IFN-alfa/ribavirin costs. Of 3,795 newly treated patients, 1,269 (mean age 50.2, 36.2% female) met the selection criteria. New TECs were common, with 61.6% of patients having ≥1 event. Anemia was identified in 29.2% of patients, fatigue in 16.4%, depression in 11.5%, and neutropenia in 11.0%. The mean incremental cost for the predefined TEC in the postindex period was $6,377 ($2,782 for medical and $3,595 for pharmacy claims). In an insured US cohort with chronic HCV infection, TECs with PEG-IFN-alfa/ribavirin were common and increased costs by approximately $6,000 per treated patient. This estimate may be conservative because it excludes indirect costs. Costs might increase with new regimens that include a protease inhibitor because additional TECs may be expected. Better-tolerated therapies that reduce the financial burden on the healthcare system and improve patient experience are needed.


Effects of 9-t-butyl doxycycline on the innate immune response to CNS ischemia-reperfusion injury.
Cerebral ischemia triggers a cascade of neuroinflammatory and peripheral immune responses that contribute to post-ischemic reperfusion injury. Prior work conducted in CNS ischemia models underscore the potential to harness non-antibiotic properties of tetracycline antibiotics for therapeutic benefit. In the present study, we explored the immunomodulatory effects of the tetracycline derivative 9-tert-butyl doxycycline (9-TB) in a mouse model of transient global ischemia that mimics immunologic aspects of the post-cardiac arrest syndrome. Pharmacokinetic studies performed in C57BL/6 mice demonstrate that within four hours after delivery, levels of 9-TB in the brain were 1.6 and 9.5-fold higher than those obtained using minocycline and doxycycline, respectively. Minocycline and 9-TB also dampened inflammation, measured by reduced TNFα-inducible, NF-κβ-dependent luciferase activity in a microglial reporter line. Notably, daily 9-TB treatment following ischemia-reperfusion injury in vivo induced the retention of polymorphonuclear neutrophils (PMNs) within the spleen while simultaneously biasing CNS PMNs towards an anti-inflammatory (CD11bLowYm1+) phenotype. These studies indicate that aside from exhibiting enhanced CNS delivery, 9-TB alters both the trafficking and polarization of PMNs in the context of CNS ischemia-reperfusion injury.


Normal tRNAs promote ribosomal frameshifting.
The addition of Ser AGC AGU tRNA to an E. coli cell-free protein synthesizing system which contains the endogenous tRNA levels results in up to 100% of the ribosomes translating the MS2 coat gene shifting into the -1 reading frame. An analogous phenomenon is seen at a much lower level without the tRNA addition, where a shift into the +1 frame can also be detected. Thus translation with the endogenous tRNA levels yields proteins which have the amino terminus of the coat protein but which are substantially larger than the coat protein and comprise about 5% of the coat translation. Since the lysis gene overlaps the 3' end of the coat gene in the +1 frame, we conclude that the reading frame shift into the +1 frame yields a hybrid protein. Also, we present evidence that ribosomes translating the synthetase gene shift into the -1 frame near the distal end of the gene. This frameshifting is promoted by thrACU ACC tRNA. Specific competitor tRNAs for both Thr and Ser tRNA-promoted frameshifting have been characterized. The generality of this new mechanism for producing additional proteins is unclear, but it investigation should increase understanding of the coding mechanism and its origin.


CHEK2 deficiency increase the response to PD-1 inhibitors by affecting the tumor immune microenvironment.
Immune checkpoint blockade (ICB) therapy has improved treatment effects in multiple cancers. Gene mutations in the DNA damage repair pathway (DDR) may cause genomic instability and may relate to the efficacy of ICB. Checkpoint kinase 2 (CHEK2) and polymerase epsilon (POLE) are important genes in the DDR. In this study, we aimed to study the impact of CHEK2 deficiency mutations on the response to ICB. We found that tumors with CHEK2 mutations had a significantly higher tumor mutational burden (TMB) compared to those with CHEK2-WT in a pancancer database. We noted that CHEK2 deficiency mutations potentiated the anti-tumor effect of anti-PD-1 therapy in MC38 and B16 tumor-bearing mice with the decrease of tumor volume and tumor weight after anti-PD-1 treatment. Mechanistically, CHEK2 deficiency tumors were with the increased cytotoxic CD8+ T-cell infiltration, especially cytotoxic CD8+ T cells, and modulated the tumor-immune microenvironment with an upregulated immune inflammatory pathway and antigen presentation pathway after anti-PD-1 treatment. Furthermore, murine models with POLE mutations confirmed that CHEK2 deficiency shaped similar mutational and immune landscapes as POLE mutations after anti-PD-1 treatment. Taken together, our results demonstrated that CHEK2 deficiency mutations may increase the response to ICB (eg. anti-PD-1) by influencing the tumor immune microenvironment. This indicated that CHEK2 deficiency mutations were a potentially predictive biomarker and CHEK2 deficiency may potentiate response to immunotherapy.


