Cholinergic chemosensory cells in the auditory tube.
The luminal composition of the auditory tube influences its function. The mechanisms involved in the monitoring are currently not known. For the lower respiratory epithelium, such a sentinel role is carried out by cholinergic brush cells. Here, using two different mouse strains expressing eGFP under the control of the promoter of choline acetyltransferase (ChAT), we show the presence of solitary cholinergic villin-positive brush cells also in the mouse auditory tube epithelium. They express the vesicular acetylcholine (ACh) transporter and proteins of the taste transduction pathway such as α-gustducin, phospholipase C beta 2 (PLC(β2)) and transient receptor potential cation channel subfamily M member 5 (TRPM5). Immunoreactivity for TRPM5 and PLCβ2 was found regularly, whereas α-gustducin was absent in approximately 15% of the brush cells. Messenger RNA for the umami taste receptors (TasR), Tas1R1 and 3, and for the bitter receptors, Tas2R105 and Tas2R108, involved in perception of cycloheximide and denatonium were detected in the auditory tube. Using a transgenic mouse that expresses eGFP under the promotor of the nicotinic ACh receptor α3-subunit, we identified cholinoceptive nerve fibers that establish direct contacts to brush cells in the auditory tube. A subpopulation of these fibers displayed also CGRP immunoreactivity. Collectively, we show for the first time the presence of brush cells in the auditory tube. These cells are equipped with all proteins essential for sensing the composition of the luminal microenvironment and for communication of the changes to the CNS via attached sensory nerve fibers.


Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results.
Aromatase inhibitors are the preferred adjuvant endocrine therapy for the majority of postmenopausal women with hormone-responsive early breast cancer. Although generally more effective than tamoxifen, aromatase inhibitor therapy is associated with increased bone loss and fracture risk. Postmenopausal women receiving adjuvant letrozole (2.5 mg/day for 5 years; N = 1065) were randomly assigned to immediate zoledronic acid (zoledronate) 4 mg every 6 months for 5 years, or delayed zoledronate (initiated for fracture or on-study bone mineral density [BMD] decrease). The primary end point was the change in lumbar spine BMD at 12 months. Lumbar spine and total hip BMD at subsequent follow-up, disease-free survival (DFS), and overall survival were assessed as secondary end points. At 60 months (final analysis), the mean change in lumbar spine BMD was +4.3% with immediate zoledronate and -5.4% with delayed intervention (P < 0.0001). Immediate zoledronate reduced the risk of DFS events by 34% (hazard ratio [HR] = 0.66; P = 0.0375) with fewer local (0.9% versus 2.3%) and distant (5.5% versus 7.7%) recurrences versus delayed zoledronate. In the delayed group, delayed initiation of zoledronate substantially improved DFS versus no zoledronate (HR = 0.46; P = 0.0334). Immediate zoledronate in postmenopausal women receiving letrozole preserved BMD and is associated with improved DFS compared with letrozole alone. Clinical Trials Registration No NCT00171340.


Assessing driver behavior using shrp2 adverse weather data.
This study explored how drivers adapt to inclement weather in terms of driving speed, situational awareness, and visibility as road surface conditions change from dry to slippery and visibility decreases. The proposed work mined existing data from the SHRP 2 NDS for drivers who were involved in weather-related crash and near-crash events. Baseline events were also mined to create related metadata necessary for behavioral comparisons. Researchers attempted, to the greatest extent possible, to match non-adverse-weather driving scenarios that are similar to the crash and near-crash event for each driver. The ideal match scenario would be at a day prior to the crash during non-adverse weather conditions having the same driver, at the same time of day, with the same traffic level on the same road on which the crash or near-crash occurred. Once the matched scenarios have been identified, a detailed analysis will be performed to determine how a driver's behavior changed from normal driving to inclement-weather driving. Data collected indicated that, irrespective of site location (i.e., state), most crashes and near-crashes occurred in rain, with only about 12% occurring in snowy conditions. Also, the number of near-crashes was almost double the number of crashes showing that many drivers were able to avoid a crash by executing an evasive maneuver such as braking or steering. Most types of near crashes were rear-end and sideswipe avoidance epochs, as the drivers may have had a difficult time merging or trying to change lanes due to low visibility or traffic. Hard braking combined with swerving were the most commonly used evasive maneuvers, occurring when drivers did not adjust their speeds accordingly for specific situations. Practical applications: Results from this study are expected to be utilized to educate and guide drivers toward more confident and strategic driving behavior in adverse weather.


ESCRT Filaments as Spiral Springs.
In a recent issue of Cell, Chiaruttini et al. (2015) reveal the mechanical properties of the mysterious spiral filaments formed by the yeast ESCRT-III protein Snf7. The spirals are shown to be springs whose bending drives membrane deformation and perhaps membrane scission.


Mediators of Intervention Effects on Depressive Symptoms Among People Living With HIV: Secondary Analysis of a Mobile Health Randomized Controlled Trial Using Latent Growth Curve Modeling.
Although several studies have investigated the effects of mobile health (mHealth) interventions on depression among people living with HIV, few studies have explored mediators of mHealth-based interventions to improve mental health in people living with HIV. Identifying influential mediators may enhance and refine effective components of mHealth interventions to improve mental health of people living with HIV. This study aimed to examine mediating factors of the effects of a mHealth intervention, Run4Love, designed to reduce depression among people living with HIV using 4 time-point measurement data. This study used data from a randomized controlled trial of a mHealth intervention among people living with HIV with elevated depressive symptoms in Guangzhou, China. A total of 300 patients were assigned to receive either the mHealth intervention (n=150) or a waitlist control group (n=150) through computer-generated block randomization. Depressive symptoms, coping, and HIV-related stigma were measured at baseline, 3-, 6-, and 9-month follow-ups. The latent growth curve model was used to examine the effects of the intervention on depressive symptoms via potential mediators. Mediating effects were estimated using bias-corrected 95% bootstrapped CIs (BCIs) with resampling of 5000. Enhanced positive coping and reduced HIV-related stigma served as effective treatment mediators in the mHealth intervention. Specially, there was a significant indirect effect of the mHealth intervention on the slope of depressive symptoms via the slope of positive coping (beta=-2.86; 95% BCI -4.78 to -0.94). The indirect effect of the mHealth intervention on the slope of depressive symptoms via the slope of HIV-related stigma was also statistically significant (beta=-1.71; 95% BCI -3.03 to -0.40). These findings indicated that enhancement of positive coping and reduction of HIV-related stigma were important mediating factors of the mHealth intervention in reducing depression among people living with HIV. This study revealed the underlying mediators of a mHealth intervention to reduce depression among people living with HIV using latent growth curve model and 4 time-point longitudinal measurement data. The study results underscored the importance of improving positive coping skills and mitigating HIV-related stigma in mHealth interventions to reduce depression among people living with HIV.


A critical 'threshold' of beta 2-integrin engagement regulates augmentation of cytokine-mediated superoxide anion release.
1. Neutrophil adhesion regulates a number of processes involved in the pathogenesis of inflammatory diseases including rheumatoid arthritis. Neutrophil destructive potential can be modulated by adhesion, allowing alteration of inflammatory cell behaviour while preserving antimicrobial defences. beta(2)-Integrin-mediated neutrophil adhesion to albumin-coated latex beads (ACLB) allows modulation of integrin clustering and ligation and analysis of the effects of adhesion on neutrophil responses. Tumour necrosis factor-alpha (TNF alpha) enhanced neutrophil binding of different diameter ACLB equally, by almost four-fold, and independently of bead size. Adhesion of neutrophils to ACLB caused a size-dependent generation and release of O(2)(-) and also potentiated TNF alpha-induced O(2)(-) release. 2. Binding of ACLB was not affected by disruption of cytoskeletal integrity with nocodazole or cytochalasin D or following blockade of tyrosine kinase activity. In contrast, tyrosine phosphorylation and an intact cytoskeleton were essential for adhesion- and cytokine-induced O(2)(-) release from neutrophils. Inhibition of adhesion- and cytokine-induced O(2)(-) release by 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazol[3,4-d]pyrimidine (PP2) indicated that a Src-family tyrosine kinase was the principal regulatory pathway mediating this response in neutrophils, a distal role for p38 MAPK was revealed by use of SB203580. 3. Tyrosine phosphorylation of c-Fgr, a Src-family tyrosine kinase, occurred following ACLB adhesion and exposure to TNF alpha, and was susceptible to inhibition by PP2. We suggest that activation of the key regulatory enzyme c-Fgr is achieved following ligation of a critical threshold of integrins following binding of large (>3 microM) ACLB.


Preoperative prediction of papillary thyroid carcinoma prognosis with the assistance of computerized morphometry of cytology samples obtained by fine-needle aspiration: preliminary report.
The purpose of this study was to analyze the relationship between cytologic features, clinical features, and recurrence of papillary thyroid cancer (PTC). We hoped to predict prognosis preoperatively. We retrospectively studied cytologic features by using computerized morphometry and clinical data of 118 patients with usual-type PTC without initial metastasis, including 34 patients with cancer recurrence in 10 years after surgery and 84 patients who did not have recurrence for more than 10 years after surgery. Another 24 patients were recruited for validation. Multivariate logistic analysis indicated that nucleus-to-cell ratio, variation of nuclear area, tumor size, and patient age were significantly related to recurrence. Cox regression analysis showed that hazard ratios were 3.34, 1.53, 1.77, and 2.6, respectively. Cytologic features of PTC analyzed with computerized morphometry significantly correlated with recurrence. It helped to predict prognosis preoperatively and may be helpful for planning further treatment.


Synthesis and antihyperglycemic activity of chalcone based aryloxypropanolamines.
A series of aryloxypropanolamines (5a-r) of different chalcones (3a-e) were synthesized and evaluated for antihyperglycemic activity in sucrose loaded (SLM) and streptozotocin (STZ) induced diabetic animal models. Among them compounds 5a, g, m, o, p and r showed significant reduction in blood glucose levels in both SLM and STZ animal models.


Autoimmune neuropathies: insights from animal models.
Autoimmune neuropathies comprise a diverse group of conditions resulting from an immune attack on the peripheral nervous system. In some of these disorders, the antigenic target has been identified. In other conditions such as chronic inflammatory demyelinating polyradiculoneuropathy, the initial trigger and the antigenic target remain elusive. Animal models have provided some important information regarding their pathogenetic mechanisms. This review summarizes the background information and recent highlights from studies in animal models such as experimental autoimmune neuritis and spontaneous autoimmune polyneuropathy in B7-2 knockout non-obese diabetic mice.


