[Effects of long term therapy with angiotensin converting enzyme inhibitor quinapril, antagonist of receptors to angiotensin II valsartan, and combination of quinapril and valsartan in patients with moderate chronic heart failure. Main results of the SADKO-CHF study].
To compare effects of therapy with angiotensin converting enzyme inhibitor quinapril (Q), angiotensin II receptor antagonist valsartan (V), and their combination in patients with stable moderate chronic heart failure (CHF). Patients (n=80) with NYHA class II-III CHF due to ischemic heart disease, dilated cardiomyopathy or decompensated hypertensive heart and ejection fraction <40% were randomized into 3 groups. Patients of group Q, V and Q+V received Q (average dose 13 mg/day, n=28), V (121 mg/day, n=26), and combination of Q and V (12 and 78 mg/day, n=26), respectively. Methods included assessment of clinical state and quality of life, echocardiography, 6 min walk test, Holter ECG monitoring with measurements of parameters of heart rate variability (HRV), and determination of neurohormones in peripheral blood. Examinations and measurements were made at baseline, in 3 and 6 months. Six months therapy with Q, V and their combination resulted in improvement of clinical and functional state of patients. More pronounced augmentation of exercise tolerance and lowering of CHF functional class were observed in group Q. Combined use of Q and V had no significant advantages over monotherapy with Q and V when effect on parameters of left ventricular remodeling were concerned. Therapy with Q was associated with "escape" of blockade of aldosterone synthesis and "reactivation" of angiotensin II formation after 6 months. The use of V and combination of V+Q allowed to achieve more stable but incomplete control of aldosterone activity. The use of Q appears to be the preferential regimen to influence activity of sympathoadrenal system and parameters of 24 hour HRV compared with V and Q+V. Long term therapy with V does not improve main parameters of 24 hour HRV.


Identification and Prioritization of Important Attributes of Disease-Modifying Drugs in Decision Making among Patients with Multiple Sclerosis: A Nominal Group Technique and Best-Worst Scaling.
Understanding the preferences of patients with multiple sclerosis (MS) for disease-modifying drugs and involving these patients in clinical decision making can improve the concordance between medical decisions and patient values and may, subsequently, improve adherence to disease-modifying drugs. This study aims first to identify which characteristics-or attributes-of disease-modifying drugs influence patients´ decisions about these treatments and second to quantify the attributes' relative importance among patients. First, three focus groups of relapsing-remitting MS patients were formed to compile a preliminary list of attributes using a nominal group technique. Based on this qualitative research, a survey with several choice tasks (best-worst scaling) was developed to prioritize attributes, asking a larger patient group to choose the most and least important attributes. The attributes' mean relative importance scores (RIS) were calculated. Nineteen patients reported 34 attributes during the focus groups and 185 patients evaluated the importance of the attributes in the survey. The effect on disease progression received the highest RIS (RIS = 9.64, 95% confidence interval: [9.48-9.81]), followed by quality of life (RIS = 9.21 [9.00-9.42]), relapse rate (RIS = 7.76 [7.39-8.13]), severity of side effects (RIS = 7.63 [7.33-7.94]) and relapse severity (RIS = 7.39 [7.06-7.73]). Subgroup analyses showed heterogeneity in preference of patients. For example, side effect-related attributes were statistically more important for patients who had no experience in using disease-modifying drugs compared to experienced patients (p < .001). This study shows that, on average, patients valued effectiveness and unwanted effects as most important. Clinicians should be aware of the average preferences but also that attributes of disease-modifying drugs are valued differently by different patients. Person-centred clinical decision making would be needed and requires eliciting individual preferences.


Climatic, Environmental and Health Impacts of Disused Coronavirus Protective Equipment: Towards Effective Regulatory and Containment Measures.
Though global health care delivery systems have been under inevitable pressure and risks from the ongoing coronavirus disease (COVID-19) pandemic, our natural human environment is also increasingly threatened. The reason is that efforts to contain the pandemic have resulted in a vast generation of medical waste from disused personal protective equipment, such as facemasks, face-shields, hand-gloves, hand-sanitisers, and related single-use products. Unprofessional management of medical waste can result in environmental contagion. This article, adopting an analytical approach, argues that COVID-19 waste represents a mode of contagion, and hence demands special regulatory attention, management, and disposal procedures at all levels of governance. The article offers an epidemiological perspective on COVID-19 waste and its place in medical waste. It provides insights into the best practices for managing COVID-19 waste and examines how global objectives and frameworks visibly support COVID-19 medical waste management globally.


The threshold dose for liver tumor promoting effects of dicyclanil in ICR mice.
To determine the threshold dose of dicyclanil (DC) that induces hepatocellular tumor-promoting effects associated with reactive oxygen species (ROS) generation via their metabolic pathways, partial hepatectomized ICR male mice were fed diets containing 0, 187.5, 375 or 750 ppm DC after an intraperitoneal injection of N-diethylnitrosamine (DEN) to initiate hepatocarcinogenesis. Immunohistochemically, the proliferating cell nuclear antigen (PCNA)-positive cell ratio was significantly increased in the DEN + 750 ppm DC group compared with the DEN alone group. However, significant increases in the number of gamma-glutamyltranspeptidase (GGT)-positive cells and formation of microsomal ROS were not observed in the DEN + DC groups compared with the DEN alone group. Real-time polymerase chain reaction (RT-PCR) showed that the expression of Cyp1a1, Cyp1a2, and OGG1genes was significantly up-regulated in mice given diets containing 375 ppm DC or more, 187.5 ppm DC or more, and 750 ppm DC, respectively. These results suggest that the threshold dose of DC that induces ROS-mediated liver tumor promotion in mice is more than 750 ppm, although expression of the Cyp1a2 gene, which is related to ROS generation, was up-regulated in the liver of mice, even at a DC dose of 187.5 ppm.


Validity and reliability of a Five Dimensional Life Satisfaction Index.
Validity of the Five Dimensional Life Satisfaction Index (Hawkins, Eklund, Kim, & Greene, 1994), which was developed to measure life satisfaction as it applies to adults with mental retardation, was examined. The index was administered to 48 adults with moderate mental retardation. Results showed (a) alternate forms reliability and internal consistency, (b) convergent and discriminant validity, and (c) construct validity.


The Splicing Variant TFIIIA-7ZF of Viroid-Modulated Transcription Factor IIIA Causes Physiological Irregularities in Transgenic Tobacco and Transient Somatic Depression of "Degradome" Characteristic for Developing Pollen.
Viroids are small, non-coding, pathogenic RNAs with a significant ability of adaptation to several basic cellular processes in plants. TFIIIA-7ZF, a splicing variant of transcription factor IIIA, is involved in replication of nuclear-replicating viroids by DNA-dependent polymerase II. We overexpressed NbTFIIIA-7ZF from Nicotiana benthamiana in tobacco (Nicotiana tabacum) where it caused morphological and physiological deviations like plant stunting, splitting of leaf petioles, pistils or apexes, irregular branching of shoots, formation of double-blade leaves, deformation of main stems, and modification of glandular trichomes. Plant aging and senescence was dramatically delayed in transgenic lines. Factors potentially involved in viroid degradation and elimination in pollen were transiently depressed in transgenic leaves. This depressed "degradome" in young plants involved NtTudor S-like nuclease, dicers, argonoute 5, and pollen extracellular nuclease I showing expression in tobacco anthers and leaves. Analysis of the "degradome" in tobacco leaves transformed with either of two hop viroids confirmed modifications of the "degradome" and TFIIIA expression. Thus, the regulatory network connected to TFIIIA-7ZF could be involved in plant pathogenesis as well as in viroid adaptation to avoid its degradation. These results support the hypothesis on a significant impact of limited TFIIIA-7ZF on viroid elimination in pollen.