Light-evoked dendritic spikes in sustained but not transient rabbit retinal ganglion cells.
Dendritic computations have a central role in neuronal function, but it is unknown how cell-class heterogeneity of dendritic electrical excitability shapes physiologically engaged neuronal and circuit computations. To address this, we examined dendritic integration in closely related classes of retinal ganglion cells (GCs) using simultaneous somato-dendritic electrical recording techniques in a functionally intact circuit. Simultaneous recordings revealed sustained OFF-GCs generated powerful dendritic spikes in response to visual input that drove action potential firing. In contrast, the dendrites of transient OFF-GCs were passive and did not generate dendritic spikes. Dendritic spike generation allowed sustained, but not transient, OFF-GCs to signal into action potential output the local motion of visual stimuli to produce a continuous wave of action potential firing in adjacent cells as images moved across the retina. Conversely, this representation was highly fragmented in transient OFF-GCs. Thus, a heterogeneity of dendritic excitability defines the computations executed by classes of GCs.


Reliability of plasma cortisol determination by a simple competitive protein binding method.
The method investigated used (3H) cortisol as the ligand, diluted human plasma as the binding protein, and florisil to separate free and bound cortisol. The precision and specificity were found to be adequate for routine use. The effects of such factors as delay in separation of plasma, storage of plasma, provenance of the binding protein, venepuncture, and venous occlusion have been studied. The extent and significance of short term, inter-daily, and longer term variation in plasma cortisol level are discussed.


Amperometric Sulfite Sensor Using Electrodecorated Pt Particles onto an Aminated Glassy Carbon Electrode Prepared by Stepwise Electrolysis.
A novel modified glassy carbon electrode with platinum (Pt)-electrodecorated and nitrogen-containing functional groups was prepared by stepwise electrolysis. The prepared electrode exhibited electrocatalytic activity towards sulfite oxidation that was better than that of a bare glassy carbon electrode. The electrocatalytic activity of sulfite oxidation has been applied to an amperometric sulfite sensor. A favorable linear relationship between the current response (ΔI) and the sulfite concentration up to 500 μM was exhibited. The detection limit was estimated to be 3 μM based on the criterion of a signal-to-noise (S/N) ratio of 3 under optimized conditions. In regards to the reproducibility, the RSD (n = 10) was 8.9% for 80 μM sulfite.


Crystal Structure Reveals the Full Ras-Raf Interface and Advances Mechanistic Understanding of Raf Activation.
Ras and Raf-kinase interact through the Ras-binding (RBD) and cysteine-rich domains (CRD) of Raf to signal through the mitogen-activated protein kinase pathway, yet the molecular mechanism leading to Raf activation has remained elusive. We present the 2.8 Å crystal structure of the HRas-CRaf-RBD_CRD complex showing the Ras-Raf interface as a continuous surface on Ras, as seen in the KRas-CRaf-RBD_CRD structure. In molecular dynamics simulations of a Ras dimer model formed through the α4-α5 interface, the CRD is dynamic and located between the two Ras protomers, poised for direct or allosteric modulation of functionally relevant regions of Ras and Raf. We propose a molecular model in which Ras binding is involved in the release of Raf autoinhibition while the Ras-Raf complex dimerizes to promote a platform for signal amplification, with Raf-CRD centrally located to impact regulation and function.


Regulation of interleukin-6 production in human fetal Kupffer cells.
Inflammatory mediators such as interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) exhibit local autocrine and paracrine effects as well as distant systemic effects on target cells. Human Kupffer cells, the fixed tissue macrophages of the liver, may modulate immune and endocrine function in early fetal development. We purified and cultured human fetal Kupffer cells to investigate the production of the cytokine, IL-6. Fetal Kupffer cells treated with bacterial lipopolysaccharide (LPS) produced IL-6 in a dose-dependent fashion with maximal secretion (1000 pg per 10(6) cells) observed within 12 h using 10 micrograms of LPS/ml. Cortisol and dexamethasone, but not oestrogen, progesterone, or testosterone, dramatically suppressed the LPS-stimulated secretion of IL-6 by fetal Kupffer cells. None of the steroids tested altered basal production or enhanced the LPS-stimulated production of IL-6 by fetal Kupffer cells. The inhibition of glucocorticoids could be reversed by the addition of RU 486, indicating that this effect was mediated by the glucocorticoid receptor. These results demonstrate that the production of IL-6 by fetal hepatic macrophages can be activated by LPS and suppressed by glucocorticoids. These studies suggest that Kupffer cells express mature macrophage function in early gestation and would be capable of regulatory roles in the growth and development of the fetus.


Transrectal ultrasound guided multi-core prostate biopsy: pain control: results of 106 patients.
To determine the efficacy of periprostatic nerve block (PPNB) for control of transrectal ultrasound (TRUS)-guided multicore prostate biopsy-related pain. A total of 106 cases with suspicion of prostate cancer underwent TRUS-guided multicore prostate biopsy under local anesthesia using a total of 10 ml of 1% lidocaine for each patient. Lidocaine was injected around the neurovascular bundle at the base of the prostate just lateral to the seminal vesicle-prostate junction. The pain score was assessed using visual analog pain score from 0 to 10. All patients were questioned for whether they would accept repeat biopsy or not, if necessary. Pain score ranged from 0 to 5 (mean: 1.4). Thirty-five percent (37/106) of patients reported a score of 0, whereas 17% (18/106), 32% (34/106), 8.4% (9/106), 6.7% (7/106), 0.9% (1/106) reported pain scores of 1, 2, 3, 4, and 5, respectively. There were no pain scores of 6-10. Answers for the question "would you accept repeat biopsy or not, if necessary?" was "yes" for 82% (87/106) of the patients. PPNB prior to multi-core TRUS-guided prostate biopsy is an easy, safe, and effective technique for the control of procedure-related pain.


