Exposure to the cytokine EGF leads to abnormal hyperactivity of pallidal GABA neurons: implications for schizophrenia and its modeling.
Previous studies on a cytokine model for schizophrenia reveal that the hyperdopaminergic innervation and neurotransmission in the globus pallidus (GP) is involved in its behavioral impairments. Here, we further explored the physiological consequences of the GP abnormality in the indirect pathway, using the same schizophrenia model established by perinatal exposure to epidermal growth factor (EGF). Single-unit recordings revealed that the neural activity from the lateral GP was elevated in EGF-treated rats in vivo and in vitro (i.e., slice preparations), whereas the central area of the GP exhibited no significant differences. The increase in the pallidal activity was normalized by subchronic treatment with risperidone, which is known to ameliorate their behavioral deficits. We also monitored extracellular GABA concentrations in the substantia nigra, one of the targets of pallidal efferents. There was a significant increase in basal GABA levels in EGF-treated rats, whereas high potassium-evoked GABA effluxes and glutamate levels were not affected. A neurotoxic lesion in the GP of EGF-treated rats normalized GABA concentrations to control levels. Corroborating our in vivo results, GABA release from GP slices was elevated in EGF-treated animals. These findings suggest that the hyperactivity and enhanced GABA release of GP neurons represent the key pathophysiological features of this cytokine-exposure model for schizophrenia.


Glia maturation factor promotes proliferation and morphologic expression of rat Schwann cells.
Glia maturation factor (GMF) is an acidic protein with a molecular weight of about 20,000 daltons, found in the adult brain of many species. Previously GMF was observed to stimulate the proliferation and subsequent maturation of rat astroblasts in culture. We investigated the effects of GMF on Schwann cells. Schwann cells were dissociated from rat sciatic nerve and purified by means of antimitotic agents and by selective immunoadsorption of contaminating fibroblasts. Cultured Schwann cells after 3 passages assumed a flat polygonal shape. Exposure of the cells to GMF converted the cells to the elongated, spindle morphology typical of Schwann cells. GMF also stimulated a 7-fold increase in DNA synthesis when compared with control cultures grown in F10 medium containing 5% fetal calf serum. The mitogenic activity of GMF was still detectable at 5 ng protein/ml medium. The maximal effect on DNA synthesis occurred 72 h after the initial exposure to GMF. Although the cells were positive for the Schwann cell marker Ran-1, GMF failed to induce the production of myelin-associated glycolipids (galactocerebroside) and proteins (Po) nor did it induce the astrocytic marker glial fibrillary acidic protein (GFAP). The effects of GMF on Schwann cells extend its biological role beyond the central nervous system.


Palladium Nanoribbon Array for Fast Hydrogen Gas Sensing with Ultrahigh Sensitivity.
A lithographically aligned palladium nano-ribbon (Pd-NRB) array with gaps of less than 40 nm is fabricated on a poly(ethylene terephthalate) substrate using the direct metal transfer method. The 200 μm Pd-NRB hydrogen gas sensor exhibits an unprecedented sensitivity of 10(9) % after bending treatment, along with fast sensing behavior (80% response time of 3.6 s and 80% recovery time of 8.7 s) at room temperature.


[Perinatal depression--recent topics].
Depression is the most common complication in perinatal period, affecting approximately 10% of women. Studies were also examined for data related to the predictors/risk factors, effects on the fetus and newborn, and treatment of depression during these periods. Psychopharmacological treatment in pregnant or breastfeeding women with depression will result primarily from a careful evaluation of their psychopathological condition. Maternal depression is associated with adverse effects on fetal and infant development. Prevention and psychological intervention is also useful for detecting mother with postnatal depression, using the EPDS. Controlled psychological trials for postnatal depression have shown the benefit of involving health professionals. Multidisciplinary specialist teams in mother and baby units have been an important role in perinatal psychiatric care.


Effect of Bronchoscopic Spray Cryotherapy and Ultra-low Temperature on Physical Properties of Metallic and Silicone Airway Stents.
Bronchoscopic spray cryotherapy (SCT) is utilized in the field of interventional pulmonology for treating benign and malignant airway stenosis as a standard tool to maintain airway patency. Stent-related complications include tumor overgrowth, granulation tissue, and epithelialization. Thermal ablation can have a limited role in such scenarios due to the risk of airway fire and damage to the existing stent. SCT is a potential therapy using ultra-low temperatures that can allow stents to remain in place during treatment. However, there has been no study demonstrating the safety of SCT on the integrity and physical properties of tracheobronchial stents. We report the results of the first study demonstrating the safety of SCT utilized to treat stent-associated granulation or malignant airway disease. The aim of this study was to demonstrate the effects of SCT on the physical properties of airway stents in an ex vivo environment. Various types of airway stents were subjected to multiple intervals of SCT for up to 30 seconds, and then the cycle was repeated 3 times. After every cycle, we compressed the stents to 60% of their original size, and compression and expansion force data was collected immediately after, at 3-minute and 5-minute intervals, and compared with the baseline readings. There was no significant change in the association between diameter and compression/expansion force, including any derangement in returning to the original diameter or any physical damage to any of the stents even after 3 prolonged SCT sessions of 30 seconds. Our study provides the first evidence that the use of SCT in conjunction with existing silicone/metal stents is feasible and does not cause any physical damage to the stents or alters their ability to maintain the original diameter.


A critical role for system A amino acid transport in the regulation of dendritic development by brain-derived neurotrophic factor (BDNF).
Dendritic development is essential for the establishment of a functional nervous system. Among factors that control dendritic development, brain-derived neurotrophic factor (BDNF) has been shown to regulate dendritic length and complexity of cortical neurons. However, the cellular and molecular mechanisms that underlie these effects remain poorly understood. In this study, we examined the role of amino acid transport in mediating the effects of BDNF on dendritic development. We show that BDNF increases System A amino acid transport in cortical neurons by selective up-regulation of the sodium-coupled neutral amino acid transporter (SNAT)1. Up-regulation of SNAT1 expression and System A activity is required for the effects of BDNF on dendritic growth and branching of cortical neurons. Further analysis revealed that induction of SNAT1 expression and System A activity by BDNF is necessary in particular to enhance synthesis of tissue-type plasminogen activator, a protein that we demonstrate to be essential for the effects of BDNF on cortical dendritic morphology. Together, these data reveal that stimulation of neuronal differentiation by BDNF requires the up-regulation of SNAT1 expression and System A amino acid transport to meet the increased metabolic demand associated with the enhancement of dendritic growth and branching.


Blood flow pattern in eye before development of type 3 macular neovascularization.
To determine the blood flow pattern of eyes before the development of type 3 macular neovascularization (MNV) by optical coherence tomography angiography (OCTA). Retrospective study. Ten eyes of 10 patients (4 men and 6 women, mean age 80.4 years) diagnosed with unilateral Type 3 MNV who developed type 3 MNV in the fellow normal eye during the follow-up period were studied. The time of onset of type 3 MNV was defined as the time when retinal exudation was detected by OCT. The blood flow of a 3 x 3 mm or 6 x 6 mm area in the deep capillary plexus (DCP) and the outer retina (OR) including the central fovea were assessed at the onset and at 6 months prior to the onset of the type 3 MNV. All MNVs that developed in the fellow eye were type 3 MNVs. Abnormal blood flow signals in the MNVs were detected in the DCP and/or the OR by OCTA at the onset in all cases. Eight of the 10 eyes had OCTA recordings prior to the development of the MNV: 3 eyes had non-exudative MNVs only in the DCP and 5 eyes had non-exudative MNVs in the DCP and OR. The exudation appeared on the average 3.5 months after the non-exudative MNV was observed in the fellow eyes. A non-exudative MNV in the fellow eyes can already be observed by OCTA in eyes before the onset of the exudation. Knowing this will help clinicians not only how to treat these eyes appropriately but will also help in determining the origin of the MNV.


Angiographic features of squamous cell carcinoma of the pancreas.
The angiographic findings in two cases of squamous cell carcinoma of the pancreas are reported. Tumor blushes were present in both cases and one case showed hypervascularity. These angiographic features distinguish this lesion from the typical adenocarcinoma of the pancreas. Squamous cell carcinoma should be included in the differential diagnosis when hypervascularity or a tumor blush are demonstrated in the pancreas.


Metabolites produced during the peroxisomal beta-oxidation of linoleate and arachidonate move to microsomes for conversion back to linoleate.
When [1-(14)C]4,7,10-16:3, a product produced after two cycles of arachidonate beta-oxidation, was incubated with rat liver peroxisomes and microsomes it was metabolized to 2-trans-4,7,10-16:4, a catabolic product; 6,9,12-18:3 and 8,11,14-20:3, anabolic products made via microsomal chain elongation of the substrate; and 7,10-16:2 and 9,12-18:2. Analysis of the acyl-CoAs produced when 6,9,12-18:3 and its catabolic product, 4,7,10-16:3, where incubated under the above conditions showed that the acyl-CoAs of all of the above compounds, as well as 5,8-14:2-CoA and 6:0-CoA accumulated. Our results show that when 5,8-14:2 and 4,7,10-16:3 are produced by peroxisomal beta-oxidation they can be further degraded to hexanoyl-CoA or move to microsomes for conversion back to linoleate, which is a precursor of arachidonate.


Density estimation based on the Hounsfield unit value of cone beam computed tomography imaging of the jawbone system.
The aim of this study is to investigate the estimation of density from the Hounsfield unit of cone beam computed tomography data in dental imaging, especially for dental implant application. A jaw phantom with various known densities of anatomical parts (e.g. soft tissue, cortical bone, trabecular bone, tooth enamel, tooth dentin, sinus cavity, spinal cord and spinal disc) has been used to test the accuracy of the Hounsfield unit of cone beam computed tomography in estimating the mechanical density (true density). The Hounsfield unit of cone beam computed tomography data was evaluated via the MIMICS software using both two-dimensional and three-dimensional methods, and the results showed correlation with the true density of the object. In addition, the results revealed that the Hounsfield unit of cone beam computed tomography and bone density had a logarithmic relation, rather than a linear one. To this end, the correlation coefficient of logarithmic correlation (R2 = 0.95) is higher than the linear one (R2 = 0.77).