Vestibular type I and type II hair cells. 1: Morphometric identification in the pigeon and gerbil.
Classically, type I and type II vestibular hair cells have been defined by their afferent innervation patterns. Little quantitative information exists on the intrinsic morphometric differences between hair cell types. Data presented here define a quantitative method for distinguishing hair cell types based on the morphometric properties of the hair cell's neck region. The method is based initially on fixed histological sections, where hair cell types were identified by innervation pattern, type I cells having an afferent calyx. Cells were viewed using light microscopy, images were digitized, and measurements were made of the cell body width, the cuticular plate width, and the neck width. A plot of the ratio of the neck width to cuticular plate width (NPR) versus the ratio of the neck width to the body width (NBR) established four quadrants based on the best separation of type I and type II hair cells. The combination of the two variables made the accuracy of predicting either type I or type II hair cells greater than 90%. Statistical cluster analysis confirmed the quadrant separation. Similar analysis was performed on dissociated hair cells from semicircular canal, utricle, and lagena, giving results statistically similar to those of the fixed tissue. Additional comparisons were made between fixed tissue and isolated hair cells as well as across species (pigeon and gerbil) and between end organs (semicircular canal, utricle, and lagena). In each case, the same morphometric boundaries could be used to establish four quadrants, where quadrant 1 was predominantly type I cells and quadrant 3 was almost exclusively type II hair cells. The quadrant separations were confirmed statistically by cluster analysis. These data demonstrate that there are intrinsic morphometric differences between type I and type II hair cells and that these differences can be maintained when the hair cells are dissociated from their respective epithelia.


Genomic regulation of CTLA4 and multiple sclerosis.
The cytotoxic T lymphocyte antigen 4 gene (CTLA4) is a critical regulator of T-cell activation and it is an important therapeutic target for cancer and autoimmune diseases. Here, we analyzed the genomic regulation of CTLA4 gene expression in order to identify single nucleotide polymorphisms (SNPs) that affect its expression and splicing, and to assess their association with Multiple Sclerosis (MS). We analyzed 152 healthy subjects and 146 patients with MS, of which 52 controls and 51 patients were used for gene expression analysis. We genotyped 17 SNPs in the CTLA4 gene using the SNaPshot Multiplex Kit, and in addition gene expression of the soluble (sCTLA4) and full length (flCTLA4) isoforms was quantified by real-time PCR, while protein levels of sCTLA4 were measured by ELISA. We found that the SNPs at -1577, +6230, +10242, +10717 and +12310 influence CTLA4 expression and the combination of the -1577 GG and +6230 GG genotypes provokes the strongest decrease in CTLA4 gene expression. We found that the SNP at -658 only acted as a regulatory SNP in patients with MS, suggesting the existence of epigenetic changes due to this disease. We also identified a decrease in CTLA4 gene expression levels in patients receiving chemotherapy, although no association was observed between MS and any of the polymorphisms studied. In conclusion, we have identified several SNPs in the CTLA4 gene and studied their influence on its genetic regulation. The involvement of CTLA4 in the pathogenesis of MS may be subtle and related to the functional changes in its pathway rather than predisposing genetic polymorphisms.


Penicillium ulleungdoense sp. nov. from Ulleung Island in Korea.
In a study of the fungal diversity on Ulleung Island in Korea, three novel strains of Penicillium were isolated. Different sites on Ulleung Island were selected for collecting endophytic fungi, and three endophytic fungal strains showed unique morphological characteristics. DNA sequence of the internal transcribed spacer, β-tubulin, calmodulin, and RNA polymerase II second largest subunit regions of the strains were analyzed and they showed unique taxonomic position from the other species of Penicillium section Sclerotiora. The new strains were named Penicillium ulleungdoense sp. nov. As the novel endophytic Penicillium taxa were discovered in a unique environment, the data could be meaningful for understanding the geographical distribution of Ascomycetes on Ulleung Island.


Invasive versus non-invasive cooling after in- and out-of-hospital cardiac arrest: a randomized trial.
Mild induced hypothermia (MIH) is indicated for comatose survivors of sudden cardiac arrest (SCA) to improve clinical outcome. In this study, we compared the efficacy of two different cooling devices for temperature management in SCA survivors. Between April 2008 and August 2009, 80 patients after survived in-hospital (IHCA) and out-of-hospital cardiac arrest (OHCA) were included in this prospective, randomized, single center study. Hypothermia was induced after randomization by either invasive Coolgard(®) cooling or non-invasive ArcticSun(®) surface cooling at 33.0 °C core body temperature for 24 h followed by active rewarming. The primary endpoint was defined as the efficacy of both cooling systems, measured by neuron-specific enolase (NSE) levels as a surrogate parameter for brain damage. Secondary efficacy endpoints were the clinical and neurological outcome, time to start of cooling and reaching the target temperature, target temperature-maintenance and hypothermia-associated complications. NSE at 72 h did not differ significantly between the 2 groups with 16.5 ng/ml, interquartile range 11.8-46.5 in surface-cooled patients versus 19.0 ng/ml, interquartile range 11.0-42.0 in invasive-cooled patients, p = 0.99. Neurological and clinical outcome was similar in both groups. Target temperature of 33.0 °C was maintained more stable in the invasive group (33.0 versus 32.7 °C, p < 0.001). Bleeding complications were more frequent with invasive cooling (n = 17 [43.6 %] versus n = 7 [17.9 %]; p = 0.03). Invasive cooling has advantages with respect to temperature management over surface cooling; however, did not result in different outcome as measured by NSE release in SCA survivors. Bleeding complications were more frequently encountered by invasive cooling.


Caudal tramadol for postoperative analgesia in pediatric hypospadias surgery.
Ninety boys, aged 13-53 months, undergoing repair of hypospadias, were allocated randomly to receive 0.8 ml kg-1 of one of three solutions into the caudal extradural space: group B received bupivacaine 2 mg kg-1, group T received tramadol 2 mg kg-1 in 0.9% saline and group BT a mixture of both. Postoperative pain was assessed hourly for 12 h after injection using a modified TPPPS pain score and additional analgesia was administered to those children whose pain scores were > 3/10. Nine patients (30%) in group T required additional analgesia within 1 h of surgery compared with only two (6.7%) and three (10%) patients in groups B and BT, respectively (P = 0.04). Mean duration before additional analgesia was required in the remaining patients was 9.3 (SD 3.0) h in group B, 10.7 (2.2) h in group T and 10.5 (2.0) h in group BT (P > 0.20). There were no significant differences between the groups in mean ventilatory frequency, sedation scores, incidence of emesis, facial flushing or pruritus. We conclude that caudal tramadol had a slow onset of action and that the addition of tramadol to bupivacaine, when both drugs were administered caudally, did not significantly prolong the duration of action of bupivacaine.


[Comparison of standard-dose epinephrine and high-dose epinephrine in cardiopulmonary arrest outside the hospital].
We compared high-dose epinephrine (HDE) with standard-dose epinephrine (SDE) in improving the outcome of resuscitation after out-of-hospital cardiopulmonary arrest. The SDE group received epinephrine 1mg, and the HDE group received epinephrine 5mg respectively every 5 minutes until the return of spontaneous circulation. There were no significant differences between the SDE group and the HDE group in the rate of return of spontaneous circulation, rate of successful resuscitation and neurologic outcome. However, the rate of successful resuscitation tended to be higher in the SDE group. The ineffectiveness of HDE was considered to be due to the existence coronary artery diseases in the majority of patients, or increase in myocardial oxygen demand by the beta 1-adrenergic effects of epinephrine.