HIV-1 Env vaccine comprised of electroporated DNA and protein co-administered with Talabostat.
Selection of potent yet low reactogenic adjuvants for protein immunization is important for HIV-1 vaccine development. Immunogenicity of electroporated DNA (HIV env) and recombinant gp120, administered with either QS-21 or the orally administered immunomodulator, Talabostat, was evaluated in BALB/c mice. Electroporation of low dose DNA elicited Th1 cytokines and anti-envelope antibodies. Immunization with gp120 protein alone with or without Talabostat elicited lower Th1 and Th2 cytokine levels but comparable anti-gp120 antibodies to QS-21-formulated protein. Boosting of DNA-primed mice with gp120/Talabostat induced similar anti-gp120 antibody titers and slightly higher levels of Th1 and Th2 cytokines relative to QS-21-formulated protein. Induction of CD8(+) and CD4(+) T cells and functional CTL activity was noted. These results highlight the potential use of orally administered Talabostat for efficient protein boosting of antibody and T-cell responses primed by DNA.


What Proportion of Patients Admitted with Stroke or Transient Ischemic Attack May Be Suitable for Newer Cholesterol-Lowering Treatment?
Protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors effectively clear low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). We evaluated stroke admissions potentially eligible for more intensive cholesterol treatment. Retrospective analysis of consecutive admissions to a hyperacute stroke unit over 5 months in 2017. Records were individually searched. Data were collected on diagnosis, risk factors, and stroke work-up. European Society of Cardiology and European Atherosclerosis Society guidelines for the management of dyslipidaemias were used for screening patients eligible for PCSK9 inhibitors. Of 650 patient admissions: 351 (54%) had acute ischemic stroke or transient ischemic attack (TIA), 80 (12%) hemorrhage, and 219 (34%) mimic syndromes. Patients with hemorrhage (n = 80), mimic syndromes (n = 219), and absent LDL-C, or non-HDL-C testing (n = 27) were subsequently excluded. 324 patients with acute ischemic stroke and TIA were further screened for PCSK9-inhibitor treatment eligibility. Forty-one (13%) patients with LDL-C greater than or equal to 1.8mmol/L (≥70 mg/dL) on maximal tolerated statin dose and with concomitant "very high vascular risk" were identified. "Very high vascular risk" was defined as a documented history of cardiovascular disease and/or peripheral arterial disease. Of 41 patients eligible for PCSK9 inhibitors, median age was 82 years (range 53-96); median vascular risk factors were 2 (range 1-5); 7 (17%) had TIA; 13 (31%) had history of preceding cerebrovascular events, 13 (31%) diabetes mellitus, 17 (42%) cardioembolic events, 9 (22%) lacunar syndrome, 11 (22%) symptomatic internal carotid artery stenosis (n = 9 were >70%), and 4 (10%) undetermined aetiology. Eighty-three percent patients eligible for PCSK9 inhibitors also had non-HDL-C values greater than or equal to 2.6 mmol/L. Up to 13% of unselected acute ischemic stroke or TIA patients admitted to a hyper-acute stroke unit were potentially suitable for more intensive cholesterol treatment. Our data may act as a useful guide for sample size selection in future stroke trials testing PCSK9 inhibitors.


Chemical Composition, Enantiomeric Distribution, and Sensory Evaluation of the Essential Oils Distilled from the Ecuadorian Species Myrcianthes myrsinoides (Kunth) Grifo and Myrcia mollis (Kunth) DC. (Myrtaceae).
The essential oils of Myrcianthes myrsinoides and Myrcia mollis, belonging to the Myrtaceae family, were obtained by steam distillation. They were analyzed by gas chromatography-mass spectrometry (GC-MS), gas chromatography-flame ionization detector (GC-FID), enantioselective gas chromatography, and gas chromatography-olfactometry (GC-O). A total of 58 compounds for Myrcianthes myrsinoides essential oil (EO) and 22 compounds for Myrcia mollis EO were identified and quantified by GC-MS with apolar and polar columns (including undetermined components). Major compounds (>5.0%) were limonene (5.3%-5.2%), 1,8-cineole (10.4%-11.6%), (Z)-caryophyllene (16.6%-16.8%), trans-calamenene (15.9%-14.6%), and spathulenol (6.2%-6.5%). The enantiomeric excess of eight chiral constituents was determined, being (+)-limonene and (+)-germacrene D enantiomerically pure. Eight components were identified as determinant in the aromatic profile: α-pinene, β-pinene, (+)-limonene, γ-terpinene, terpinolene, linalool, β-elemene and spathulenol. For M. mollis, the major compounds (>5.0%) were α-pinene (29.2%-27.7%), β-pinene (31.3%-30.0%), myrcene (5.0%-5.2%), 1,8-cineole (8.5%-8.7%), and linalool (7.7%-8.2%). The enantiomeric excess of five chiral constituents was determined, with (S)-α-pinene and (+)-germacrene D enantiomerically pure. The metabolites β-pinene, 1,8-cineole, γ-terpinene, terpinolene, linalool, and (E)-β-caryophyllene were mainly responsible for the aroma of the EO. Finally, the M. myrsinoides essential oil has an inhibitory activity for cholinesterase enzymes (IC50 of 78.6 μg/ml and 18.4 μg/ml vs. acethylcholinesterase (AChE) and butyrylcholinesterase (BChE) respectively). This activity is of interest to treat Alzheimer's disease.


The impact of Gelrite and activated carbon on the elemental composition of two conifer embryogenic tissue initiation media.
The elemental composition of plant tissue culture media was studied in response to (1) different levels of Gelrite and activated carbon (AC) in semisolid media and (2) different levels and types of AC in liquid media. Doubling the level of Gelrite from 2 g/l to 4 g/l reduced available magnesium (20%), calcium (16%), zinc (17%) and manganese (24%) and increased potassium (6%). AC adsorbed copper (90-95%) and zinc (35-51%) from both liquid and semisolid media. Two significantly different ACs gave minor differences in adsorption. No adsorption was indicated for inorganic anions. Nonacid-washed AC released significant levels of magnesium (44% increase), calcium (16% increase) and silica (a 75% increase to 1.8 mg/l). The elemental composition of media may need to be adjusted when increasing the Gelrite level or adding AC.


Multiple Pharmacotherapy Adaptations for Smoking Cessation Based on Treatment Response in Black Adults Who Smoke: A Randomized Clinical Trial.
Adapting to different smoking cessation medications when an individual has not stopped smoking has shown promise, but efficacy has not been tested in racial and ethnic minority individuals who smoke and tend to have less success in quitting and bear a disproportionate share of tobacco-related morbidity and mortality. To evaluate efficacy of multiple smoking cessation pharmacotherapy adaptations based on treatment response in Black adults who smoke daily. This randomized clinical trial of adapted therapy (ADT) or enhanced usual care (UC) included non-Hispanic Black adults who smoke and was conducted from May 2019 to January 2022 at a federally qualified health center in Kansas City, Missouri. Data analysis took place from March 2022 to January 2023. Both groups received 18 weeks of pharmacotherapy with long-term follow-up through week 26. The ADT group consisted of 196 individuals who received a nicotine patch (NP) and up to 2 pharmacotherapy adaptations, with a first switch to varenicline at week 2 and, if needed, a second switch to bupropion plus NP (bupropion + NP) based on carbon monoxide (CO)-verified smoking status (CO ≥6 ppm) at week 6. The UC group consisted of 196 individuals who received NP throughout the duration of treatment. Anabasine-verified and anatabine-verified point-prevalence abstinence at week 12 (primary end point) and weeks 18 and 26 (secondary end points). The χ2 test was used to compare verified abstinence at week 12 (primary end point) and weeks 18 and 26 (secondary end points) between ADT and UC. A post hoc sensitivity analysis of smoking abstinence at week 12 was performed with multiple imputation using a monotone logistic regression with treatment and gender as covariates to impute the missing data. Among 392 participants who were enrolled (mean [SD] age, 53 [11.6] years; 224 [57%] female; 186 [47%] ≤ 100% federal poverty level; mean [SD] 13 [12.4] cigarettes per day), 324 (83%) completed the trial. Overall, 196 individuals were randomized to each study group. Using intent-to-treat and imputing missing data as participants who smoke, verified 7-day abstinence was not significantly different by treatment group at 12 weeks (ADT: 34 of 196 [17.4%]; UC: 23 of 196 [11.7%]; odds ratio [OR], 1.58; 95% CI, 0.89-2.80; P = .12), 18 weeks (ADT: 32 of 196 [16.3%]; UC: 31 of 196 [15.8%]; OR, 1.04; 95% CI, 0.61-1.78; P = .89), and 26 weeks (ADT: 24 of 196 [12.2%]; UC: 26 of 196 [13.3%]; OR, 0.91; 95% CI, 0.50-1.65; P = .76). Of the ADT participants who received pharmacotherapy adaptations (135/188 [71.8%]), 11 of 135 (8.1%) were abstinent at week 12. Controlling for treatment, individuals who responded to treatment and had CO-verified abstinence at week 2 had 4.6 times greater odds of being abstinent at week 12 (37 of 129 [28.7%] abstinence) than those who did not respond to treatment (19 of 245 [7.8%] abstinence; OR; 4.6; 95% CI, 2.5-8.6; P < .001). In this randomized clinical trial of adapted vs standard of care pharmacotherapy, adaptation to varenicline and/or bupropion + NP after failure of NP monotherapy did not significantly improve abstinence rates for Black adults who smoke relative to those who continued treatment with NP. Those who achieved abstinence in the first 2 weeks of the study were significantly more likely to achieve later abstinence, highlighting early treatment response as an important area for preemptive intervention. ClinicalTrials.gov Identifier: NCT03897439.


Spectroscopic investigation of phase transformation of calcium oxalate dehydrates (renal calculi) using acidic Bryophyllum pinnatom powder.
Urolithiasis is one of most common renal disorders, characterized by the formation of kidney stones (renal calculi) through the crystallization process within the urinary system. The frequently observed renal calculi are calcium oxalate renal calculi and treatment is done by shock wave method or lithotripsy which is harmful for other cells of the internal system. The objective of this work was to evaluate in vitro diagnosis of calcium oxalate kidney stones in the aqueous solution of Bryophyllum pinnatum. The B. pinnatum powder was mixed in apple cider vinegar and lemon juice separately to make solution 1 and 2 respectively. Apple cider vinegar and lemon juice were used as solvents due to their acidic and body compatible nature. Two surgically removed stones was dipped in solution 1 and 2. After two weeks, kidney stone of weight 2.7 g is completely dissolved in solution 2 while a considerable weight reduction of other kidney stone has been observed in solution 1. Fourier transform infrared (FTIR) spectroscopy results show the presence of two strong absorption peaks at 610 and 912 (cm-1) in both solutions after dissolution of urinary stones are related to calcium oxalate dehydrate (COD). Raman spectra further confirm the dissolution of COD in solution having Raman shifts at 504 and 910 (cm-1). Cluster formation and aggregation of particles has been observed in scanning electron microscopy images. This in vitro study proves that a mixture of Bryophyllum pinnatum powder and lemon juice is a best remedy to remove kidney stones.