Transcriptomic Analysis of Annexin A10 and Chemosensitivity in Gastric Adenocarcinoma Cells.
Gastric cancer (GC) is the third-leading cause of cancer-related deaths worldwide; thus, novel diagnostic and therapeutic biomarkers are needed. Annexin A10 (ANXA10) is a calcium- and phospholipid-binding protein. As far as we are aware, there are no reports describing the detailed functions of ANXA10 in GC. Therefore, we investigated the downstream mRNA variation and the effects of ANXA10 on chemoresistance in GC cell lines. ANXA10 knockout GC cell lines were generated, and we performed functional analyses, chemosensitivity drug testing, and microarray analyses. Additionally, immunohistochemistry for ANXA10 was performed on 40 patients with GC who had received 5-fluorouracil (5-FU)-based chemotherapy to compare their prognosis and clinicopathological factors. ANXA10 knockout GC cells showed significantly increased proliferation, invasion, and sensitivity to 5-FU. The overall survival of ANXA10-positive cases was considerably lower than that of ANXA10-negative cases in GC patients who received 5-FU-based chemotherapy. Microarray analysis revealed candidate pathways regulated by ANXA10 and claudin 1 (CLDN1), keratin 80 (KRT80), RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1), and solute carrier family 7 member 5 (SLC7A5) genes. ANXA10 knockout increased the susceptibility of GC cell lines to 5-FU; ANXA10 may be a predictive indicator for response to 5-FU treatment in GC cases. ANXA10 may be involved in the pathogenesis of GC, in collaboration with CLDN1, KRT80, RBCK1, and SLC7A5.


Human T cell immunosenescence and inflammation in aging.
The aging process is driven by a finite number of inter-related mechanisms that ultimately lead to the emergence of characteristic phenotypes, including increased susceptibility to multiple chronic diseases, disability, and death. New assays and analytical tools have become available that start to unravel some of these mechanisms. A prevailing view is that aging leads to an imbalance between stressors and stress-buffering mechanisms that causes loss of compensatory reserve and accumulation of unrepaired damage. Central to this paradigm are changes in the immune system and the chronic low-grade proinflammatory state that affect many older individuals, even when they are apparently healthy and free of risk factors. Independent of chronological age, high circulating levels of proinflammatory markers are associated with a high risk of multiple adverse health outcomes in older persons. In this review, we discuss current theories about causes and consequences of the proinflammatory state of aging, with a focus on changes in T cell function. We examine the role of NF-κB activation and its dysregulation and how NF-κB activity differs among subgroups of T cells. We explore emerging hypotheses about immunosenescence and changes in T cell behavior with age, including consideration of the T cell antigen receptor and regulatory T cells (Tregs). We conclude by illustrating how research using advanced technology is uncovering clues at the core of inflammation and aging. Some of the preliminary work in this field is already improving our understanding of the complex mechanisms by which immunosenescence of T cells is intertwined during human aging.


Changes in aortic stiffness and augmentation index after acute converting enzyme or vasopeptidase inhibition.
Augmentation index (AI), a measure of enhanced wave reflection, has been proposed as a bedside measure of aortic stiffness. However, because AI is potentially sensitive to various factors other than vessel wall stiffness, the utility of AI as a stiffness indicator may be limited. To assess relations between AI and vascular properties, we used arterial tonometry and aortic Doppler flow to evaluate trough (24 hours) and peak (4 hours) pulsatile hemodynamics and pulse wave velocity in 159 individuals with systolic hypertension at the completion of a 12-week period of monotherapy with the vasopeptidase inhibitor omapatrilat (80 mg; n=75) or the converting enzyme inhibitor enalapril (40 mg; n=84). Characteristic impedance (Zc) was calculated from the ratio of change in carotid pressure and aortic flow in early systole. Systolic ejection period (SEP), timing of wave reflection, and AI were assessed from the carotid waveform. Comparable acute reductions in mean pressure were associated with greater reductions in peripheral resistance with enalapril, whereas neither drug had an acute effect on Zc. Both drugs reduced AI, but neither drug altered the timing of wave reflection. Both drugs increased heart rate and shortened SEP. Multiple regression analysis demonstrated that the acute reduction in AI was most affected by reductions in SEP and peripheral resistance. Change in AI was inversely related to change in Zc and pulse wave velocity did not enter the model. Our findings indicate that AI is a complex surrogate marker that is inversely related to changes in proximal aortic stiffness in systolic hypertension.


Management of cerebral arteriovenous malformations associated with symptomatic congestive intracranial hypertension.
We report on management strategies and clinical outcomes in 4 cases of acute symptomatic congestive intracranial hypertension associated with cerebral arteriovenous malformations (AVMs). Congestion resulted from high-volume shunts exhausting the drainage capacity of the cerebral venous system in 3 patients, and from sudden venous outflow obstruction in 1 patient. Two AVMs were suggested to be surgically accessible, whereas two AVMs were deemed to be inoperable. Surgically accessible AVMs were treated with embolization followed by complete surgical resection. Inoperable AVMs were treated with partial embolization. Both AVM embolization followed by surgical resection and partial AVM embolization effectively reduced intracranial pressure and achieved sustained patient recovery. Hence, an endovascular approach may be considered to manage AVM-related congestive intracranial hypertension either in combination with surgical AVM removal, or as a palliative approach in inoperable AVMs.


Functionalization effect on a Pt/carbon nanotube composite catalyst: a first-principles study.
Chemical interactions between Pt and both pristine and defective carbon nanotubes (CNTs) that were functionalized with various surface functional groups, including atomic oxygen (-O), atomic nitrogen (-N), hydroxyl (-OH) and amine (-NH2) groups, were investigated through first-principles calculations. Our calculations suggest that the oxygen or nitrogen of the surface functional group can promote better structural stability of a Pt/CNT complex in terms of the binding energy enhancement between Pt and CNTs. Enhanced binding of the Pt/CNT complex would improve the long-term durability of the complex and thus enhance the catalytic activity of Pt catalysts supported on CNTs. Among the functional groups investigated, atomic nitrogen resulted in the most consistent increase in the Pt binding energies on pristine or defective CNTs. Moreover, atomic nitrogen decoration on the surface of CNTs rather than substitution into the CNTs appears to be more desirable. A d-band centre analysis and H2 adsorption calculations also revealed that the catalytic activity of Pt can be improved via efficient functionalization of the CNT support.


Risk factors associated with prolonged postoperative stay following free tissue transfer: an analysis of 2425 patients from the American College of Surgeons National Surgical Quality Improvement Program database.
Length of stay following surgical procedures has a considerable impact on healthcare resource use. This study characterizes risk factors predictive of a prolonged length of stay following free tissue transfer using the American College of Surgeons National Surgical Quality Improvement Program database. The 2005 to 2011 National Surgical Quality Improvement Program databases were reviewed for all identifiable free tissue transfer cases. Free tissue transfers for breast and nonbreast reconstruction were analyzed separately. Prolonged length of stay was defined as greater than the 75th percentile in each cohort group. A logistic regression model was developed for prolonged postoperative length of stay following breast and nonbreast reconstruction. The authors identified 2425 patients, and 885 (36 percent) had a prolonged length of stay, determined to be greater than 5 days and greater than 13 days in the breast (577 patients) and nonbreast (308 patients) reconstruction groups, respectively. Higher American Society of Anesthesiologists class and prolonged operative time were associated with a prolonged length of stay for both groups. Declining preoperative albumin level (p < 0.0001), increasing age (p = 0.0068), history of diabetes (OR, 2.16; p = 0.0215), perioperative transfusion requirement (OR, 3.64; p = 0.0311), dependent functional status (p = 0.0101), and preoperative irradiation (OR, 4.01; p = 0.0062) were also predictors for a prolonged length of stay in the nonbreast reconstruction group. This study identified key predictors of prolonged length of stay following free tissue transfer. The diverging findings between cohorts with regard to the impact of comorbidities on length of stay highlight possible avenues to improve healthcare resource use.


5-Hydroxytyrosol inhibits HIV-1 replication in primary cells of the lower and upper female reproductive tract.
We investigated the potential anti-HIV-1 activity of the candidate microbicide 5-hydroxytyrosol (5-HT) both in primary human cervical tissue explants (CTE), established from tissues of women undergoing histerectomy, and in endometrium-associated leukocytes (EAL). CTE were exposed to either the laboratory-adapted HIV-1BaL or to primary viral isolates in the presence or absence of 5-HT or 3TC/lamivudine as control and were then monitored for 12 days in terms of HIV-1 p24 Gag antigen production in culture supernatants. HIV-1BaL replication was also evaluated in EAL by reverse transcriptase (RT) activity. The highest nontoxic concentrations of 5-HT (200 and 100 μM for CTE and EAL, respectively) exerted a significant inhibitory effect on virus replication in both primary cell systems. 5-HT did not cause significant alterations of the activation profile of CD4+ and CD8+ T cells, in terms of CD4, CCR5, CD25, CD69 and HLA-DR expression, although it decreased the percentage of CD38+CD8+ T cells. Thus, 5-HT deserves consideration as a potential candidate microbicide for preventing HIV-1 transmission or curtailing its replication in the female reproductive tract.


Left Ventricular Thrombus in the Setting of Normal Left Ventricular Function in Patients with Crohn's Disease.
Crohn's disease results in a hypercoagulable state increasing the risk of venous or arterial thromboembolism. Cardiac involvement has not been routinely identified. Two cases are presented to illustrate that patients with Crohn's disease may represent an exception to the rule that left ventricular apical thrombus should be associated with an underlying wall motion abnormality and reduction in left ventricular ejection fraction.


Characterization of the two conformations adopted by the T3SS inner-membrane protein PrgK.
The pathogenic bacterium Salmonella enterica serovar Typhimurium utilizes two type III secretion systems (T3SS) to inject effector proteins into target cells upon infection. The T3SS secretion apparatus (the injectisome) is a large macromolecular assembly composed of over twenty proteins, many in highly oligomeric states. A sub-structure of the injectisome, termed the basal body, spans both membranes and the periplasmic space of the bacterium. It is primarily composed of three integral membranes proteins, InvG, PrgH, and PrgK, that form ring structures through which components are secreted. In particular, PrgK possesses a periplasmic region consisting of two globular domains joined by a linker polypeptide. We showed previously that in isolation, this region adopts two distinct conformations, of with only one is observed in the assembled basal body complex. Here, using NMR spectroscopy, we further characterize these two conformations. In particular, we demonstrate that the interaction of the linker region with the first globular domain, as found in the intact basal body, is dependent upon the cis conformation of the Leu77-Pro78 peptide. Furthermore, this interaction is pH-dependent due to coupling with hydrogen bond formation between Tyr75 and His42 in its neutral Nδ1 H tautomeric form. This pH-dependent interaction may play a role in the regulation of the secretion apparatus disassembly in the context of bacterial infection.