[Two case reports on intra-tumor injection therapy of dendritic cells].
DC (dendritic cells) vaccine therapy against cancer has attracted attention in recent years. However, the existence of the immunosuppressive state in cancer individuals leads to anergy and failure in cytotoxic T cell (CTL) induction and DC migration to the target organ. It has been reported that injected intra-tumor DC is expected to work phagocytosis of the tumor as a localized effect, the consequent CTL induction in the tumor and the regional lymphnodes, resulting in a systemic effect. Two cases reported in this article were performed with intra-tumor DC injection therapy by means of EUS (endoscopic ultrasonography) which indicated interesting immunoreaction.


Miniaturized X-ray powder diffraction assay (MixRay) for quantitative kinetic analysis of solvent-mediated phase transformations in pharmaceutics.
Many pharmaceutical compounds exhibit polymorphism, which may result in solvent-mediated phase transformations. Since the polymorphic form has an essential influence on physicochemical characteristics such as solubility or dissolution rate, it is crucial to know the exact polymorphic composition of a drug throughout pharmaceutical development. This study addressed the need to perform quantitative X-ray analysis of polymorphic mixtures on a 96-well scale (MixRay). A calibration of polymorphic mixtures (anhydrate and hydrate) was performed with three model drugs, caffeine, piroxicam, and testosterone, and linear correlations were obtained for all compounds. The MixRay approach for piroxicam was applied to a solubility and residual solid screening assay (SORESOS) to quantify the amount of hydrate and anhydrate corresponding to kinetic bulk concentrations. Changes in these drug concentrations correlated well with the kinetic changes in the residual solid. The influence of excipients on the solid state and kinetic concentrations of piroxicam was also studied. Excipients strongly affected polymorphic transformation kinetics of piroxicam and concentrations after 24h depended on the excipient used. The new calibration X-ray method combined with bulk concentration analysis provides a valuable tool for both pharmaceutical profiling and early formulation development.


Crassulacean Acid Metabolism and Photochemical Efficiency of Photosystem II in the Adaxial and Abaxial Parts of the Succulent Leaves of Kalanchoë daigremontiana Grown at Four Photon Flux Densities.
Kalanchoë daigremontiana, a species possessing crassulacean acid metabolism, was grown at four photon flux densities (1300, 400, 60, and 25 micromole photons per square meter per second). In leaves which had developed at 1300 and 400 micromole photons per square meter per second, CO(2) was mainly incorporated through the lower, shaded leaf surfaces, and the chlorenchyma adjacent to the lower surfaces showed a higher degree of nocturnal acid synthesis than the chlorenchyma adjacent to the upper surfaces. In leaves acclimated to 60 and 25 micromole photons per square meter per second, the gradient in CAM activity was reversed, i.e. more CO(2) was taken up through the upper than through the lower surfaces and nocturnal acidification was higher in the tissue next to the upper surfaces. Total net carbon gain and total nocturnal acid synthesis were highest in leaves which had developed at 400 micromole photons per square meter per second. Chlorophyll content was markedly reduced in leaves which had developed at 1300 micromole photons per square meter per second, especially in the exposed adaxial parts. There was also a sustained reduction in photosystem II photochemical efficiency as indicated by measurements of the ratio of variable over maximum chlorophyll a fluorescence. These findings suggest that, at high growth photon flux densities, the reduced activity of the exposed portions of these succulent leaves is caused by (a) the adverse effects of excess light, (b) together with a genotypic component which favors CO(2) uptake and acid synthesis in the abaxial (lower) leaf parts even when light is not or only marginally excessive. This latter component is predominant at medium photon flux densities, e.g. at 400 micromole photons per square meter per second. It becomes overridden, however, under conditions of deep shade when strongly reduced light levels in the abaxial parts of the leaf chlorenchyma severely limit photosynthesis.


Solid crystal network of self-assembled cyclodextrin and nonionic surfactant pseudorotaxanes.
The title system allows the straightforward formation of three-dimensional crystals of self-assembled pseudorotaxanes formed by the nonionic surfactant Igepal CO-520 and beta-cyclodextrin (beta-CD) in aqueous solution. The work involves a combination of X-ray powder diffraction, high resolution electron transmission microscopy, and (13)C CP/MAS NMR studies of the solid crystal, supported by single crystal structural analysis. The results indicate a lamellar self-assembly of pseudorotaxanes with preferential orientation and disorder in the structure. For the single crystal, the unit cell was found to be triclinic (P1) and contains a beta-CD dimer. The surfactant molecules are located in the channel formed by these dimers along the c axis of the crystal network. The individual pseudorotaxane structure is formed by a dimer of beta-CDs threaded by the oxyethylene hydrophilic segment of Igepal CO-520, and a beta-CD dimer that binds the hydrophobic region of the surfactant. Thus, as in a CD polyrotaxane structure, this system results in an ordered self-assembly of pseudorotaxanes through the formation of a network of hydrogen bonds between head-to-head beta-CD dimers. Moreover, the analysis of the (1)H NMR spectra in solutions of pseudorotaxanes formed by beta-CD and Igepals with different lengths of the hydrophilic tails indicates equal stoichiometry patterns of both oxyethyelene and hydrophobic regions for the different supramolecules. Whereas the common hydrophobic moiety threads two macrocycles, the ratio between complexed oxyehtlyene segments and beta-CD is 2.5 for the hydrophilic tails. All these results show that nonionic surfactants can be used as alternative and effective linear threads to polymers and copolymers in the synthesis of supramolecular polyrotaxane solid crystals with CDs.


[Structural biology for developing antimalarial compounds].
The human malaria parasite Plasmodium falciparum is responsible for the death of more than a million people each year. The emergence of strains of this malaria parasite resistant to conventional drug therapy has stimulated the search for antimalarial compounds with novel modes of action. Here the structure-function relationship studies for two Plasmodium proteins are presented. One example is the structural studies for S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum (PfSAHH) and the other example is those for 1-deoxy-D-xylulose reductoisomerase from Plasmodium falciparum (PfDXR). In the former study, the clue for design of species specific PfSAHH inhibitors was obtained by the structural comparison of the active site of PfSAHH with that of human SAHH (HsSAHH). Our study revealed that the inhibitor selectivity depends on the difference of only one amino acid residue in the active site; Cys59 in PfSAHH vs. Thr60 in HsSAHH. In the latter study, the inhibition of PfDXR enzyme by fosmidomycin has proved to be efficient in the treatment of uncomplicated malaria in recent clinical trials conducted in Gabon and Thailand. Our crystal structure analyses of PfDXR/inhibitor complexes revealed the molecular basis of fosmidomycin's action in P. falciparum. We expect that the structure-function relationship studies on Plasmodium proteins are useful for developing the more effective antimalarial compounds.


Toward a reconceptualization of communication cues to action in the Health Belief Model: HIV test counseling.
In the present study, the persuasive communication of HIV test counselors as cues to action in clients' decisions to practice safer sex was examined. Results indicated that contrary to expectations, hypothesized relationships inherent in the Health Belief Model (HBM) were not supported for the pre-HIV test survey. However, clients' perceptions of the severity of HIV/AIDS, their susceptibility to HIV/AIDS, the benefits of and barriers to practicing safer sex, and self-efficacy were correlated with compliance with safer-sex recommendations reported on the post-HIV test survey. Intriguing results revolved around communication cues to action. HIV test counseling session transcripts were content analyzed to determine the persuasive messages used by HIV test counselors that may have cued clients' health beliefs and safer-sex behaviors. The inductively-derived coding scheme emphasized the complexity of the interpersonal interaction taking place during counseling sessions. Results indicated that in some cases, use of certain persuasive strategies was related to short-term adoption of safer-sex recommendations. These findings bolstered the argument for a move toward reconceptualizing the HBM by centralizing communication cues to action.