Motorneuron protection by N-acetyl-cysteine after ventral root avulsion and ventral rhizotomy.
Motor recovery after proximal nerve injury remains extremely poor, despite advances in surgical care. Several neurobiological hurdles are implicated, the most fundamental being extensive cell death within the motorneuron pool. N-acetyl-cysteine almost completely protects sensory neurons after peripheral axotomy, hence its efficacy in protecting motorneurons after ventral root avulsion/rhizotomy was investigated. In adult rats, the motorneurons supplying medial gastrocnemius were unilaterally pre-labelled with retrograde tracer (true-blue/fluoro-gold), prior to L5 and 6 ventral root avulsion, or rhizotomy. Groups received either intraperitoneal N-acetyl-cysteine (ip, 150 or 750 mg/kg/day), immediate or delayed intrathecal N-acetyl-cysteine treatment (it, 2.4 mg/day), or saline; untreated animals served as controls. Either 4 (avulsion model) or 8 (rhizotomy model) weeks later, the pre-labelled motorneurons' mean soma area and survival were quantified. Untreated controls possessed markedly fewer motorneurons than normal due to cell death (avulsion 53% death; rhizotomy 26% death, P<0.01 vs. normal). Motorneurons were significantly protected by N-acetyl-cysteine after avulsion (ip 150 mg/kg/day 40% death; it 30% death, P<0.01 vs. no treatment), but particularly after rhizotomy (ip 150 mg/kg/day 17% death; ip 750 mg/kg/day 7% death; it 5% death, P<0.05 vs. no treatment). Delaying intrathecal treatment for 1 week after avulsion did not impair neuroprotection, but a 2-week delay was deleterious (42% death, P<0.05 vs. 1-week delay, 32% death). Treatment prevented the decrease in soma area usually found after both types of injury. N-acetyl-cysteine has considerable clinical potential for adjuvant treatment of major proximal nerve injuries, including brachial plexus injury, in order that motorneurons may survive until surgical repair facilitates regeneration.


Evidence Supporting an Association Between Expression of Major Histocompatibility Complex II by Microglia and Optic Nerve Degeneration During Experimental Glaucoma.
We acquired age-matched and sex-matched Sprague-Dawley rats from 2 independent breeding establishments. Serendipitously, we observed that constitutive, and bacterial toxin-induced, expression of major histocompatibility complex (MHC) class II RT1B chain in the uveal tract was much lower in one of the cohorts. Activated microglia are known to upregulate MHC II RT1B expression during optic nerve (ON) degeneration induced by raised intraocular pressure (IOP). We investigated whether, in a model of experimental glaucoma, microglial upregulation of MHC II RT1B was less efficacious and ON degeneration correspondingly less severe in the cohort of rats with low MHC II RT1B expression. Experimental glaucoma was induced by lasering the trabecular meshwork using a standard protocol. After 2 weeks of elevated IOP, retinal ganglion cells (RGC) survival, ON degeneration, and microglial responses were determined in both cohorts of rats. Raised IOP-induced expression of MHC II RT1B by microglia was muted in the "Low" cohort compared with the "High" cohort. Axonal degeneration, RGC loss, and microgliosis were all significantly lower in the cohort of rats with low basal and induced expression of MHC II RT1B, despite both cohorts displaying IOP responses that were indistinguishable in terms of peak IOP and IOP exposure. Expression of MHC II RT1B by activated microglia in the ON during experimental glaucoma was associated with more severe RGC degeneration. Further studies are needed to elucidate the role of MHC II during experimental glaucoma.


On the structure-function relationship of acyl carrier protein of Escherichia coli.
The conformations of Escherichia coli acyl carrier protein (ACP) and acetylated ACP have been studied as a function of pH and salt concentration by circular dichroism measurements. The results show that the amino groups of ACP in their protonated form are important for maintaining the native conformation of the protein at physiological pH. However, externally added cations (divalent more effectively than monovalent ones) can substitute for the ammonium groups in maintaining the ordered structure pf ACP. It is suggested that both the ammonium groups of ACP and externally added cations reduce the repulsion between carboxylate groups of ACP and thereby prevent the unfolding of the protein. A reduction of the number of negatively charged carboxylate groups by either protonation or chemical modification abolished the requirement for either ammonium groups or other cations. A qualitative agreement between the effect of salt on the conformation and on the biological activity of acetylated ACP has been observed. The single arginine residue of acetylated ACP has been modified by treatment with a trimer of 2,3-butanedione with the resulting derivative of ACP retaining most of its biological activity.


Peripheral atherosclerosis in acute coronary syndrome patients with plaque rupture vs plaque erosion: A prospective coronary optical coherence tomography and peripheral ultrasound study.
Plaque rupture (PR) and plaque erosion (PE) are 2 distinct, different, and most common culprit lesion morphologies responsible for acute coronary syndrome (ACS). However, the prevalence, distribution, and characteristics of peripheral atherosclerosis in ACS patients with PR vs PE has never been studied. The aim of this study was to assess peripheral atherosclerosis burden and vulnerability evaluated by vascular ultrasound in ACS patients with coronary PR vs PE identified by optical coherence tomography (OCT). Between October 2018 and December 2019, 297 ACS patients who underwent preintervention OCT examination of the culprit coronary artery were enrolled. Peripheral ultrasound examinations of carotid, femoral, and popliteal arteries were performed before discharge. Overall, 265 of 297 (89.2%) patients had at least one atherosclerotic plaque in a peripheral arterial bed. Compared with coronary PE, patients with coronary PR had a higher prevalence of peripheral atherosclerotic plaques (93.4% vs 79.1%, P < .001), regardless of location: carotid, femoral, or popliteal arteries. The number of peripheral plaques per patient was significantly larger in the coronary PR group than coronary PE (4 [2-7] vs 2 [1-5], P < .001). Additionally, there was a greater prevalence of peripheral vulnerable characteristics including plaque surface irregularity, heterogeneous plaque, and calcification in patients with coronary PR vs PE. Peripheral atherosclerosis exists commonly in patients presenting with ACS. Patients with coronary PR had greater peripheral atherosclerosis burden and more peripheral vulnerability compared to those with coronary PE, suggesting that comprehensive evaluation of peripheral atherosclerosis and multidisciplinary cooperative management maybe necessary, especially in patients with PR. clinicaltrials.gov (NCT03971864).


FaSSIF-V3, but not compendial media, appropriately detects differences in the peak and extent of exposure between reference and test formulations of ibuprofen.
The predictive capacity of in vitro dissolution tests using 50mM phosphate buffer at pH 6.8 to anticipate in vivo bioequivalence outcomes for highly permeable and poorly soluble weak acids has been questioned. In previous work, it was shown that using a lower buffer capacity could correctly distinguish the in vivo behavior of products containing ibuprofen free acid and those containing its salts. To assess whether adjustments in the composition of the medium, including matching the phosphate buffer concentration to the reported pH0 of dissolving ibuprofen free acid in bicarbonate buffer, as well as in the stirring rate, could detect differences in the extent and peak of exposure between reference and test formulations. Using the recently revised fasted state simulated intestinal fluid (FaSSIF-V3) with reduced phosphate buffer concentration (5mM), it was possible to predict in vivo differences in peak and extent of exposure between test and reference formulations of ibuprofen. For ibuprofen products, a modified Biopharmaceutics Classification System (BCS) based biowaiver dissolution test may be a way forward to approve generic products without having to perform pharmacokinetic studies. More studies with other BCS Class 2 weakly acidic compounds would be necessary to assess whether this approach could be applied more generally.


Evaluating Implementation Costs of an Enhanced Recovery After Surgery (ERAS) Protocol in Colorectal Surgery: A Systematic Review.
Enhanced recovery after surgery (ERAS) protocols have been well documented in the current literature to improve healthcare outcomes by decreasing length of stay, resource utilization, and morbidity without increasing readmission rates or complications. This subsequently leads to a net decrease in hospital costs. However, the initial costs of implementing such a program have not been well described, which is crucial information for hospitals with less resources. The aim of this study was to provide a cohesive review of the current literature for the costs of implementing a colorectal surgery ERAS protocol. A comprehensive review was conducted on five databases (Google Scholar, Web of Science, PROSPERO, PubMed, and Cochrane) with the assistance of a professional librarian. All relevant English articles published between 1995 and June 2021 were screened for eligibility prior to inclusion in the review. Cost data were converted to US dollars based on the exchange rate at the end time of the study period for standardization. Seven studies were included for review. The studies evaluated a range of 50-1295 patients through their respective ERAS programs, which were followed for 5 to 22 months. ERAS implementation costs ranged from $57 to $1536 per patient. Components for each ERAS program varied for each study, but ultimately, the greatest costs were attributed to personnel. Despite data heterogeneity and inconsistencies between cost breakdowns, a majority of the implementation cost was found to be secondary to personnel. This review demonstrates the need for a more standardized approach for reporting ERAS implementation costs through an open database as well as a potential streamlining of the ERAS protocol to facilitate implementation in institutions with less financial resources.


A controlled study of the effectiveness of EEG biofeedback training on-children with attention deficit hyperactivity disorder.
In order to study the treatment of the children with attention deficit hyperactivity disorder (ADHD), the integrated visual and auditory continuous performance test (IVA-CPT) was clinically applied to evaluate the effectiveness of electroencephalogram (EEG) biofeedback training. Of all the 60 children with ADHD aged more than 6 years, the effective rate of EEG biofeedback training was 91.6% after 40 sessions of EEG biofeedback training. Before and after treatment by EEG biofeedback training, the overall indexes of IVA were significantly improved among predominately inattentive, hyperactive, and combined subtype of children with ADHD (P<0.001). It was suggested that EEG biofeedback training was an effective and vital treatment on children with ADHD.


Acute intravenous administration of dietary constituent theanine suppresses noxious neuronal transmission of trigeminal spinal nucleus caudalis in rats.
Theanine is a non-dietary amino acid linked to the modulation of synaptic transmission in the central nervous system, although the acute effects of theanine in vivo, particularly on nociceptive transmission in the trigeminal system, remain to be determined. The present study investigated whether acute intravenous theanine administration to rats attenuates the excitability of wide dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Extracellular single unit recordings were made from 15 SpVc neurons in response to orofacial mechanical stimulation of pentobarbital-anesthetized rats, and responses to non-noxious and noxious mechanical stimuli were analyzed. The mean firing frequency of SpVc WDR neurons in response to all mechanical stimuli was dose-dependently inhibited by theanine (10, 50, and 100mM, i.v.) with the maximum inhibition of discharge frequency reached within 5min. These inhibitory effects were reversed after approximately 10min. The relative magnitude of theanine's inhibition of SpVc WDR neuronal discharge frequency was significantly greater for noxious than non-noxious stimulation. Iontophoretic application of l-glutamate induced the mean firing frequency of SpVc WDR neuron responding to noxious mechanical stimulation was also inhibited by intravenous administration of 100mM theanine. These results suggest that acute intravenous theanine administration suppresses glutaminergic noxious synaptic transmission in the SpVc, implicating theanine as a potential complementary and alternative therapeutic agent for the treatment of trigeminal nociceptive pain.


