Usefulness of Self-Reported Physical Activity and Clinical Outcomes in Older Patients With Atrial Fibrillation.
Current guidelines encourage regular physical activity (PA) to gain cardiovascular health benefit. However, little is known about whether older adults with atrial fibrillation (AF) who engage in the guideline-recommended level of PA are less likely to experience clinically relevant outcomes. We did a retrospective study based on the data from Systemic Assessment of Geriatric Elements in AF (SAGE-AF) prospective cohort study. The study population consisted of older participants with AF (≥65 years) and a congestive heart failure, hypertension, age, diabetes, stroke vascular disease, age 65 to 75 and sex(CHA2DS2-VASc) score ≥2. PA was quantified by self-reported Minnesota Leisure Time PA questionnaire. Competing risk models were used to examine the association between PA level and clinical outcomes over 2 years while controlling for several potentially confounding variables. A total of 1,244 participants (average age 76 years; 51% men; 85% non-Hispanic White) were studied. A total of 50.5% of participants engaged in regular PA. Meeting the recommended level of PA was associated with lower mortality over 2 years (adjusted hazard ratio 0.60, 95% confidence interval 0.38 to 0.95) but was not associated with rates of stroke or major bleeding. In conclusion, older adults with AF who engaged in guideline-recommended PA are more likely to survive in the long term. Healthcare providers should promote and encourage engagement in PA and tailor interventions to address barriers of engagement.


Successful treatment of an extensively drug-resistant pseudomonal ulcer associated with contaminated artificial tears.
To report a case of bacterial keratitis caused by an extensively drug-resistant (XDR) Pseudomonas aeruginosa strain linked to contaminated artificial tears in the United States. The ulcer was successfully treated without perforation or extracorneal spread. An 81-year-old patient presented with a corneal ulcer of the right eye. The patient had a notable complex ocular history including glaucoma and corneal edema from corneal decompensation after prolonged retained lens fragment. Despite starting hourly fortified tobramycin and vancomycin eye drops, the infiltrate grew significantly by the next day. Bacterial culture grew Pseudomonas aeruginosa that was resistant to all tested antibiotics except for intermediate susceptibility to colistin and susceptibility to cefiderocol. Tobramycin-soaked collagen shields were applied daily for three days, and the patient was started on fortified colistin eye drops. The ulcer improved and, after seven weeks of therapy, the infiltrate resolved and resulted in a large central corneal scar. A combination of fortified colistin and tobramycin (administered via a combination of fortified eye drops and tobramycin-soaked collagen shields) appears to be an effective treatment option for extensively drug-resistant Pseudomonas aeruginosa corneal ulcers.


Aspiration, but not injection, decreases cultured equine mesenchymal stromal cell viability.
Recently, equine multipotent mesenchymal stromal cells (MSC) have received significant attention as therapy for various conditions due to their proposed regenerative and immune-modulating capacity. MSC are commonly administered to the patient through a hypodermic needle. Currently, little information is available on the effect of such injection has on equine MSC immediate and delayed viability. We hypothesize that viability of equine MSC is not correlated with needle diameter during aspiration and injection. Using a 3 mL syringe, manual injection of equine cord blood (CB) or bone marrow-derived (BM) MSC with no needle and needles ranging in size from 18 to 30 Ga did not affect immediate MSC viability. Similarly, 24 h post-injection, MSC delayed viability was not different between any of the tested needles as determined by a resazurin-based proliferation assay. Using a 3 mL syringe, aspiration of MSC through 20, 25, and 30 Ga needles resulted in significant decreases in immediate viability with no change in delayed viability when compared to aspiration without a needle. BM- and CB-MSC were observed to be of similar size with a diameter ± SD of 19.8 ± 2.7 and 20.4 ± 2.2 μm, respectively. In comparison, the smallest needles, (30 Ga) have an internal diameter of 160 μm. Following injection, needle diameter did not affect immediate or delayed viability of equine MSC. Following aspiration through needles sizes 20 Ga and smaller, immediate viability, but not delayed viability, decreased. As a result, an 18 Ga or larger needle should be utilized for aspiration of cell suspensions. In contrast, needle selection for MSC injection should be based on clinical preference and experience rather than concerns over decreasing MSC viability.


Apoptosis and biochemical biomarkers of stress in spiders from industrially polluted areas exposed to high temperature and dimethoate.
The aim of this study was to evaluate the relations between apoptosis and the activity of antioxidant enzymes (superoxide dismutase; catalase) and quantitative changes in stress protein positive cells (Hsp70; metallothionein) in midgut glands of funnel web spiders Agelena labyrinthica (Agelenidae) and wolf spiders Pardosa lugubris (Lycosidae) exposed to high temperature and pesticide under laboratory conditions. The spiders were collected from two meadow ecosystems differently polluted with metals (Olkusz and Pilica, southern Poland). Under stress conditions, P. lugubris had fewer apoptotic cells in the midgut glands than A. labyrinthica. In P. lugubris from both sites, the observed increase in the percentage of metallothionein and Hsp70-positive cells, simultaneous with intensification of superoxide dismutase and catalase activity, suggests an anti-apoptotic function of those proteins in representatives of wandering spiders. In the midgut glands of A. labyrinthica, heat shock and dimethoate increased the number of Annexin V-positive cells as well as the amounts of mitochondria with low transmembrane potential (DeltaPsi(m)) versus the control. The changes in the percentage of MT- and Hsp70-positive cells in funnel web spiders were less than in wolf spiders. The absence of change in SOD and CAT activity in A. labyrinthica shows that the participation of those enzymes in antioxidant reactions is minimal in this species.


Medial Frontal Cortex GABA Concentrations in Psychosis Spectrum and Mood Disorders: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies.
Abnormalities of GABAergic (gamma-aminobutyric acidergic) systems may play a role in schizophrenia and mood disorders. Magnetic resonance spectroscopy allows for noninvasive in vivo quantification of GABA; however, studies of GABA in schizophrenia have yielded inconsistent findings. This may stem from grouping together disparate voxels from functionally heterogeneous regions. We searched PubMed for magnetic resonance spectroscopy studies of GABA in the medial frontal cortex (MFC) in patients with schizophrenia, bipolar disorder, and depression and in individuals meeting criteria for ultra-high risk for psychosis. Voxel placements were classified as rostral-, rostral-mid-, mid-, or posterior MFC, and meta-analyses were conducted for each group for each subregion. Of 341 screened articles, 23 studies of schizophrenia, 6 studies of bipolar disorder, 20 studies of depression, and 7 studies of ultra-high risk met the inclusion criteria. Meta-analysis revealed lower mid- (standardized mean difference [SMD] = -0.28, 95% CI, -0.48 to -0.07, p < .01) and posterior (SMD = -0.29, 95% CI, -0.49 to -0.09, p < .01) MFC GABA in schizophrenia and increased rostral MFC GABA in bipolar disorder (SMD = 0.76, 95% CI, 0.25 to -1.25, p < .01). In depression, reduced rostral MFC GABA (SMD = -0.36, 95% CI, -0.64 to -0.08, p = .01) did not survive correction for multiple comparisons. We found no evidence for GABA differences in individuals at ultra-high risk for psychosis. While limited by small numbers of published studies, these results substantiate the relevance of GABA in the pathophysiology of psychosis spectrum and mood disorders and underline the importance of voxel placement.


The effects of the Dark Triad personality traits on health protective behaviours: dyadic approach on self-reports and partner-reports.
The growing evidence show that romantic partners' personality traits mutually influence each other's health. The research on relationship between personality and health behaviours should include both partner's perspectives - relations between individuals' traits and their own outcomes (actor effects), and relations between individuals' traits and their partners' outcomes (partner effects). The objective of this study was to examine the actor and partner effects of the Dark Triad (DT) personality traits (psychopathy, Machiavellianism and narcissism) on the health protective behaviours (HPB) in romantic couples. A convenience sample of 188 heterosexual romantic couples participated in a cross-sectional round-robin study. Three predictor measures were Self-Report Psychopathy Scale-III, Narcissistic Personality Inventory and MACH-IV inventory, whereas HPB inventory was used as criterion variable. Data were analysed using the Actor-Partner Interdependence Model (APIM). The results suggest that men's psychopathy, and to a lesser extent men's Machiavellianism exert deleterious effects on their own and their partner's HPB. The majority of these effects replicated across both self-reports and partner-reports. Women's DT traits exerted weaker actor and partner effects on the HPB than men's DT traits. Findings show that men's psychopathy and Machiavellianism have detrimental effects on their own as well as their partner's HPB.


KSHV viral load and Interleukin-6 in HIV-associated pediatric Kaposi sarcoma-Exploring the role of lytic activation in driving the unique clinical features seen in endemic regions.
Kaposi sarcoma (KS) is among the most common childhood malignancies in central, eastern, and southern Africa. Although its unique clinical features have been established, biological mechanisms related to the causative agent, KS-associated herpes-virus (KSHV), have yet to be explored in children. We performed a prospective observational pilot study to explore associations between KSHV viral load (VL), human interleukin-6 (IL-6) and IL-10 levels, and clinical characteristics of 25 children with KS in Lilongwe, Malawi from June 2013-August 2015. The median age was 6.4 years. Lymphadenopathy was the most common site of KS involvement (64%), followed by skin and oral mucosa (44% each), woody edema (12%), and pulmonary (8%). Baseline samples for plasma KSHV VL, IL-6 and IL-10 analyses were available for 18/25 patients (72%) at time of KS diagnosis. KSHV VL was detectable at baseline in 12/18 (67%) patients, the median baseline IL-6 level was 8.53 pg/mL (range 4.31-28.33), and the median baseline IL-10 level was 19.53 pg/mL (range 6.91-419.69). Seven (39%) patients presented with an IL-6 level > 10 pg/mL (exceeding twice the upper limit of normal). Detectable KSHV VL was significantly associated with lymphadenopathic KS (p = 0.004), while having undetectable KSHV VL was associated with a higher likelihood of presenting with hyperpigmented skin lesions (p = 0.01). Detectable KSHV VL and elevated IL-6 levels are present in a subset of children with KS. Lytic activation of KSHV and associated elevation in KSHV VL may contribute to the unique clinical manifestations of pediatric KS in KSHV-endemic regions of Africa.