Evaluation of intraoperative bleeding in shoulder arthroscopy with preoperative injection of epinephrine saline: a retrospective comparative study.
Several studies report the positive effects of epinephrine saline irrigation in shoulder arthroscopy. Cardiovascular adverse effects have been described. The Wide Awake Local Anesthesia No Tourniquet limits bleeding. The aim of this study is to evaluate the effects of epinephrine saline infiltrations of the shoulder on arthroscopic visual comfort. We carried out a retrospective comparative study in 2 groups of patients. We included all patients admitted to the department for a rotator cuff surgery. Our exclusion criteria were any other surgical indication and patient refusal. The protocol consisted in making 3 preoperative shoulder infiltrations of 20 mL of epinephrine saline at 0.005 mg/mL. Injections were performed in all patients in group 1, and no specific treatment was performed in group 2 (control group). Data collection was performed the same way in both groups. The main judgment criterion was the evaluation of the surgeon's overall visual comfort using the visual analog scale (VAS) at the end of the procedure. We also evaluated the intraoperative discomfort related to bleeding every 15 minutes by an objective scale (the visual numeric rating scale [VNRS]), as well as the cumulative bleeding time, operating time, the quantity of irrigation fluid used, the blood pressure at the times of the bleeding, the mean blood pressure during the surgery, and the presence of thromboembolic and cardiovascular adverse events. We included 30 patients in group 1 and 30 patients in the control group. The mean VAS value at the end of the intervention was significantly higher in group 1 than in the control group: VAS = 10 in group 1 vs. VAS = 5 in group 2 (P < .0001) (higher is better). We also observed a significant decrease in VNRS between the 2 groups: VNRS = 0.25 in group 1 vs. VNRS = 1.00 in group 2 (P < .0001) (lower is better). The bleeding time was significantly lower in patients in group 1 (1 minute 39 seconds) compared with patients in group 2 (9 minutes 57 seconds) (P < .0001). No significant difference was demonstrated concerning the operating times, the quantity of irrigation fluid used, and the blood pressure data of the 2 groups. No adverse effects were observed. The infiltration of low doses of epinephrine as performed in Wide Awake Local Anesthesia No Tourniquet procedures seems effective in improving visualization in arthroscopy by reducing the bleeding. It can be a simple, efficient, and cost-effective technique with no iatrogenic risk to improve the surgeon's comfort in arthroscopic procedures.


Antimutagenic activity of green tea polyphenols.
For centuries green tea has been a widely consumed beverage throughout the world. It is known to contain a number of pharmacologically active compounds. In this study water extracts of green tea (WEGT) and their major constituents, green tea polyphenols (GTP), were examined for antimutagenic activity. WEGT and GTP were found to significantly inhibit the reverse mutation induced by benzo[alpha]pyrene (BP), aflatoxin B1 (AFB1), 2-aminofluorene, and methanol extracts of coal tar pitch in Salmonella typhimurium TA100 and/or TA98 in the presence of a rat-liver microsomal activation system. GTP also inhibited gene forward mutation in V79 cells treated with AFB1 and BP, and also decreased the frequency of sister-chromatid exchanges and chromosomal aberrations in V79 cells treated with AFB1. The addition of GTP during and after nitrosation of methylurea resulted in a dose-dependent inhibition of mutagenicity. Studies to define the mechanism of the antimutagenic activity of GTP suggest that it may affect carcinogen metabolism, DNA adduct formation, the interaction of ultimate carcinogen or the scavenging of free radicals.


Correlation Connections between Individual-and-Typological Features, Indices of Performance of Goal-Directed Activity, and Heart Rate Variability Parameters.
Correlation analysis of the performance of goal-directed activity and heart rate variability parameters in people with different individually-typological features was conducted on the model of endosurgical training. It was found that people with low level of intro-extroversion and neuroticism, but high index of situational anxiety were more successful during goal-directed behavior. The subjects with low level of neuroticism finished the tasks more quickly, both at the beginning and at the end of the observations. It was established that the number of mistakes in subjects with low personal anxiety on the 10th day of training was lower than in high-anxious individuals. It is shown that people with high rate of intro-extroversion are characterized by more pronounced increase in parasympathetic influences during basic endosurgical training. Hence, the achievement of the result in extroverts in these experimental conditions is provided by lower physiological penalty than in introverts. The definition of psychophysiological indices could be recommended for inclusion in the complex of measures for the assessment of proficiency in the training of endosurgeons.