Increased antagonist muscle activity in cervical SCI patients suggests altered reciprocal inhibition during elbow contractions.
After spinal cord injury (SCI), the antagonist muscles activation is increased during voluntary contractions and reflex conditioning protocols. This increase can be the result of both muscle atrophy and reciprocal facilitation mechanism. It remains however unclear to what extent increased antagonist muscles activation could be rather attributable to central vs. peripheral changes during voluntary contractions achieved by SCI participants. We investigated the activations of elbow extensors and flexors during isometric elbow flexion and extension contractions performed at 3 force levels by 10 healthy participants and 8 participants with cervical SCI (cSCI). At similar force level and absolute net torque in flexion, the antagonist muscles activation was increased for the participants with cSCI. At similar absolute net torque in extension, the activations of agonist and antagonist muscles were increased for the participants with cSCI. During flexion contractions, increased antagonist muscles activation may be explained by extensors atrophy or reciprocal facilitation. During extension contractions, increased antagonist muscles activation may reflect the importance of reciprocal facilitation as antagonist muscles were evaluated as intact by clinical testing and maximal net joint torque recording. These results in cSCI participants revealed an increased activation of antagonist muscles, which may reflect a reorganization of the spinal reflexes and their supraspinal control involved during isometric elbow contractions.


Hepatic arterial infusion of floxuridine and dexamethasone plus high-dose Mitomycin C for patients with unresectable hepatic metastases from colorectal carcinoma.
In vitro data suggest increased cytotoxicity with Mitomycin C (Mit-C) and Floxuridine (FUDR). Based on these data, we performed a phase II trial of hepatic arterial infusion (HAI) of FUDR and Dexamethasone (Dex) plus high-dose Mit-C for patients with unresectable hepatic metastases from colorectal carcinoma. High-dose Mit-C (15 mg/m2) was added via the pump sideport to HAI FUDR and Dex for 14 days of a 28-day cycle. Mit-C was given on days 1 and 29, and FUDR was given indefinitely until disease progression or discontinuation of therapy due to toxicity. Sixty-three patients with unresectable liver metastases were entered. The chemotherapy-naïve group (n = 26) and those previously treated (n = 37) had similar response and median survival: 73% and 70%, and 23 and 20 months, respectively. The major toxicities were liver bilomas (7.9%), elevation in bilirubin level >3 (22%), and biliary sclerosis (9.5%). Hematologic and gastrointestinal toxicity was less than 2%. The addition of high-dose Mit-C to HAI FUDR and Dex produced a high response rate even in previously treated patients. The median survival was 21 months even though half the patients were previously treated with chemotherapy. Biliary toxicity was higher than expected; therefore, alternatives to high dose Mit-C should be investigated when exploring additions to HAI therapy with FUDR and Dex.


Unpredictable feeding impairs glucose tolerance in growing lambs.
Irregular eating is associated with insulin resistance and metabolic disease in adults but may affect young, growing children differently. We investigated the metabolic effects of unpredictable feeding in female juvenile lambs randomly assigned to receive, for six weeks, maintenance feed given twice daily in equal portions (Control Group, C; n = 24) or the same weekly feed amount in aliquots of variable size at unpredictable times (Unpredictable Group, U; n = 21). Intravenous glucose tolerance tests (IVGTT), insulin tolerance tests (ITT), and measurement of diurnal plasma cortisol concentrations were performed pre and post the dietary intervention. Groups were compared using t test and RM ANOVA. Weight gain was similar in both groups (C 18 ± 2%; U 16 ± 2% of initial body weight). Glucose area under the curve (AUC) was unchanged in C (AUC pre 818 ± 34, post 801 ± 33 mmol.min.l(-1)), but increased by 20% in U (pre 830 ± 25, post 1010 ± 19 mmol.min.l(-1); p<0.0001), with an inadequate insulin response to glucose load (log(AUC insulin first 40 minutes) post intervention C 1.49 ± 0.04 vs U 1.36 ± 0.04 ng.min.ml(-1); p = 0.03). Insulin tolerance and diurnal variation of plasma cortisol concentrations were not different between groups. Unpredictable feeding impairs insulin response to glucose in growing lambs despite high quality food and normal weight gain. Irregular eating warrants investigation as a potentially remediable risk factor for disordered glucose metabolism.


Rhodaneses minimize the accumulation of cellular sulfane sulfur to avoid disulfide stress during sulfide oxidation in bacteria.
Heterotrophic bacteria and human mitochondria often use sulfide: quinone oxidoreductase (SQR) and persulfide dioxygenase (PDO) to oxidize sulfide to sulfite and thiosulfate. Bioinformatic analysis showed that the genes encoding RHOD domains were widely presented in annotated sqr-pdo operons and grouped into three types: fused with an SQR domain, fused with a PDO domain, and dissociated proteins. Biochemical evidence suggests that RHODs facilitate the formation of thiosulfate and promote the reaction between inorganic polysulfide and glutathione to produce glutathione polysulfide. However, the physiological roles of RHODs during sulfide oxidation by SQR and PDO could only be tested in an RHOD-free host. To test this, 8 genes encoding RHOD domains in Escherichia coli MG1655 were deleted to produce E. coli RHOD-8K. The sqrCp and pdoCp genes from Cupriavidus pinatubonensis JMP134 were cloned into E. coli RHOD-8K. SQRCp contains a fused RHOD domain at the N-terminus. When the fused RHOD domain of SQRCp was inactivated, the cells oxidized sulfide into increased thiosulfate with the accumulation of cellular sulfane sulfur in comparison with cells containing the intact sqrCp and pdoCp. The complementation of dissociated DUF442 minimized the accumulation of cellular sulfane sulfur and reduced the production of thiosulfate. Further analysis showed that the fused DUF442 domain modulated the activity of SQRCp and prevented it from directly passing the produced sulfane sulfur to GSH. Whereas, the dissociated DUF442 enhanced the PDOCp activity by several folds. Both DUF442 forms minimized the accumulation of cellular sulfane sulfur, which spontaneously reacted with GSH to produce GSSG, causing disulfide stress during sulfide oxidation. Thus, RHODs may play multiple roles during sulfide oxidation.


Interstitial ectopic pregnancy--management with laparoscopically-guided local methotrexate infiltration.
This case describes the use of ultrasound to diagnose an interstitial ectopic pregnancy and the subsequent management and ultrasound follow-up. Interstitial pregnancy is a rare but potentially life-threatening complication of pregnancy. Management options depend upon the timing of diagnosis, and the desire for maintenance of fertility. Methotrexate injection, under ultrasonographic or laparoscopic guidance, seems to be the management of choice when the ectopic is diagnosed at an early stage.


Mutator bacteria as a risk factor in treatment of infectious diseases.
We show in a gnotobiotic mouse model that, in addition to direct selection of antibiotic-resistant bacteria, some antibiotic treatments also select for mutator alleles. Because of these mutator alleles' high mutation rates, the initial treatment failure increases the probability of failures in subsequent treatments with other drugs.


Physical activity: a synopsis and comment on "community-wide interventions for increasing physical activity".
In this synopsis, we summarize and comment on Baker and colleagues' Cochrane review of studies on the population-level impact of community-wide physical activity (PA) interventions. Insufficient PA remains a major public health problem. Community-wide interventions offer an opportunity to extend reach by increasing the proportion of the population experiencing the intervention. A previous Cochrane review of community-wide PA interventions concluded that evidence for effectiveness was mixed. Hence, Baker and colleagues incorporated new data about community-based PA interventions. This Cochrane review concluded there is an overall lack of evidence that community-wide interventions improve PA outcomes at the population level. Recommendations are that future research should use high quality research design, more explicitly test ways to increase reach, and utilize objective measurements of PA to increase validity. We suggest that future research should first optimize the intervention by systematically evaluating treatment components and selecting a maximally efficient and effective treatment package.


Histopathological features in leprosy, post-kala-azar dermal leishmaniasis, and cutaneous leishmaniasis.
Leprosy, cutaneous leishmaniasis, and post-kala-azar dermal leishmaniasis are common infectious diseases, the latter two being seen mainly in endemic areas. With increased migration within the country, these diseases are now frequently being seen in major cities. This brief review article focused mainly on histopathology will be useful for the dermatologists and pathologists to be familiar with the basic histopathology of these lesions.


Atrioventricular nodal ablation is an effective management strategy for atrial fibrillation in patients with hypertrophic cardiomyopathy.
Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HCM) and can be challenging to manage. Atrioventricular nodal (AVN) ablation may be an effective management strategy for AF in these patients. The purpose of this study was to assess the efficacy of AVN ablation in HCM patients who have failed medical therapy and/or catheter ablation for AF. A multicenter study with retrospective analysis of a prospectively collated HCM registry was performed. AVN ablation patients were identified. Baseline characteristics and device and procedural indications were collected. Symptoms defined by New York Heart Association and European Heart Rhythm Association classification and echocardiographic findings during follow-up were assessed. Fifty-nine patients were included in the study. Indications for AVN ablation were 6 (10.2%) inappropriate implantable cardioverter-defibrillator shock, 35 (59.3%) ineffective rate control, and 18 (30.5%) to regularize rhythm for symptom improvement. During post-AVN ablation follow-up of 79.4 ± 61.1 months, left ventricular ejection fraction (LVEF) remained stable (pre-LVEF 48.9% ± 12.6% vs post-LVEF 50.1% ± 10.1%; P = .29), even in those without a cardiac resynchronization therapy (CRT) device (pre-LVEF 54.3% ± 8.0% vs post-LVEF 53.8% ± 8.0%; P = .65). Forty-nine patients (83.1%) reported an improvement in symptoms regardless of AF type (17/21 [81.0%] paroxysmal vs 32/38 [84.2%] persistent; P = 1.00), presence of baseline left ventricular impairment (22/26 [84.6%] LVEF ≤50% vs 27/33 [81.8%] LVEF ≥50%; P = 1.00) or CRT device (27/32 [84.4%] CRT vs 22/27 [81.5%] no CRT; P = 1.00). Symptoms improved in 16 patients (89.0%) who underwent AVN ablation to regularize rhythm. AVN ablation improved symptoms without impacting left ventricular function in the majority of patients. The data suggest that AVN ablation is an effective and safe management approach for AF in HCM and should be further evaluated in larger prospective studies.


Intrasellar carotid anastomosis simulating pituitary microadenoma.
Arterial communication between the cavernous segments of the carotid arteries associated with agenesis of the unilateral internal carotid artery is a rare anomaly. Two cases of this anomalous artery with an abnormal sella turcica due to the intrasellar course are reported.