An experimental and theoretical study of the aggregate structure of calix[6]arenes in Langmuir films at the water/air interface.
In this paper, the aggregate formation of para-tert-butylcalix[6]arene molecules (Calix6) in dimeric structures was investigated at the water/air interface using experimental and theoretical studies. A specific orientation for such Calix6 molecules was observed with an average area of 133 Å(2), which corresponds to a flat-on orientation with the OH groups parallel to the interface. By varying the pressure on the Calix6 monolayer, the molecules tend to organize at the water/air interface and subsequently, at higher pressures, aggregates were formed atop the monolayer as cluster structures. Morphological characterization by the Brewster Angle Microscopy technique showed the formation of larger domains at lower pressures. Based on such experimental evidence, molecular dynamics (MD) simulations were performed to investigate possible dimeric structures for aggregated Calix6 molecules, which are localized at the water/air interface, where one molecule remains in the water phase and the other remains in the air phase. By increasing surface pressure, experimental and theoretical results corroborate the intermolecular interactions among Calix6 molecules. These results are relevant because a dimeric structure has a molecular cavity, which is a candidate for host-guest chemistry, an ion receptor or a drug-delivery system.


Tissue engineering of an auricular cartilage model utilizing cultured chondrocyte-poly(L-lactide-epsilon-caprolactone) scaffolds.
To determine the potential development in vivo of tissue-engineered auricular cartilage, chondrocytes from articular cartilage of bovine forelimb joints were seeded on poly(L-lactic acid-epsilon-caprolactone) copolymer scaffolds molded into the shape of a human ear. Copolymer scaffolds alone in the same shape were studied for comparison. Chondrocyte-seeded copolymer constructs and scaffolds alone were each implanted in dorsal skin flaps of athymic mice for up to 40 weeks. Retrieved specimens were examined by histological and molecular techniques. After 10 weeks of implantation, cell-seeded constructs developed cartilage as assessed by toluidine blue and safranin-O red staining; a vascular, perichondrium-like capsule enveloped these constructs; and tissue formation resembled the auricular shape molded originally. Cartilage matrix formation increased, the capsule persisted, and initial auricular configuration was maintained through implantation for 40 weeks. The presence of cartilage production was correlated with RT-PCR analysis, which showed expression of bovine-specific type II collagen and aggrecan mRNA in cell-seeded specimens at 20 and 40 weeks. Copolymer scaffolds monitored only for 40 weeks failed to develop cartilage or a defined capsule and expressed no mRNA. Extensive vascularization led to scaffold erosion, decrease in original size, and loss of contour and shape. These results demonstrate that poly(L-lactic acid-epsilon-caprolactone) copolymer seeded with articular chondrocytes supports development and maintenance of cartilage in a human ear shape over periods to 40 weeks in this implantation model.


Rational Design of CRISPR/Cas12a-RPA Based One-Pot COVID-19 Detection with Design of Experiments.
Simple and effective molecular diagnostic methods have gained importance due to the devastating effects of the COVID-19 pandemic. Various isothermal one-pot COVID-19 detection methods have been proposed as favorable alternatives to standard RT-qPCR methods as they do not require sophisticated and/or expensive devices. However, as one-pot reactions are highly complex with a large number of variables, determining the optimum conditions to maximize sensitivity while minimizing diagnostic cost can be cumbersome. Here, statistical design of experiments (DoE) was employed to accelerate the development and optimization of a CRISPR/Cas12a-RPA-based one-pot detection method for the first time. Using a definitive screening design, factors with a significant effect on performance were elucidated and optimized, facilitating the detection of two copies/μL of full-length SARS-CoV-2 (COVID-19) genome using simple instrumentation. The screening revealed that the addition of a reverse transcription buffer and an RNase inhibitor, components generally omitted in one-pot reactions, improved performance significantly, and optimization of reverse transcription had a critical impact on the method's sensitivity. This strategic method was also applied in a second approach involving a DNA sequence of the N gene from the COVID-19 genome. The slight differences in optimal conditions for the methods using RNA and DNA templates highlight the importance of reaction-specific optimization in ensuring robust and efficient diagnostic performance. The proposed detection method is automation-compatible, rendering it suitable for high-throughput testing. This study demonstrated the benefits of DoE for the optimization of complex one-pot molecular diagnostics methods to increase detection sensitivity.


m6A RNA Methylation Regulators Elicit Malignant Progression and Predict Clinical Outcome in Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and N6-methyladenosine (m6A) is a predominant internal modification of RNA in various cancers. We obtained the expression profiles of m6A-related genes for HCC patients from the International Cancer Genome Consortium and The Cancer Genome Atlas datasets. Most of the m6A RNA methylation regulators were confirmed to be differentially expressed among groups stratified by clinical characteristics and tissues. The clinical factors (including stage, grade, and gender) were correlated with the two subgroups (cluster 1/2). We identified an m6A RNA methylation regulator-based signature (including METTL3, YTHDC2, and YTHDF2) that could effectively stratify a high-risk subset of these patients by univariate and LASSO Cox regression, and receiver operating characteristic (ROC) analysis indicated that the signature had a powerful predictive ability. Immune cell analysis revealed that the genes in the signature were correlated with B cell, CD4 T cell, CD8 T cell, dendritic cell, macrophage, and neutrophil. Functional enrichment analysis suggested that these three genes may be involved in genetic and epigenetic events with known links to HCC. Moreover, the nomogram was established based on the signature integrated with clinicopathological features. The calibration curve and the area under ROC also demonstrated the good performance of the nomogram in predicting 3- and 5-year OS in the ICGC and TCGA cohorts. In summary, we demonstrated the vital role of m6A RNA methylation regulators in the initial presentation and progression of HCC and constructed a nomogram which would predict the clinical outcome and provide a basis for individualized therapy.


Effects of factor VIII levels on the APTT and anti-Xa activity under a therapeutic dose of heparin.
In pregnant women, activated partial thromboplastin time (APTT) does not precisely reflect the anticoagulant effect of a therapeutic dose of heparin. However, the measurement of anti-Xa activity can be used to monitor the anticoagulant effect of heparin, since the plasma concentrations of coagulation factors increase in pregnant women. We evaluated the in vitro effects of increased concentrations of fibrinogen and other coagulation factors (FVII, FVIII, and FIX) on the results of assays of APTT and anti-Xa activity in plasma samples with various therapeutic concentrations of unfractionated heparin (UFH). In the presence of UFH, APTT was shortened by increased concentrations of fibrinogen, FVII, or FVIII, and this effect was much stronger when the FVIII concentration was increased. In the plasma samples containing 0.5 or 0.7 U/mL of UFH, the APTT was shortened by approximately half or one-third, respectively, when 6 U FVIII/mL was added to the sample. The anti-Xa activity was not influenced by increased concentrations of the coagulation factors. In the present study, we also evaluated the sensitivities to UHF of four APTT reagents, and found a 1.65-fold difference in the sensitivity to UFH among APTT reagents. Our results demonstrate that increased FVIII concentration shortens APTT under therapeutic doses of UFH, and that APTT thus underestimates the anticoagulant effect of UFH in pregnant women, mainly due to the increased FVIII concentration.


Postcholecystectomy syndrome in the laparoscopic era.
sWe describe the management of a cystic duct remnant calculus in a 45-year-old male patient who had undergone a laparoscopic cholecystectomy and re-presented with abdominal pain and jaundice. Magnetic resonance cholangiopancreatography was utilized to confirm the diagnosis of an impacted calculus within the remnant cystic duct along with several small retained common bile duct stones. Four sequential endoscopic procedures successfully removed all retained common bile duct calculi to alleviate the biliary obstruction; however, we were unable to treat the cystic duct remnant calculus endoscopically. The patient finally underwent successful laparoscopic excision of a 2.5-cm cystic duct remnant containing its impacted calculus. It remains unclear if cystic duct remnant calculi may become more prevalent as a cause of postcholecystectomy syndrome in future due to the large numbers of laparoscopic cholecystectomies performed in the past 2 decades.


N-Alkylated C-Glycosyl Amino Acid Derivatives: Synthesis by a One-Pot Four-Component Ugi Reaction.
C-glycosides represent an important group of naturally occurring glycosylation derivatives but are also efficient mimetics of native O-glycosides. Here, a one-pot four-component methodology is described toward a library of N-alkylated C-glycosyl amino acid derivatives comprising seven different isopropylidene-protected carbohydrate units. The applied methodology tolerates different amines and isocyanides and provides access to Ugi products in yields up to 85 %. X-ray analysis of selected products bearing three different carbohydrate motifs and comparison of their crystal structures with similar ones deposited in Cambridge Crystallographic Database revealed that four structures adopt different conformations, mostly not typical for peptide structures. This property opens the possibility to exploit here described N-alkylated C-glycosyl amino acid derivatives as templates to access different biotic and abiotic secondary structures.


Studies on the mechanism of action of colloidal bismuth subcitrate. II. Interaction with pepsin.
The effects of colloidal bismuth subcitrate (CBS) on porcine pepsin have been studied in vitro. CBS inhibited pepsin activity in a pH-dependent manner. CBS was not active at pH 4.0 but inhibited pepsin activity at pH 1.0 (IC50: 2.3 +/- 0.09 mmol/l) and pH 2.0 (IC50: 8.9 +/- 0.7 mmol/l). This inhibition was reversible. In the presence of the sulfhydryl ligand mercaptoethanol, which prevents precipitation of CBS, the inhibitory potency of CBS increased. CBS bound to both positively (Amberlite) and negatively charged (Dowex) ion exchangers in a pH-dependent manner. With increasing acidity, binding to Amberlite increased, whereas binding to Dowex decreased. From these data we conclude that negatively charged bismuth salts derived from CBS bind at pH 2.0 and 1.0 via an ionic interaction to positively charged groups of pepsin, thereby inactivating the enzyme.


[Individual developmental care based on the Newborn Individualized Developmental Care and Assessment Program (NIDCAP)].
The number of preterm deliveries is increasing. Major advances in neonatology now enable even infants with a very low gestational age to survive. These infants have to spend months in the intensive care unit, while they have to deal with a lot of painful medical procedures, nursing care units, excessive noise and light, all differing from the normal uterine environment. The immature preterm infant nervous system is in a vulnerable phase of development. Early exposure to stress, or the mismatch of the preterm infant brain with the unphysiologic intensive care environment, may be linked to long-term developmental impairments reported in these children. The Newborn Individualized Developmental Care and Assessment Program (NIDCAP) is a systematic method of assessing the individual needs of preterm newborns. In an attempt to mimic uterine environment, care according to the NIDCAP principles is reducing infant distress and in the same way supporting the individual aibilities. Thus NIDCAP may have an effect on the preterm infant neurodevelopmental outcome.