Uranium uptake by hectorite and montmorillonite: a solution chemistry and polarized EXAFS study.
The mechanism of U(VI) retention on montmorillonite and hectorite at high ionic strength (0.5 M NaCl) was investigated by solution chemistry and, at near-neutral pH, polarized EXAFS spectroscopy. Uranium(VI) sorption increases from pH 3 to 7 on the two clays, but with a steeper edge for hectorite. Uranium(VI) is no longer retained at pH > 9, presumably owing to the formation of soluble anionic complexes. Polarized EXAFS showed that U(VI) retains its uranyl conformation on montmorillonite (U_mont) and hectorite (U_hect), with uranyl O at 1.79(2) A for U_mont and 1.82(2) A for U_hect, and split equatorial O shells at 2.29(2) and 2.47(2) A (U_mont), or 2.35(2) and 2.53(2) A (U_hect). An additional atomic shell of approximately 0.5 Al/Si at 3.3 A is detected for U_mont, but neither the oxygen nor the cationic shell exhibit clear angular dependence. These results indicate the formation of mononuclear complexes at the edges of montmorillonite platelets, with the orientation of the uranyl axis equal to the magic angle, as constrained by the edges' structural properties. In contrast to U_mont, the U-O signal varies with the polarization angle in U_hect, and the cationic Mg/Si contribution at 3.2 A is weak. The structure of this surface complex is not completely elucidated; it may correspond either to sorption on silanol sites, or to coprecipitation. These results lay out the fundamental molecular-scale basis to understand U retention by neoformed clay layers of nuclear glasses.


Sociodemographic disparities in the management of advanced lung cancer: a narrative review.
Treatment of advanced non-small cell lung cancer (NSCLC) has markedly changed in the past decade with the integration of biomarker testing, targeted therapies, immunotherapy, and palliative care. These advancements have led to significant improvements in quality of life and overall survival. Despite these improvements, racial and socioeconomic disparities in lung cancer mortality persist. This narrative review aims to assess and synthesize the literature on sociodemographic disparities in the management of advanced NSCLC. A narrative overview of the literature was conducted using PubMed and Scopus and was narrowed to articles published from January 1, 2010, until July 22, 2020. Articles relevant to sociodemographic variation in (I) chemoradiation for stage III NSCLC, (II) molecular biomarker testing, (III) systemic treatment, including chemotherapy, targeted therapy, and immunotherapy, and (IV) palliative and end of life care were included in this review. Twenty-two studies were included. Sociodemographic disparities in the management of advanced NSCLC varied, but recurring findings emerged. Across most treatment domains, Black patients, the uninsured, and patients with Medicaid were less likely to receive recommended lung cancer care. However, some of the literature was limited due to incomplete data to adequately assess appropriateness of care, and several studies were out of date with current practice guidelines. Sociodemographic disparities in the management of advanced lung cancer are evident. Given the rapidly evolving treatment paradigm for advanced NSCLC, updated research is needed. Research on interventions to address disparities in advanced NSCLC is also needed.


Modulation of keratin intermediate filament distribution in vivo by induced changes in cyclic AMP-dependent phosphorylation.
Treatment of PtK1 cells with 5 mM acrylamide for 4 hr induces reversible dephosphorylation of keratin in concert with reversible aggregation of intermediate filaments (Eckert and Yeagle, Cell Motil. Cytoskeleton 11:24-30, 1988). We have examined this phenomenon by 1) in vitro phosphorylation of isolated PtK1 keratin filaments and 2) combined treatments of PtK1 cells with both acrylamide and agents which elevate intracellular cAMP levels. PtK1 keratins were incubated in gamma-32P-ATP in the presence or absence of cAMP-dependent kinase (A-kinase) and cAMP. Levels of phosphorylation were analyzed by electrophoresis and autoradiography. Phosphorylation of keratin polypeptides (56 kD, 53 kD, 45 kD, 40 kD) occurred without added kinase, suggesting the presence of an endogenous kinase which remains with intermediate filaments in residues of Triton X-100 extracted cells. Phosphorylation levels were increased by A-kinase but not by cAMP alone, indicating the presence of cAMP-dependent phosphorylation sites in addition to sites phosphorylated by the endogenous kinase. To study the possible role of cAMP-dependent phosphorylation in acrylamide-induced aggregation of keratin filaments, we treated cells with acrylamide in the presence of 8-bromo-cAMP (brcAMP), pertussis toxin (PT), isobutylmethylxanthine (IBMX), or forskolin, which increase intracellular cAMP levels. The distribution and phosphorylation levels of keratin filaments, as well as intracellular cAMP levels, were determined for each of these treatments. In addition to aggregation and dephosphorylation of keratin filaments reported previously, treatment of cells with acrylamide alone also results in reduced levels of intracellular cAMP. 8-bromo-cAMP, IBMX, and forskolin prevent acrylamide-induced aggregation of keratin filaments and result in both normal levels of keratin phosphorylation and normal intracellular cAMP levels. PT was apparently ineffective. These observations suggest that 1) PtK1 keratins are phosphorylated by cAMP-dependent kinase and an endogenous, cAMP-independent kinase and 2) alteration of levels of cAMP-dependent phosphorylation may be involved in aggregation of keratin filaments in response to acrylamide.


Candidate vaccine antigens identified by antibodies from mice vaccinated with 15- or 50-kilorad-irradiated cercariae of Schistosoma mansoni.
In murine schistosomiasis, the highest levels of resistance to cercarial challenge are obtained by vaccination with radiation-attenuated cercariae. To identify candidate vaccine antigens relevant to the vaccine model, we examined parasite antigens recognized by antibodies from mice vaccinated with irradiated cercariae of Schistosoma mansoni. To optimize recognition of a wide spectrum of antigens, several factors that influence the level of protection in this model were varied; specifically, we examined the effect of (i) single versus multiple vaccinations with irradiated cercariae, (ii) the dose of irradiation (15 or 50 kilorads) administered to the cercariae, and (iii) the genetic background of mouse strains, high-responder (C57BL/6J) versus moderate-responder (CBA/J) mice. We found that the number of vaccinations did not alter antibody specificity but modified the relative antibody titers against particular antigens. The dose of irradiation used to attenuate the immunizing cercariae had a similar effect on antibody titers but in addition influenced antibody specificity. Only mice that had been vaccinated with moderately irradiated cercariae recognized cathepsin B (Sm31) and Sm32. Interestingly, when vaccinated mice of the two strains, C57BL/6J and CBA/J, were compared, differences in antibody responses to particular antigens were observed. Both strains recognized the integral membrane protein Sm23, glutathione S-transferase, and cathepsin B, whereas Sm32 and paramyosin were recognized only by CBA/J mice, and heat shock protein 70 was recognized exclusively by C57BL/6J mice. In this study, we conclusively identified six distinct antigens that are specifically recognized by the humoral immune response of vaccinated mice.


[Time trends of H. pylori infection and related drug use in patients with peptic ulcer bleeding in a hospital in Beijing from 2010 to 2019].
Objective: To explore the time trends of H. pylori infection and related drug use in patients with peptic ulcer bleeding (PUB) in recent ten years. Methods: PUB patients in Peking University Third Hospital from 2010 to 2019 were included. Time trends of H. pylori infection, related drugs (non-steroidal anti-inflammatory drugs, aspirin, antiplatelet drugs, anticoagulant drugs, glucocorticoids) use and non-H. pylori-non-drug ulcer in PUB patients were analyzed. Results: A total of 1 140 PUB patients were included from 2010 to 2019 (including 925 males and 215 females). The age M(Q1,Q3)was 53.5 (33.0, 66.0) years, with 833 patients <65 years old. The positive rates of H. pylori were 79.3%, 75.7%, 73.1%, 71.6%, 77.0%, 70.4%, 69.7%, 63.1%, 51.4%, 50.9%, respectively, showing a decreasing trend (χ²=32.386, P<0.001), and the decreasing trends were significant in different ulcer location, age and gender subgroups(all P<0.05). The proportions of PUB patients using at least one of the above drugs were 23.1%, 28.6%, 34.0%, 39.5%, 33.8%, 35.9%, 28.7%, 39.8%, 40.9%, 41.8%, respectively, showing an increasing trend (χ²=6.857, P=0.009), and the proportions of patients with antiplatelet drugs and anticoagulant drugs history showed increasing trends. The proportions of non-H. pylori-non-drug patients were 12.3%, 22.1%, 14.6%, 13.2%, 7.7%, 13.0%, 16.9%, 18.7%, 22.6% and 20.9%, respectively, showing an increasing trend (χ²=4.808, P=0.028). Accordingly, the proportions of elderly (≥65 years old) patients (χ²=4.608, P=0.032) and large ulcer (≥2 cm) patients (χ²=8.173, P=0.004) showed increasing trends. Conclusion: In the last decade, the positive rate of H. pylori in PUB patients showed a decreasing trend, while the proportions of patients with antiplatelet drugs and anticoagulant drugs history and the proportion of non-H. pylori-non-drug patients showed increasing trends.