Association between hematological parameters and metabolic syndrome components in a Chinese population.
Insulin resistance, an essential core contributing to the metabolic syndrome (MS), has been demonstrated in some studies to be associated with white blood cell (WBC) or red blood cell (RBC) counts. The present study was undertaken to assess systemically the relationship between WBC or RBC counts and various clinical features of MS in a large Chinese population at Taiwan. A total of 4938 subjects (2891 men and 2047 women with a mean age of 50.1 +/- 12.6 years), who had attended health examination at this hospital were enrolled. The Adult Treatment Panel III (ATP III) definition of MS components was adopted in this study with the exception of the definition of obesity. This was defined as body mass index (BMI) greater than 27 kg/m(2). Overall, 14% had high serum total triglyceride (TG), 8% had low high-density lipoprotein (HDL) cholesterol, and 18% were obese. WBC counts showed a statistically significant (P < .001) correlation with TG (r = .265), HDL(r = -.187), fasting glucose (r = .084), and BMI (r = .172) but not with blood pressure levels. In addition, RBC counts correlated significantly (P < .001) with TG (r = .250), HDL(r = -.269), fasting glucose (r = .098), and BMI (r = .228). WBC and RBC counts in subjects grouped according to the presence of 0, 1, 2, and >or= 3 features of MS were 6268 +/- 1633, 6555 +/- 1782, 6995 +/- 1880, and 7185 +/- 1696 cells/mm(3), and 4.63 +/ -0.56 x 10(6), 4.73 +/- 0.54 x 10(6), 4.84 +/- 0.60 x 10(6), and 4.91 +/- 0.55 x 10(6) cells/mm(3), respectively (P for trend <.001). Subjects in the highest quartile of WBC or RBC counts demonstrated a three- or twofold increase, respectively, in the odds ratio for MS with 3 or more metabolic features compared to subjects in the lowest quartile of WBC or RBC counts. Increased WBC and RBC counts, albeit normal, were associated with a variety of MS features in a Taiwan Chinese population, suggesting that hematological parameters could potentially be used as indicators of this syndrome.


Indicator polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) in seafood from Xiamen (China): levels, distributions, and risk assessment.
Indicator polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were determined in 289 seafood samples including fishes, crustaceans, and shellfish collected from six administrative regions in Xiamen of China. The residual levels of PCBs, dichlorodiphenyltrichloroethane and its metabolites (DDTs), and hexachlorocyclohexanes (HCHs) ranged <LOD-64 (median 1.8) ng g-1 wet weight (ww), 0.03-88 (median 1.4) ng g-1 ww, and <LOD-5.5 (median <LOD) ng g-1 ww, respectively. The most abundant compounds were PCB101, p,p'-DDT, and β-HCH. Significant differences in the amounts of PCBs and DDTs were recorded among the species, whereas no significant differences were observed among the species with regard to HCH concentrations. Within the regions investigated, the concentrations of PCBs were much lower in Haicang than in other regions and HCHs were detected with highest concentration in Siming, while no significant differences were observed in DDT concentrations. Principal component analysis (PCA) showed that PCB and OCP pollutions came from similar sources in Xiamen. But the pollution sources of Xiangan were diverse. The predominance of PCBs might be attributed to the past usage of domestically produced commercial PCB mixtures, and the profiles of OCPs might indicate their current use in agriculture. Results of carcinogenic risk assessment based on the 50th or 95th percentile exposure levels exceeded the threshold, suggesting that the PCBs should be of concern. On the other hand, the hazard quotients (HQs) of noncancer risks were all far below than 1.


The effects of ladasten on dopaminergic neurotransmission and hippocampal synaptic plasticity in rats.
Derivatives of adamantane, like memantine, are potentially neuroprotective drugs for the favourable care of Alzheimer's and Parkinson's diseases. A further adamantane derivate is N-(2-adamantyl)-N-(para-bromophenyl)-amine (ladasten) which is capable to modulate animal performance in different learning paradigms. To clarify if some of those behavioural alterations are mediated by modulation of catecholamine syntheses we studied the effects of single administration of ladasten (50 mg/kg, per os) on catecholamines' biosynthesis in the ventral tegmental area, nucleus accumbens, hypothalamus, striatum and hippocampus. We found that ladasten differentially regulates tyrosine hydroxylase mRNA and protein as well as dopamine and L-DOPA content. We then investigated the effects of ladasten on activity-dependent hippocampal synaptic plasticity in vitro and found that application of 10 microM ladasten transforms short-term potentiation of synaptic transmission to a long-lasting form. A transformation of short-term into long-term potentiation was also observed, when ladasten was applied 40 min after a single 100 Hz 200 ms tetanization. This reinforcement was blocked by the protein synthesis inhibitor anisomycin and could be attenuated by the D1/D5 receptor antagonist SCH23390. These results suggest that ladasten induces reinforcement of short-term potentiation via protein synthesis and dopamine dependent mechanisms.