Release of guanosine triphosphate binding protein alpha subunits from mouse myocardial membranes: basic properties and their alterations in acute murine Chagas disease.
The aim was to investigate the arrangement of heterotrimeric alpha beta gamma G proteins in myocardial membranes using GTP gamma S dependent release characteristics of their alpha subunits in acute murine Chagas disease. The properties of GTP gamma S dependent alpha subunit release were monitored immunochemically as well as by cholera toxin and pertussis toxin catalysed [32P]ADP ribosylation. GTP gamma S, as opposed to other nucleotides, caused optimal and virtually instantaneous release of soluble 40 kDa [32P]ADP ribosylated protein in pertussis toxin treated membranes. When determined immunochemically, infection decreased both the sensitivity to GTP gamma S dependent release of alpha i subunits and appeared to facilitate the appearance of GTP gamma S dependent release of alpha i3. GTP gamma S also caused the release of soluble 45 and 40 kDa proteins as detected by cholera toxin-[32P]ADP ribosylated membranes and immunochemical analysis. With regard to cholera toxin-[32P]ADP ribosylated Gs substrates sensitive to GTP gamma S dependent release, infection (1) decreased the amount of 45 kDa alpha s protein, (2) increased the amount of 40 kDa protein, and (3) enhanced sensitivity to GTP gamma S. In contrast, there was no effect of infection on the magnitude or sensitivity to GTP gamma S dependent release of immunochemical alpha s. The diverse characteristics of GTP gamma S dependent release of the very similar alpha subunits from myocardial membranes and their unique sensitivity to infection with T cruzi suggest that these very similar proteins are arranged within the plasma membrane in such a manner as to modify their biochemical behaviour.


Calcium-independent activation of two plant leaf calcium-regulated protein kinases by unsaturated fatty acids.
Two soluble Ca2+-dependent protein kinases from silver beet leaves (enzymes I and II) can be resolved from each other by chromatography on DEAE-cellulose. Enzyme II is substantially activated by arachidonic, oleic and linoleic acids in the absence of Ca2+ but not at high Ca2+ concentrations. Stearic and arachidic acids do not substantially activate either enzyme at low free Ca2+. Enzyme I differs from enzyme II in exhibiting a much lower degree of Ca2+-independent activation by unsaturated fatty acids.


The Prognosis of Type III Biliary Atresia with Hilar Cyst.
To compare the outcome of biliary atresia (BA) patients with and without hilar cyst on preoperative ultrasound. A single center retrospective review of patients of BA with (n = 27) and without hilar cyst (n = 27) over a 5 y period was done. The patients were analyzed using propensity score matching to reduce selection bias. All patients were diagnosed as type III BA by histologic examination and cholangiograms. Clinicopathological characteristics and survival outcomes were compared between the two groups. There were no significant intergroup differences between baseline characteristics and outcomes after Kasai portoenterostomy surgery in two groups. BA with hilar cyst group showed comparable survival outcomes to the BA without cyst group (cumulative 1-y, 2-y and 5-y overall survival rates with native liver 61.4% vs. 65.8%, P = 0.041; 45.0% vs. 49.0%, P = 0.57; 45.0% vs. 49.0%, P = 0.57). And the Kaplan-Meier survival curves showed no significant difference in cumulative survival with native liver between the two groups (P = 0.58). Type III BA with hilar cyst had no better prognosis compared with Type III BA without cyst.


Reinforcing CPR skills without mannequin practice.
We studied the effectiveness of two refresher methods on skills that did not involve mannequin practice. Sixty-seven Seattle subjects trained one year earlier were pretested and randomly assigned to one of two treatments that covered the technique of one-rescuer CPR: reading a three-page review (n = 33); or viewing a 15-minute videotape (n = 34). Subjects were tested on a recording mannequin immediately after the refresher. Pretest scores were low on almost all skills. After treatment, both groups demonstrated significant improvement (P less than .01), especially on checking the carotid pulse, correct hand position, and ventilation volume. Although students who had watched the tape performed better on compression rate (P less than .05), there was virtually equivalent improvement on the other skills regardless of treatment. Both methods showed promise for reversing skills degradation without mannequin practice.


Xanthotoxin, a novel inducer of platelet formation, promotes thrombocytopoiesis via IL-1R1 and MEK/ERK signaling.
Thrombocytopenia is a common hematological disease caused by many factors. It usually complicates critical diseases and increases morbidity and mortality. The treatment of thrombocytopenia remains a great challenge in clinical practice, however, its treatment options are limited. In this study, the active monomer xanthotoxin (XAT) was screened out to explore its medicinal value and provide novel therapeutic strategies for the clinical treatment of thrombocytopenia. The effects of XAT on megakaryocyte differentiation and maturation were detected by flow cytometry, Giemsa and phalloidin staining. RNA-seq identified differentially expressed genes and enriched pathways. The signaling pathway and transcription factors were verified through WB and immunofluorescence staining. Tg (cd41: eGFP) transgenic zebrafish and mice with thrombocytopenia were used to evaluate the biological activity of XAT on platelet formation and the related hematopoietic organ index in vivo. XAT promoted the differentiation and maturation of Meg-01 cells in vitro. Meanwhile, XAT could stimulate platelet formation in transgenic zebrafish and recover platelet production and function in irradiation-induced thrombocytopenia mice. Further RNA-seq prediction and WB verification revealed that XAT activates the IL-1R1 target and MEK/ERK signaling pathway, and upregulates the expression of transcription factors related to the hematopoietic lineage to promote megakaryocyte differentiation and platelet formation. XAT accelerates megakaryocyte differentiation and maturation to promote platelet production and recovery through triggering IL-1R1 and activating the MEK/ERK signaling pathway, providing a new pharmacotherapy strategy for thrombocytopenia.


A qualitative study of individuals at risk for or who have chronic obstructive pulmonary disease: what do they understand about their disease?
This qualitative study examined chronic obstructive pulmonary disease (COPD) knowledge and attitudes among patients at risk for or with COPD. Participants perceived lung cancer as the primary lung disease of concern to their health and were largely unaware of COPD. Overall, the primary care patients expressed a desire to obtain additional information regarding their lung condition and, among smokers, information to help motivate them to quit smoking. An age-related metaphor, "MyLungAge" was well received and understood and may help facilitate successful management of COPD patients. Providing patients with their lung age at the point of diagnosis may be an optimum time to promote behavioral change and will require further investigation.


Superactivated charcoal versus cholestyramine for cholesterol lowering: a randomized cross-over trial.
To evaluate the relative abilities of superactivated charcoal (20 g twice daily) and cholestyramine (8 g twice daily) to lower plasma cholesterol concentrations acutely, six hypercholesterolemic patients were studied using a randomized cross-over design. After a 1-week dietary control period, each subject received 3 weeks of each treatment regimen on separate occasions. Superactivated charcoal and cholestyramine reduced total plasma cholesterol by 21.8 +/- 3.8% and 16.2 +/- 2.4%, respectively. Side effects were mild and similar for both treatments. At the dosage regimens studied, superactivated charcoal and cholestyramine have comparable ability to lower plasma cholesterol concentrations.


One-pot preparation of chiral beta-amino esters by rhodium-catalyzed three-components coupling reaction.
Chiral beta-amino esters are synthesized in one-pot from three components, amines, aldehydes, and ethyl bromoacetate, under the rhodium-catalyzed Reformatsky-type reaction condition, where complete diastereoselection is achieved in the nucleophilic addition step of ethyl bromoacetate to the imines prepared in


Bacterial biofilm inhibitors: An overview.
Bacteria that cause infectious diseases adopt biofilms as one of their most prevalent lifestyles. Biofilms enable bacteria to tolerate environmental stress and evade antibacterial agents. This bacterial defense mechanism has rendered the use of antibiotics ineffective for the treatment of infectious diseases. However, many highly drug-resistant microbes have rapidly emerged owing to such treatments. Different signaling mechanisms regulate bacterial biofilm formation, including cyclic dinucleotide (c-di-GMP), small non-coding RNAs, and quorum sensing (QS). A cell density-dependent phenomenon, QS is associated with c-di-GMP (a global messenger), which regulates gene expression related to adhesion, extracellular matrix production, the transition from the planktonic to biofilm stage, stability, pathogenicity, virulence, and acquisition of nutrients. The article aims to provide information on inhibiting biofilm formation and disintegrating mature/preformed biofilms. This treatment enables antimicrobials to target the free-living/exposed bacterial cells at lower concentrations than those needed to treat bacteria within the biofilm. Therefore, a complementary action of antibiofilm and antimicrobial agents can be a robust strategic approach to dealing with infectious diseases. Taken together, these molecules have broad implications for human health.


Effects of hypoxia on the gill morphological structure, apoptosis and hypoxia-related gene expression in blunt snout bream (Megalobrama amblycephala).
The blunt snout bream (Megalobrama amblycephala) is a typical hypoxia-sensitive fish, and hypoxia stress leads to reduced vitality and yield during aquaculture. To explore the specific adaptation mechanism under hypoxia, the blunt snout bream was treated with hypoxia (DO = 2.0 ± 0.1 mg/L) for 24 h, followed by 3 h of recovery. Our results depicted that the gill filament structure of blunt snout bream changed after hypoxia. During hypoxia for 24 h, the gill filament structure was altered, including a more than 80% expansion of the lamellar respiratory surface area and a proportionate apoptosis decrease in interlamellar cell mass (ILCM) volume. Thus, the water-blood diffusion distance was shortened to less than 46%. During hypoxia for 24 h, the activity of ROS in gill tissue increased significantly (p < 0.05), while the mitochondrial membrane potential decreased significantly (p < 0.05). During hypoxia, mRNA expression level of anti-apoptotic gene Bcl-2 in the gills of blunt snout bream decreased significantly (p < 0.05), while the expression of pro-apoptotic gene Bax mRNA increased significantly (p < 0.05). Thus, the ratio of Bax/Bcl-2 mRNA increased in the gills of blunt snout bream to promote the activity of Caspase-3. Together, our results indicated hypoxia-induced apoptosis in the gills of blunt snout bream through the mitochondrial pathway. In addition, a decreased expression of Phd1 and an increased expression of Hif-1α in gills under hypoxia stress indicates that blunt snout bream may cope with hypoxia-induced apoptosis by enhancing the HIF pathway. These results provide new insights into fish's adaptation strategies and mechanisms of hypoxia.


Propagation of beluga echolocation signals.
The propagation characteristics of high-frequency echolocation signals (peak energies above 100 kHz) of the beluga (Delphinapterus leucas) were measured while the animal performed a target detection task. The whale was trained to station on a bite plate so that its transmission beam could be measured in the vertical and horizontal planes using hydrophone arrays. The transitional region between the acoustic near- and farfields was also located using an array of hydrophones that extended directly in front of the animal in the horizontal plane. Three distinct modes of signals were observed. Mode 1 signals had click intervals greater than the time required for the signals to travel to the target and back (two-way transit time). Mode 2 signals had click intervals shorter than the two-way transit time, and mode 3 signals had high repetition rates with an average click interval of 1.7 ms, approximately 2% of the two-way transit time. The average click intervals for the modes 1 and 2 signals were 193 and 44 ms, respectively. The vertical and horizontal beam patterns of the mode 1 signals had similar 3-dB beamwidths of approximately 6.5 degrees. The major axis of the vertical beam was directed approximately 5 degrees above the plane defined by the animal's teeth. The near- to farfield transition region was approximately 0.64-0.75 m from the tip of the animal's mouth.