Guidelines for diagnosis and treatment of depression in older adults: A report from the Japanese Society of mood disorders.
The Committee for Treatment Guidelines of Mood Disorders, Japanese Society of Mood Disorders, published a Japanese guideline for the treatment of late-life depression in 2020. Based on that guideline, the present guideline was developed and revised to incorporate the suggestions of global experts and the latest published evidence. In the diagnosis of late-life depression, it is important to carefully differentiate it from bipolar disorders, depressive states caused by physical and organic brain disease, drug effects, and dementia, and to determine the comorbidity between late-life depression and dementia. It is necessary to fully understand the clinical characteristics and psychosocial background of late-life depression, evaluate the patient's condition, and provide basic interventions based on these factors. Problem-solving therapy, reminiscence therapy/life review therapy, and behavioral activation therapy, and other forms of psychotherapy can reduce depressive symptoms. In terms of pharmacotherapy, newer antidepressants or non-tricyclic antidepressants are recommended for late-life depression, and it is recommended that the efficacy of least the minimal effective dosage should first be determined. Switching antidepressants and aripiprazole augmentation can be used to treatment-resistant therapy. Electroconvulsive therapy and repetitive transcranial magnetic stimulation have demonstrated usefulness for late-life depression. Exercise therapy, high-intensity light therapy, and diet therapy also show some effectiveness and are useful for late-life depression. Continuation therapy should be maintained for at least 1 year after remission.


Thyroid Dysfunction in Patients Admitted in Cardiac Care Unit: Prevalence, Characteristic and Hospitalization Outcomes.
Cardiovascular disease is one of the main causes of hospital admission and mortality, and thyroid dysfunction increases the risk of developing acute or exacerbation of chronic cardiac conditions. The aim of this study is to investigate the prevalence of thyroid hormone abnormality among patients in the cardiac care unit (CCU) patients and its relation to admission diagnosis, clinical, biochemical data, and hospital-related outcomes. We conducted a retrospective cohort observational that included adult patients who were admitted to the CCU. We excluded those with known thyroid dysfunction and those who received amiodarone or IV contrast. A total of 374 patients with a mean age of 62.7+14.7 years old were included. Ischemic changes were observed in 70.6% of the patients based on the admission diagnosis. In comparison to the non-ischemic group, the ischemic group was more likely to be male (P=0.010), to be active/former smokers (P=0.011), to have diabetes (P=0.009), to have diastolic dysfunction (P=<0.001), to have undergone thrombolysis (P=<0.001), and to have been referred to a tertiary center (P=<0.001). Euthyroidism was observed in 57.8% of the patients based on the thyroid function test at admission. Compared to patients with thyroid dysfunction, those with Euthyroidism were more likely to be active/former smokers (P=0.002), to have lower heart rates (P=0.018), to not have chronic kidney disease (P=0.016), to not have heart failure (P=0.006), to have lower thyroid-stimulating hormone (TSH) levels (P=<0.001), and to have lower tricuspid regurgitation (P=0.042). Thyroid dysfunction is common among patients admitted to the CCU. Non-significant positive correlations between TSH and hospitalization length, tertiary center referral, 30-day readmission, and in-hospital mortality when adjusting for potential confounders.


Hydrophobicity Tuning by the Fast Evolution of Mold Temperature during Injection Molding.
The surface topography of a molded part strongly affects its functional properties, such as hydrophobicity, cleaning capabilities, adhesion, biological defense and frictional resistance. In this paper, the possibility to tune and increase the hydrophobicity of a molded polymeric part was explored. An isotactic polypropylene was injection molded with fast cavity surface temperature evolutions, obtained adopting a specifically designed heating system layered below the cavity surface. The surface topology was characterized by atomic force microscopy (AFM) and, concerning of hydrophobicity, by measuring the water static contact angle. Results show that the hydrophobicity increases with both the temperature level and the time the cavity surface temperature was kept high. In particular, the contact angle of the molded sample was found to increase from 90°, with conventional molding conditions, up to 113° with 160 °C of cavity surface temperature kept for 18 s. This increase was found to be due to the presence of sub-micro and nano-structures characterized by high values of spatial frequencies which could be more accurately replicated by adopting high heating temperatures and times. The surface topography and the hydrophobicity resulted therefore tunable by selecting appropriate injection molding conditions.


Fluid overload deteriorate chylothorax: evaluation in a canine model.
No conservative treatments for chylothorax have yet been established, and surgical ligation of the thoracic duct is required in many cases. In the present study, we investigated the management of body fluid in a canine chylothorax model. Twelve beagle dogs were divided evenly into three groups: A, B, and C. Under general anesthesia, the thoracic duct was cut and opened, and the amount of lymph fluid leakage was measured. Intravenous extracellular fluid infusion was started at 5mL/kg/h for the first 2h, and then between 2 and 4h, the infusion rate was increased to 10 mL/kg/h in group A and to 20mL/kg/h in group B. During the first 2h after cutting the thoracic duct, the mean lymph fluid leakage rates in groups A, B, and C were 0.466, 0.635, and 0.575 mL/kg/h, respectively. The rates of leakage did not differ significantly among the groups. Between 2 and 4h, the mean rates of leakage were 0.750, 1.43, and 0.544mL/kg/h, respectively, being significantly higher in groups A and B than in group C. The amount of lymph fluid ascending the thoracic duct correlates with the amount of intravenous fluid infusion. For the management of chylothorax, it is important to avoid fluid overload.


Bacteriolytic activity caused by the presence of a novel lactococcal plasmid encoding lactococcins A, B, and M.
Lactococcus lactis subsp. lactis biovar diacetylactis DPC938 was identified as a bacteriocin-producing strain which exhibited a bacteriolytic effect on other lactococci. Lysis of such target strains was associated with decreases in optical density and release of the intracellular enzyme lactate dehydrogenase. DPC938 exhibits cross-immunity to L. lactis subsp. cremoris 9B4 (M.J. van Belkum, B.J. Hayema, A. Geis, J. Kok, and G. Venema, Appl. Environ. Microbiol. 55:1187-1191, 1989), a strain which produces the bacteriocins lactococcins A, B, and M. Genetic analyses revealed that a 15.5-kb region of DNA encoding these bacteriocins is highly conserved in 9B4, DPC938, and DPC3286, an overproducing derivative of DPC938. This region is located on a 72- and a 78-kb nonmobilizable plasmid in DPC938 and DPC3286, respectively. The bacteriolytic effect exhibited by DPC938 and DPC3286 on sensitive cultures is most probably due to the concerted action of all three bacteriocins. Since these cultures exhibit a lytic effect on lactococci, they have a potential application in the dairy industry as accelerators of starter lysis and hence accelerators of cheese ripening.


Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis.
Hydroxychloroquine or chloroquine with or without azithromycin have been widely promoted to treat coronavirus disease 2019 (COVID-19) following early in vitro antiviral effects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this systematic review and meta-analysis was to assess whether chloroquine or hydroxychloroquine with or without azithromycin decreased COVID-19 mortality compared with the standard of care. PubMed, Web of Science, Embase Cochrane Library, Google Scholar and MedRxiv were searched up to 25 July 2020. We included published and unpublished studies comparing the mortality rate between patients treated with chloroquine or hydroxychloroquine with or without azithromycin and patients managed with standard of care. Patients ≥18 years old with confirmed COVID-19. Chloroquine or hydroxychloroquine with or without azithromycin. Effect sizes were pooled using a random-effects model. Multiple subgroup analyses were conducted to assess drug safety. The initial search yielded 839 articles, of which 29 met our inclusion criteria. All studies except one were conducted on hospitalized patients and evaluated the effects of hydroxychloroquine with or without azithromycin. Among the 29 articles, three were randomized controlled trials, one was a non-randomized trial and 25 were observational studies, including 11 with a critical risk of bias and 14 with a serious or moderate risk of bias. After excluding studies with critical risk of bias, the meta-analysis included 11 932 participants for the hydroxychloroquine group, 8081 for the hydroxychloroquine with azithromycin group and 12 930 for the control group. Hydroxychloroquine was not significantly associated with mortality: pooled relative risk (RR) 0.83 (95% CI 0.65-1.06, n = 17 studies) for all studies and RR = 1.09 (95% CI 0.97-1.24, n = 3 studies) for randomized controlled trials. Hydroxychloroquine with azithromycin was associated with an increased mortality (RR = 1.27; 95% CI 1.04-1.54, n = 7 studies). We found similar results with a Bayesian meta-analysis. Hydroxychloroquine alone was not associated with reduced mortality in hospitalized COVID-19 patients but the combination of hydroxychloroquine and azithromycin significantly increased mortality.


Identification and mapping of paralogous genes on a known genomic DNA sequence.
The completion of whole genome sequencing projects offers the opportunity to examine the organization of genes and the discovery of evolutionarily related genes in a given species. For the beginners in the field, through a specific example, this chapter provides a step-by-step procedure for identifying paralogous genes, using the genome browser at UCSC (http://genome.ucsc.edu/). The example describes identification and mapping in the human genome, the paralogs of TCF12/HTF4. The example identifies TCF3 and TCF4 as paralogs of the TCF12/HTF4 gene. The example also identifies a related sequence, corresponding to a pseudogene, in one of the introns of the JAK2 gene. The procedure described should be applicable to the discovery and creation of maps of paralogous genes in the genomic DNA sequences that are available at the genome browser at UCSC.


Insulin.
Due to its versatile nature and its corresponding anabolic and anticatabolic properties, insulin has been prohibited in sports since 1999. Numerous studies concerning its impact on glycogen formation, protein biosynthesis, and inhibition of protein breakdown have illustrated its importance for healthy humans and diabetics as well as elite athletes. Various reports described the misuse of insulin to improve performance and muscle strength, and synthetic analogs were the subject of several studies describing the beneficial effects of biotechnologically modified insulins. Rapid- or long-acting insulins were developed to enhance the injection-to-onset profile as well as the controllability of administered insulin, where the slightest alterations in primary amino acid sequences allowed the inhibition of noncovalent aggregation of insulin monomers (rapid-acting analogs) or promoted microprecipitation of insulin variants upon subcutaneous application (long-acting analogs). Information on the metabolic fate and renal elimination of insulins has been rather limited, and detection assays for doping control purposes were primarily established using the intact compounds as target analytes in plasma and urine specimens. However, recent studies revealed the presence of urinary metabolites that have been implemented in confirmation methods of sports drug testing procedures. So far, no screening tool is available providing fast and reliable information on possible insulin misuse; only sophisticated procedures including immunoaffinity purification followed by liquid chromatography and tandem mass spectrometry have enabled the unambiguous detection of synthetic insulins in doping control blood or urine samples.


Transcriptional profiling of Francisella tularensis infected peripheral blood mononuclear cells: a predictive tool for tularemia.
In this study, we analyzed temporal gene expression patterns in human peripheral blood mononuclear cells (PBMCs) infected with the Francisella tularensis live vaccine strain from 1 to 24 h utilizing a whole human Affymetrix gene chip. We found that a considerable number of induced genes had similar expression patterns and functions as reported previously for gene expression profiling in patients with ulceroglandular tularemia. Among the six uniquely regulated genes reported for tularemia patients as being part of the alarm signal gene cluster, five, namely caspase 1, PSME2, TAP-1, GBP1, and GCH1, were induced in vitro. We also detected four out of the seven potential biomarkers reported in tularemia patients, namely TNFAIP6 at 4 h and STAT1, TNFSF10, and SECTM1 at 16 and 24 h. These observations underscore the value of using microarray expression profiling as an in vitro tool to identify potential biomarkers for human infection and disease. Our results indicate the potential involvement of several host pathways/processes in Francisella infection, notably those involved in calcium, zinc ion binding, PPAR signaling, and lipid metabolism, which further refines the current knowledge of F. tularensis infection and its effects on the human host. Ultimately, this study provides support for utilizing in vitro microarray gene expression profiling in human PBMCs to identify biomarkers of infection and predict in vivo immune responses to infectious agents.


Post-Tarasoff legal developments and the mental health literature.
Since Tarasoff first established the duty of psychotherapists to warn or otherwise protect third parties when a patient is considered dangerous, the mental health literature has continued to address the two most controversial issues in that case: the questionable ability of clinicians to predict violent behavior, and the role of confidentiality in psychotherapy. The author examines recent trends in the law in light of this research and concludes that so-called anti-Tarasoff statutes recently passed by some states appropriately take into account the mental health literature and effectively balance competing public policy concerns.


Relationship Between Sulcal Characteristics and Brain Aging.
This study aimed to determine whether sulcal morphology differs between middle age (MA) and older healthy individuals. Furthermore, we sought to determine whether age-related differences in sulcal characteristics were more strongly associated with differences in local or global cortical volumes. Participants (age 44-50, N = 403; age 64-70, N = 390) from the Personality and Total Health Through Life (PATH) study were included. Sulci were 17.3% wider, on average, in old age (OA) compared to MA participants, with the largest difference in the left superior frontal sulcus. Differences in sulcal width were generally higher in males than females. Differences in the width of the superior frontal and central sulci were significantly associated with differences in the volume of adjacent local gyri, while age-related differences in the width of lateral and superior temporal sulci were associated with differences in whole brain cortical volume. These findings suggest that sulcal characteristics provide unique information about changes in local and global brain structure in aging.


Treatment results and prognostic factors in patients with malignant fibrous histiocytoma.
The objective of this study is to investigate the treatment results, prognostic factors, the role of postoperative radiotherapy, and the usefulness of American Joint Committee on Cancer (AJCC) Staging System (2002) for soft tissue sarcomas in malignant fibrous histiocytoma (MFH). Between November 1987 and December 2000, 76 patients with localized MFH underwent surgery as the primary treatment modality with or without radiotherapy in our institution and were reviewed retrospectively. Patients with regional nodal disease, distant metastases or retroperitoneal disease were excluded from our study. All patients had at least 27 months of follow-up. The 5-year overall survival rate, local control rate, and distant metastasis-free rate were 74%, 62%, and 87%, respectively. In multivariate analysis, AJCC 2002 staging system was the only independent prognostic factor for overall survival rates (p=0.0017). Postoperative radiotherapy was the only significant factor for local control rates (p=0.0024). In conclusion, staging system is a prognostic predictor for overall survival rates and postoperative radiotherapy can improve local control. However, the optimal adjuvant treatment strategy for MFH should still be further explored.