Impact of inferior vena cava ligation on mortality in trauma patients.
Inferior vena cava (IVC) injuries are potentially lethal and require prompt intervention. Repair of complex IVC injuries may require the use of a prosthetic graft or a complicated panel or spiral vein graft reconstruction to avoid the need for ligation. Collateral venous drainage may be sufficient to allow acceptable results from IVC ligation; however, previous studies have suffered from low numbers and have differing results. The aims of this study were to assess the outcomes of isolated IVC injuries overall and to compare IVC ligation with repair. Patients in the National Trauma Data Bank from 2007 to 2014 with an IVC injury were evaluated. Isolated IVC injury was defined as patients with nonvascular Abbreviated Injury Scale scores <4 and no other named vascular injury. The primary outcome was mortality; secondary outcomes were in-hospital amputation-free survival, major lower extremity amputation, lower extremity compartment syndrome, acute kidney injury (AKI), deep venous thrombosis (DVT), and pulmonary embolism (PE). Overall, 1075 (0.018%) patients had IVC injuries and 443 met inclusion criteria. On univariate analysis, in comparing IVC ligation and primary repair, ligation was not associated with mortality (23% vs 16%; P = .102) but was associated with blunt mechanism (22% vs 11%; P = .009), higher fasciotomy rate (11% vs 0%; P < .001), trend toward lower in-hospital amputation-free survival (76% vs 84.4%, P = .056), and higher rates of AKI (9% vs 4%; P = .060) and PE (3% vs 1%, P = .087). Similarly, major lower extremity amputation, compartment syndrome, and DVT were not different between groups. IVC ligation was not independently associated with mortality (adjusted odds ratio [AOR], 1.54; P = .197), in-hospital amputation-free survival (AOR, 0.61; P = .141), major amputation (AOR, Inf; P = .99), lower extremity compartment syndrome (AOR, 0.82; P = .827), or PE (AOR, 6.72; P = .052), but it was independently associated with fasciotomy (AOR, 31.4; P = .002), AKI (AOR, 2.7; P = .048), and DVT (AOR, 2.3; P = .021). IVC ligation was not independently associated with mortality or lower extremity amputation, but it was associated with AKI and need for fasciotomy.


Use of Novel Antidiabetic Agents in Patients with Type 2 Diabetes and COVID-19: A Critical Review.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). The latter is a pandemic that has the potential of developing into a severe illness manifesting as systemic inflammatory response syndrome, acute respiratory distress syndrome, multi-organ involvement and shock. In addition, advanced age and male sex and certain underlying health conditions, like type 2 diabetes mellitus (T2DM), predispose to a higher risk of greater COVID-19 severity and mortality. This calls for an urgent identification of antidiabetic agents associated with more favourable COVID-19 outcomes among patients with T2DM, as well as recognition of their potential underlying mechanisms. It is crucial that individuals with T2DM be kept under very stringent glycaemic control in order to avoid developing various cardiovascular, renal and metabolic complications associated with more severe forms of COVID-19 that lead to increased mortality. The use of novel antidiabetic agents dipeptidyl peptidase 4 inhibitors (DPP4i), sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) in subjects with T2DM may have beneficial effects on COVID-19 outcomes. However, relevant studies either show inconsistent results (DPP4i) or are still too few (SGLT2i and GLP-1RAs). Further research is therefore needed to assess the impact of these agents on COVID-19 outcomes.


Synthesis and molecular characterization of chitosan/alginate blends based polyurethanes biocomposites.
The present work aims to examine the structural properties of polyurethanes bio-composites with mole ratios of alginate and chitosan. For this concern, a two-step reaction mechanism was carried out; in the first step isocyanate (-NCO) terminated pre-polymer was synthesized by the reaction of hexamethylene diisocyanate (HMDI) and hydroxyl-terminated polybutadiene (HTPB). The pre-polymer was further extended with 1,4-butanediol (BDO), chitosan (CS) and alginate (ALG) in the second step. Structural and functional group elucidation was done by using Fourier Transform Infra-red (FT-IR) and proton nuclear magnetic resonance (1H NMR) spectroscopy. The crystallinity of the prepared samples was investigated by using X-ray diffraction (XRD) method, the maximum observed intensity was 7704 a.u. The thermal properties of polyurethane composites were carried out using thermogravimetric analysis (TGA) and differential scanning calorimeter (DSC). The TGA results showed that thermal stability of RPU-5 was 20 °C more than RPU-1 at each corresponding degradation temperature. It is observed all physical parameters like crystallinity, glass transition temperature, melting point are much dependent on ratio of chain extenders. Overall, CS based samples along with small amount of ALG showed better thermal properties.


Pharmacokinetics, pharmacodynamics and toxicity of Baicalin liposome on cerebral ischemia reperfusion injury rats via intranasal administration.
Baicalin (BA) is a major active component from the traditional Chinese medicine, which has been widely used to treat brain diseases. Previously, the baicalin liposome (BA-LP) was prepared to improve its low bioavailability. However, the existence of the obstacles such as the blood-brian-barrier (BBB) still make it difficult to enter brain effectively. Meanwhile, many reports have shown that drugs can be transported into brain through intranasal administration without the BBB. Therefore, we aim to explore the effect of BA-LP on middle cerebral artery occlusion (MCAO) rats via i.n. administration. The results showed that BA and BA-LP had no obvious impact on mucosa after i.n. administration. And in pharmacokinetics study after i.n. administration, the value of t 1/2 and AUC 0-t in BA-LP group were significantly higher than that of the BA group (p < 0.05), indicating BA-LP could prolong the extension time of BA in vivo and further improve the bioavailability. In the brain biodistribution, the BA-LP group showed a higher BA concentration in brain tissues. Pharmacodynamics studies showed that BA-LP through i.n. administration could significantly improve the neurological deficits, cerebral infarction and brain pathological status in rats with MCAO surgery. Obviously, the BA-LP was more effective after nasal administration than intravenous administration, suggesting the nasal administration is more advantageous route in brain concentration enrichment. In conclusion, BA-LP could be safely used in i.n. administration, which can effectively improve brain targeting effect and thus protect the MCAO rats. Furthermore, successful use of the BA-LP via nasal delivery can provide a model for other drugs with neuroprotective effect and further promote the cure rate of brain diseases.