Submicron oil-in-water emulsion formulations for mefloquine and halofantrine: effect of electric-charge inducers on antimalarial activity in mice.
Stearylamine, oleic acid, phosphatidylserine and dicetylphosphate have been studied to determine their capacity to induce electric charge on non-ionic submicron emulsions containing halofantrine and mefloquine. The in-vivo antimalarial activity of drug-loaded emulsions, evaluated in mice, was affected by the nature of the additives used. In particular, the electric-charge inducers markedly affected the pharmacological activity of mefloquine, but not of halofantrine. After subcutaneous administration ED50 values (the doses affording 50% protection) were 3 and 15 mg kg(-1), respectively, for halofantrine and mefloquine emulsions without charge inducers. The mefloquine-loaded emulsions with charge inducers were active at 10 mg kg(-1) for dicetylphosphate, 17 mg kg(-1) for phosphatidylserine, 23 mg kg(-1) for oleic acid and 27 mg kg(-1) for stearylamine, again after subcutaneous administration. This work has enabled the formulation of stable emulsions, incorporating drugs with high antimalarial activity, which are proposed for parenteral delivery of these fairly soluble drugs.


Delayed enhancement cardiac magnetic resonance imaging reveals typical patterns of myocardial injury in patients with various forms of non-ischemic heart disease.
Late gadolinium-hyperenhancement (LHE) on cardiac magnetic resonance imaging (CMR) has been linked to cardiovascular risk in ischemic and non-ischemic heart disease. We aimed to systematically categorize LHE-patterns in a variety of non-ischemic heart diseases (NIHD) and to explore their relationship with left ventricular (LV) function. In a retrospective database search, 156 patients with NIHD who exhibited LHE on CMR were identified. All images were re-analyzed stepwise. LHE was correlated to LV functional parameters. Cardiac magnetic resonance (CMR) was conducted on 1.5 T scanners. Typically, LHE spared the subendocardium. Consistent LHE-patterns were observed in myocarditis, hypertrophic and dilated cardiomyopathy and systemic vasculitis. No conclusive LHE-patterns were observed in patients with aortic stenosis, arterial hypertension, lupus erythematosus, sarcoidosis, ventricular arrhythmia and in a mixed subgroup of rare NIHDs. There was no significant relationship between LHE and ejection fraction. There was no correlation between enddiastolic volume and LHE in either myocarditis (P = 0.13) or dilated cardiomyopathy (P = 0.62). LHE was unrelated to LV-mass in aortic stenosis (P = 0.13) and hypertrophic cardiomyopathy (P = 0.38). Distinct LHE patterns exist in various NIHDs and their visualization may ultimately aid diagnosis. Unlike in ischemic heart disease, the structure-function relationship does not appear to be strong.


[On the similarity in the effects of different cryopreservation conditions on the growth and development of plants].
The morphological characteristics of 35 wild plant species were studied after freezing of seeds under the conditions of deep, fast, and programmed freezing (-196 degrees C) and non-deep freezing (-10 degrees C). The seeds were stored frozen for a month. The seeds of all the species were characterized by a low humidity. The field and laboratory seed germination capacity, leaf growth, the quantity and length of shoots, the quantity of generative organs, and the variability of these characteristics were studied. It was shown that the direction of changes under different cooling conditions was the same except for the laboratory germination capacity of some species. The direction was determined by the species features rather than cooling conditions.


Use of SBA-15 for furosemide oral delivery enhancement.
The objective of this research was to realize a new oral solid dosage form in order to improve the release of furosemide (FURO) in its preferential absorption region. In fact FURO is a drug labeled in class IV of the Biopharmaceutical Classification System (BCS) characterized by low and variable bioavailability due to both low solubility and low permeability and because of its weakly acid nature is preferentially absorbed in the stomach whereas its solubility is hampered. FURO was included in the mesoporous silica material SBA-15 obtaining an inorganic-organic compound fully characterized by: thermogravimetric analysis (TGA), X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FT-IR) and nitrogen adsorption-desorption analysis and then submitted to in vitro dissolution. The results showed a remarkable dissolution rate improvement in comparison to the crystalline drug and to the marketed product Lasix®. The inclusion product was also submitted to physical stability studies that revealed the matrix ability to prevent re-organization in crystal nucleus of the drug molecules.


Evaluation of the impact of concurrent gonadotropin-releasing hormone (GnRH) antagonist administration on GnRH agonist-induced gonadotrope desensitization.
To evaluate the impact of chronic GnRH antagonist therapy on the extent of GnRH agonist-induced gonadotrope desensitization. Prospective and controlled. Primate Research Center. Six reproductive age cycling female baboons (Papio cyanocephalus anubis). The animals were divided into two groups. Group A received a total of 19 pulses of 0.83 microgram/kg leuprolide acetate (LA) on a 12-hour dosing schedule. Group B received Nal-Lys (3 mg/kg then 1 mg/kg every other day) for 1 week and then added an identical 19 pulses of LA while continuing Nal-Lys therapy. Characterization of the gonadotropin response was done by collecting serum samples at -15, 0, 15, 30, 60, 90, 120, 240, and 480 minutes relative to the injection of the LA. After equivalent baseline responses, the baboons pretreated with Na-Lys had an increased LH and FSH response to the administration of the LA. After a total of 19 pulses of the LA, the Nal-Lys-treated animals had an increased FSH response in comparison to the untreated controls. This indicates that the extent of gonadotrope desensitization was reduced in the presence of the GnRH antagonist. The presence of GnRH antagonist reduces the extent of gonadotrope desensitization in response to the administration of repetitive pulses of GnRH agonist.


miR-409-3p suppresses breast cancer cell growth and invasion by targeting Akt1.
Altered levels and functions of microRNAs (miRNAs) are correlated with carcinogenesis. While miR-409-3p has been shown to play important roles in several cancer types, its function in the context of breast cancer (BC) remains unknown. In this study, miR-409-3p was significantly downregulated in BC tissues and cell lines, compared with the corresponding control counterparts. Overexpression of miR-409-3p inhibited BC cell proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Notably, miR-409-3p induced downregulation of Akt1 protein through binding to its 3' untranslated region (UTR). Conversely, restoring Akt1 expression rescued the suppressive effects of miR-409-3p. Our data collectively indicate that miR-409-3p functions as a tumor suppressor in BC through downregulating Akt1, supporting the targeting of the novel miR-409-3p/Akt1 axis as a potentially effective therapeutic approach for BC.


Energy enzymes from the flight muscle of the house sparrow, Passer domesticus-II. Physical and chemical properties related to purification of the glycolytic enzymes.
The isoelectric points (pI0), molecular weights and ammonium sulfate precipitation ranges for most of the glycolytic enzymes from house sparrow (Passer domesticus) flight muscle were determined. The pI0 for each enzyme is as follows: HK (6.8), PGI (6.7), PFK (5.4), Ald (7.2), TPI (7.5), PGK (7.1), PGM (6.1), Enol (6.2), PyK (6.6), and LDH (8.3). The molecular weight for each enzyme is as follows: PGI (145,000), Ald (160,000), TPI (60,000), PGK (35,000), PGM (60,000), Enol (100,000), PyK (200,000), and LDH (145,000). The ammonium sulfate precipitation range for each enzyme is as follows: PGI (0-80%), PFK (40-50%), Ald (40-65%), TPI (30-90%), PGK (70-90%), PGM (30-80%), Enol (45-80%), PyK (55-85%), and LDH (40-65%).


Shift to Pseudomonic acid B production in P. fluorescens NCIMB10586 by mutation of mupirocin tailoring genes mupO, mupU, mupV, and macpE.
Mupirocin, a polyketide-derived antibiotic from Pseudomonas fluorescens NCIMB10586, is a mixture of pseudomonic acids (PA) that target isoleucyl-tRNA synthase. The mup gene cluster encodes both type I polyketide synthases and monofunctional enzymes that should play a role during the conversion of the product of the polyketide synthase into the active antibiotic (tailoring). By in-frame deletion analysis of selected tailoring open-reading frames we show that mupQ, mupS, mupT, and mupW are essential for mupirocin production, whereas mupO, mupU, mupV, and macpE are essential for production of PA-A but not PA-B. Therefore, PA-B is not simply produced by hydroxylation of PA-A but is either a precursor of PA-A or a shunt product. In the mupW mutant, a new metabolite lacking the tetrahydropyran ring is produced, implicating mupW in oxidation of the 16-methyl group.


Effects of a Whatsapp-delivered physical activity intervention to enhance health-related physical fitness components and cardiovascular disease risk factors in older adults.
This pilot study evaluated the feasibility and preliminary effectiveness of a 10-week WhatsApp-based intervention aimed at enhancing health-related physical fitness components and cardiovascular disease (CVD) risk factors compared with a face-to-face condition. Participants (N.=32) were assigned to one of three groups: training group (N.=16), mobile group (N.=7) and control group (N.=9). Training group and mobile group performed the same training program, based on strength training with elastics bands and aerobic exercise, during 10 weeks; only the delivery mode differed. The mobile group increased handgrip strength, aerobic capacity and decreased systolic blood pressure and heart rate after exercise though there were no significant differences respect to control group. The training group decreased significantly systolic blood pressure (P=0.038), diastolic blood pressure (P=0.005), mean arterial pressure (P=0.006) and heart rate after exercise (P=0.002), respect to control group. Comparison between training and mobile group showed that WhatsApp-based physical activity intervention was less effective than face-to-face condition. The results indicate that the use of an online social network produced slight changes in some health-related physical fitness components and CVD risk factors.


A review of age-related changes in cerebellar β-adrenergic function and associated motor learning.
The present review provides an overview of age-related changes in cerebellar β-adrenergic function, associated motor learning, causal agents and possible treatments. Norepinephrine acts as a neuromodulator of Purkinje cell activity. With aging, however, the ability of norepinephrine to modulate Purkinje cell activity and specifically GABAergic inhibition of Purkinje cell activity is decreased. This age-associated deficit in cerebellar noradrenergic function correlates with deficits in acquisition of a motor learning task. Aged rats are delayed in acquiring a motor learning task that requires rats to adjust footfalls in order to cross a runway. The degree of deficit in cerebellar β-adrenergic activity correlated positively with the degree of impairment in task acquisition. One possible causal agent for the β-adrenergic deficit is free radical damage. Hyperoxia, which may generate free radical damage, induces cerebellar β-adrenergic deficits in young rats but diet restriction and treatment with antioxidants can delay or reverse age-related deficits in cerebellar β-adrenergic function in old rats.