The amino acid composition of crystalline pepsin.
The amino acid composition of twice recrystallized pepsin (Worthington Biochemical Corporation) has been determined chromatographically on columns of Amberlite IR 120 resin. The results of the analyses obtained on four different preparations indicate a close agreement in their amino acid composition. Pepsin is unique in that it has a great predominance of acidic amino acids over basic ones. Moreover, all the preparations contain a small and constant amount of hydroxyproline, corresponding to about 0.1 residue per molecule.


Achieving Fast Oxygen Reduction on Oxide Electrodes by Creating 3D Multiscale Micro-Nano Structures for Low-Temperature Solid Oxide Fuel Cells.
Fast oxygen reduction reaction (ORR) at the cathode is a key requirement for the realization of low-temperature solid oxide fuel cells (SOFCs). While the design of three-dimensional (3D) structures has emerged as a new and promising approach to improving the electrochemical performance of SOFC cathodes, achieving versatile structures and structural stability is still challenging. In this study, we demonstrate a novel architectural design for a superior cathode with fast ORR activity. By employing a completely new fabrication process comprising a 3D printing technique and pulsed laser deposition (PLD), we design 3D La0.8Sr0.2CoO3-δ (LSC) micro-nano structures with the desired shape. 3D-printed yttria-stabilized ZrO2 (YSZ) microstructures significantly increase the ratio of surface area to volume while maintaining suitable ionic conductivity comparable to that of single-crystalline YSZ substrates. Scanning electron microscopy and energy dispersive X-ray microanalysis reveal the formation of crack- or void-free YSZ microstructures and the uniform deposition of LSC films by PLD on the YSZ microstructures. The 3D LSC micro-nano structures show significantly enhanced oxygen surface exchange coefficients (kchem) extracted from electrical conductivity relaxation (ECR) measurements by up to 3 orders of magnitude relative to the bulk LSC. Furthermore, electrochemical impedance spectroscopy measurements verify the kchem values from ECR and no directional difference in the measured ORR activity depending on the shape of 3D microstructures. The dramatic enhancement of the ORR activity of LSC is attributed to the increased film surface areas resulting from the 3D YSZ microstructures.


Periodontal disease in seropositive rheumatoid arthritis: scoping review of the epidemiological evidence.
The link between periodontal disease (PD) and rheumatoid arthritis (RA) has been hypothesized to lie in the anti-cyclic citrullinated protein antibody (ACPA) molecules present in seropositive RA. This review aimed to discuss how RA and specifically ACPA-positive RA link to PD, and appraise the epidemiological evidence on the relationship between ACPA-positive RA and PD. Articles were searched following the PRISMA guideline across the MEDLINE, Web of Science, Scopus and Cochrane Library databases. A total of 21 articles met the inclusion criteria of reporting the epidemiological data on the different ACPA status of the subjects with RA and PD (or periodontitis) parameters. A discrepancy is noted in the epidemiological evidence on the difference in the prevalence and severity of PD between ACPA-positive and ACPA-negative RA patients. Although the link between RA and PD is mostly discussed in terms of ACPA, reports on the different manifestations of PD between the two RA subsets remains inconclusive.


[The Role of Psychiatrists as Personal Support Specialists].
Robert P. Liberman introduced "Personal Support Specialists" as a role of psychiatrists who support patients' lives and help them discover the meaning of life, as well as helping with daily activities and personal difficulties. They need to have multiple perspectives on medical, subjective, social, and life recoveries. Important areas to help patients practically are job-assis- tance, supporting love and marriage, and independent living in the community. I usually use Seikatsu-Rinsho (The way of Living Learning), cognitive behavioral therapy, and Seikatsu-ryouhou (Life-centered Therapy) by Hiroshi Utena as basic principles in my practice. Recently, I shed light on an -individual value system to evolve these principles. Reflecting on two recovery stories I co-encountered, contents of psychiatric interviews and roles of psychiatrists are discussed. There remain many difficulties which modern psychiatry has not resolved, such as negative symptoms and marked disabilities in social life. We as psy- chiatrists should know how to evolve and maintain hope and intrinsic motivation to support a patient's life.


Juvenile eosinophilic fasciitis: three case reports with review of the literature.
Eosinophilic fasciitis is an uncommon scleroderma-like disorder characterised by induration and thickening of skin and soft tissue, usually associated with peripheral eosinophilia, poorly characterised in childhood. We report 3 paediatric cases of eosinophilic fasciitis showing unusual clinical and histopathological features with a review of the literature. All cases presented progressive motility impairment started from upper limbs with no skin abnormalities. All cases showed systemic inflammatory involvement and 2 patients had acute complications. Two patients developed disabling outcomes despite appropriate treatments. Eosinophilic fasciitis may present unusual clinical and histopathological features during childhood and requires early recognition in order to prevent acute complications and disabling outcomes.


Oncolytic herpes simplex virus vectors and chemotherapy: are combinatorial strategies more effective for cancer?
Despite aggressive treatments, including chemotherapy and radiotherapy, cancers often recur owing to resistance to conventional therapies. Oncolytic viruses such as oncolytic herpes simplex virus (oHSV) represent an exciting biological approach to cancer therapy. A range of viral mutations has been engineered into HSV to engender oncolytic activity. While oHSV as a single agent has been tested in a number of cancer clinical trials, preclinical studies have demonstrated enhanced efficacy when it is combined with cytotoxic anticancer drugs. Among the strategies that will be discussed in this article are combinations with standard-of-care chemotherapeutics, expression of prodrug-activating enzymes to enhance chemotherapy and small-molecule inhibitors. The combination of oHSV and chemotherapy can achieve much more efficient cancer cell killing than either single agent alone, often through synergistic interactions. This can be clinically important not just for improving efficacy but also for permitting lower and less toxic chemotherapeutic doses. The viral mutations in an oHSV vector often determine the favorability of its interactions with chemotherapy, just as different cancer cells, due to genetic alterations, vary in their response to chemotherapy. As chemotherapeutics are often the standard of care, combining them with an investigational new drug, such as oHSV, is clinically easier than combining multiple novel agents. As has become clear for most cancer therapies, multimodal treatments are usually more effective. In this article, we will discuss the recent progress of these combinatorial strategies between virotherapy and chemotherapy and future directions.


Dengue Baidu Search Index data can improve the prediction of local dengue epidemic: A case study in Guangzhou, China.
Dengue fever (DF) in Guangzhou, Guangdong province in China is an important public health issue. The problem was highlighted in 2014 by a large, unprecedented outbreak. In order to respond in a more timely manner and hence better control such potential outbreaks in the future, this study develops an early warning model that integrates internet-based query data into traditional surveillance data. A Dengue Baidu Search Index (DBSI) was collected from the Baidu website for developing a predictive model of dengue fever in combination with meteorological and demographic factors. Generalized additive models (GAM) with or without DBSI were established. The generalized cross validation (GCV) score and deviance explained indexes, intraclass correlation coefficient (ICC) and root mean squared error (RMSE), were respectively applied to measure the fitness and the prediction capability of the models. Our results show that the DBSI with one-week lag has a positive linear relationship with the local DF occurrence, and the model with DBSI (ICC:0.94 and RMSE:59.86) has a better prediction capability than the model without DBSI (ICC:0.72 and RMSE:203.29). Our study suggests that a DSBI combined with traditional disease surveillance and meteorological data can improve the dengue early warning system in Guangzhou.


Hyaluronic acid injections relieve knee pain.
To evaluate the efficacy of intra-articular viscosupplementation therapy with hyaluronic acid for pain relief of knee osteoarthritis, we conducted a meta-analysis of randomized, double-blinded, placebo-controlled trials. We searched systematically for randomized, double-blinded, placebo-controlled trials of hyaluronic acid (hyaluronan and hylan G-F20) for pain relief of knee osteoarthritis. Studies reporting pain visual analogue scale (VAS) differences were included in the meta-analysis. Changes in pain were measured by VAS for placebo and treatment, and summary estimates of the differences between the 2 arms were calculated at 1 week, 5 to 7 weeks, 8 to 12, and 15 to 22 weeks after the last intra-articular injection. Sources of heterogeneity were assessed using information on quality score, type of viscosupplementation, and VAS change in pain with activity or rest. Heterogeneity across the studies was significant in all analyses (P<.01); therefore a random effect model was used. Pain was measured either on activity or at rest. Eleven trials (9 hyaluronan and 2 hylan G-F 20) allowed calculation of the summary estimate of difference in change of VAS pain at 1 week, 6 of the 11 allowed the estimation between 5 to 7 weeks and 8 to 12 weeks, and only 3 at 15 to 22 weeks. The summary estimates of VAS differences between therapy and placebo injection: at 1 week, 4.4 (95% confidence interval [CI], 1.1-7.2); at 5 to 7 weeks, 17.7 (7.5-28.0); at 8 to 12 weeks, 18.1 (6.3-29.9) and at 15 to 22 weeks, 4.4 (-15.3 to 24.1). Intra-articular viscosupplementation was moderately effective in relieving knee pain in patients with osteoarthritis at 5 to 7 and 8 to 10 weeks after the last injection but not at 15 to 22 weeks.


Desensitization of cAMP Accumulation via Human β3-Adrenoceptors Expressed in Human Embryonic Kidney Cells by Full, Partial, and Biased Agonists.
β3-Adrenoceptors couple not only to cAMP formation but, at least in some cell types, also to alternative signaling pathways such as phosphorylation of extracellular signal-regulated kinase (ERK). β3-Adrenoceptor agonists are used in long-term symptomatic treatment of the overactive bladder syndrome; it is only poorly understood which signaling pathway mediates the clinical response and whether it undergoes agonist-induced desensitization. Therefore, we used human embryonic kidney cells stably transfected with human β3-adrenoceptors to compare coupling of ligands with various degrees of efficacy, including biased agonists, to cAMP formation and ERK phosphorylation, particularly regarding desensitization. Ligands stimulated cAMP formation with a numerical rank order of isoprenaline ≥ L 755,507 ≥ CL 316,243 > solabegron > SR 59,230 > L 748,337. Except for the weakest agonist, L 748,337, pretreatment with any ligand reduced cAMP responses to freshly added isoprenaline or forskolin to a similar extent. On the other hand, we were unable to detect ERK phosphorylation despite testing a wide variation of conditions. We conclude that a minor degree of efficacy for cAMP formation may be sufficient to induced full desensitization of that response. Transfected human embryonic kidney cells are not suitable to study desensitization of ERK phosphorylation by β3-adrenoceptor stimulation.