Control of membrane lipid synthesis in Escherichia coli during growth and during the stringent response.
The regulation of phospholipid synthesis in cells of Escherichia coli was studied in vivo during growth and during the stringent response to amino acid starvation. Strains harboring the hybrid plasmid pLC44-14 (Clark, L., and Carbon, J. (1976) Cell 9, 91-99), which had increased levels of glycerophosphate acyltransferase, were used to study the involvement of this enzyme in the control of phospholipid synthesis. In addition, regulation was studied by measuring the levels of three early intermediates of phospholipid synthesis:phosphatidic acid, CDP-diglyceride, and dCDP-diglyceride. The liponucleotides were measured by a new enzymatic method which allows determinations to be made on crude lipid extracts. Results from experiments on growing cells are consistent with regulation of membrane lipid synthesis occurring in fatty acid synthesis or at the level of glycerophosphate acylation, but not at any later step. Experiments on the inhibition of lipid synthesis during the stringent response make it possible to rule out explanations which involve the inhibition of a single enzyme; enzymes both before and after the liponucleotides in phospholipid synthesis must be affected.


PyMod: sequence similarity searches, multiple sequence-structure alignments, and homology modeling within PyMOL.
In recent years, an exponential growing number of tools for protein sequence analysis, editing and modeling tasks have been put at the disposal of the scientific community. Despite the vast majority of these tools have been released as open source software, their deep learning curves often discourages even the most experienced users. A simple and intuitive interface, PyMod, between the popular molecular graphics system PyMOL and several other tools (i.e., [PSI-]BLAST, ClustalW, MUSCLE, CEalign and MODELLER) has been developed, to show how the integration of the individual steps required for homology modeling and sequence/structure analysis within the PyMOL framework can hugely simplify these tasks. Sequence similarity searches, multiple sequence and structural alignments generation and editing, and even the possibility to merge sequence and structure alignments have been implemented in PyMod, with the aim of creating a simple, yet powerful tool for sequence and structure analysis and building of homology models. PyMod represents a new tool for the analysis and the manipulation of protein sequences and structures. The ease of use, integration with many sequence retrieving and alignment tools and PyMOL, one of the most used molecular visualization system, are the key features of this tool.Source code, installation instructions, video tutorials and a user's guide are freely available at the URL http://schubert.bio.uniroma1.it/pymod/index.html.


Aminotriazines with indole motif as novel, 5-HT7 receptor ligands with atypical binding mode.
Developing new and selective 5-HT7R ligands may have a key impact on the treatment of central nervous system diseases including depression. We have found that indoleaminotriazine core fused with alkyl aryl moiety exhibits high affinity and selectivity to 5-HT7R. SAR analysis demonstrated that the ethyl or ethoxy group (5c 5-HT7R Ki = 8 nM; 5d 5-HT7R Ki = 55 nM) is the optimal carbon linker between triazine and aryl moiety. The results of the molecular dynamics simulations show stable interaction with E7.34 upon binding to a 5-HT7R. Compounds 5c and 5d were tested for early ADMET parameters. Compounds are not hepatotoxic and exhibit moderate potential interaction with other drugs metabolized by CYP3A4 or CYP2D6.


IL-33 alleviates DSS-induced chronic colitis in C57BL/6 mice colon lamina propria by suppressing Th17 cell response as well as Th1 cell response.
Interleukin (IL)-33, a member of the IL-1 cytokine family, is associated with autoimmune diseases including inflammatory bowel diseases (IBD). A few studies on animal models have shown that IL-33 can suppress Th1 cell response and improve Th2 cell response in mesenteric lymph nodes (MLN) and sera. However, there is little data published about the effect of IL-33 on Th17 cell in and Th1/Th2 cell in colon lamina propria. The aim of this study was to investigate the effect of IL-33 on Th17 cell in colon lamina propria of mice with dextran sulfate sodium (DSS) induced chronic colitis. We studied the influence of IL-33 on colonic tissue injury and clinical symptoms of colitis. The T cell subsets were measured by flow cytometry and the production of cytokines secreted by lamina propria lymphocytes (LPL) was measured by Enzyme-Linked Immunosorbent Assay (ELISA) and quantitative real-time PCR. We have found that rIL-33 treatment led to a significant alleviation of DSS induced chronic colitis as evidenced by 1) alleviation of weight loss, DAI, macroscopic changes and histological score; 2) down-regulating the rates and absolute cell numbers of Th17 and Th1 cell in LPL; 3) inducing secretion of lower levels of IFN-γ and IL-17A. It is therefore concluded that IL-33 may play a therapeutic role in DSS-induced chronic colitis in mice by suppressing Th17 response and switching Th1 to Th2 response.


[Evaluation of the hepatitis B prevention program in newborn infants. I. National data, 1990].
To evaluate the effectiveness of the national programme for prevention of perinatal hepatitis B infections. The regional public health laboratories and provincial immunization administrations in the Netherlands. Retrospective evaluation. Starting October 1989 routine screening of pregnant women for HBsAg was performed and passive-active immunisation of infants of HBsAg-positive mothers was added to the national immunisation programme. Infants receive hepatitis B immunoglobulin at birth and hepatitis B vaccine at 3,4,5, and 11 months of age, concomitant with the DTP-polio vaccine. The effectiveness of screening and intervention in 1990 was evaluated. Screening covered about 85% of the pregnant population and the prevalence (0.44%) was less than expected. About 60% of the infants born to HBsAg-positive mothers were registered for vaccination. Of these infants the average coverage was 83% for immunoglobulin, and 90%, 86%, 80% and 55% for the four successive hepatitis B vaccinations. There was considerable delay in vaccine administration; frequently doses were administered later than recommended. Compliance with screening and vaccination appeared incomplete. Recommendations for the simplification of the current programme are made.


Complex shoulder arthroplasty in patients with skeletal dysplasia can decrease pain and improve function.
Patients with skeletal dysplasia are prone to the development of degenerative shoulder disease requiring shoulder arthroplasty at a younger age than in the general population. To date there have been no published reports on the complexities or outcome of shoulder arthroplasty in this unique patient group. This is a review of 13 shoulder arthroplasties in 10 patients with skeletal dysplasia with mean follow-up of 7 years (2-17.6 years). There were 4 men and 6 women with a mean age of 53.1 years (23-76 years), mean height of 148 cm (122-177 cm), and mean weight of 60 kg (27-80 kg). The mean Oxford Shoulder Score increased from 13 (5-20) preoperatively to 28 (18-38) at final follow-up. Patients improved significantly in 2 of 8 Short Form 36 health-related quality of life domains: physical function (P = .04) and bodily pain (P = .04). Function was better in those who underwent nonconstrained total shoulder arthroplasty as opposed to hemiarthroplasty. Four (31%) required reoperation: 1 excision of heterotopic ossification, 1 relocation for anterior instability, and 2 revisions for periprosthetic fracture and glenoid erosion. Shoulder arthroplasty is effective at relieving pain, optimizing movement, and improving function for patients with skeletal dysplasia; however, compared with the general population, there is a higher complication rate and function is not as good. Furthermore, this procedure is less effective at restoring health-related quality of life than total hip arthroplasty or total shoulder arthroplasty performed for osteoarthritis in the general population. Custom implants may be required to compensate for short stature and rotator cuff and glenoid deficiency.


Suspended particle adhesion on aquatic plant surfaces: implications for 137Cs and 133Cs uptake rates and water-to-plant concentration ratios.
Suspended particle adhesion on aquatic biota can significantly increase the apparent concentration of radionuclides above their endogenous value, leading to an overestimation of the uptake rate and concentration ratios. This study is an attempt to assess quantitatively the importance of suspended particle adhesion on periphyton samples (biological material coating submerged surfaces). The concentrations of 137Cs and stable Cs (133Cs) in periphyton, suspended particles and filtered water were measured to determine the net water-to-periphyton concentration ratios for 137Cs and stable Cs. The net amount of 133Cs (or 137Cs) taken up by periphyton was calculated by subtracting from the total amount of 133Cs (or 137Cs) on the collected material (periphyton + inorganic particles), the 133Cs (or 137Cs) due to the inorganic particles adhering to periphyton. The mass of suspended particles adhering to the periphyton surface was calculated using scandium as an indicator of the mineral fraction of the suspended particles. The relationship between the concentration ratios for 137Cs and stable Cs and suspended particle adhesion on periphyton external surfaces is discussed.


Pelvic gunshot wound presenting as bladder clot concealing a left external iliac injury.
This is the first reported case of a pelvic gunshot wound with a bladder injury masking a coinciding left external iliac artery injury. A high index of suspicion for an acute and traumatic ilio-vesical fistula should be raised in the presence of the following triad: bright red hematuria, bladder distension from clot retention, hemodynamic instability after bladder decompression "Mukendi's triad." Iliac artery injury from gunshot wounds is very rare and a lethal injury associated with high mortality rate. Concurrent ballistic external iliac artery and bladder injuries resulting in an acute ilio-vesical shunt or fistula and discovered at the time of presentation are extremely rare.In this report, we present an unprecedented case of multiple pelvic gunshot wounds presented with a distended injured bladder full of clots concealing a left external iliac injury by tamponade effect.


Mesocorticolimbic monoamines in a rodent model of chronic neuropathic pain.
Chronic pain manifests in multiple disorders and is highly debilitating. While its pathophysiology is not fully understood, the involvement of the mesocorticolimbic monoaminergic systems have been shown to play a critical role in chronic pain emergence and/or maintenance. In this study, we analyzed the levels of monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in mesocorticolimbic areas - medial prefrontal cortex, orbitofrontal cortex, striatum, nucleus accumbens and amygdala - 1 month after a neuropathic lesion, Spared Nerve Injury (SNI). In SNI animals, were observed a marginal decrease of DA and 5-HT in the striatum and a rightward shift in the levels of NA in the nucleus accumbens. While mesocorticolimbic monoamines might be relevant for chronic pain pathophysiology its content appears to be relatively unaffected in our experimental conditions.


Lack of vegetative and endocrine circadian rhythms in fatal familial thalamic degeneration.
A total lack of neuroendocrine and vegetative circadian rhythms was observed in a patient with a familial degeneration of the anterior and dorso-medial thalamic nuclei. Our findings support the role of the thalamus in regulating the periodicity of endocrine and vegetative functions.


Genetic analysis of two viroceptor genes of orf virus.
In the present study, we analyzed the chemokine-binding protein (CBP) and the GM-CSF/IL-2 inhibition factor (GIF) of orf virus (ORFV) isolates of sheep and goat origin from different geographical regions of India. Both are immunomodulatory proteins known for their unique strategy of establishing short-term immunity and re-infection in their host. The GIF gene is highly conserved, whereas the CBP gene is highly variable. Both the proteins have conserved potential N-glycosylation sites. The GIF protein contains the "WDPWV" motif responsible for receptor activation. In addition, the SUSHI/short consensus repeats (SCR) domain is reported for the first time in ORFV. Both proteins could potentially be used as immunotherapeutic agents in inflammatory diseases related to the overexpression of specific cytokines.