Sedation of mechanically ventilated adults in intensive care unit: a network meta-analysis.
Sedatives are commonly used for mechanically ventilated patients in intensive care units (ICU). However, a variety of sedatives are available and their efficacy and safety have been compared in numerous trials with inconsistent results. To resolve uncertainties regarding usefulness of these sedatives, we performed a systematic review and network meta-analysis. Randomized controlled trials comparing sedatives in mechanically ventilated ICU patients were included. Graph-theoretical methods were employed for network meta-analysis. A total of 51 citations comprising 52 RCTs were included in our analysis. Dexmedetomidine showed shorter MV duration than lorazepam (mean difference (MD): 68.7; 95% CI: 18.2-119.3 hours), midazolam (MD: 10.2; 95% CI: 7.7-12.7 hours) and propofol (MD: 3.4; 95% CI: 0.9-5.9 hours). Compared with dexmedetomidine, midazolam was associated with significantly increased risk of delirium (OR: 2.47; 95% CI: 1.17-5.19). Our study shows that dexmedetomidine has potential benefits in reducing duration of MV and lowering the risk of delirium.


Spinal epidural haematoma mimicking spontaneous subarachnoid haemorrhage.
Spinal epidural haematoma is increasingly picked up using magnetic resonance imaging, especially following trauma. The presentation can be varied especially if there is a trivial history of trauma. Spontaneous subarachnoid haemorrhage can occur in spinal haematoma as a rare and unusual presentation and can be easily misdiagnosed. The key to early diagnosis is a strong suspicion and careful repeated neurological examination. We present an illustrative case.


Improved estimates of abortion rates in tsetse (Glossina spp.).
Abortion rates were assessed among 170, 846 tsetse (154,228 Glossina pallidipes and 19,618 Glossina morsitans morsitans) sampled in Zimbabwe in 1988-1999. The study produced improved estimates of abortion rates and how these varied with fly age and size and temperatures experienced during pregnancy. An abortion was diagnosed if the uterus was empty and the largest oocyte <0.82 of the expected mature length. Abortion rates for G. pallidipes and G. m. morsitans were 0.64% (95% ci: 0.59-0.69) and 0.83% (0.62-1.10) for trapped flies and 2.03% (1.77-2.31) and 1.55% (1.20-1.98) for flies from artificial refuges. Abortion rates increased with increasing temperature and decreased with increasing wing length and wing fray. Contrary to laboratory findings, abortion rates did not increase in the oldest flies. Percentages of tsetse with empty uteri, regardless of abortion status, were significantly higher than estimated abortion percentages. For tsetse from traps, 4.01% (95% ci: 3.90-4.13) of G. pallidipes and 2.52% (2.14-2.95) of G. m. morsitans had empty uteri; for flies from artificial refuges, the percentages were 12.69% (12.07-13.34) and 14.90% (13.82-16.02), respectively. Abortion losses are small relative to losses at all other stages of life.


The Neutrophil-to-Lymphocyte Ratio is a Prognostic Biomarker in An Ethnically Diverse Patient Population with Advanced Pancreatic Cancer.
The neutrophil-to-lymphocyte ratio (NLR) is associated with decreased overall survival in patients with pancreatic adenocarcinoma (PAC) in studies including few minority patients. We investigated the association between NLR and survival in patients with advanced PAC in an ethnically diverse population. We retrospectively evaluated 226 patients with advanced PAC treated at Montefiore Medical Center between 2006 and 2015. Adjusted Cox proportion hazard regression models were utilized to derive effect estimates for survival duration. Patients with a NLR ≤ 5 (126 patients, median age 66 years) were more likely to be non-Hispanic Black (30.8% vs. 20%), while patients with a NLR > 5 (70 patients, median age 66 years) were more likely to be non-Hispanic White (21.4% vs. 12.2%) or Hispanic (44.3% vs. 34%). A NLR > 5 compared with a NLR ≤ 5 was significantly associated with a worse overall survival when adjusted for a priori and exploratory variables from the univariate analysis (median survival 7.4 vs. 12 months, HR 1.650, 95% CI 1.139, 2.390). In an ethnically diverse population, elevated NLR is an independent marker of poor prognosis and a potentially valuable factor in driving therapeutic decisions and defining prognosis for patients in the locally advanced or metastatic for PAC setting, meriting investigation in prospective clinical trials.


Potentiation of pulmonary arteriolar vasoconstriction to endothelin-1 by inhibition of nitric oxide synthesis in the intact lung.
To observe pulmonary arteriolar effects of endothelin-1 (ET-1) in the intact lung and determine if constriction to ET-1 is potentiated by inhibition of nitric oxide (NO) synthesis. In anesthetized male Sprague-Dawley rats with open chest, the lungs were ventilated with air through the lower trachea and in vivo responses of pulmonary arterioles were examined by video microscopy. Observations were made when the lungs were statically inflated with oxygen to a pressure of approximately 10 cm H2O for brief periods. A lens with a dipping cone was held at the pleural surface. ET-1 (10(-7)-10(-5)M; approximately 0.1 ml) was applied topically to the fluid layer under the dipping cone. ET-1 (10(-6)M) constricted parent arterioles 60 +/- 5 microns in diameter by 52 +/- 12% (range: 20-100%) and branches 45 +/- 3 microns in diameter by 36 +/- 4% (19-48%). Constriction persisted and there was a dramatic long-lasting decrease in flow. Alveolar walls quickly became pale, indicating reduced capillary perfusion. A lower concentration of ET-1 (10(-7)M) constricted (p > 0.05) parent arterioles 61 +/- 4 microns in diameter by 7 +/- 3% initially, and by 13 +/- 8% after 14 +/- 2 minutes, while smaller branches did not respond. In separate experiments, infusion of the NO synthase inhibitor L-NAME (1 mg/kg per minute), modestly (10 +/- 3%) decreased (p < 0.05) baseline parent arteriolar diameter from 72 +/- 7 microns to 64 +/- 5 microns. Branch diameter changed insignificantly from 42 +/- 7 microns to 38 +/- 7 microns. After L-NAME, ET-1 (10(-7)M) constricted (p < 0.05) parent arterioles by 17 +/- 4% initially and 40 +/- 14% after 14 +/- 2 minutes. Concurrently, branches constricted (p < 0.05) by 14 +/- 4% and 26 +/- 15%. Arterioles less than 80 microns in diameter were very responsive to ET-1, which could be a factor in altering pulmonary microvascular resistance. Inhibition of NO synthesis appears to potentiate constriction to ET-1.


A Functionalized Polydopamine Theranostic Nanoprobe for Efficient Imaging of miRNA-21 and In Vivo Synergetic Cancer Therapy.
MicroRNAs (miRNAs) are emerging as vital biomarkers since their abnormal expression is associated with various disease types including cancer. Therefore, it is essential to develop a sensitive and specific platform to monitor the dynamic expression of miRNAs for early clinical diagnosis and treatment. In this study, we designed a functionalized polydopamine (PDA)-based theranostic nanoprobe for efficient detection of miRNA-21 and in vivo synergistic cancer therapy. PDA was modified with polyethylene glycol (PEG) and the obtained PDA-PEG nanoparticles showed good stability in different solutions. PDA-PEG nanoparticles were loaded with fluorescein isothiocyanate (FITC)-labeled hairpin DNA (hpDNA) and an anticancer drug doxorubicin (DOX). In the absence of miRNA-21, PDA effectively quenched the fluorescence of FITC-labeled hpDNA. The presence of miRNA-21 specifically recognized hpDNA and induced the dissociation of hpDNA from PDA-PEG and subsequently recovered the fluorescence signals. Upon cellular uptake of these nanoprobes, a dose-dependent fluorescence activation and synergetic cytotoxic effect were observed due to the release of DOX and inhibition of miRNA-21 function. Furthermore, PDA-PEG-DOX-hpDNA nanoparticles can afford long-term monitoring of miRNA-21 and combined therapeutic efficacy in the nude mice bearing 4T1 tumors. Our results demonstrate the capability of PDA-PEG-DOX-hpDNA as a theranostic nanoprobe for continuously tracking of miRNAs and synergetic cancer therapy.


Recurrent dislocation of the patella. Histochemical and electromyographic evidence of primary muscle pathology.
The role of muscle function in the aetiology of recurrent dislocation of the patella has been examined. Eleven of the 12 patients we studied had joint hypermobility. Muscle biopsies from eight of nine patients treated by surgery had a predominance of abnormal Type 2C fibres, and three of six patients whose quadriceps muscles were studied by electromyography also had abnormal results. Our preliminary findings suggest that there may be a primary muscular defect in many cases of recurrent dislocation of the patella.


Role of glycosylation in the anticancer activity of antibacterial peptides against breast cancer cells.
Antibacterial peptides (ABPs) with cancer-selective toxicity have received much more attention as alternative chemotherapeutic agents in recent years. However, the basis of their anticancer activity remains unclear. The modification of cell surface glycosylation is a characteristic of cancer cells. The present study investigated the effect of glycosylation, in particular sialic acid, on the anticancer activity of ABPs. We showed that aurein 1.2, buforin IIb and BMAP-28m exhibited selective cytotoxicity toward MX-1 and MCF-7 breast cancer cells. The binding activity, cytotoxicity and apoptotic activity of ABPs were enhanced by the presence of O-, N-glycoproteins, gangliosides and sialic acid on the surface of breast cancer cells. Among N-, O-glycoproteins and ganglioside, O-glycoproteins almost had the strongest effect on the binding and cytotoxicity of the three peptides. Further, up-regulation of hST6Gal1 in CHO-K1 cells enhanced the susceptibility of cells to these peptides. Finally, the growth of MX-1 xenograft tumors in mice was significantly suppressed by buforin IIb treatment, which was associated with induction of apoptosis and inhibition of vascularization. These data demonstrate that the three peptides bind to breast cancer cells via an interaction with surface O-, N-glycoproteins and gangliosides. Sialic acids act as key glycan binding sites for cationic ABP binding to glycoproteins and gangliosides. Therefore, glycosylation in breast cancer cells plays an important role in the anticancer activity of ABPs, which may partly explain their cancer-selective toxicity. Anticancer ABPs with cancer-selective cytotoxicity will be promising candidates for anticancer therapy in the future.


Renal cell carcinoma. Cytogenetic analysis of tumors and cell lines.
Successful cytogenetic analysis was performed on 27 samples from 25 patients with RCC, including 7 of 11 tumors studied and 20 cell lines. Clonal chromosomal abnormalities were detected in all 27 samples. The most frequently involved chromosomes were 7, 1, 3, 9, and the Y (20, 17, 17, 14, and 10 cases, respectively). Polysomy 7 or rearrangement of 7q was seen in 80% (20/25) of the patients, and loss or rearrangement of 3p was seen in 48% (12/25); of the latter, four patients had loss of the whole chromosome and 10 patients had deletions or translocations involving 3p, with breakpoints at either 3p11-14 or 3p21-23 (5/7 translocation breakpoints were at 3p21-23). Loss of the sex chromosomes was seen in 15 patients, including -Y in 10/22 males. Other clonal changes included structural abnormalities of chromosome 1 centromere and the long arm, breakpoints at or near the centromere of chromosome 9 (10 patients), polysomy 16, monosomy 17, polysomy 20, and monosomy 22. With the exception of chromosome 3p loss, which was primarily confined to the nonpapillary cases, no specific clonal abnormality was noted for any particular subtype of RCC. Trisomy or tetrasomy 7 and -Y were seen in all subtypes of renal cell carcinoma.