Segmental Cervical Aplasia in a Colombian Creole Mare with Mosaic X-Chromosome Aneuploidy.
A 4-year-old Colombian Creole mare was presented for diagnosis because the external orifice of her cervix was not detectable when a uterine lavage as therapy for uterine fluid accumulation was attempted. Clinical and ultrasonographic evaluation of the genital tract revealed that ovaries were of normal size and showed structures suggestive of regular ovarian activity. However, granular free-floating fluid material distending the uterus was detected by ultrasound. Upon vaginal examination, the normal external cervical morphology was not evident. The vagina ended in a blind bag with a small papilla with no evident external cervical os. Cytology of uterine fluid obtained by transvaginal aspiration showed findings compatible with mucometra. Cytogenetic analysis revealed an abnormal karyotype (63,X and 64,XX both 45% and 65,XXX 10%). A diagnosis of congenital segmental cervical aplasia was proposed possibly related to the mosaicism detected. To our knowledge, this is the first case of this reproductive pathology in a mare with regular ovarian activity and confirmed aneuploidy in mosaic form of the X sex chromosome.


Aquatic environmental changes and anthropogenic activities reflected by the sedimentary records of the Shima River, Southern China.
Reconstructing historical sedimentary records is essential for better understanding the effects of anthropogenic activities on river environments. We used lead-210 to date riverine sediment core from the Shima River in China. We obtained a sedimentary history of 34 years (1982-2015) for core S2, which had a length of 34 cm. The sedimentation rate of 0.304-2.04 cm y-1 was controlled by both flood events and anthropogenic activities. The conservative element content depth profiles remained relatively constant, suggestive of a relatively stable sediment provenance; therefore, the increase in the sedimentation rate over time was mainly the result of domestic and industrial wastewater effluent and the construction of a rubber dam at the middle and lower reach of the Shima River. From 1982 to 2015, the nutrient and trace metal depth profiles could be divided in three periods based on their trends. From 1982 to 1993, the vertical profiles of nutrients (organic carbon, total phosphorus, and total nitrogen) and three trace metals (nickel, zinc, and manganese) were relatively stable; however, the gradual decrease in copper and cadmium was likely associated with a reduction in agricultural chemical application. From 1993 to 2003, a population explosion and rapid industrialization were responsible for an increase in the input of pollutants into the Shima River, which was partly attenuated by water from the Dong River, leading to a gradual increase in nutrient and trace metal contents. Finally, from 2003 to 2015, the Shima River stopped being used as a source of water due to its deteriorating water quality. The relatively lower velocity of the water flow after the recovery of its flow direction and the reconstruction of the rubber dam in 2009 provided advantageous sedimentary conditions, promoting nutrient accumulation and significant trace metal enrichment.


Long-term multimodal imaging characterization of persistent retinal neovascularization using DL-alpha-aminoadipic acid in pigmented and white rabbits.
Intravitreal (IVT) injection of DL-alpha-aminoadipic acid (AAA) is a new animal model for retinal neovascularization (RNV) reported in rabbits. This study performs longitudinal multimodal imaging for up to 1 year to evaluate DL-AAA RNV in both New Zealand white (NZW) rabbits and Dutch-Belted pigmented (DBP) rabbits. Detailed characterization and quantification of this model were performed in these two strains in 32 eyes by optical coherence tomography (OCT), fundus photography, and fluorescein angiography (FA) for up to 16 weeks following DL-AAA administration in 32 eyes and up to 52 weeks in 5 eyes. H & E histology was also performed in these two strains 8 weeks after injection of DL-AAA. RNV was successfully generated using 50 μL 80 mM DL-AAA solution for DBP rabbits and 80 μL 80 mM DL-AAA for NZW rabbits. The incidence of persistent vascular leakage is 100% (15/15) for DBP rabbits and 70.6% (12/17) for NZW rabbits at 16 weeks. Complications with NZW rabbits ultimately decreased the efficiency in NZW rabbits to 58.8% (10/17) of NZW rabbits getting persistent (to 16 weeks) vascular leakage without ocular complications as compared with 100% (15/15) in DBP rabbits. Five eyes (2 DBP and 3 NZW) were selected from those demonstrating RNV at 16 weeks and were monitored for up to 52 weeks. All 5 demonstrated persistent RNV to 52 weeks. Quantification of the mean leakage area (MLA) in DBP rabbits is more accurate than in NZW rabbits since the reduced contrast between the leakage and background in NZW rabbits makes it more challenging to quantify. DL-AAA can induce persistent and quantifiable RNV in both DBP and NZW rabbits. DBP rabbits have a higher success rate, lower required volume of DL-AAA, and more accurate method for quantification that could be more desirable.