Structural basis of the novel S. pneumoniae virulence factor, GHIP, a glycosyl hydrolase 25 participating in host-cell invasion.
Pathogenic bacteria produce a wide variety of virulence factors that are considered to be potential antibiotic targets. In this study, we report the crystal structure of a novel S. pneumoniae virulence factor, GHIP, which is a streptococcus-specific glycosyl hydrolase. This novel structure exhibits an α/β-barrel fold that slightly differs from other characterized hydrolases. The GHIP active site, located at the negatively charged groove in the barrel, is very similar to the active site in known peptidoglycan hydrolases. Functionally, GHIP exhibited weak enzymatic activity to hydrolyze the PNP-(GlcNAc)5 peptidoglycan by the general acid/base catalytic mechanism. Animal experiments demonstrated a marked attenuation of S. pneumoniae-mediated virulence in mice infected by ΔGHIP-deficient strains, suggesting that GHIP functions as a novel S. pneumoniae virulence factor. Furthermore, GHIP participates in allowing S. pneumoniae to colonize the nasopharynx and invade host epithelial cells. Taken together, these findings suggest that GHIP can potentially serve as an antibiotic target to effectively treat streptococcus-mediated infection.


Impact of levodopa treatment in the voice pattern of Parkinson's disease patients: a systematic review and meta-analysis.
Investigate the association between levodopa therapy and vocal characteristics in Parkinson's disease patients. Studies published at MEDLINE, LILACS, and SciELO, from 1960 to December 2016. A systematic review and meta-analysis was performed using the following keywords: Parkinson's disease; levodopa; L-dopa; voice; speech disorders; dysphonia; dysarthria. After analyzing titles and abstracts, two independent reviewers selected all clinical trials that met the eligibility criteria and selected the articles and the data recorded in a previously standardized table. Trials published in English between 1960 and December 2016 individuals with clinical diagnosis of Parkinson's disease; use of levodopa therapy in stable doses; acoustic analysis combined or not with auditory-perceptual analysis to evaluate the vocal parameters under investigation. The following vocal parameters were analyzed: fundamental frequency (F 0), jitter, and vocal intensity. Standardized mean differences (SMD) were calculated using the Comprehensive Meta-analysis V2 software. Nine articles met the eligibility criteria and were selected, with a total of 119 individuals. From these, six articles with 83 individuals were included in the meta-analysis. During the levodopa therapy "on" state, modifications in F 0 (SMD=0.39; 95% CI - 0.21-0.57) and jitter (SMD=0.23; 95% CI - 0.02-0.45) were observed. Vocal intensity was not affected (SMD=0.09; 95% CI - 0.22-0.39) by levodopa ingestion. Data of the included studies were controversial in the auditory-perceptual analysis of voice. Levodopa therapy modifies F0 and jitter. No changes in vocal intensity were observed in either the "on" or "off" states of levodopa therapy.


Self-reported prevalence of obesity among 20,329 adults from large territories of Greece, Serbia and Turkey.
The aim of this study was to investigate the prevalence of overweight, obesity and body mass index (BMI) distribution in people living in large territories of Greece, Serbia and Turkey. A cross-sectional multi-national epidemiological survey was designed on the basis of self-reported information on height and weight using the formula kg/m2. Overall, 20,329 individuals, aged 20-68 yrs, 8,973 males and 11,356 females, participated in the study. Of these, 4,032 were selected from northern Greece, 10,069 from southwest Turkey and 6,228 from central Serbia. More specifically, participants from northern Greece were recruited from central Macedonia, from Southwest Turkey from the Kayseri region and from central Serbia from the greater Belgrade area. Our results showed that 12.4% of the population studied was obese and 31.3% overweight. The corresponding figures for participants from Greece were 19.9% and 35.4%, from Turkey 12.0% and 30.9% and from Serbia 8.2% and 29.4%, respectively. Overall, male participants had a higher mean BMI than females. However, Greek females were more obese in comparison with males. The opposite was true of the other two countries. Finally, in both males and females mean BMI tended to increase with age up to 50-59 years, and declined slightly thereafter. In conclusion, the overall prevalence of obesity and overweight in the Balkan peninsula does not differ from that reported in other European countries. However, BMI values between different countries of the Balkan peninsula are fairly variable, Greece leading in the prevalence of obesity with Serbia having the lowest prevalence of obesity. The data from this survey underline the need for health intervention aimed at preventing obesity, especially in Greece.


Primary Carnitine Deficiency: A Rare, Reversible Metabolic Cardiomyopathy.
A 24-year-old female with a diagnosis of primary carnitine deficiency, a rare inherited metabolic disorder predominantly described in the paediatric literature that causes cardiomyopathy, presented for evaluation after three months of nonadherence with prescribed carnitine therapy. Initial echocardiography demonstrated severe left ventricular dilation (104 ml/m2) (normal < 76 ml/m2) with moderate systolic dysfunction (ejection fraction 40%) and severe right ventricular dilation with mild systolic dysfunction. Carnitine replacement was commenced, and a cardiac magnetic resonance imaging (MRI) performed five days later demonstrated dramatic improvement in biventricular function with normalization of left and right ventricular systolic function. To our knowledge, this is only the second case describing the rapid reversal of cardiomyopathy in an adult patient with this rare condition.


Soft-tissue masses: histologic basis for decreased signal (short T2) on T2-weighted MR images.
Most soft-tissue masses and tumors of various etiologies and histologies have high signal intensity on T2-weighted pulse sequences (long T2). Of 47 soft-tissue masses, seven had a low signal (short T2) on T2-weighted pulse sequences. All seven masses were tumors, and histologic review showed that their composition differed from that of the other 40 lesions with a long T2 in that the seven masses were relatively acellular and had more collagen. The tumors with a short T2 included one malignant and six benign soft-tissue tumors. Malignant fibrous histiocytoma and aggressive fibromatosis showed paradoxical signal intensities in that they showed both long and short T2. All of the tumors with low signal intensity on T2-weighted images had significant fibrous elements and marked hypocellularity. This study suggests that the less commonly encountered short T2 may be seen in both benign and malignant soft-tissue lesions. A part of the explanation for the low signal on T2-weighted sequences appears to be the relative acellularity and abundant collagen of these tumors in comparison with those that have the same histologic diagnoses but show a high signal. The histologic composition of the tumor rather than the histologic diagnosis appears to influence the MR signal on T2-weighted sequences.


Neuroimmune pharmacological approaches.
Intestinal inflammation is a major health problem which impairs the quality of life, impacts mental health and is exacerbated by stress and psychiatric disturbances which, in turn, can affect disease prognosis and response to treatment. Accumulating evidence indicates that the immune system is an important interface between intestinal inflammation and the enteric, sensory, central and autonomic nervous systems. In addition, the neuroimmune interactions originating from the gastrointestinal tract are orchestrated by the gut microbiota. This article reviews some major insights into this complex homeostatic network that have been achieved during the past two years and attempts to put these advances into perspective with novel opportunities of pharmacological intervention.


New Criteria on Global Stabilization of Delayed Memristive Neural Networks With Inertial Item.
In this paper, we are concerned with global stabilization for a kind of delayed memristive neural network with an inertial term. By building a new Lyapunov functional and designing a feedback controller, we obtain some new results on global stabilization of the addressed delayed memristive inertial neural networks (MINNs). An adaptive control strategy is also designed to realize the global stabilization. Compared with the reduced-order method used in the existing literature, we consider the stabilization directly from the MINNs themselves without a reduced-order method. In addition, the new results proposed here are shown as algebraic criteria, which are easy to test. At last, some simulations are given to show the validity of the derived criteria.


Predictors of Thromboembolic Events in Patients with Ventricular Assist Device.
Ventricular assist device patients (VAD) are at increased risk for thromboembolism. Biomarkers of hemolysis, such as lactate dehydrogenase (LDH) and poorly controlled international normalized ratio (INR) has been identified as predictors of thromboembolism. Patients aged 19 years and older who had a continuous flow VAD placed from 2006 to 2012 were included in this study (N = 115). We assessed the relationship of LDH elevation (≥600 IU/L) at different time points and thromboembolism. Over the 51.3 person-years of follow-up, a total of 23 first thromboembolic events occurred. Patients with elevated LDH on the day of VAD implantation had an increased risk for thromboembolism (hazard ratio [HR]: 4.72, 95% confidence interval [CI]: 1.44-15.4; p = 0.01). There was an increased risk of thromboembolism with early LDH elevation within the first month post-VAD (HR: 4.95, 95% CI: 1.69-14.4; p = 0.003) and estimated glomerular filtration rate <30 before VAD implantation (HR: 4.74, 95% CI: 1.12-20.1; p = 0.0346), whereas there was a decreased risk with good anticoagulation control (HR: 0.30, 95% CI: 0.10-0.86; p = 0.0247). Our study is the first to highlight the association between LDH elevation on the day of implantation and post-VAD thromboembolism. This study details the increased risk of thromboembolism with early LDH elevation and the importance of maintaining time in therapeutic INR range.


The "tract" of history in the treatment of lumbar degenerative disc disease.
In this paper past, present, and future treatments of degenerative disc disease (DDD) of the lumbar spine are outlined in a straight forward manner. This is done to review previous knowledge of the disease, define current treatment procedures, and discuss future perspectives. An analysis of a subject of this magnitude dictates that one describes as accurate a history as possible: an anatomical/historical "tract" with emphasis on all possible deviations. Although spinal disorders have been recognized for a long time, the view of DDD as a particular disease entity is a more recent development. In this paper, the authors attempt to outline the history of DDD of the lumbar spine in an unbiased and scientific fashion. Physiological, diagnostic, and therapeutic implications will all be addressed in this study.


Dynamics of colloids in a narrow channel driven by a nonuniform force.
Using Brownian dynamics simulations, we investigate the dynamics of colloids confined in two-dimensional narrow channels driven by a nonuniform force Fdr(y) . We considered linear-gradient, parabolic, and deltalike driving-force profiles. This driving force induces melting of the colloidal solid (i.e., shear-induced melting), and the colloidal motion experiences a transition from elastic to plastic regime with increasing Fdr. For intermediate Fdr (i.e., in the transition region) the response of the system, i.e., the distribution of the velocities of the colloidal chains upsiloni(y) , in general does not coincide with the profile of the driving force Fdr(y), and depends on the magnitude of Fdr, the width of the channel, and the density of colloids. For example, we show that the onset of plasticity is first observed near the boundaries while the motion in the central region is elastic. This is explained by: (i) (in)commensurability between the chains due to the larger density of colloids near the boundaries, and (ii) the gradient in Fdr. Our study provides a deeper understanding of the dynamics of colloids in channels and could be accessed in experiments on colloids (or in dusty plasma) with, e.g., asymmetric channels or in the presence of a gradient potential field.