Rhodococcus sp. strain TM1 plays a synergistic role in the degradation of piperidine by Mycobacterium sp. strain THO100.
Mycobacterium sp. strain THO100 and Rhodococcus sp. strain TM1 were isolated from a morpholine-containing enrichment culture of activated sewage sludge. Strain THO100, but not strain TM1, was able to degrade alicyclic amines such as morpholine, piperidine, and pyrrolidine. The mixed strains THO100 and TM1 showed a better growth on piperidine as the substrate than the pure strain THO100 because strain TM1 was able to reduce the level of glutaraldehyde (GA) produced during piperidine degradation. GA was toxic to strain THO100 (IC(50) = 28.3 microM) but less toxic to strain TM1 (IC(50) = 215 microM). Strain THO100 possessed constitutive semialdehyde dehydrogenases, namely Sad1 and Sad2, whose activities toward succinic semialdehyde (SSA) were strongly inhibited by GA. The two isozymes were identified as catalase-peroxidase (KatG = Sad1) and semialdehyde dehydrogenase (Sad2) based on mass spectrometric analyses of tryptic peptides and database searches of the partial DNA sequences of their genes. In contrast, strain TM1 containing another constitutive enzyme Gad1 could oxidize both SSA and GA. This study suggested that strain TM1 possessing Gad1 played a synergistic role in reducing the toxic and inhibitory effects of GA produced in the degradation of piperidine by strain THO100.


Influence of preoperative voice assessment on treatment plan prior to airway surgery.
Voice quality has emerged as an additional long-term outcome measure for patients with a history of airway surgery. The goal of this study was to evaluate the impact of preoperative voice assessment on the surgical management of patients who required complex airway surgery. Retrospective case series. We analyzed clinical data for all patients who underwent an airway reconstruction procedure from September 1, 2012 to September 1, 2017 and had a voice clinic evaluation prior to surgery at a tertiary-care pediatric hospital. Each participant underwent a full clinical voice evaluation that yielded acoustic, imaging, perceptual, and handicapping index data. Six hundred forty-three patients underwent 831 airway surgeries (laryngotracheoplasty, cricotracheal resection, slide tracheoplasty, laryngeal cleft repair). Ninety-one (14.2%) of the 643 patients underwent a formal voice clinic evaluation prior to airway surgery; 39/91 (42.9%) were female. The mean age was 10.4 years (95% confidence interval [CI]: 9.2-11.6) with 31/91 (32.9%) participants demonstrating vocal fold immobility and 33/91 (36.3%) vocal fold hypomobility. A voice clinic evaluation provided new information for 62/91 (68.1%) patients, mainly for laryngeal dynamic components (vocal fold motion, source of phonation, arytenoid prolapse) and confirmed suspected disorders for the remaining patients. The average baseline Pediatric Voice Handicap Index overall score was 38.9 (95% CI: 33.3-44.5), and the average overall severity rating of the Consensus Auditory-Perceptual Evaluation of Voice was 54 (95% CI: 45.2-62.8). A voice clinic evaluation influenced management of 56/91 (61.5%) patients either by modification of the surgical plan (26/56, 46%) and/or adjusting voice therapy (21/56, 37.5%). Voice evaluation prior to airway reconstruction provided key information that influenced the management for most of the patients. Formal voice evaluation should be considered prior to complex airway surgery. 4 Laryngoscope, 128:2858-2863, 2018.


Medication use during the perinatal period.
To briefly describe the drug therapy administered during the perinatal period of pregnancy for common maternal and fetal complications, and to identify those agents that should not be used for these conditions. References were obtained from an ongoing literature search of peer-reviewed obstetric and gynecologic journals and other selected medical and pharmacy journals available in the English language. Primary search vehicle was a weekly review of the tables of contents of nearly 1,300 medical journals provided by Reference Update (Institute of Scientific Information, Philadelphia). MEDLINE searches were also conducted using key terms for each subtopic. Specific references were selected for each topic based on the adequacy of their study design, patient population, and a recent publication date. Reviews were used if a large number of primary references would have been required to adequately describe the topic. Most references reflected the current opinions expressed in the Educational (Technical) Bulletin and Committee Opinion series published by the American College of Obstetricians and Gynecologists. Recent, well-conducted studies that arrived at different conclusions were also included. Data obtained from each reference reflected the conclusions of the authors based on their research or an analysis of the research on others on the appropriate use of the drug(s) for the specific condition being treated. Drug therapy during the perinatal period is frequently required and can be beneficial for the mother, fetus, and newborn. Many complications previously associated with severe morbidity and mortality, such as infections, premature rupture of membranes, preterm labor, hypertension, maternal pain during labor, and postpartum hemorrhage, are now controlled with appropriate pharmacologic therapy. All health professionals who provide services to pregnant women should be knowledgeable in this drug therapy.


Rare FGFR fusion genes in cervical cancer and transcriptome-based subgrouping of patients with a poor prognosis.
Although cervical cancer is often characterized as preventable, its incidence continues to increase in low- and middle-income countries, underscoring the need to develop novel therapeutics for this disease.This study assessed the distribution of fusion genes across cancer types and used an RNA-based classification to divide cervical cancer patients with a poor prognosis into subgroups. RNA sequencing of 116 patients with cervical cancer was conducted. Fusion genes were extracted using StarFusion program. To identify a high-risk group for recurrence, 65 patients who received postoperative adjuvant therapy were subjected to non-negative matrix factorization to identify differentially expressed genes between recurrent and nonrecurrent groups. We identified three cases with FGFR3-TACC3 and one with GOPC-ROS1 fusion genes as potential targets. A search of publicly available data from cBioPortal (21,789 cases) and the Center for Cancer Genomics and Advanced Therapeutics (32,608 cases) showed that the FGFR3 fusion is present in 1.5% and 0.6% of patients with cervical cancer, respectively. The frequency of the FGFR3 fusion gene was higher in cervical cancer than in other cancers, regardless of ethnicity. Non-negative matrix factorization identified that the patients were classified into four Basis groups. Pathway enrichment analysis identified more extracellular matrix kinetics dysregulation in Basis 3 and more immune system dysregulation in Basis 4 than in the good prognosis group. CIBERSORT analysis showed that the fraction of M1 macrophages was lower in the poor prognosis group than in the good prognosis group. The distribution of FGFR fusion genes in patients with cervical cancer was determined by RNA-based analysis and used to classify patients into clinically relevant subgroups.


Characteristics of penile growth in pubertal rats and a non-invasive method to lengthen the penis.
Males with short penises may suffer from sexual dysfunction and psychological problems. However, currently, managing short penis is a huge challenge. To explore whether inhibition of lysyl oxidase (LOX) activity (anti-LOX) combined with a vacuum device could lengthen the penis of pubertal rat. Male rats of different ages were purchased, their exposed penile lengths and weights were measured, and protein expression and lysyl oxidase activity in the corpus cavernosum were analyzed. Fifteen-day-old rats were then purchased and divided into six groups: control, Anti-lysyl oxidase, -200 mm Hg (vacuum device under -200 mm Hg value), -200 mm Hg + Anti-lysyl oxidase, -300 mm Hg, and -300 mm Hg + Anti-lysyl oxidase groups. After the intervention duration of 7 weeks, rats' penile length was measured and erectile function was assessed. The corpus cavernosum was harvested for histopathology and molecular assessments. Exposed penile length and weight significantly increased with age, especially between 4 and 8 weeks. Both the protein expression and lysyl oxidase activity in corpus cavernosum were the highest at 2 weeks; however, they quickly decreased with age and slowly declined after 8 weeks. Anti-lysyl oxidase significantly increased the penile length by 10.79% over controlled rats, -200 mm Hg + Anti-lysyl oxidase lengthened it by 14.05%, and -300 mm Hg + Anti-lysyl oxidase increased it by 19.84%. Anti-lysyl oxidase significantly reduced lysyl oxidase activity to decrease pyridinoline concentration; however, it did not change desmosine (P = .28), hydroxyproline (P = .14), and total elastin (P = .06) levels. Anti-lysyl oxidase with or without a vacuum device did not diminish erectile function or impair the normal microstructure of corpus cavernosum. The rats' penile growth peaks occurred between 4 and 8 weeks. Anti-lysyl oxidase with a vacuum device promoted penile lengthening by inhibiting pyridinoline production to induce tunica albuginea remodeling. The penile lengthening effect was more obvious in pubertal rats than the adult rats. None of the procedures decreased erectile function.


Spontaneous remission of hepatic myelopathy in a patient with alcoholic cirrhosis: A case report.
Hepatic myelopathy (HM) is a rare neurological complication of advanced cirrhosis. Prognosis of patients with HM is generally poor without timely liver transplantation or interventional therapy. Self-resolving HM in patients with alcoholic cirrhosis has never been reported. A 53-year-old man with alcoholic cirrhosis and recurrent overt hepatic encephalopathy for 1 year was admitted for lower extremity weakness, slow movement, and stumbling gait. The patient was diagnosed with HM after excluding other causes of spastic paraparesis. The patient refused liver transplantation. However, the patient kept total abstinence and received a multidisciplinary treatment for complications of decompensated cirrhosis. The symptoms of HM resolved gradually after 2 years of treatment. All complications of alcoholic cirrhosis resolved after 4 years of follow-up. The case demonstrates that HM can resolve in patients without liver transplan-tation after total abstinence and systemic management of complications.


Targeted modification of gut microbiota and related metabolites via dietary fiber.
Intake of dietary fiber has been proven to have several beneficial effects in maintaining host homeostasis and health. Here, we investigated the effects of different fibers on gut microbiota and related metabolites in rats. Healthy rats were supplemented with guar gum, carrageenan, glucomannan, β-glucan, arabinoxylan, apple pectin, xylan, arabinogalactan, and xanthan gum, and these dietary fibers exhibited commonality and specificity on gut microbiota and related metabolites. The abundance of Phascolarctobacterium, Prevotella, Treponema, Butyricimonas, Bacteroides, and Lactobacillus was selectively increased by different dietary fibers, whereas the abundance of Clostridium perfringens and Bacteroides fragilis were decreased by all of these fibers. Indole-3-lactic acid was significantly increased by β-glucan treatment, indicating the relationship between indole-3-lactic acid and Lactobacillus. Furthermore, Some species from Bacteroides were validated to produce indole-3-lactic acid, indole-3-acetic acid, and kynurenine (such as B. fragilis, B. ovatus, B. thetaiotaomicron, and B. xylanisolvens). These results provide important information on dietary guidelines based on the modification of gut microecology.