Risk profile and operative outcomes in patients with and without Marfan syndrome undergoing thoracoabdominal aortic aneurysm repair.
To compare operative and long-term outcomes between patients with and without Marfan syndrome undergoing thoracoabdominal aortic aneurysm repair. We identified all consecutive patients undergoing thoracoabdominal aortic aneurysm repair between 1997 and 2022. Primary outcome was composite of major adverse events. Secondary outcomes were individual complications and long-term survival. Inverse probability of treatment weighting was performed. Weighted Kaplan-Meier curves were used to estimate long-term survival. Multivariable analysis identified factors associated with major adverse events. Six hundred eighty-four patients underwent open thoracoabdominal aortic aneurysm repair. Ninety (13.1%) had Marfan syndrome, whereas 594 (86.9%) did not. Marfan patients were younger (46 years [range, 36-56 years] vs 69 years [range, 61-76 years]; P < .001). Extent II or III aneurysms (57 out of 90 [63.3%] vs 211 out of 594 [35.6%]; P < .001) and type I or III chronic dissection (77 out of 90 [85.3%] vs 242 out of 594 [40.8%]; P < .001) were more common. Cardiovascular risk factors were less frequent in Marfan patients. There was no difference in major adverse events between groups (12 out of 90 [13.3%] vs 100 out of 594 [16.8%]; P = .49). Operative mortality was similar between groups (3 out of 90 [3.3%] vs 28 out of 594 [4.7%]; P = .75). Unweighted survival at 10 years was 78.7% vs 46.8% (P = .001). Weighted Kaplan-Meier curves showed no difference in long-term survival (adjusted hazard ratio, 0.79; 95% CI, 0.32-1.99; P = .62; Log-rank P = .12). At multivariable analysis, renal insufficiency (odds ratio, 2.29; 95% CI, 1.43-3.68; P < .01) and urgent/emergency procedure (odds ratio, 2.17; 95% CI, 1.35-3.48; P < .01) were associated with major adverse events, whereas Marfan syndrome was not (odds ratio, 1.56; 95% CI, 0.69-3.49; P = .28). Open thoracoabdominal aortic aneurysm repair can be performed with similar operative outcomes in patients with and without Marfan syndrome despite differing risk profiles. Operative/perioperative strategies must be tailored to specific needs of each patient to optimize outcomes.


Effects of subclinical depression, anxiety and somatization on brain structure in healthy subjects.
Dimensional approaches in highly prevalent psychiatric disorders like depression or anxiety could lead to a better understanding of pathogenesis and advantages in early detection and prevention. In an effort to better understand associations of brain structural variation across the depression/anxiety spectra, we investigated minor subclinical symptoms in a non-clinical healthy population. We studied 177 healthy subjects from the community, who underwent high-resolution T1-weighted 3T MRI and completed the symptom-checklist-90 (SCL-90-R). Using voxel-based morphometry (VBM) analysis with CAT12 software, we correlated SCL-90-R-subscales for depression, anxiety, and somatization with gray matter across the brain. Significant positive gray matter correlations emerged across all three scales in different areas: the depression subscale correlated positively with gray matter in the Rolandic operculum, superior temporal gyrus (left) and postcentral gyrus (bilateral), the anxiety subscale correlated positively with middle temporal gyrus, Rolandic operculum, middle cingular gyrus and precuneus bilaterally, and the somatization subscale with left inferior prefrontal cortex. Somatization also showed negative correlations with cerebellar vermis and right supplementary motor area. Our study is limited to VBM and does not include surface-based measures. It also only contains subjects with very small psychological distress by partly overlapping symptoms. Our findings are consistent with a non-linear relationship between symptom severity and cortical volume in several brain areas involved in both emotion regulation as well as altered in clinically manifest depressive/anxiety disorders.


[A carcinogens--methods for detecting environmental muta/carcinogens].
The major causes of cancer in the developed countries are now thought to be environmental or man-made factors. Because most carcinogens are also mutagens, the detection and identification of muta/carcinogens to humans seem to be very important in the environmental sciences. We describe here, i) in vitro and in vivo short-term assays for muta/carcinogens in the environment, ii) possible method for monitoring human exposure to muta/carcinogens, and iii) some trials for estimating human risk for the development of cancers due to environmental mutagens.


Microdialysis of proteins: performance of the CMA/20 probe.
Unlike all other currently available sampling techniques, microdialysis allows the continuous recovery of dialysed fluid from the interstitial space of living tissue. Microdialysis has been extensively used to study small molecules such as neurotransmitters, metabolites and drugs in the brain and other tissues. There has been increasing interest in measuring proteins using microdialysis. Optimizing protein recovery requires slow buffer flow rates, large pore membranes and osmotic balancing. An examination of a widely used commercially available large pore (100kDa MWCO) polymeric microdialysis probe, the CMA/20 (polyethersulfone) over 6 days of continuous microdialysis showed that: (1) published molecular weight cut-off values may not predict the size of proteins that can be recovered. This membrane had an effective molecular weight cut-off values (MWCO) of about 29kDa, (2) protein recoveries decrease over time, (3) small proteins are much less affected than larger ones and (4) there can be significant differences in the recovery of proteins similar in size perhaps due to reaching of a critical size, protein aggregation, shape, surface charge or hydrophobicity.


The Rieske FeS center from the gram-positive bacterium PS3 and its interaction with the menaquinone pool studied by EPR.
The Rieske 2Fe2S center from Bacillus PS3, a Gram-positive thermophilic eubacterium, has been studied by EPR spectroscopy. Its redox midpoint potential at pH 7.0 was determined to be +165 +/- 10 mV and was found to decrease with an apparent slope of -80 mV/pH unit above pH 7.9. The Qo-site inhibitor stigmatellin induced spectral changes analogous to those reported for Rieske centers from mitochondria and chloroplasts. The redox midpoint potential of the PS3 Rieske cluster was not affected by stigmatellin. The orientation of the g tensor was similar to other Rieske centers (gz and gy are oriented parallel, gx is oriented perpendicular to the membrane plane). The shape of the EPR spectrum of the Rieske cluster from PS3 changed as a function of the redox state of the menaquinone (MK) pool. This permitted the redox midpoint potential of the MK pool to be determined in the membrane. Values of -60 +/- 20 mV at pH 7.0 and of -130 +/- 20 mV at pH 8.0 were obtained. The results are compared with already published data from other Rieske centers. It is proposed that all Rieske centers that function in electron transport chains using MK as pool quinone show common features that distinguish them from Rieske centers operating in ubiquinone- or plastoquinone-based electron transfer chains.


An enhanced isothermal amplification assay for viral detection.
Rapid, inexpensive, robust diagnostics are essential to control the spread of infectious diseases. Current state of the art diagnostics are highly sensitive and specific, but slow, and require expensive equipment. Here we report the development of a molecular diagnostic test for SARS-CoV-2 based on an enhanced recombinase polymerase amplification (eRPA) reaction. eRPA has a detection limit on patient samples down to 5 viral copies, requires minimal instrumentation, and is highly scalable and inexpensive. eRPA does not cross-react with other common coronaviruses, does not require RNA purification, and takes ~45 min from sample collection to results. eRPA represents a first step toward at-home SARS-CoV-2 detection and can be adapted to future viruses within days of genomic sequence availability.


Evaluating geodesic active contours in microcalcifications segmentation on mammograms.
Breast cancer is the most commonly occurring type of cancer among women, and it is the major cause of female cancer-related deaths worldwide. Its incidence is increasing in developed as well as developing countries. Efficient strategies to reduce the high death rates due to breast cancer include early detection and tumor removal in the initial stages of the disease. Clinical and mammographic examinations are considered the best methods for detecting the early signs of breast cancer; however, these techniques are highly dependent on breast characteristics, equipment quality, and physician experience. Computer-aided diagnosis (CADx) systems have been developed to improve the accuracy of mammographic diagnosis; usually such systems may involve three steps: (i) segmentation; (ii) parameter extraction and selection of the segmented lesions and (iii) lesions classification. Literature considers the first step as the most important of them, as it has a direct impact on the lesions characteristics that will be used in the further steps. In this study, the original contribution is a microcalcification segmentation method based on the geodesic active contours (GAC) technique associated with anisotropic texture filtering as well as the radiologists' knowledge. Radiologists actively participate on the final step of the method, selecting the final segmentation that allows elaborating an adequate diagnosis hypothesis with the segmented microcalcifications presented in a region of interest (ROI). The proposed method was assessed by employing 1000 ROIs extracted from images of the Digital Database for Screening Mammography (DDSM). For the selected ROIs, the rate of adequately segmented microcalcifications to establish a diagnosis hypothesis was at least 86.9%, according to the radiologists. The quantitative test, based on the area overlap measure (AOM), yielded a mean of 0.52±0.20 for the segmented images, when all 2136 segmented microcalcifications were considered. Moreover, a statistical difference was observed between the AOM values for large and small microcalcifications. The proposed method had better or similar performance as compared to literature for microcalcifications with maximum diameters larger than 460μm. For smaller microcalcifications the performance was limited.


Mode of delivery and its influence on women's satisfaction with childbirth.
Many factors affect women's satisfaction with the experience of childbirth. Some of these are known, but most have not been fully evaluated. The influence of the mode of delivery is unclear. This study investigated the extent to which satisfaction with childbirth depends on the mode of delivery, and evaluated factors determining postpartum satisfaction. Women with singleton pregnancies at term were included prospectively. After childbirth, all women meeting the inclusion criteria received a standardised questionnaire - the German version of Salmon's Item List (SIL-Ger) - for completion before discharge to evaluate the birth experience. The chi-squared test, Fisher's exact test, and Kruskal-Wallis test were used for statistical analysis. Univariate and multivariate linear regression analyses were used to assess associations between demographic and pregnancy-associated variables and variables influencing the perception of childbirth in the total SIL-Ger score. Univariate and multivariate binary logistic regression models were used to evaluate effects of demographic and clinical parameters on SIL-Ger scores of <70 versus SIL-Ger scores of ≥ 70. All covariates with a P value ≤ 0.10 in the univariate analysis were included in multivariate logistic regression models. All tests were two-sided, and P values<0.05 were considered statistically significant. The analysis included 335 questionnaires. No differences were observed between different modes of delivery (normal 84.5 ± 14.6, primary caesarean 87.0 ± 13.5, secondary caesarean 83.2 ± 13.8, emergency caesarean 79.3 ± 7.3, operative vaginal delivery 83.9 ± 13.6; P=0.503). Multivariate analysis identified two independent factors associated with higher SIL-Ger scores: good/very good satisfaction with childbirth (P<0.001) and good/very good involvement in decision-making afterwards (P=0.005). Severe pain perception during childbirth was associated with lower SIL-Ger scores (P=0.003). Absence of a person of trust during childbirth was linked with scores<70 (P=0.005), indicating a negative experience. Good/very good satisfaction with childbirth (P<0.001) reduced the probability of a score<70. Mode of delivery does not directly influence women's satisfaction with childbirth. Involvement in decision-making, support during labour and effective analgesia appear to be the most important factors that improve women's birth experience.