Emotional and Behavioral Problems in Children and Adolescents in Central Kenya.
Emotional and behavioral problems (EBP) during childhood and adolescence are a common concern for parents and mental health stakeholders. However, little has been documented about their prevalence in Kenyan children and adolescents. This study aimed to close this gap. The study included Child Behavior Checklist reports from 1022 Kenyan parents on their children (ages 6-18 years) and Youth Self-Reports from 533 adolescents (ages 12-18) living in Kenya's Central Province. EBP in Kenya are highly prevalent compared to multi-cultural standards for parent reports, with 27 and 17% scoring in the borderline and clinical range, respectively. Based on parent reports, younger children scored higher on EBP than older children, and higher on internalizing problems. Based on self-reports girls scored higher than boys, particularly on internalizing problems. The study provides evidence on elevated parent-reported EBP in Kenyan youths. Mental health providers should focus on interventions that reduce EBP in Kenyan youths.


A chromogenic assay for evaluation of alpha 2-macroglobulin level in serum and cerebrospinal fluid.
A photometric assay using the chromogenic substrate carbobenzoxy-valyl-glycyl-arginine-p-nitroanilide acetate (CHROMOZYM TRY) for the determination of alpha 2-macroglobulin which binds trypsin as a trypsin-protein complex, thus preserving its amidolytic activity, even in the presence of aprotinin, has been studied in serum as well as in cerebrospinal fluid (CSF). Normal range in sera was found to be mean = 10.2 +/- 3.3 kU/l (male), mean = 10.9 +/- 3.2 kU/l (female), and mean = 11.9 +/- 5.0 U/l in CSF. Within-run precision in sera was ascertained to be C.V. = 2.06%, and in CSF C.V. = 2.15%, respectively. There was a good correlation with immunochemical methods: r = 0.974 in 60 sera (p less than 0.001) and r = 0.976 in 16 pathological samples of CSF (p less than 0.001).


Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats.
Pathological angiogenesis represents a critical hallmark for chronic liver diseases. Understanding the mechanisms regulating angiogenesis is essential to develop new therapeutic strategies that specifically target pathological angiogenesis without affecting physiological angiogenesis. Here we investigated the contribution and therapeutic impact of the endogenous angioinhibitor vasohibin-1 in portal hypertension and cirrhosis. The spatiotemporal expression profiling of vasohibin-1 and its relationship with vascular endothelial growth factor (VEGF), angiogenesis, and fibrogenesis was determined through the analysis of human cirrhotic liver specimens, widely accepted in vivo animal models of portal hypertension and cirrhosis, and in vitro angiogenesis assays. Effects of vasohibin-1 overexpression by adenoviral-mediated gene transfer on angiogenesis, fibrogenesis, and portal hypertension-associated hemodynamic alterations were also studied in rats. We found that vasohibin-1 and VEGF are up-regulated, in mesentery and liver, in cirrhotic and precirrhotic portal hypertensive rats and cirrhosis patients. Our results are consistent with vasohibin-1/VEGF cascades being spatially and temporally coordinated through a negative-feedback loop driving pathological angiogenesis. Paradoxically, further overexpression of vasohibin-1 by adenoviral gene transfer exerts multifold beneficial effects in portal hypertension and cirrhosis: reduction of pathologic angiogenesis, attenuation of liver fibrogenesis partly mediated through inhibition of hepatic stellate cell activation, and significant decreases in portocollateralization, splanchnic blood flow, portohepatic resistance, and portal pressure. The explanation for this apparent contradiction is that, unlike endogenous vasohibin-1, the ectopic overexpression is not regulated by VEGF and therefore disrupts the negative-feedback loop, thus generating constant, but lower levels of VEGF synthesis sufficient to maintain vascular homeostasis but not pathological angiogenesis. Our study provides evidence that vasohibin-1 regulates portal hypertension-associated pathological angiogenesis and highlights that increasing vasohibin-1 might be a promising novel therapeutic strategy for portal hypertension and cirrhosis.


Compartment Syndrome After Tibial Intramedullary Nail Removal and Intramedullary Debridement: A Case Report.
A 45-year-old man who sustained an open tibial shaft fracture treated with intramedullary (IM) nailing 9 years earlier presented with persistent pain and concern for occult infection. He underwent tibial nail removal and debridement with reamer-irrigator-aspirator. Postoperative course was complicated by acute compartment syndrome. This is a unique case of postoperative compartment syndrome after IM debridement and tibial hardware removal. A high index of suspicion should be prioritized in patients who complain of severe or unexpected pain to mitigate delays in diagnosis and aid in early treatment.


Interacting molecular motors: efficiency and work fluctuations.
We investigate the model of "reversible ratchet" with interacting particles, presented by us earlier [F. Slanina, EPL 84, 50009 (2008)]. We further clarify the effect of efficiency enhancement due to interaction and show that it is of energetic origin, rather than a consequence of reduced fluctuations. We also show complicated structures emerging in the interaction and density dependence of the current and response function. The fluctuation properties of the work and input energy indicate in detail the far-from-equilibrium nature of the dynamics.


Clinimetric properties of the Turkish version of the De-Morton Mobility Index (DEMMI) in intensive care unit survivors - a cross-sectional observational study.
To investigate the intra-rater reliability and the construct validity of the Turkish version of the De-Morton Mobility Index (DEMMI) in intensive care unit (ICU) survivors. Construct validity of the DEMMI was measured by correlating it with physical functioning scales. Known group comparison was made according to the Medical Research Council Sum Score (MRC-SS). Internal consistency was determined by measuring Cronbach α coefficient. Test-retest reliability was assessed by performing the DEMMI by the same researcher after 24 h and calculating the intraclass correlation coefficient (ICC). The minimal detectable change (MDC) value was calculated. One hundred and two patients discharged from the ICU were included. The ICC for intra-reliability was 0.972. The internal consistency was excellent (Cronbach = 0.991). The DEMMI total score was correlated with the Barthel Index (r = 0.791), Katz Index of Independence in Activities of Daily Living (r = 0.722), MRC-SS (0.614), ICU length of stay (r = -0.515), and total mechanical ventilation duration (r = -0.488). The DEMMI was able to differentiate between MRC-SS subgroups (p < 0.001), whereby higher strength was associated with higher DEMMI scores. The MDC was determined to be 6.82 out of 100 points. The Turkish version of the DEMMI is reliable and valid for measuring mobility in ICU survivors. NCT05196997Implications for RehabilitationThe Turkish version of the de-Morton Mobility Index (DEMMI) is a reliable and valid outcome measure for the assessment of functional mobility in intensive care unit survivors.The Turkish version of the DEMMI could guide clinicians working in the field of intensive care in the planning of rehabilitation programs after discharge.


Antiproton stopping at low energies: confirmation of velocity-proportional stopping power.
The stopping power for antiprotons in various solid targets has been measured in the low-energy range of 1-100 keV. In agreement with most models, in particular free-electron gas models, the stopping power is found to be proportional to the projectile velocity below the stopping-power maximum. Although a stopping power proportional to velocity has also been observed for protons, the interpretation of such measurements is difficult due to the presence of charge exchange processes. Hence, the present measurements constitute the first unambiguous support for a velocity-proportional stopping power due to target excitations by a pointlike projectile.


Underutilization of Palliative Care for Patients with Advanced Peripheral Arterial Disease.
Advanced peripheral arterial disease is associated with an overall annual mortality between 20-40%. Amputees are at particularly high risk for perioperative and long-term mortality and may benefit from palliative care programs to improve quality of life and to align medical treatments with their goals of care. As studies of palliative care in vascular patients are scarce, we sought to examine palliative care utilization using below knee amputation (BKA) as a surrogate for advanced peripheral arterial disease. All patients who underwent below knee amputation over a 5-year period at a single large academic medical center were identified through chart review. Demographics, preoperative conditions, intraoperative factors, and perioperative outcomes were recorded. The primary outcome was palliative care consultation at the time of the amputation. The secondary outcomes included one-year mortality and palliative care consultation prior to death. The cohort comprised 111 patients (76 men, 35 women) who received BKA for chronic limb threatening ischemia. Three patients (2.7%) received palliative care consultations at the time of their amputation. Of these, one had been obtained remotely for an oncologic condition and the others for surgical decision-making. Follow-up was available for 73 patients. One-year mortality was 21.9% (n = 16) at a mean of 102 ± 86 days after BKA. Among patients who died within 1 year of their amputation, 37.5% (n = 6) received palliative care consultations prior to their death. The median interval between amputation and palliative consultation was 26 (IQR 14-81) days. The median interval between palliative consultation and death was 9 (IQR 4-39) days. Palliative care services were rarely provided to patients with advanced peripheral arterial disease. When obtained, consultations occurred closer to death than to amputation suggesting a missed opportunity to receive the benefits of early evaluation. Future studies can be aimed at identifying a cohort of vascular patients who would most benefit from early palliative evaluation and determining if palliative consultations alter health care utilization patterns and outcomes for vascular patients.


What do patients want to happen to their dentures before surgery?
The removal of dentures before having an anaesthetic can be an undignified and distressing event. However, there has been a gradual change in practice and dentures are now often left in place during an anaesthetic. This enquiry into patients' preferences was carried out to find out what patients would like to happen to their dentures, and to see if there were any differences in opinions among age groups. A postal questionnaire was sent out to patients who wore dentures following discharge after surgery. One hundred replies were analysed. There was a spread of opinions across the age groups and by gender. Nurses need to allow patients the choice of what to do in relation to their dentures when going to theatre, although the anaesthetist must make the final decision of whether or not to remove them immediately before the anaesthetic if they feel patient safety could be compromised.


The lncRNA MALAT1 is a novel biomarker for gastric cancer metastasis.
The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is frequently over-expressed and serves as a prognostic marker in human cancers. However, little is known about the role of MALAT1 in gastric cancer. Here, we reported that the tissue and plasma MALAT1 levels were significantly higher in gastric cancer patients with distant metastasis (P<0.01) than patients without distant metastasis and the healthy controls. In addition, high levels of plasma MALAT1 independently correlated to a poor prognosis for gastric cancer patients (hazard ratio, 0.242; 95% CI, 0.154-0.836; P=0.036; Cox regression analysis). Functional studies revealed that knockdown of MALAT1 could inhibit cell proliferation, cell cycle progression, migration and invasion, and promote apoptosis in gastric cancer cells. Furthermore, the miR-122-IGF-1R signaling correlated with the dysregulated MALAT1 expression in gastric cancer. These data suggest that MALAT1 could function as an oncogene in gastric cancer, and high MALAT1 level could serve as a potential biomarker for the distant metastasis of gastric cancer.