Downregulation of DNMT3A by miR-708-5p Inhibits Lung Cancer Stem Cell-like Phenotypes through Repressing Wnt/β-catenin Signaling.
Purpose: Lung cancer is the leading cause of cancer-related death in the world, and emerging evidences suggest that lung cancer stem cells (CSC) are associated with its poor prognosis, tumor recurrence, and therapy resistance. Here we reveal a novel role for miR-708-5p in inhibiting lung CSC-like features.Experimental Design: Phenotypic effects of miR-708-5p on the lung CSC-like properties were examined by in vitro sphere formation assay and in xenografted animal models. Immunoblotting, dual luciferase reporter, and immunocytochemistry were performed to determine the target of miR-708-5p. DNA methylation of CDH1 promoter region was tested using bisulfate sequencing. Genome-wide miRNA sequencing data of 990 patients from The Cancer Genome Atlas (TCGA) dataset and 148 patients from China cohort were analyzed to excavate the pathogenic implications of miR-708-5p.Results: Expression of miR-708-5p inhibits the CSC traits of NSCLC cells in vitro while antagonizing miR-708-5p promotes tumorigenesis in vivo miR-708-5p directly suppresses the translation of DNMT3A, which results in a substantial reduction of global DNA methylation and the upregulated expression of tumor suppressor CDH1. The upregulation of CDH1 decreased the activity of Wnt/β-catenin signaling and then impaired the stemness characteristics of NSCLC cells. Clinically, patients with high miR-708-5p expression show significantly better survival and lower recurrence. Furthermore, miR-708-5p has a promising potential to apply to differentiating histologic subtypes in NSCLC.Conclusions: Our findings support that miR-708-5p suppresses NSCLC initiation, development, and stemness through interfering DNMT3A-dependent DNA methylation. miR-708-5p may function as a novel diagnostic and prognostic biomarker in NSCLC. Clin Cancer Res; 24(7); 1748-60. ©2017 AACR.


Application of the Postnatal Growth and Retinopathy of Prematurity (G-ROP) criteria at a tertiary referral hospital.
Application of current retinopathy of prematurity (ROP) screening criteria results in many unnecessary examinations, because only 5%-10% of infants screened require treatment. Application of screening criteria established by the Postnatal Growth and Retinopathy of Prematurity Study could significantly reduce unnecessary examinations without sacrificing sensitivity to detect treatment-requiring ROP. We evaluated the performance of the G-ROP criteria in a population of high-risk, outborn infants. The medical records of consecutive infants screened and/or treated for ROP at Children's Health Care of Atlanta Hospitals from May 1, 2013, to September 6, 2019, were reviewed retrospectively. The sensitivity of the G-ROP birthweight and gestational age screening criteria to detect treatment-requiring ROP was calculated. During the study period, 901 children underwent examinations for ROP; of these, 5 were excluded from the analysis because birth weight (BW) data was lacking. Of the 896 remaining patients, 120 patients were treated for ROP. Application of G-ROP birth weight and gestational age (GA) criteria alone resulted in a sensitivity of 99.2% to detect infants requiring treatment. Application of weight gain criteria was problematic, because many patients were transferred into our institutions after the specified intervals of 10-19, 20-29, and 30-39 days. G-ROP BW and GA screening criteria were highly sensitive in detecting treatment-requiring ROP. Applying weight gain criteria in referral centers can be problematic. Intake procedures at referral centers should include documentation of weight gain during 10-19, 20-29, and 30-39 days of life.


A validated method for the determination of paracetamol and its glucuronide and sulphate metabolites in the urine of HIV+/AIDS patients using wavelength-switching UV detection.
Paracetamol is a safe drug which has been used as an in-vivo probe to determine phase II metabolism in a HIV+/AIDS population. Due to the biohazard nature of HIV-infected samples, a high performance liquid chromatography (HPLC) assay which offers minimal sample manipulation and maximal specificity was developed. This reverse-phase HPLC method uses wavelength-switching UV detection for the simultaneous determination of paracetamol and its glucuronide and sulfate metabolites in HIV-infected urine samples. The solvent systems involves a simple isocratic elution with a composition of 50 mM sodium acetate buffer, pH adjusted to 3.5; acetonitrile (96:4 v/v) modified with 0.35% trifluroacetic acid. The validated method is highly reproducible with an inter-assay variation of < 7%. This method also shows good precision and sensitivity, making it an ideal assay for phenotyping studies to determine the extent of glucurondiation and sulfation activities.


Bis{4-methylbenzyl 2-[4-(propan-2-yl)benzyl-idene]hydrazine-carbodi-thio-ato-κ2N2,S}nickel(II): crystal structure and Hirshfeld surface analysis.
The complete mol-ecule of the title hydrazine carbodi-thio-ate complex, [Ni(C19H21N2S2)2], is generated by the application of a centre of inversion. The NiII atom is N,S-chelated by two hydrazinecarbodi-thio-ate ligands, which provide a trans-N2S2 donor set that defines a distorted square-planar geometry. The conformation of the five-membered chelate ring is an envelope with the NiII atom being the flap atom. In the crystal, p-tolyl-C-H⋯π(benzene- i Pr), i Pr-C-H⋯π(p-tol-yl) and π-π inter-actions [between p-tolyl rings with inter-centroid distance = 3.8051 (12) Å] help to consolidate the three-dimensional architecture. The analysis of the Hirshfeld surface confirms the importance of H-atom contacts in establishing the packing.


The association and reliability of the frontal plane projection angle during the lateral step down test on knee function in patients with patellofemoral pain.
The lateral step-down test is used by physical therapists (PT) to identify movement faults in patients with patellofemoral pain (PFP). The FPPA is a measure of knee valgus and PTs have access to open source video analysis software and high quality smart phones and video cameras to implement 2D video analysis into practice. The purpose of our study was to determine the reliability of PTs measuring the frontal plane projection angle (FPPA) during the lateral step-down test, and to determine if the FPPA was associated with pain, self-reported knee function and fear of movement. Twenty-two subjects (mean age[SD] = 27.8 [6.6] years, females n = 14, males n = 8) with PFP were analyzed by six PTs using 2D video analysis software. The FPPA was measured during the lateral step down test. Numeric Pain Rating Scale (NPRS), Anterior Knee Pain Scale (AKPS) and the Tampa Scale of Kinesiophobia (TSK) were collected. Intraclass correlation (ICC) was used to assess for PT measurement reliability. Correlations between outcomes were calculated using Spearman correlation coefficient and standard error of measurement (SEM) and minimal detectable change (MDC) were reported. Reliability amongst PTs measuring the FPPA was good (ICC [95 %CI] = 0.85 [0.72-0.93]; SEM = 3.33°, MDC = 9.20°). There were no significant correlations (p > 0.05) between FPPA and NPRS(ρ = -0.046), AKPS(ρ = 0.066), or TSK(ρ = -0.204). Although reliability measuring FPPA was good, the large SEM and MDC associated with this measurement may limit its clinical utility in those with PFP.


The effect of different treatment modalities on the calcification potential and cross-linking stability of bovine pericardium.
Porcine heart valves and bovine pericardium exhibit suitable properties for use as substitutes in cardiothoracic surgery, but must meet several requirements to be safe and efficient. Treatment with glutaraldehyde (GA) render some of these requirements, but calcification and degradation post-implant remain a problem. This study aimed to identify additional biochemical treatments that will minimize calcification potential without compromising the physical properties of pericardium. Pericardium treated with GA calcified severely after 8 weeks in the subcutaneous rat model, compared to tissue treated with higher concentrations of glycosaminoglycans (GAG) and commercial Glycar patches. GA, lower concentrations GAG and Glycar pericardium had high denaturation temperatures due to enhanced cross-linking. Tensile strength of GA tissue was significantly lower than GAG-treated or Glycar tissues, due to lower water content with resultant lower flexibility and suppleness. Pericardium treated with 0.01 M GAG gave acceptable denaturation temperatures, tensile strength and reduced calcification potential. All tissue treatments evoked comparable host immune responses, and no significant difference in resistance to enzymatic degradation. Ineffective stabilization and fixation of cross-links following GAG treatment, as well as limited penetration into the pericardium, resulted in GAG leaching out into the surrounding host tissue or storage medium, and prohibits safe clinical use of such tissue.


Changes in pulmonary mean transit time demonstrated by the scintigraphic first pass technique in patients receiving radiation therapy.
Pulmonary mean transit time was assessed in 32 patients. A significant difference in this parameter is demonstrated between normals and those patients who have received radiotherapy.


Lipoprotein (a) and vascular disease in diabetic patients.
In order to assess the potential role of lipoprotein (a) as a risk factor for cardiovascular disease in diabetes mellitus, plasma concentrations were measured in a large group (n = 500) of non-insulin-dependent (NIDDM, n = 355) and insulin-dependent (IDDM, n = 145) patients. Concentrations of lipoprotein (a) were compared in diabetic patients with (n = 153) or without (347) documented vascular disease (ischaemic heart disease, peripheral vascular disease or macroangiopathy). They were significantly higher (p < 0.05) in patients with ischaemic heart disease (mean [interquartile range] 15.5 (5.0-38.0) vs 9.0 (4.5-26.0) mg/dl) or macroangiopathy (13.0 (5.0-38.0) vs 9.0 (4.0-25.0) mg/dl) compared to patients without manifestations of vascular disease. In addition, stepwise logistic regression analysis identified lipoprotein (a) levels > or = 30 mg/dl as being independently associated with the presence of cardiovascular disease. Lipoprotein (a) was an independent risk factor for ischaemic heart disease and macroangiopathy in this group of IDDM and NIDDM patients.


Lactational retrorsine exposure changes maternal milk components and disturbs metabolism homeostasis of offspring rats.
Pyrrolizidine alkaloids (PAs) are a type of plant-derived environmental toxins, which pose a health hazard to human and livestock via contaminating soil, water, plants and food. In this study, we aimed to investigate the effect of lactational retrorsine (RTS, a typical toxic PA) exposure on breastmilk components and glucose-lipid metabolism of offspring rats. Dams were intragastrically administered with 5 mg/(kg·d) RTS during lactation. After metabolomic analyses, 114 differential constituents were identified in breastmilk between control and RTS groups, featured by reduction of lipids and lipid-like molecules, while presence of abundant RTS and its derivative in RTS-exposed milk. RTS exposure induced liver injury in pups, but the leakage of transaminases in serum recovered in their adulthood. Serum glucose levels were lower in pups but higher in male adult offspring from RTS group. RTS exposure also induced hypertriglyceridemia, hepatic steatosis and decreased glycogen content in both pups and adult offspring. Additionally, suppression of PPARα-FGF21 axis persisted in offspring liver after RTS exposure. These data indicated that inhibition of PPARα-FGF21 axis induced by milk deficient in lipid contents, together with hepatotoxic injury caused by RTS in breastmilk, may disrupt glucose and lipid metabolism of pups, and the persistent suppression of PPARα-FGF21 axis may program metabolic disorder of glucose and lipid in adult offspring.