Quantification of nicotinic acetylcholine receptors in the human brain with PET: bolus plus infusion administration of 2-[18F]F-A85380.
Quantitative analysis of most positron emission tomography (PET) data requires arterial blood sampling and dynamic scanning when the radioligand is administered as a bolus injection. Less invasive studies can be accomplished if the radioligand is administered as a bolus plus constant infusion (B/I). The purpose of the current study was to evaluate a B/I paradigm for quantifying high affinity nicotinic acetylcholine receptors (nAChRs) with PET and 2-[(18)F]F-A85380 (2FA). Seven volunteers underwent a study in which 2FA was administered as a bolus injection and another study in which the 2FA was administered by B/I (Kbolus=500 min). We evaluated the feasibility of using scans of a 2 h duration starting 6 h after the start of the 2FA administration and data from venous blood. Radioactivity in the brain and in arterial and venous plasma reached steady state by 6 h. Volumes of distribution (V(T)) calculated from the ratio of radioactivity in the brain areas of interest to the radioactivity corresponding to unbound, unmetabolized 2FA in venous plasma at steady state in the B/I studies were very similar to those calculated from time activity curves of unbound, unmetabolized 2FA in arterial plasma and regional brain radioactivity from 8-h dynamic scans after bolus administration of 2FA. The results of repeated PET studies with 2FA showed a high reproducibility of V(T) measurements. We conclude that B/I methodology will be useful for clinical and research studies of brain nAChRs.


Perioperative interstitial irradiation in the conservative management of early breast cancer.
Conservation of the breast in early breast cancer with limited resection and radiation is proving to be as effective as modified radical mastectomy in survival and in loco-regional control. Management at the University of Kansas Medical Center consists of an interstitial implant at the time of lumpectomy to facilitate perioperative irradiation with Iridium-192 to the tumor bed. An axillary node dissection is also performed at that time. Two to 3 weeks later external beam irradiation is delivered to the entire breast. One hundred and twenty-three breasts in 120 patients have been treated between June 1982 and June 1986. There were 49 pathological Stage I, 63 Stage II, 8 Stage III carcinomas, and 3 carcinomas in situ, consisting of 72 T1, 43 T2, 5 T3, and 3 TIS lesions. Patients have been followed for a median of 30 months. One patient had a "true" recurrence in the breast. Another patient developed recurrence in a different quadrant. Ninety percent of the patients had good to excellent cosmetic results, 7% were considered fair, and 3% had poor results. Seven patients developed mild arm edema, 4 were found to have moderate edema, and 1 had severe arm edema. Our preliminary results indicate that interstitial irradiation immediately after excision results in excellent local control, with very satisfactory cosmesis and no morbidity due to the simultaneous excision and irradiation.


Cyclooxygenase 2 contributes to bradykinin-induced microvascular responses in peripheral arterioles after cardiopulmonary bypass.
Diabetic patients are associated with impaired peripheral microvascular function after cardiopulmonary bypass (CPB) and cardiac surgery. We hypothesized that upregulation of the inducible cyclooxygenase 2 (COX-2) contributes to altered microvascular reactivity of peripheral arterioles in diabetic patients undergoing CPB and cardiac surgery. Skeletal muscle samples of nondiabetic (ND) patients and patients with diabetes mellitus (DM; n = 8 per group) undergoing cardiac surgery were harvested before and after CPB. The protein expression/localization of COX-2 was assayed by Western blotting and immunohistochemistry. Peripheral arterioles were dissected from the harvested skeletal muscle tissue samples, the isolated arterioles (80-180 μm) were cannulated and pressurized, and changes in diameter were measured with video microscopy. In-vitro relaxation responses of precontracted arterioles were examined in the presence of the endothelium-dependent vasodilator bradykinin (10-10 to 10-6M) and in the presence or absence of the selective COX-2 inhibitor NS398 (10-5M). The post-CPB protein levels of the inducible COX-2 were significantly increased compared with pre-CPB values in both the ND and DM groups (P < 0.05), whereas, this increase was higher in DM than that of ND (P < 0.05). In the DM arterioles, not the ND vessels, bradykinin-induced relaxation response was inhibited in the presence of the specific COX-2 inhibitor NS398 at baseline (P < 0.05). After CPB, bradykinin-induced relaxation response of the ND and DM arterioles was inhibited in the presence of the specific COX-2 inhibitor NS398, but this effect was more pronounced in the diabetic patients (P < 0.05). Diabetes and CPB are associated with upregulation in COX-2 expression/activation in human peripheral microvasculature. This alteration may lead to altered peripheral microvascular reactivity in diabetic patients undergoing cardiac surgery.


[Membrane-ionic mechanism of the depressing action of adrenaline on giant neurons].
The depressing action of epinephrine on the giant neurons is due to a progressively increasing passive potassium conductivity of the membrane, hyperpolarization and derangement of its generating properties. The triggering factor in the mechanism of the developing epinephrine hyperpolarization is an epinephrine induced increment of passive potassium conduction of the neuronal membrane.


Evaluation by microarray of the potential safety of Sarracenia purpurea L. (Sarraceniaceae) a traditional medicine used by the Cree of Eeyou Istchee.
The purpose of this study was to assess safety of the traditional antidiabetic extracts of either S. purpurea or its lead active principle, morroniside at the transcriptional level. The overarching objective was to profile and validate transcriptional changes in the cytochrome P450 family of genes, in response to treatment with S. purpurea ethanolic extract or its lead active, morroniside. Transcriptional activity was profiled using a 19K human cDNA microarray in C2BBe1 cells, clone of Caco-2 intestinal cells, which are a model of first-pass metabolism (1, 2). Cells were treated with S. purpurea extract for 4 and 24 hrs, as well as the pure compound morroniside for 4 hrs, to determine their effects. No evidence of cytochrome P450 transcriptome regulation or of transcriptional activation of other diabetes relevant mRNA was detected after rigorous quantitative-PCR validation of microarray results. Our data do not support a transcriptional mechanism of action for either S. purpurea extract or its lead active, morroniside. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.


Biomechanical evaluation of a modified proximal humeral locking plate application for distal extra-articular diaphyseal humeral fractures.
The extra-articular distal humerus locking plate (EADHP) is widely used for distal extra-articular diaphyseal humeral fracture fixation. However, it occasionally causes skin prominence and discomfort. The upside-down use of a proximal humerus internal locking system (PHILOS) plate is suggested as an alternative option, but it lacks biomechanical evidence. The purpose of this study was to compare the biomechanical performance between two different fixation methods: the modified use of the PHILOS plate on the anterior cortex versus conventional use of an EADHP on the posterior cortex. Twelve pairs of fresh-frozen cadaveric humeri were used and 7 mm gap osteotomy was performed at 50 mm proximal to the lateral epicondyle to simulate an AO/OTA 12-C1.3 fracture type. Single load to failure was measured after five stiffness tests of the plate-bone constructs in anterior/posterior bending, internal/external torsion, and axial compression. There were no significant differences in metrics between the two groups, except for the load to failure in posterior bending, which was significantly higher for PHILOS (1589.3 ± 234.5) compared to EADHP (1430.1 ± 188.6), p < .023. In conclusion, the modified use of the PHILOS plate showed comparable biomechanical performance compared to the conventional EADHP. The new fixation method offers potential clinical advantages, considering the patient's position and surgical approach at the time of surgery as well as postoperative soft tissue irritation. Therefore, this could be an option for distal humeral extra-articular diaphyseal fracture fixation when the use of EADHP is not suitable or preferred.


Ovine nasal adenopapilloma: incidence and clinicopathologic studies.
Nasal adenopapillomas were observed in 9 Y'anKasa and 1 Y'anKasa-Suffolk crossbred sheep (8 females and 2 males) over a 20-month period. The neoplasms originated from the epithelium of the lateral mass of the ethmoid bone. Gross and histologic features and clinical signs were similar in all cases. Influence of sex, age, or genetics was not established.


Eurycomanone suppresses expression of lung cancer cell tumor markers, prohibitin, annexin 1 and endoplasmic reticulum protein 28.
Bioactive compounds from the medicinal plant, Eurycoma longifolia Jack have been shown to promote anti-proliferative effects on various cancer cell lines. Here we examined the effects of purified eurycomanone, a quassinoid found in Eurycoma longifolia Jack extract, on the expression of selected genes of the A549 lung cancer cells. Eurycomanone inhibited A549 lung cancer cell proliferation in a dose-dependent manner at concentrations ranging from 5 to 20 μg/ml. The concentration that inhibited 50% of cell growth (GI(50)) was 5.1 μg/ml. The anti-proliferative effects were not fully reversible following the removal of eurycomanone, in which 30% of cell inhibition still remained (p<0.0001, T-test). At 8 μg/ml (GI(70)), eurycomanone suppressed anchorage-independent growth of A549 cells by >25% (p<0.05, T-test, n=8) as determined using soft agar colony formation assay. Cisplatin, a chemotherapy drug used for the treatment of non small cell lung cancer on the other hand, inhibited A549 cells proliferation at concentrations ranging from 0.2 μg/ml to 15 μg/ml with a GI(50) of 0.58 μg/ml. The treatment with eurycomanone reduced the abundance expression of the lung cancer markers, heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, p53 tumor suppressor protein and other cancer-associated genes including prohibitin (PHB), annexin 1 (ANX1) and endoplasmic reticulum protein 28 (ERp28) but not the house keeping genes. The mRNA expressions of all genes with the exception of PHB were significantly downregulated, 72 h after treatment (p<0.05, T-test, n=9). These findings suggest that eurycomanone at viable therapeutic concentrations of 5-20 μg/ml exhibited significant anti-proliferative and anti-clonogenic cell growth effects on A549 lung cancer cells. The treatment also resulted in suppression of the lung cancer cell tumor markers and several known cancer cell growth-associated genes.


Synthesis, Characterization and Antimicrobial Activities of 1,4- Disubstituted 1,2,3-Triazole Compounds.
1,2,3-triazoles are five-membered heterocyclic scaffold; their broad-spectrum biological activities are known. Researchers around the world are increasingly being interested in this emerging area, owing to its immense pharmacological scope. This work summarizes the synthesis of 1,2,3-triazoles and the significance of this pattern as a lead structure for new drug molecules discovery. 1,2,3-triazoles can be obtained on a multigram scale through "click chemistry" under ambient conditions. Sixteen compounds were synthesized and evaluated on five microbial strains E. coli, E. faecalis, P. aeruginosa, S. aureus and C. albicans. NMR, MS and IR were used to characterize all compounds. They were evaluated with their Minimum Inhibitory Concentrations (MICs) and interesting results were obtained with compounds 12a, 12b, 3, 2a and 2c, with MIC 0.14 μM (P. aeruginosa), 1.08 μM (E. coli), 1.20 μM (E. faecalis and C. albicans), 3.5 μM (E. faecalis) and 4.24 μM (C. albicans), respectively. P. aeruginosa and C. albicans were the most sensitive among all the strains. The synthesized compounds were found as potential antimicrobial agents against Gram (+), Gram (-) strains and fungi.