The association between road traffic noise and type 2 diabetes: a systematic review and meta-analysis of cohort studies.
The association between road traffic noise and type 2 diabetes (T2DM) was inconsistent. To address this, we have synthesized available cohort studies about their association by meta-analysis. PubMed, Web of Science, EBSCO, Cochrane Library, EMBASE, and Scopus databases were searched up to July 2022. The Quality-effect model (QE) was used to incorporate the results of included studies. The possibility of publication bias was assessed by the Doi plots and Luis Furuya-Kanamori index. Sensitivity analyses included leave-one-out meta-analysis, subgroup meta-analysis, and meta-regressions. The Recommendations for Assessment, Development, and Evaluation (GRADE) guidelines were conducted to evaluate the overall quality of evidence. Eight cohort studies with 4,989,846 participants and 416,799 diabetes cases were included. Based on the fully adjusted models from 8 cohort studies (10 estimates; Lden range ≈ 15-98.5 dB(A)), we found "high" evidence of RR per 10 dB(A) = 1.07 (1.05, 1.10), high heterogeneity (I2 = 0.91%, p < 0.001), and high publication bias (LKF index = 4.55). Sensitivity analyses showed stable model results, and the GRADE assessment suggested the current overall quality of evidence is high. Comprehensive evidence from cohort studies supports that increasing exposure to road traffic noise may be associated with higher risk of T2DM.


Polyelectrolyte properties of biopolymers: conductivity and secondary structure of polyriboadenylic acid and its salts in solutions.
Polyriboadenylates of alkali metals were obtained from (1) K(+)-poly(A) (salts 1) and (2) H(+)-poly(A) (salts II) by the ion-exchange method. The conductivity of these salts as well as of H(+)-poly(A) were studied. Salts I and II of the same counterion were shown to have significantly different conductivity coefficients (f) and polyion conductances (lambda 0p). the charge density parameter (xi) was 1.3 and 2.5, respectively, with lambda 0p equal to 44 and 83 ohm-1 cm2 mole-1 for poly(A)-I and poly(A)-II salts, respectively. This is credited to the difference in the conformations of corresponding polyions. The linear dependence of equivalent conductivity on the square root of polymer concentration (Kohlrausch coordinates), earlier obtained for DNA, is also satisfied for the studied polynucleotides. A comparison of the slopes of straight lines in Kohlrausch coordinates for poly(A), simple electrolytes, and for earlier studied polyribouridylic acid salts lends credence to the concepts, developed by a number of authors, that DNA can act as a "buffer" against the ion-ion interaction in concentrated electrolyte solutions. Using the approximation that the polyion conductance is independent of the counterion nature, parameter f (agreeing in this case with Eisenberg parameter phi) has been shown to decrease as the polynucleotide concentration is increased; the decrease is caused by the relaxation effect. The transference numbers of counterions, which have negative values in poly (A)-II solutions, grow with the increase in polymer concentration; the higher the xi, the more apparent is this increase. This is explained by the increase in the fraction of conductivity along the polyion chains ("surface" conductivity) with the growth of polyelectrolyte concentration.


A conveniently synthesized Pt (IV) conjugated alginate nanoparticle with ligand self-shielded property for targeting treatment of hepatic carcinoma.
The clinical translation remains a major challenge for platinum drug loaded nanoparticle due to the complexity of composition and preparation. Here we employed only three ingredients to prepare Pt (IV) prodrug-loaded ligand-induced self-assembled nanoparticles (GA-ALG@Pt NPs) via facile one-pot route for liver tumor treatment. GA-ALG@Pt NPs were found equipped with intelligently ligand self-shielded property in which the internal GA could be induced to expose by initial cellular recognition, resulting in strengthened cellular uptake (20%-30%) and prolonged blood circulation time (3.43 times). Appreciable tumor targeting ability (2 times) and especially tumor selectivity (2.5 times) were obtained. Glutathione-triggered release of therapeutic agent generated satisfactory antitumor effect. Bio-safety is also a distinguishing feature of GA-ALG@Pt NPs that greatly relief the nephrotoxicity and systematic toxicity of cisplatin. This conveniently synthesized nanoparticle processes superior targeting capacity and biosecurity, supplying an effective approach to translational cancer therapy in the future.