Esmarch closure of laparotomy incisions in unstable trauma patients.
Fascial closure after laparotomy may be time-consuming and extremely difficult, especially in the setting of massive bowel edema. In the trauma patient with deteriorating hemodynamic status, hypothermia, or worsening hypoxia, expeditious abdominal wall closure is essential to facilitate rapid transport to the intensive care unit for further stabilization. With the increasing utilization of the abbreviated laparotomy in unstable trauma patients, innovative techniques for speedy fascial closure must be evaluated. We developed the Esmarch closure--a simple, rapid method for closing the abdominal wall at the end of abbreviated laparotomies.


Gene cloning and characterization of a novel esterase from activated sludge metagenome.
A metagenomic library was prepared using pCC2FOS vector containing about 3.0 Gbp of community DNA from the microbial assemblage of activated sludge. Screening of a part of the un-amplified library resulted in the finding of 1 unique lipolytic clone capable of hydrolyzing tributyrin, in which an esterase gene was identified. This esterase/lipase gene consists of 834 bp and encodes a polypeptide (designated EstAS) of 277 amino acid residuals with a molecular mass of 31 kDa. Sequence analysis indicated that it showed 33% and 31% amino acid identity to esterase/lipase from Gemmata obscuriglobus UQM 2246 (ZP_02733109) and Yarrowia lipolytica CLIB122 (XP_504639), respectively; and several conserved regions were identified, including the putative active site, HSMGG, a catalytic triad (Ser92, His125 and Asp216) and a LHYFRG conserved motif. The EstAS was overexpressed, purified and shown to hydrolyse p-nitrophenyl (NP) esters of fatty acids with short chain lengths (< or = C8). This EstAS had optimal temperature and pH at 35 degrees C and 9.0, respectively, by hydrolysis of p-NP hexanoate. It also exhibited the same level of stability over wide temperature and pH ranges and in the presence of metal ions or detergents. The high level of stability of esterase EstAS with its unique substrate specificities make itself highly useful for biotechnological applications.


Sero-surveillance of dengue in the city Lahore, Pakistan.
To conduct sero-surveillance of dengue cases, and to find out the demographic and socio-economic status of dengue patients. This community-based, cross-sectional, descriptive study was conducted at the Institute of Public Health, Lahore, Pakistan, from July to December each year in 2011, 2012 and 2013, and comprised patients suspected to have dengue. Blood samples of dengue patients in five randomly selected union councils of the 10 towns of the city were subjected to the dengue test. Information about demographic and socio-economic characteristics was obtained with the help of pre-tested semi-structured questionnaire. SPSS 16 was used for data analysis. Of the 5,544 dengue patients, 5.263 (94.9%) patients were diagnosed in 2011, followed by 25(0.45%) and 256(4.6%) in 2012 and 2013, respectively. Sero-surveillance of these dengue patients in 2011 showed that on an average 3,094 (58.79%) cases had primary infection, 1,506 (28.61%) had old infection, while only 663 (12.6%) had secondary infection. Similar pattern was observed in 2012 and 2013. It was found that 2,379 (42.9%) participants were aged between 15-30 years and 2,203 (39.7%) between 31-45 years. Besides, 3,618 (65.3%) participants were males and 1,926 (34.7%) females. Also, 2,865 (51.4%) participants were labourers, 2,746 (49.5%) and 2,260 (40.7%) were educated up to primary and secondary levels, respectively. Although sporadic dengue cases were recorded from July to December, most of the cases were observed in late rainy and early post-rainy seasons. The incidence of dengue was highest in people of 15-45years of age, particularly males, labourers and those with low income.


[Advanced Parkinson's disease].
The stage of advanced Parkinson's disease usually occurs 10 years after the diagnosis but sometimes after 30 years. It is characterized by a severe handicap with gait disorders, posture changes, speech abnormalities and deglutition perturbations. Cognitive disorders (hallucinations, delirium, delusions, dementia) did not occur in all patients. Dysautonomic disorders are usual. Treatment is difficult and may include paradoxical prescriptions such as both apomorphine pump and clozapine.


Effect of Aerobic Exercise on White Matter Tract Microstructure in Young and Middle-Aged Healthy Adults.
Recent evidence suggests that being physically active can mitigate age-related white matter (WM) changes. In a randomized clinical trial, the effect of 6-month aerobic exercise (AE) or stretching/toning interventions on measures of WM microstructure (WMM) was assessed in a sample of 74 adults aged 20-67 years. Major WM pathways were reconstructed. No significant group-level change in WM tract microstructure following an AE training was observed. Without adjustment for multiple comparisons, an increase in fractional anisotropy (FA) and a decrease in mean diffusivity (MD) of the uncinate fasciculus were observed post-intervention in the AE group in comparison with the stretching group. In the AE group, a significant increase in cardiorespiratory fitness was measured but did not correlate with FA and MD change. The present results of this study are in accordance with similar studies in healthy adults that did not show significant benefit on WMM after participating in an AE program. Clinical Trial Registration: Clinicaltrials.gov identifier, NCT01179958.


Altering the relative abundance of GABA A receptor subunits changes GABA- and ethanol-responses in Xenopus oocytes.
Variations in GABRA2 and GABRG3, genes encoding the alpha2 and gamma3 subunits of the pentameric GABA(A) receptor, are associated with the risk of developing alcoholism in adults, conduct disorder at younger ages, and with differences in electroencephalographic power in the beta frequency range. The SNPs associated with alcoholism did not alter the coding of these genes, and extensive DNA sequencing of GABRA2 did not find coding changes in the high-risk haplotypes. Therefore, we hypothesize that the associations arise from differences in gene expression. Here we report studies in Xenopus oocytes to examine the functional effects of altering the relative abundance of these 2 receptor subunits on GABA current and response to ethanol, as a model of potential effects of regulatory differences. When human alpha2beta2gamma3 subunits are co-expressed, increasing the amount of the alpha2 subunit mRNA increased GABA current; in contrast, increasing the amount of the gamma3 subunit decreased GABA currents. Acute ethanol treatment of oocytes injected with a 1:1:1 or 2:2:1 ratio of alpha2:beta2:gamma3 subunit mRNAs resulted in significant potentiation of GABA currents, whereas ethanol inhibited GABA currents in cells injected with a 6:2:1 ratio. Overnight treatment with ethanol significantly reduced GABA currents in a manner dependent on the ratio of subunits. These studies demonstrate that changes in relative expression of GABA(A) receptor subunits alter the response of the resulting channels to GABA and to ethanol.


A novel and de novo splice-donor site mutation in intron 3 of the GH-1 gene in a patient with isolated growth hormone deficiency.
Heterozygous mutations at the splice-donor site of inron 3 of the GH-1 gene are known to affect growth hormone (GH) mRNA splicing and cause isolated GH deficiency (IGHD), which is inherited in an autosomal dominant trait. We report here a novel and de novo heterozygous IVS3 + 6T --> G mutation of the GH-1 gene in a Japanese patient with IGHD. RT-PCR analyses of the GH-1 minigene transcripts demonstrated that the IVS3 + 6T --> G mutation causes complete skipping of exon 3. We found a heterozygous IVS4 + 18G --> T polymorphism of the GH-1 gene in the patient, which was shared by the father, but not by the mother. Sequencing of individual alleles of the patient's GH-1 gene confirmed that the IVS3 + 6T --> G mutation and the IVS4 + 18G --> T polymorphism exist on the same chromosome. These findings indicate that the IVS3 + 6T --> G mutation arose in a germ cell of the father and caused IGHD in the patient.