Severity and workload related to adverse events in the ICU.
To analyze whether an increase in patient severity and nursing workload are correlated to a greater incidence of adverse events (AEs) in critical patients. A prospective single cohort study was performed on a sample of 138 patients hospitalized in an intensive care unit (ICU). A total of 166 AEs, occurred, affecting 50.7% of the patients. Increased patient severity presented a direct relationship to the probability of AEs occurring. However, nursing workload did not present a statistically significant relationship with the occurrence of AEs. The results cast light on the importance of using evaluation tools by the nursing personnel in order to optimize their daily activities and focus on patient safety. Analisar se o aumento da gravidade do paciente e a carga de trabalho de enfermagem está relacionado à maior incidência de Eventos Adversos (EAs) em pacientes críticos. Estudo de coorte única, prospectivo, com amostra de 138 pacientes internados em uma Unidade de Terapia Intensiva (UTI). Ao todo, foram evidenciados 166 EAs, que acometeram 50,7% dos pacientes. O aumento da gravidade do paciente apresentou relação direta com a chance de ocorrência de EAs. Entretanto, a carga de trabalho de enfermagem não apresentou relação estatisticamente significativa, na ocorrência de EAs. Os resultados permitem refletir acerca da importância da equipe de enfermagem, em utilizar instrumentos de avaliação, com o objetivo de melhorar e planejar suas ações diárias, com foco na segurança do paciente.


Transvenous electrical cardioversion of equine atrial fibrillation: patient factors and clinical results in 72 treatment episodes.
Transvenous electrical cardioversion (TVEC) has been developed for treatment of atrial fibrillation (AF) in horses. The relationship among patient variables, treatment response, and outcome in a typical referral population has not been evaluated. Patient variables such as age, sex, weight, and duration of arrhythmia affect prognosis for response to treatment and the energy level at which cardioversion occurs. TVEC was applied to 72 episodes of lone AF in 63 client-owned performance horses, with the majority (54) being Standardbred racehorses. Catheterization of the right atrium (RA) and pulmonary artery (PA) through the jugular vein was used for electrode placement before horses were placed under general anesthesia. Biphasic, truncated exponential shock waves were delivered at incremental energy levels until cardioversion was achieved or a maximum single-energy level of 300 J was reached (cumulative energy 50-1,960 J). A multivariate model was constructed to evaluate influence of patient factors on cardioversion energy. Cardioversion was achieved in 71 of 72 episodes (62 of 63 horses) at a mean energy of 165.43 +/- 8.75 J. Cardioversion energy was higher for females than for males, and for interaction terms, weight was negatively related to energy in females and positively related in males. Age was positively related to cardioversion energy in females. No relationship was identified between duration of arrhythmia before treatment and prognosis for response or cardioversion energy. TVEC is highly effective in the treatment of lone AF in horses. Although age and sex influence cardioversion energy level, duration of arrhythmia does not.


Spatial transcriptome atlas reveals pulmonary microstructure-specific COVID-19 gene signatures in cynomolgus macaques.
Characterizing the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the molecular level is necessary to understand viral pathogenesis and identify clinically relevant biomarkers. However, in humans, the pulmonary host response during disease onset remains poorly understood. Herein, we utilized a spatial transcriptome atlas to identify pulmonary microstructure-specific COVID-19 gene signatures during the acute phase of lung infection in cynomolgus macaques. The innate immune response to virus-induced cell death was primarily active in the alveolar regions involving activated macrophage infiltration. Inflamed vascular regions exhibited prominent upregulation of interferon and complement pathway genes that mediate antiviral activity and tissue damage response. Furthermore, known biomarker genes were significantly expressed in specific microstructures, and some of them were universally expressed across all microstructures. These findings underscore the importance of identifying key drivers of disease progression and clinically applicable biomarkers by focusing on pulmonary microstructures appearing during SARS-CoV-2 infection.


Metal-Ion-Modified Black Phosphorus with Enhanced Stability and Transistor Performance.
Black phosphorus (BP), a burgeoning elemental 2D semiconductor, has aroused increasing scientific and technological interest, especially as a channel material in field-effect transistors (FETs). However, the intrinsic instability of BP causes practical concern and the transistor performance must also be improved. Here, the use of metal-ion modification to enhance both the stability and transistor performance of BP sheets is described. Ag+ spontaneously adsorbed on the BP surface via cation-π interactions passivates the lone-pair electrons of P thereby rendering BP more stable in air. Consequently, the Ag+ -modified BP FET shows greatly enhanced hole mobility from 796 to 1666 cm2 V-1 s-1 and ON/OFF ratio from 5.9 × 104 to 2.6 × 106 . The mechanisms pertaining to the enhanced stability and transistor performance are discussed and the strategy can be extended to other metal ions such as Fe3+ , Mg2+ , and Hg2+ . Such stable and high-performance BP transistors are crucial to electronic and optoelectronic devices. The stability and semiconducting properties of BP sheets can be enhanced tremendously by this novel strategy.


Clinical Value of Bilateral Balanced Frontotemporoparietal Decompressive Craniectomy in Severe Diffuse Traumatic Brain Injury.
To explore the clinical value of bilateral balanced frontotemporoparietal decompressive craniectomy (bbDC) in severe diffuse traumatic brain injury by comparison to the unilateral frontotemporoparietal decompressive craniectomy (uDC). Twenty three patients with severe diffuse traumatic brain injury from April 2015 to December 2019 were selected, including 10 cases underwent bbDC (bilateral group) and 13 cases underwent uDC (unilateral group). Compared with the postsurgical intracranial pressure (ICP), cerebral perfusion pressure, cerebral blood flow volume, postsurgical imaging score, the occurrence of complications as well as the 6 month outcome (Glasgow Outcome Scale, GOS) of two groups. 1. The postsurgical ICP was lower in the bbDC group than in the uDC group, while the postsurgical CCP and cerebral blood flow volume were higher in the bbDC group than in the uDC group. 2. Postsurgical imaging scores of the bbDC group were lower, indicating that the decompression effect of bbDC was more exhaustive than that of the uDC group. 3. The incidence of intraoperative acute cerebral bulging was lower in bbDC group than in uDC group. 4. The bbDC could effectively reduce the proportion of patients with the worst prognosis (dead+vegetative state). For patients with severe, diffuse traumatic brain injury combined with bilateral or unilateral pupil dilation, bilateral balanced decompression craniotomy is an effective method, which should be performed as soon as possible. As compared to unilateral decompression, the decompression effect on the brainstem is more thorough; the incidence of acute cerebral bulging, postoperative incisional hernia, and postoperative cerebral infarction involving a large area are reduced. ICP can be better controlled, cerebral perfusion pressure and cerebral blood flow increases, improving the patient's survival rate, quality of life, and prognosis.


Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction.
Glycogen synthase kinase 3 (GSK-3) inhibition has emerged as a potential therapeutic target for several diseases, including cancer. However, the role for GSK-3 regulation of human cardiac electrophysiology remains ill-defined. We demonstrate that SB216763, a GSK-3 inhibitor, can acutely reduce conduction velocity in human cardiac slices. Combined computational modeling and experimental approaches provided mechanistic insight into GSK-3 inhibition-mediated changes, revealing that decreased sodium-channel conductance and tissue conductivity may underlie the observed phenotypes. Our study demonstrates that GSK-3 inhibition in human myocardium alters electrophysiology and may predispose to an arrhythmogenic substrate; therefore, monitoring for adverse arrhythmogenic events could be considered.


Therapeutic effects of KANK2 in myocardial infarction rats might be associated with the NF-κB p65 inhibition.
KN motif and ankyrin repeat domains 2 (KANK2) may inhibit the activation of (NF-kappaB) p65, which plays a role in myocardial injury. Thus, our study aims to discover the effect of KANK2 on myocardial infarction (MI) induced by ligating the left anterior descending coronary artery (LAD) through regulating NF-κB p65 in vivo. MI rats underwent LAD ligation were administered with intramyocardial injections of KANK2/Control activation plasmids. Six weeks after MI, pressure-volume (P/V) loops was used to investigate the cardiac function of rats, then the following detections were performed, including TTC staining, HE staining, immunofluorescence, Masson' s trichrome staining, ELISA assay, TUNEL staining, immunohistochemistry, qRT-PCR and Western blotting. MI rats decreased in maximum pressure (pmax), ejection fraction (EF%), peak rate of pressure rise (dpdtmax) and decline (-dpdtmax) with increased end diastolic pressure (EDP), which was partially reversed by KANK2 overexpression. Besides, KANK2 CRISPR activation plasmids reduced infarct size with less collagen fiber proliferation and neutrophil infiltration in infarct tissues, as well as suppressed pro-inflammatory factors expressions in MI rats. Moreover, injection of KANK2 activation plasmid decreased collagen deposition, aggravated cardiomyocyte apoptosis, enhanced the capillary density, and increased the expressions of VEGF and bFGF in the infarct and peri-infarct regions of MI rats. KANK2 lowered myocardial NF-κB p65 expression in MI rats. KANK2 may play its therapeutic role in MI through improving cardiac function, decreasing myocardial collagen deposition, reducing cardiomyocyte apoptosis, and increasing angiogenesis, which might be associated with the reduction of NF-κB p65 expression.


A new tool to assess family caregivers' burden during end-of-life care.
A significant challenge in virtually all caregiving studies is the measurement of burden, particularly within the specific context of palliative care. Existing tools in the caregiving field are not specifically designed for palliative care. A new tool, which specifically assesses family caregivers' (FC) burden within the palliative care context, was systematically developed and validated. This paper describes the steps taken to develop this tool and to examine its psychometric properties. The Caregiver's Burden Scale in End-of-Life Care (CBS-EOLC) is a 16-item self-report questionnaire. Internal consistency reliability: Cronbach's alpha = 0.95. Construct validity: Most inter-item associations were consistent with the conceptual framework that emerged from qualitative data analyses. Convergent validity: Interscale correlations: a) Zarit's Burden Interview (BI) = 0.72 (p < 0.01); b) POMS (fatigue) = 0.69 (p < 0.01); d) POMS (vigour) = -0.27 (p < 0.05). Social desirability was tested with the Crowne & Marlowe questionnaire (r = -0.24). Sensitivity: Associations were consistent with patients' functional status (ECOG) and FCs' unmet needs. The CBS-EOLC is a reliable and valid measure available in French and English.