Screening male primary care patients for intimate partner violence perpetration.
Primary prevention of intimate partner violence (IPV) at the level of the primary care provider is unexplored. We sought to identify whether men disclose current IPV perpetration when asked by a primary care provider. Cross-sectional study. Consecutive male patients of 6 providers in public health, university, and VA hospital clinics. Men were screened for IPV perpetration during routine visits, then given a Conflict Tactics Scale questionnaire (CTS2) to complete and mail back anonymously. One hundred twenty-eight men were screened; 46 (36%) returned CTS2 questionnaires. Twenty-three and 2 men disclosed past and current perpetration to providers, respectively. Providers assessed lethality/safety issues in 58% of those reporting a perpetration history (including both with current perpetration), responded with direct counseling to 63% (including both with current perpetration), and referred 17% for services related to the screening (including 1 with current perpetration). Nine and 26 men reported current, CTS2-assessed physical and psychological aggression of a partner, respectively. Men appear to underreport current IPV perpetration in face-to-face primary care encounters when compared to other methods of reporting. Men may more readily report past IPV perpetration in face-to-face encounters.


Fetal hypertension: an insight into the pathogenesis of the twin-twin transfusion syndrome.
To investigate if systemic hypertension occurs in fetuses with twin-to-twin transfusion syndrome (TTTS). We conducted an observational cohort study in a tertiary care centre in 23 pregnant women with TTTS. Polyhydramnios stuck twin sequence occurred at a median gestational age of 22 weeks (range 15-27). Biventricular myocardial hypertrophy was diagnosed in 22/23 recipient fetuses. In cases with atrioventricular valve regurgitation (AVR), it was possible to estimate the fetal systolic systemic blood pressure by ultrasound, on the basis of the simplified Bernouilli equation. The diagnosis of fetal hypertension (FHT) was made when the estimated systolic arterial pressure was equal to or above 1.6-fold the expected value. In 10 pregnancies (group A), fetal blood pressure could be assessed in recipients with AVR. The maximum velocities ranged from 2.9 to 5 m/s, leading to estimates of systemic fetal arterial pressure from 37 to 104 mmHg, that is, 1.6- to 2.8-fold the expected values. In 13 pregnancies (group B), fetal blood pressure could not be assessed in the absence of AVR. In group A, perinatal death (16/20) and hydrops (7/20) were significantly more frequent than in group B (8/26 and 1/26 respectively). Fetal systemic hypertension may occur in recipient twins and could play a role in the pathophysiology of TTTS.


[Massive transfusion with the Rapid Infusion System. Its effect on core body temperature].
Extensive blood loss requires adequate volume replacement. However the infused volume cannot be adequately warmed especially when high infusion rates are necessary. Subsequently, hypothermia develops and results in hemodynamic instability and coagulopathy. The Rapid Infusion System (RIS) allows high infusion rates (up to 1.5 l/min) while at the same time guaranteeing sufficient warming. The efficacy of the RIS was investigated in 43 consecutive patients who required a massive transfusion. The average volume transfused in these patients was 31.7 +/- 4.5 l (minimum: 7.8 l; maximum: 165.3 l) which is equal to an average exchange of 6.4 times the circulating blood volume (maximum: 39.4 blood volumes). The replacement of such high blood volumes has not yet been published in a series of patients. Despite these high transfusion rates, the body core temperature was maintained at 35.85 +/- 0.1 degrees C. Only five patients had a body core temperature below 34 degrees C, all were trauma patients and four of these five patients already had a preoperative temperature below 34 degrees C. The mortality in this study was 28%, which is markedly reduced in comparison to previous publications although they all considered at patients with significantly less blood loss. Maintaining normothermia and normovolemia by the use of the RIS may explain the improved outcome.


Urotrauma - The Success of an AUA Legislative Initiative: A Legislative Primer.
Urogenital injury has been increasing among American soldiers engaged in foreign operations because of improvised explosive devices. The American Urological Association led a legislative coalition that in 2013 was successful in having Congress enact law improving the care of soldiers who have suffered urotrauma. Reviewing the legislative effort from the beginning to the present provides many valuable insights into the components of federal legislative success that can be applied to future efforts. Since 2008 the American Urological Association has advocated for the passage of federal legislation promoting care for U.S. military veterans with urotraumatic injuries. Direct observations of the stakeholders in the development and passage of legislation are used to describe the interaction of policy and politics in the passage of the National Defense Authorization Act in 2013. The passage of the National Defense Authorization Act in 2013 included a provision that promoted care for U.S. military veterans with urotraumatic injuries. Key components for the passage of legislation include 1) identification of a clear urological patient care policy need, 2) engaging a coalition of stakeholders, 3) an organizational posture of persistence and adaptability, and 4) the fostering of new and existing Congressional relationships among urologist advocates and organized urology's advocacy partners.


Adjunctive use of verapamil in patients with refractory temporal lobe epilepsy: a pilot study.
The present study aimed to determine if adjunctive use of verapamil, as a P-glycoprotein (P-gp) inhibitor, is efficacious in decreasing seizure frequency in patients with refractory temporal lobe epilepsy. This was an open-label pilot study. Adult patients with refractory temporal lobe epilepsy were studied. Baseline seizure type and seizure count were determined. Patients were divided randomly into two groups. Group A received verapamil 120 mg/day (n=13), and group B received 240 mg/day (n=6). All patients were followed for eight weeks. The proportion of responders, which consist of patients with more than 50% reduction in seizure frequency from baseline, was tabulated. Nineteen patients were studied. Seven patients (36.84%) reached the responder rate. Three patients (50%) in group B were among the responders; two of these patients achieved seizure freedom. Four patients (30.7%) in group A responded favorably to verapamil. Developing new means of improving the effectiveness of existing antiepileptic drugs is a desirable way of tackling the dilemma of medically refractory epilepsy. Hypothetically, P-gp inhibitors (e.g., verapamil) might be used to counteract the removal of AEDs from the epileptogenic tissue. Such a strategy was adopted in this non-placebo-controlled, open-label, pilot study. We observed a significant achievement in seizure control associated with adjunctive use of verapamil in patients with refractory temporal lobe epilepsy.


Electrophysiological Study for Nerve Root Entrapment in Patients With Isthmic Spondylolisthesis.
A case series study. To investigate the electrophysiological location of nerve root entrapment in patients with isthmic spondylolisthesis. Although the lesion of the nerve root in patients with isthmic spondylolisthesis has been thought to be located at the pars interarticularis due to proliferation of fibrous cartilage, there is no electrophysiological study in relation to this accomplished fact. We performed an electrophysiological study in 12 patients with isthmic spondylolisthesis during surgery. All patients presented with low-grade isthmic spondylolisthesis and unilateral radiculopathy, and underwent single-level posterior lumbar interbody fusion with instrumentation. After a total facetectomy, nerve root action potentials were recorded by stimulating the ipsilateral peroneal nerve at the popliteal fossa. Four needle electrodes were inserted into the affected nerve root at the intraspinal canal, pars interarticularis, disk level, and extralateral to the disk. The waveforms that showed either a positive waveform pattern or polyphasic waveform pattern were regarded as abnormal potentials. We also confirmed surgical records and preoperative images to investigate the relationship to the electrophysiological findings. An abnormal waveform pattern was demonstrated at the pars interarticularis in 6 patients, at the disk level in 5, and at the extralateral site in 1. On the basis of the electrophysiological findings of this study, the nerve root lesion was not always found on only the pars interarticularis in patients with isthmic spondylolisthesis. A relationship between the electrophysiological findings and surgical records or preoperative images was not found. The electrophysiological investigation in this study shows that the nerve root entrapment in patients with isthmic spondylolisthesis occurs not only at the pars interarticularis but also distal to the isthmus. This study suggests the possibility of insufficiency of decompression only at the pars interarticularis for patients with isthmic spondylolisthesis.


Metal homeostasis in Hypogymnia physodes is controlled by lichen substances.
The hypothesis was tested that the lichen substances produced by the epiphytic lichen Hypogymnia physodes control the intracellular uptake of divalent transition metals. Incubating lichen thalli with and without their natural content of lichen substances with metal solutions showed that the lichen substances of H. physodes selectively inhibit the uptake of Cu(2+) and Mn(2+), but not of Fe(2+) and Zn(2+). Such behavior is ecologically beneficial, as ambient concentrations of Cu(2+) and Mn(2+) in precipitation and bark are known to limit the abundance of H. physodes, whereas limiting effects of Fe(2+) or Zn(2+) have never been found. This suggests that increasing the Cu(2+) and Mn(2+) tolerance stimulated the evolution of lichen substances in H. physodes. The depsidone physodalic acid is apparently most effective at reducing Cu(2+) and Mn(2+) uptake among the seven lichen substances produced by H. physodes. Probably lichen substances play a general role in the metal homeostasis of lichens.


Interictal respiratory variability predicts severity of hypoxemia after generalized convulsive seizures.
Severe respiratory dysfunction induced by generalized convulsive seizures (GCS) is now thought to be a common mechanism for sudden unexpected death in epilepsy (SUDEP). In a mouse model of seizure-induced death, increased interictal respiratory variability was reported in mice that later died of respiratory arrest after GCS. We studied respiratory variability in epilepsy patients as a predictive tool for severity of postictal hypoxemia, a potential biomarker for SUDEP risk. We then explored the relationship between respiratory variability and central CO2 drive, measured by the hypercapnic ventilatory response (HCVR). We reviewed clinical, video-electroencephalography, and respiratory (belts, airflow, pulse oximeter, and HCVR) data of epilepsy patients. Mean, SD, and coefficient of variation (CV) of interbreath interval (IBI) were calculated. Primary outcomes were: (1) nadir of capillary oxygen saturation (SpO2 ) and (2) duration of oxygen desaturation. Poincaré plots of IBI were created. Covariates were evaluated in univariate models, then, based on Akaike information criteria (AIC), multivariate regression models were created. Of 66 GCS recorded in 131 subjects, 30 had interpretable respiratory data. In the multivariate model with the lowest AIC value, duration of epilepsy was a significant predictor of duration of oxygen desaturation. Duration of tonic phase and CV of IBI during the third postictal minute correlated with SpO2 nadir, whereas CV of IBI during non-rapid eye movement sleep had a negative correlation. Poincaré plots showed that long-term variability was significantly greater in subjects with ≥200 s of postictal oxygen desaturation after GCS compared to those with <200 s desaturation. Finally, HCVR slope showed a negative correlation with measures of respiratory variability. These results indicate that interictal respiratory variability predicts severity of postictal oxygen desaturation, suggesting its utility as a potential biomarker. They also suggest that interictal respiratory control may be abnormal in some patients with epilepsy.