In Silico Analysis of Differential Gene Expression in Three Common Rat Models of Diastolic Dysfunction.
Standard therapies for heart failure with preserved ejection fraction (HFpEF) have been unsuccessful, demonstrating that the contribution of the underlying diastolic dysfunction pathophysiology differs from that of systolic dysfunction in heart failure and currently is far from being understood. Complicating the investigation of HFpEF is the contribution of several comorbidities. Here, we selected three established rat models of diastolic dysfunction defined by three major risk factors associated with HFpEF and researched their commonalities and differences. The top differentially expressed genes in the left ventricle of Dahl salt sensitive (Dahl/SS), spontaneous hypertensive heart failure (SHHF), and diabetes 1 induced HFpEF models were derived from published data in Gene Expression Omnibus and used for a comprehensive interpretation of the underlying pathophysiological context of each model. The diversity of the underlying transcriptomic of the heart of each model is clearly observed by the different panel of top regulated genes: the diabetic model has 20 genes in common with the Dahl/SS and 15 with the SHHF models. Advanced analytics performed in Ingenuity Pathway Analysis (IPA®) revealed that Dahl/SS heart tissue transcripts triggered by upstream regulators lead to dilated cardiomyopathy, hypertrophy of heart, arrhythmia, and failure of heart. In the heart of SHHF, a total of 26 genes were closely linked to cardiovascular disease including cardiotoxicity, pericarditis, ST-elevated myocardial infarction, and dilated cardiomyopathy. IPA Upstream Regulator analyses revealed that protection of cardiomyocytes is hampered by inhibition of the ERBB2 plasma membrane-bound receptor tyrosine kinases. Cardioprotective markers such as natriuretic peptide A (NPPA), heat shock 27 kDa protein 1 (HSPB1), and angiogenin (ANG) were upregulated in the diabetes 1 induced model; however, the model showed a different underlying mechanism with a majority of the regulated genes involved in metabolic disorders. In conclusion, our findings suggest that multiple mechanisms may contribute to diastolic dysfunction and HFpEF, and thus drug therapies may need to be guided more by phenotypic characteristics of the cardiac remodeling events than by the underlying molecular processes.


Adjuvant radiotherapy and lymph node dissection in pancreatic cancer treated with surgery and chemotherapy.
The objective of this study was to determine the effects of postoperative radiation therapy (PORT) and lymph node dissection (LND) on survival in patients with pancreatic cancer. The 2004 to 2008 Surveillance, Epidemiology, and End Results (SEER) database was analyzed to identify patients with pancreatic cancer who underwent surgery and received chemotherapy and to evaluate the correlation between overall survival (OS), PORT, and LND. In total, 2966 patients were identified who underwent pancreatic resection (1842 PORT, 1124 no PORT). Median survival, 1-year OS, and 3-year OS were 21 months, 77%, and 28%, respectively, with PORT versus 20 months, 70%, and 25%, respectively, without PORT (P = .02). Subset analysis revealed that the benefit of PORT was limited to lymph node-positive (N1) patients. Median survival, 1-year OS, and 3-year OS for patients with N1 disease were 19 months, 73%, and 25%, respectively, for those who received PORT versus 18 months, 67%, and 20%, respectively, for those who did not receive PORT (P < .01). An increasing lymph node count was associated with increased survival on multivariate analysis in all patients and in patients with N1 disease (both P < .001). Significant cutoff points for OS based on LND in patients with N1 disease were identified for those who had ≥8, ≥10, ≥12, ≥15, and ≥20 lymph nodes resected. Multivariate analysis for OS revealed that increasing age, T3 and T4 tumors, N1 stage, and moderately and poorly differentiated grade were prognostic for increased mortality, while female gender, PORT, and LND were prognostic for decreased mortality. In patients with N1 disease, other than patient age, all of these factors remained significant. In patients with N0 disease, only T1 and T2 tumor classification and having a tumor that was less than high grade were associated with survival benefit. This SEER analysis demonstrated an associated survival benefit of PORT and LND in patients with N1, surgically resected pancreatic cancer who received chemotherapy.


Rapid Determination of Isomeric Benzoylpaeoniflorin and Benzoylalbiflorin in Rat Plasma by LC-MS/MS Method.
Benzoylpaeoniflorin (BP) is a potential therapeutic agent against oxidative stress related Alzheimer's disease. In this study, a more rapid, selective, and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed to determine BP in rat plasma distinguishing with a monoterpene isomer, benzoylalbiflorin (BA). The method showed a linear response from 1 to 1000 ng/mL (r > 0.9950). The precision of the interday and intraday ranged from 2.03 to 12.48% and the accuracy values ranged from -8.00 to 10.33%. Each running of the method could be finished in 4 minutes. The LC-MS/MS method was validated for specificity, linearity, precision, accuracy, recovery, and stability and was found to be acceptable for bioanalytical application. Finally, this fully validated method was successfully applied to a pharmacokinetic study in rats following oral administration.


Comparison of the XTT and resazurin assays for quantification of the metabolic activity of Staphylococcus aureus biofilm.
We assessed whether resazurin was as efficient as XTT in the measurement of the metabolic activity of 209 clinical Staphylococcus aureus biofilm using an vitro model comparing the percentage of formazan and resorufin. The overall categorical agreement was 61.2% (r=0.024), which means that resazurin can not substitute XTT.


miR-206 regulates alveolar type II epithelial cell Cx43 expression in sepsis-induced acute lung injury.
The present study investigated the relationship between connexin 43 (Cx43) expression in alveolar type II epithelial cells (ATII) and alveolar air-blood barrier permeability, and the effect of microRNA-206 (miR-206) on the expression of Cx43 in sepsis-induced acute lung injury. For the in vivo study, rats were divided into the sham, caecum ligation and perforation (CLP), CLP+Cx43 inhibitors (Cx43-In) and CLP+miR-206 analogs (miR-206-Mi) groups. CLP method was used to prepare an acute lung injury model of sepsis. Following successful modeling, lung tissue was collected for hematoxylin and eosin (HE) staining, and the wet to dry weight ratio (W/D) and protein content in bronchoalveolar lavage fluid (BALF) were detected. Cx43 expression in lung tissue was determined by immunohistochemistry and western blot analysis. Additionally, miR-206 and Cx43 expression levels in lung tissue were detected by reverse transcription-quantitative polymerase chain reaction. Rat ATII cells were cultured in Transwells plates to form monolayers, then treated with Cx43 mRNA inhibitors or miR-206 analogs. The cell monolayers were then stimulated with lipopolysaccharide and their permeability was evaluated by detecting fluorescein-labeled dextran at the lower chamber of the Transwells. The dual luciferase reporter gene assay was used to investigate whether miR-206 targeted the 3' untranslated region of Cx43 mRNA to regulate Cx43 expression, thereby regulating the permeability of the alveolar air-blood barrier. Results demonstrated that the CLP method induced damage to the alveolar structure, thickened the alveolar wall, caused hyperemia and hemorrhage in the pulmonary interstitium and caused infiltration of inflammatory cells. Edema in the pulmonary interstitium and alveolar space, exudation of neutrophilic granulocyte and pink edema fluid in alveolar cavities were also observed. W/D ratio, the BALF protein content, and expression of Cx43mRNA and Cx43 were increased significantly, whilst miR-206 expression decreased compared with the control group. The lung tissue inflammatory response was attenuated, and the W/D ratio and BALF protein content decreased in the Cx43-In and miR-206-Mi groups compared with the CLP group. Moreover, Cx43 mRNA and protein expression were decreased significantly in the Cx43-In and miR-206-Mi groups. In addition, the dual luciferase reporter gene assay determined that the untranslated region of Cx43 mRNA had a complementary sequence to miR-206. Of note, Cx43 mRNA expression in the miR-206-Mi group was not significantly decreased in vitro. In conclusion, the increase in ATII cell Cx43 expression during sepsis-induced acute lung injury resulted in an increase in the permeability of the alveolar air-blood barrier. miR-206 targeted the Cx43 mRNA 3'untranslated region to downregulate Cx43 expression, which further improved the permeability of the alveolar air-blood barrier.


Interspecific variation of thermoregulation between small migratory and resident passerines in Wenzhou.
Physiological adaptation arises from several fundamental sources of phenotypic variation. Most analyses of metabolic adaptation in birds have focused on the basal metabolic rate (BMR), the lower limit of avian metabolic heat production. In this study, we investigated thermoregulation in three passerine species; the yellow-billed grosbeak Eophona migratoria, white-rumped munia Lonchura striata and black-throated bushtit Aegithalos concinnus, in Wenzhou, China. Metabolic rate was measured using the closed-circuit respirometer containing 3.5 L animal chambers. Body temperature (Tb) was measured during metabolic measurements using a lubricated thermocouple. The minimum thermal conductance of these species was calculated by measuring their Tb and metabolic rates. The yellow-billed grosbeak remained largely normothermic, and the white-rumped munia and black-throated bushtit exhibited variable Tb at ambient temperatures (Ta). Mean metabolic rates within thermal neutral zone were 2.48±0.09 O2(mL)/g/h for yellow-billed grosbeaks, 3.44±0.16 O2(mL)/g/h for white-rumped munias, and 3.55±0.20 O2(mL)/g/h for black-throated bushtits, respectively. Minimum thermal conductance of yellow-billed grosbeak, white-rumped munia and black-throated bushtit were 0.13±0.00, 0.36±0.01, and 0.37±0.01 O2(mL)/g/h/℃, respectively. The ecophysiological characteristics of these species were:(1) the yellowbilled grosbeak had relatively high Tb and BMR, a low lower critical temperature and thermal conductance, and a metabolic rate that was relatively insensitive to variation in Ta; all of which are typical of cold adapted species and explain its broader geographic distribution; (2) the white-rumped munia and blackthroated bushtit had high thermal conductance, lower critical temperature, and relatively low BMR, all which are adapted to warm environments where there is little selection pressure for metabolic thermogenesis. Taken together, these data illustrate small migratory and resident passerines that exhibit the different characteristics of thermoregulation.


Reproducibility of polypeptide spot positions in two-dimensional gels run using carrier ampholytes in the isoelectric focusing dimension.
The reproducibility of complex protein patterns in two-dimensional (2-D) gels run with carrier ampholytes in the first dimension has been investigated. Two different laboratories collaborated in the study and 18 or 19 gels were run in each laboratory for comparison. The electrophoresis chemicals, running devices, and samples were standardized in both labs. The resulting 37 gels were scanned with a charge-coupled device (CCD) camera and spots were located, counted, quantified, and matched using a commercially available image analysis system. Subsequently, the reproducibility of spot position was determined. To perform the statistical analysis, the test gels were initially each matched to a master reference gel. Next, three sets of 12 gels (the image analysis software database could analyze only 12 gels at a time) were analyzed and the isoelectric point (pI) and molecular weight (M(r)) positional variation of all the spots that matched across the gels in each set was determined. The resulting statistical analysis indicates very high reproducibility of the carrier ampholyte technique.