Achieving Safe Liberation During Weaning From VV-ECMO in Patients With Severe ARDS: The Role of Tidal Volume and Inspiratory Effort.
Weaning from venovenous extracorporeal membrane oxygenation (VV-ECMO) has not been not well studied. VV-ECMO can be discontinued when patients tolerate noninjurious mechanical ventilation (MV) during a sweep gas-off trial (SGOT). However, predictors of safe liberation are unknown. Can safe liberation from VV-ECMO be predicted at the bedside? Two observational studies of adults weaned from VV-ECMO for severe ARDS at Toronto General Hospital were conducted. MV settings, respiratory mechanics, and clinical variables were analyzed to predict safe liberation from VV-ECMO, defined a priori as avoida7ce of ECMO recannulation, increased MV support, need for rescue therapy, or hemodynamic instability developed within 48 h following decannulation. During both studies, 83 patients were weaned from VV-ECMO, 21 (25%) of whom did not meet the criteria for safe liberation. In the retrospective study, higher tidal volume per predicted body weight (OR, 1.58; 95% CI, 1.05-2.40; P = .03) and heart rate (OR, 1.07; 95% CI, 1.022-1.15; P = .01) at the end of SGOT were significantly associated with increased odds of unsafe liberation when adjusted for age (OR, 1.02; 95% CI, 0.95-1.09; P = .63) and sequential organ failure assessment score (OR, 1.16; 95% CI, 0.86-1.56; P = .34). Change in ventilatory ratio had an imprecise association (OR, 2.7; 95% CI, 0.94-7.95; P = .06) with unsafe liberation when adjusted for age (OR, 1.03; 95% CI, 0.96-1.10; P = .42), sequential organ failure assessment score (OR, 1.11; 95% CI, 0.81-1.51; P = .52), and heart rate (OR, 1.07; 95% CI, 1.01-1.13; P = .02). In the prospective study, patients who had unsafe liberation from VV-ECMO also had significantly higher inspiratory efforts (esophageal pressure swings, 9 [7-13] vs 18 [7-25] cm H2O; P = .03) and worse outcomes (longer MV duration, ICU and hospital length of stay). Patients with higher tidal volume, heart rate, ventilatory ratio, and esophageal pressures swings during SGOT were less likely to achieve safe liberation from VV-ECMO.


Mothers' Diet and Family Income Predict Daughters' Healthy Eating.
Understanding the degree to which parents may influence healthy behaviors may provide opportunities to intervene among populations at increased risk of diseases, such as breast cancer. In this study, we examined the association between daughters' healthy eating habits and family lifestyle behaviors among girls and their families by using baseline data from the LEGACY (Lessons in Epidemiology and Genetics of Adult Cancer from Youth) Girls Study. Our objective was to examine the relationship between daughters' healthy eating and family lifestyle behaviors and to compare these associations between families with and without a history of breast cancer. We examined demographic and lifestyle data from a cohort of 1,040 girls aged 6 to 13 years from year 1 (2011) of the LEGACY study. Half had a family history of breast cancer (BCFH). We used mixed-effects linear regression to assess the influence of the mother and father's physical activity, family relationship scores, the mother's diet, the family's income, and the daughter's sports participation, age, body mass index (BMI), and race/ethnicity on the daughter's Healthy Eating Index (HEI) score. Daughters' healthy eating was significantly correlated with the mother's diet (r[668] = 0.25, P = .003) and physical activity (r[970] = 0.12, P = .002), the father's physical activity (r[970] = 0.08, P = .01), and the family income (r[854] = 0.13, P = .006). Additionally, the mother's diet (β coefficient = 0.71, 95% CI, 0.46-0.88, P = .005) and family income (β coefficient = 3.28, 95% CI, 0.79-5.78, P = .002) significantly predicted a daughter's healthy eating. Analyses separated by family history status revealed differences in these associations. In families without a history of breast cancer, only the mother's diet (β coefficient = 0.62; 95% CI, 0.29-0.95; P = .001) significantly predicted the daughter's healthy eating. In families with a history of breast cancer, the mother's diet (β coefficient = 0.73, 95% CI, 0.42-1.03, P = .006) and family income (β coefficient = 6.24; 95% CI, 2.68-9.80; P = .004) significantly predicted a daughter's healthy eating. A mother's diet and family income are related to the daughter's healthy eating habits, although differences exist among families by family history of breast cancer.


Synthesis and biological evaluation of quinoxaline derivatives as specific c-Met kinase inhibitors.
A series of novel quinoxaline derivatives were synthesized and evaluated for their inhibitory activity against c-Met kinase enzyme. Most of the tested compounds exhibited potent inhibitory activity. All the synthesized quinoxaline compounds were further examined against c-Met overexpressed human gastric cancer cell line (MKN-45), which showed good inhibitory activity. Among the synthesized compounds, compound 4 exhibited better tumor growth inhibition in the animal model study; we also confirmed its acceptable drug property and highly selective target activity.


Reccomendations for the detection, study and referral of inflammatory low-back pain in primary care.
To design a strategy for the early detection and referral of patients with possible spondyloarthritis based on recommendations developed, agreed upon, and directed to primary care physicians. We used a modified RAND/UCLA methodology plus a systematic literature review. The information was presented to a discussion group formed by rheumatologists and primary care physicians. The group studied the process map and proposed recommendations and algorithms that were subsequently submitted in two Delphi rounds to a larger group of rheumatologists and primary care physicians. The final set of recommendations was derived from the analysis of the second Delphi round. We present the recommendations, along with their mean level of agreement, on the early referral of patients with possible spondyloarthritis. The panel recommends that the study of chronic low back pain in patients under 45 years be performed in four phases 1) clinical: key questions, 2) clinical: extra questions, 3) physical examination, and 4) additional tests. The level of agreement with these simple recommendations is high. It is necessary to design strategies for the education and sensitization from rheumatology services to maintain an optimal collaboration with primary care and to facilitate referral to rheumatology departments.