Pain Measurement in Mechanically Ventilated Patients with Traumatic Brain Injury: Behavioral Pain Tools Versus Analgesia Nociception Index.
Pain is highly prevalent in critically ill trauma patients, especially those with a traumatic brain injury (TBI). Behavioral pain tools such as the behavioral pain scale (BPS) and critical-care pain observation tool are recommended for sedated noncommunicative patients. Analysis of heart rate variability (HRV) is a noninvasive method to evaluate autonomic nervous system activity. The analgesia nociception index (ANI) device (Physiodoloris®, MDoloris Medical Systems, Loos, France) allows noninvasive HRV analysis. The ANI assesses the relative parasympathetic tone as a surrogate for antinociception/nociception balance in sedated patients. The primary aim of our study was to evaluate the effectiveness of ANI in detecting pain in TBI patients. The secondary aim was to evaluate the impact of norepinephrine use on ANI effectiveness and to determine the correlation between ANI and BPS. We performed a prospective observational study in 21 deeply sedated TBI patients. Exclusion criteria were nonsinus cardiac rhythm; presence of pacemaker; atropine or isoprenaline treatment; neuromuscular blocking agents; and major cognitive impairment. Heart rate, blood pressure, and ANI were continuously recorded using the Physiodoloris® device at rest (T1), during (T2), and after the end (T3) of the painful stimulus (tracheal suctioning). In total, 100 observations were scored. ANI was significantly lower at T2 (Median [min - max] 54.5 [22-100]) compared with T1 (90.5 [50-100], P < 0.0001) and T3 (82 [36-100], P < 0.0001). Similar results were found in the subgroups of patients with (65 measurements) or without (35) norepinephrine. During procedure, a negative linear relationship was observed between ANI and BPS (r2 = -0.469, P < 0.001). At the threshold of 50, the sensitivity and specificity of ANI to detect patients with BPS ≥ 5 were 73% and 62%, respectively, with a negative predictive value of 86%. Our results suggest that ANI is effective in detecting pain in ventilated sedated TBI patients, including those patients treated with norepinephrine.


Dietary curcumin post-treatment enhances the disappearance of B(a)P-derived DNA adducts in mouse liver and lungs.
To study the post-treatment effects of dietary curcumin on the levels of benzo(a)pyrene [B(a)P]-induced DNA adducts, mice were administered oil or B(a)P and randomized into 7 subgroups after 24 h. One of the subgroups from both the oil and B(a)P groups was killed at 24 h while the remaining 6 subgroups were shifted to powdered control or 0.05% curcumin diet and killed after 24, 72 and 120 h (experiment 1), and 7, 14, and 28 days (experiment 2). Quantitative comparisons of BPDE-DNA nuclear adducts (area and intensity) in immunohistochemically stained lungs and liver sections was carried out by IHC profiler. A time-dependent decrease in the levels of adducts in B(a)P-treated animals was further enhanced by curcumin exposure compared to the levels in time-matched controls. To assess the contribution of apoptosis and cell proliferation in observed curcumin-mediated enhanced decrease of BPDE-DNA adducts, comparative evaluation of apoptosis and cell proliferation markers was undertaken. Results suggested enhancement of B(a)P-induced apoptosis in liver and lungs by curcumin during 24-120 h while no such enhancement was observed at 7-28 days. Results suggest curcumin-mediated enhancement in apoptosis (experiment 1) and adduct dilution (experiment 2) to be the reason for the observed higher decrease of BPDE-DNA adducts.


Possible role of c-fos, c-N-ras and c-mos proto-oncogenes in muscular development.
Time course analyses of various proto-oncogene transcripts compared with cytoskeleton-specific and muscle-specific messenger RNAs (mRNAs) were carried out during growth and differentiation of a clonal line of rat myoblasts that retain the capacity to form non-contractile fibres in vitro. Throughout their growth phase, these cells express consistent levels of c-fos, c-myc, c-Ki-ras and c-N-ras RNA and no c-mos RNA. When the cultures approach confluency the level of c-fos RNA rises sharply 3-4-fold, peaks, and rapidly declines when muscle-specific transcripts start accumulating, to become negligible in myotube-forming cells. These changes occur whatever the concentration in seric factors. By contrast, the level of c-N-ras RNA rises up to 3-fold and both c-myc and c-Ki-ras RNAs are slowly eliminated during the myogenic process, whereas no c-mos RNA is detectable. However, skeletal muscles from prenatal fetuses and adult animals were reproducibly found to contain both low and high levels of c-mos RNA respectively. These data and the demonstration that inactivation of the c-fos gene correlates with the loss of myogenic capability in six lines of neoplastic myoblasts, including four lines transformed by the v-fos oncogene, suggest a physiological function for this proto-oncogene during early stages of myogenesis and for the c-N-ras and c-mos genes in later stages of muscular development.


Anakinra: efficacy in the management of fever during neutropenia and mucositis in autologous stem cell transplantation (AFFECT-2)-study protocol for a multicenter randomized double-blind placebo-controlled trial.
Since decades, fever and infections have been the most important complications of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) in the treatment of hematologic malignancies. Neutropenia has long been considered to be the most important risk factor for these complications. However, recent studies have shown that not neutropenia, but the development of mucositis is the most important cause of these complications. Currently, limited options for the prevention and treatment of mucositis are available, of which most are only supportive. The pro-inflammatory cytokine interleukin-1 (IL-1) plays a crucial role in the pathogenesis of mucositis. Pre-clinical studies of chemotherapy-induced mucositis have shown that recombinant human IL-1 receptor antagonist anakinra significantly ameliorated intestinal mucositis. In our pilot study AFFECT-1, we examined the safety and maximal tolerated dose of anakinra in patients with multiple myeloma, treated with high-dose melphalan (HDM) and autologous HSCT, selecting a dose of 300 mg daily for the phase IIb trial. The aim of the AFFECT-2 study is to determine the efficacy of anakinra in preventing fever during neutropenia (FN) and mucositis in this study population. A multicenter, randomized, placebo-controlled, double-blind phase IIb trial will be conducted. Ninety patients with multiple myeloma scheduled for treatment with HDM and autologous HSCT will be included. Patients will be randomized between intravenous treatment with anakinra (300 mg) or placebo. Each group will be treated from day - 2 (day of HDM; day 0 is HSCT) up until day + 12. Outcome measures will be assessed at baseline, during admission, at discharge or day + 30, at day + 90, and + 1 year. The primary outcome will be reduction of FN. Secondary outcome measures include mucositis scores, bloodstream infections, citrulline levels, quality of life, and fatigue severity. The AFFECT-2 trial will examine the efficacy of anakinra in the management of fever during neutropenia and mucositis in patients with multiple myeloma treated with HDM and autologous HSCT. The results of this study may provide a new treatment option for these important complications. Also, this study will give us more insight in the pathophysiology of mucositis, including the role of IL-1 and the role of the microbiota in mucositis. Clinicaltrials.gov NCT04099901 . Registered on September 23, 2019. EudraCT: 2018-005046-10.


Effects of simvastatin and atorvastatin on inflammation markers in plasma.
To study the effect of statins on plasma markers for inflammation. Patients with hypercholesterolemia were randomized in one of the following treatments: Simvastatin (S) + placebo: S 40 mg for 6 weeks - S 80 mg for 6 weeks - S 80 mg for 24 weeks and Atorvastatin (A) + placebo: A 20 mg for 6 weeks - A 40 mg for 6 weeks - A 80 mg for 24 weeks. Forty-seven patients with hypercholesterolemia were recruited in four different outpatient clinics. Samples were obtained at randomization after 6, 12 and 36 weeks. Plasma or serum was analysed for lipids and for inflammation markers: C-reactive protein (CRP), serum amyloid A (SAA), soluble phospholipase A2 (SPLA2), intercellular adhesion molecule-1 (ICAM-1) and interleukin-6 (IL-6). The reduction in LDL was similar for the two statins, except at the highest dose of atorvastatin (41 vs. 47%). The increase in HDL tended to be more pronounced in the simvastatin group, significantly so on the highest dose of atorvastatin (P < 0.05). CRP and SAA was significantly reduced by atorvastatin, whilst no reduction was seen for simvastatin. There was a significant difference in treatment effects between the two statins. Both statins caused a reduction in SPLA2. For IL-6 and ICAM-1 only small and inconsistent reductions were observed for both statins. Atorvastatin reduced the liver-derived acute-phase reactants, CRP and SAA, whilst the effect of simvastatin was small or absent. Small and inconsistent effects were seen for both statins on plasma levels of IL-6 and ICAM-1.


The natural decline of an introduced species following its initial increase in abundance; an explanation for Ommatoiulus moreletii in Australia.
The black Portuguese millipede, Ommatoiulus moreletii, an exotic species first reported in Australia in 1953, shows a pattern of initial eruption and subsequent decline in abundance following its introduction to sites in South Australia. Comparative sampling of new, erupted populations and older, declined populations was done in an attempt to find testable hypotheses to account for the decline. We report on laboratory and field experiments which show that a native rhabditid nematode appears to be the causal agent for the decline of populations of O. moreletii in South Australia. Implications for the biological control of introduced species are discussed in terms of this work.


Comparative study on brain pharmacokinetics of Buyang Huanwu Decoction in normal and cerebral ischemia rats using brain microdialysis combined with LC-MS/MS.
To conduct a comparative study on the brain pharmacokinetics of seven ingredients (i. e. senkyunolide A, ferulic acid, formononetin, calycosin, ononin, calycosin-O-β-D-glucopyranoside, and paeoniflorin), which were the compounds of Buyang Huanwu Decoction (BHD), in normal and cerebral ischemia rats administrated intragastrically with BHD. The samples of normal and permanent middle cerebral artery occlusion (pMCAO) rats were collected by using brain microdialysis technique. The concentrations of seven ingredients were determined by the HPLC-MS/MS method. After the BHD were administrated intragastrically to the rats for seven consecutive days, brain microdialysis probes were inserted into the hippocampus of rats, and then the brain microdialysates were collected at 20 min time intervals for 5 h. The separation of the seven ingredients and internal standard (IS) was carried out on an ACQUITY UPLC BEH C18 (2.1 mm × 100 mm, 1.7 μm) chromatographic column, using a mobile phase consisting of acetonitrile (containing 0.1% formic acid) and water (containing 0.1% formic acid) for gradient elution within 13 min. The ionization was conducted using an ESI source in positive ion mode. Multiple reaction monitoring mode was used for quantification of ingredients in BHD. Linearity, accuracy, precision, matrix effect and stability of LC-MS/MS method were all satisfactory, successfully applied to compare the pharmacokinetics of the analytes between normal and model rats after intragastric administration of BHD. Compared with the normal group, the model group after the administration of the BHD showed that T 1/2 of formononetin and ononin were longer, and except for calycosin-O-β-D-glucopyranoside (P < 0.01), there was no significant difference between the normal group and the model group. The C max of senkyunolide A and calycosin of model group were increased, while the T max of senkyunolide A was decreased, and except for the T max of PF, the differences between the two groups were statistically significant (P < 0.01). The LC-MS/MS method combined with microdialysis was successfully applied to the comparative study of brain pharmacokinetics of seven ingredients in BHD. After intragastric administration of BHD, there were differences in the pharmacokinetics of seven ingredients in the brain hippocampus between normal rats and model rats, probably related to the characteristics of the ingredients and the effects of cerebral ischemia on the absorption and distribution of the ingredients.