Hemoglobin A1C testing frequency among patients with type 2 diabetes within a US payer system: a retrospective observational study.
The American Diabetes Association (ADA) guidelines recommend A1C testing schedules for patients with type 2 diabetes; however, level of real-world guideline adherence remains unclear. The current study evaluated A1C testing frequency and its association with glycemic control and cardiovascular outcomes. A retrospective study was conducted utilizing Aetna's Enterprise Data Warehouse. Adult patients with a medical claim for type 2 diabetes in 2017 (index date) were included. Patients had continuous enrollment through December 2019 and ≥1 reported A1C measurement from 2017 to 2019. Follow-up was up to 36 months post-index date. Of the 112,572 eligible patients, 50.0% were female and median age was 70 years; 32.9% of patients with controlled baseline A1C (<8%, 64 mmol/mol) received less than the 2 tests/year recommended by the ADA, while 60.6% of patients with uncontrolled baseline A1C received less than the quarterly testing recommended by the ADA. More frequent testing was associated with age (65-75 years), uncontrolled baseline A1C and presence of comorbidities. In separate multivariable models, 2-3 A1C tests/year were associated with greater likelihood of A1C < 8% (64 mmol/mol) vs. <2 tests/year (OR = 1.07, 95% confidence interval [CI] 1.02-1.12), while >3 tests/year was associated with a modestly increased risk of cardiovascular events vs. <2 tests/year (OR = 1.08, 95% CI 1.01-1.15). A large proportion of type 2 diabetes patients were not tested per guideline recommendations. The relationship between A1C testing frequency and glycemic control was inconsistent, though there was a significant association between more frequent testing and experiencing a CV event.


[BEX2 regulates cell cycle through the interaction with INI1/hSNF5].
BEX2 (Brain expressed X-linked protein 2), a 13 kDa protein, is highly expressed in brain and testis. It is reported that the protein expression of BEX2 dramatically alters during the embryo development, but little is known about its function. By means of yeast two-hybrid screening, we isolated that INI1/hSNF5 was a binding partner for BEX2, a key component of SWI/SNF chromosome remolding complex. GST Pull-down experiment interaction is physical and specific. Further analysis using truncated mutations demonstrated that the two partner for BEX2, a key component of SWI/SNF chromosome remolding complex. GST Pull-down experiment confirmed that BEX2 can interact with INI1/hSNF5 directly and specifically. Truncated mutations analysis further demonstrated that the two conserved reverse repeats sequences within INI1/hSNF5 were necessary for the interaction. Sub-cellular localization showed that both BEX2 and INI1/hSNF5 mainly localized in cell nucleus, which indicated that the interaction may be involved in the regulation of gene expression. Our experiments also showed that co-overexpressing of the two proteins affected cell cycle by increasing the cells in S phase, indicating that BEX2 could regulate cell cycle by interacting with INI1/hSNF5.


Acute cardiovascular effects of epidural spinal cord stimulation.
Several animal studies support the contention that thoracic spinal cord stimulation (SCS) might decrease arterial blood pressure. To determine if electrical stimulation of the dorsal spinal cord in humans will lower mean arterial pressure (MAP) and heart rate (HR). Case Series Ten normotensive subjects that were clinically indicated for SCS testing were studied. Two of the 10 patients who underwent testing were excluded from the analysis because they did not respond to the Cold Pressor Test (CPT). Systolic blood pressure, diastolic blood pressure, and heart rate were measured continuously at the wrist (using the Vasotrac device). SCS was administered with quadripolar leads implanted into the epidural space under fluoroscopic guidance. SCS was randomly performed either in the T1-T2 or T5-T6 region of the spinal cord during normal conditions as well as during transient stress induced by CPT. The CPT was conducted by immersing the non-dominant hand in ice-cold water for 2 minutes. There were moderate decreases in MAP and HR during SCS at the T5-T6 region compared to baseline that did not reach statistical significance. However, SCS at the T1-T2 region tended to increase MAP and HR compared to baseline but the change did not reach statistical significance. Arterial blood pressure was transiently elevated by 9.4 +/- 3.8 mmHg using CPT during the control period with SCS turned off and also during SCS at either the T1-T2 region or T5-T6 region of the spinal cord (by 9.2 +/- 5 mmHg and 10.7 +/- 8.4 mmHg, respectively). During SCS at T5-T6, the CPT significantly increased MAP by 5.9+/-7.1 mmHg compared to control CPT (SCS off). This study demonstrated that SCS at either the T1-T2 or T5-T6 region did not significantly alter MAP or HR compared to baseline (no SCS). However, during transcient stress (elevated sympathetic tone) induced by CPT, there was a significant increase in MAP and moderate decrease in HR during SCS at T5-T6 region, which is not consistent with previous data in the literature. Acute SCS did not result in adverse cardiovascular responses and proved to be safe.


Evaluation of coagulation factor abnormalities in long-acting anticoagulant overdose.
Newer Rodenticides of the long-acting anticoagulant or "superwarfarin" class are gaining popularity. Since few cases of severe, prolonged anticoagulation after ingestion have been reported, the course of toxicity is not precisely understood. In this case of an intentional ingestion of brodifacoum, a longitudinal analysis of specific coagulation factor derangements was carried out in an attempt to guide a future treatment strategy for this type of toxicity. Results of this analysis demonstrated a profound decrease in levels of factors II, VII, IX, and X, lasting at least 43 days post ingestion. Treatment with subcutaneous vitamin K1 in doses up to 100 milligrams per day was without complication and was effective in reversing the coagulopathy produced by brodifacoum.


Dance of the Sugar: Two Case Reports of Chorea Associated With Nonketotic Hyperglycemia.
Hyperglycemia-induced chorea/ballism is a rare clinical entity that often occurs in the setting of nonketotic hyperglycemia due to poor glycemic control in elderly patients with a diagnosis of type 2 diabetes mellitus (DM). This condition is typically characterized by hemichorea/hemiballism and unique brain imaging findings in the contralateral basal ganglia. Treatment involves the correction of blood glucose, and most cases resolve without additional therapy. Here we report two cases of this condition in which patients with type 2 DM presented with nonketotic hyperglycemia and typical neuroimaging findings. Although rare, clinicians should be aware of this condition in patients with diabetes who present with sudden abnormal movements since its prompt diagnosis and treatment often lead to a favorable outcome.


A Review of Patient-Reported Outcome Labeling of FDA-Approved New Drugs (2016-2020): Counts, Categories, and Comprehensibility.
A review of new drug approvals (NDAs) by the US Food and Drug Administration (FDA) for 2006 to 2015 showed that approximately 20% of new drugs had labeling based on patient-reported outcomes (PROs). The purpose of this study was to review labeling text based on PRO endpoints for NDAs from 2016 to 2020, with a special focus on the comprehensibility of such statements when included. We reviewed drug approval reports on the Drugs@FDA web page of the FDA website to determine the number of NDAs from 2016 to 2020. For all identified NDAs, drug approval package and product labels were reviewed. NDAs from 2016 to 2020 were grouped by disease category as per International Classification of Diseases 10th Revision. Data were summarized for diseases that traditionally rely on PROs for evaluating treatment benefit (PRO dependent) and for diseases that traditionally do not rely on PROs (non-PRO dependent). Results were compared with NDAs from 2006 to 2010. NDAs amounting to 228 were identified from 2016 to 2020, 26.3% of which had labeling statements based on PRO endpoints. From 2006 to 2015 and from 2016 to 2020, PRO labeling statements were included in 46.5% (46 of 99) and 50.0% (47 of 94), respectively, of NDAs for PRO-dependent new molecular entities and in 6.0% (12 of 199) and 9.7% (13 of 199), respectively, of NDAs for non-PRO-dependent new molecular entities. Comprehensibility of labeling statements based on PRO endpoints was judged to be complex in 56.7% of product labels. The increase in labeling text based on PRO endpoints in product labels is encouraging. However, there is room for improvement on the comprehensibility of labeling statements based on PRO endpoints.


Biopersistence of inhaled nickel oxide nanoparticles in rat lung.
In order to investigate whether or not airborne nanoparticles with a minimum agglomeration could be used for exposure tests on animals, we developed a nanoparticle generation system and examined the biological effects of the particles in an inhalation study. The generation system was composed of an ultrasonic nebulizer and diffusion dryers, and 30 Wistar male rats were exposed to nickel oxide (NiO) nanoparticles for 4 wk (6 h/day). The geometric mean diameter of the particles and the daily average exposure concentration determined by a combination of a differential mobility analyzer and a condensation nucleus counter in the exposure chamber were 139 +/- 12 nm and 1.0 +/- 0.5 x 10(5) particles/cm3, respectively. At 4 days and 1 and 3 mo after the inhalation, each group of 10 rats were sacrificed and NiO nanoparticles deposited in the lung were determined by chemical analysis and the biopersistence (biological half time) was calculated. The deposited amount of NiO nanoparticles in the rat lungs at 4 days after the inhalation was 29 +/- 4 microg. The retained particle amount in the rat lungs after the inhalation exponentially decreased and the calculated biological half time was 62 days. The histopathological change was not severe just after the inhalation nor throughout the observation time. We concluded that nanoparticles with a minimum agglomeration were dispersed stably in the chamber and exposed to rats for 4 wk and that deposited amounts in the rat lungs and the biopersistence of the particles and the biological response in lung were detected.


Cooperative Nitrogen Activation and Ammonia Synthesis on Densely Monodispersed Mo-N-C Sites.
The production of ammonia from nitrogen reduction reaction (NRR) under mild conditions is one of the most challenging issues in modern chemistry. The linear scaling relationship between the adsorption energies of -N2H and -NH2 on a single active site is a well-established bottleneck. By investigating a series of densely monodispersed Mo-N-C sites embedded in graphene using first-principles calculations, we found that previously underappreciated neighboring effects between adjacent active sites may help break the limit: they not only improve the energetics of potential determining steps of NRR but also promote an alternative associative mechanism based on a cooperative bridge-on adsorption of N2 by two Mo-N-C sites of ∼6 Å apart. Further, a barrier of 0.71 eV for N-N bond dissociation is achieved by proper ratio of coordinated C/N atoms of Mo. Our work suggests the cooperation of two adjacent active sites may offer an alternative strategy of nitrogen fixation.