A new insight into the definition of microcephaly in Zika congenital syndrome era.
This study aimed to compare the anthropometric measurements and body proportionalities of neonates born before the Zika virus epidemic with those born during this period. We compared 958 neonates born during the pre-Zika epidemic with 264 neonates born during the epidemic period. The newborns had their head circumference, weight, and length classified according to the Fenton & Kim growth chart. We considered disproportionate those individuals that presented microcephaly and adequate weight or length for sex and gestational age, and those whose head circumferences were lower than the ratio ((length / 2) + 9.5) - 2.5cm. We estimated the frequencies of Zika positivity and brain imaging findings among neonates with microcephaly born during the epidemic period, concerning the anthropometric and body proportionality parameters. Low weight and proportionate microcephaly were similar among newborns from both periods. However, the frequencies of newborns with microcephaly with a very low length and disproportionate microcephaly were higher among the neonates of the epidemic period with brain abnormalities and positive for Zika virus. We conclude that, at birth, the disproportion between head circumference and length can be an indicator of the severity of microcephaly caused by congenital Zika.


Is clinical primary care surveillance for tularaemia a useful addition to laboratory surveillance? An analysis of notification data for Finland, 2013 to 2019.
BackgroundIn Finland, surveillance of tularaemia relies on laboratory-confirmed case notifications to the National infectious Diseases Register (NIDR).AimThe aim of the study was to assess the suitability and usefulness of clinical surveillance as an addition to laboratory notification to improve tularaemia surveillance in Finland.MethodsWe retrieved NIDR tularaemia surveillance and primary healthcare data on clinically diagnosed tularaemia cases in Finland between 2013 and 2019. We compared incidences, demographic distributions and seasonal trends between the two data sources.ResultsThe median annual incidence was 0.6 (range: 0.1-12.7) and 0.8 (range: 0.6-7.2) per 100,000 for NIDR notifications and primary healthcare notifications, respectively. Cases reported to NIDR were slightly older than cases reported to primary healthcare (median: 53 years vs 50 years, p = 0.04), but had similar sex distribution. Seasonal peaks differed between systems, both in magnitude and in timing. On average, primary healthcare notifications peaked 3 weeks before NIDR. However, peaks in NIDR were more pronounced, for example in 2017, monthly incidence per 100,000 of NIDR notifications peaked at 12.7 cases in September, while primary healthcare notifications peaked at 7.2 (1.8 ratio) in August.ConclusionsClinically diagnosed cases provide a valuable additional data source for surveillance of tularaemia in Finland. A primary healthcare-based system would allow for earlier detection of increasing incidences and thereby for early warning of outbreaks. This is crucial in order to implement targeted control and prevention measures as early as possible.


Association of interleukin-15 single nucleotide polymorphisms with resistance to brucellosis among Iranian patients.
Interleukin (IL)-15, a Th1-related cytokine, triggers inflammatory cells' recruitment and increases the expression of interferon gamma (IFN-γ), which is an important cytokine in the immunity against brucellosis. Different single-nucleotide polymorphisms (SNPs) have been observed in the IL-15 gene, so this study aimed to investigate the probable association between these SNPs and susceptibility to brucellosis among Iranian patients. A total of 190 patients with brucellosis and 83 healthy milk farmers who consumed contaminated raw milk and dairy products from animals involved with brucellosis were included in this study. All the patients and the controls were genotyped for four IL-15 polymorphisms at positions 267, 367, 13687 and 14035 using polymerase chain reaction-restriction fragment length polymorphisms. The 267C and 13687A alleles, haplotypes CGCT and CAAA and the 267CC and 13687AA genotypes were significantly more frequent in the controls than in the patients (P = 0.014, 0.03, 0.006, 0.024, 0.026 and 0.01, respectively), so the variation in the IL-15 gene may be one of the factors affecting the resistance to brucellosis. In contrast, the frequency of haplotypes CGCA and TACT was significantly higher in patients compared with controls (P = 0.015 and 0.007, respectively), and interestingly the last one was observed only in the patients; therefore, it may serve as a predictive factor for brucellosis. In conclusion, it could be suggested that IL-15 genetic variants can affect resistance or susceptibility to human brucellosis among Iranian patients.


Regional reproducibility of pulsed arterial spin labeling perfusion imaging at 3T.
Arterial spin labeling (ASL) is a promising non-invasive magnetic resonance imaging (MRI) technique for measuring regional cerebral blood flow (rCBF) or perfusion in vivo. To evaluate the feasibility of ASL as a biomarker for clinical trials, it is important to examine test-retest reproducibility. We investigated both inter- and intra-session reproducibility of perfusion MRI using a pulsed ASL (PASL) sequence PICORE Q2TIPS with an echo-planar imaging (EPI) readout. Structural MRI regions of interest (ROIs) were extracted individually by automated parcellation and segmentation methods using FreeSurfer. These cortical and subcortical ROIs were used to assess regional perfusion stability. Our results indicated regional variability in grey matter rCBF. Although rCBF measurements were characterized by intersubject variation, our results also indicated relatively less within-subject variability estimated as within-subject standard deviation (SD(W)) (intersession SD(W): 2.0 to 8.8; intrasession SD(W): 2.8 to 9.6) and acceptable reliabilities as measured using intraclass correlation coefficient (ICC) (intersession ICC: 0.68 to 0.94; intrasession ICC: 0.66 to 0.95) for regional MRI perfusion measurements using the PICORE Q2TIPS technique. Overall, our findings suggest that PASL is a technique with good within and between session reproducibility. Further reproducibility studies in target populations relevant for specific clinical trials of neurovascular related agents will be important and the present results provide a framework for such assessments.


[Properties of the replicator region of the natural plasmid pLG13 containing genes of the EcoRV restriction-modification system].
The previously constructed plasmid pILRV8 that induces endonuclease EcoRV gene overexpression kills cells of some E. coli strains under the induction of this enzyme synthesis. Cell transformation by natural plasmid pLG13 carrying genes of the EcoRV restriction--modification system was found to appreciably enhance cell viability ("survival") under endonuclease overproduction. A plasmid pLG13 region located in immediate proximity to the methylase gene was shown to be responsible for the above effect. This region was also capable for autonomous replication. The analysis of the DNA primary structure in the found replicator region allowed to refer the pLG13 to ColE1 family plasmids. Perturbations in the region lead to loss of the "survival" effect and change of the plasmid replicative properties. A relationship between the replicon elements, the EcoRV genes region and "survival" effect is discussed. Based on the replicon found multicopy vector molecules have been constructed.


Adenovirus-mediated and tumor-specific transgene expression of the sodium-iodide symporter from the human telomerase reverse transcriptase promoter enhances killing of lung cancer cell line in vitro.
The sodium-iodide symporter (NIS) protein can mediate the active radioiodine uptake. The human telomerase reverse transcriptase (hTERT) promoter is known to be selectively reactivated in majority of tumors and hence could be used for tumor targeting. We constructed a recombinant adenovirus containing the human sodium iodide symporter (hNIS) gene directed by the hTERT promoter, characterized the ability of infected cells in uptaking iodide, and explored the therapeutic efficacy of (131)I in a lung cancer cell line in vitro. The hTERT promoter was amplified by PCR from DNA isolated from log-phase HepG2 cells, subcloned into lineralized FL*-hNIS/pcDNA3, and then the hTERT-hNIS sequence was subcloned into the shuttle plasmid pAdTrack. The recombinant adenovirus Ad-hTERT-hNIS was constructed by AdEasy system. A positive control adenovirus Ad-CMV-hNIS and a negative control adenovirus Ad-CMV were created similarly. A549 cells were transduced with recombinant adenoviruses. (125)I uptake studies and sodium perchlorate suppression studies were used to confirm hNIS expression and function. Toxic effects of (131)I on tumor cells were studied by in vitro clonogenic assay. We first successfully constructed an adenovirus mediated transgene expression system of the hNIS under the control of hTERT promoter. When infected with recombinant adenovirus constructs expressing hNIS directed by hTERT- and CMV-promoters (Ad-hTERT-hNIS and Ad-CMV-hNIS, respectively), the lung cancer cell line A549 had increased ability to uptake radioiodide up to 23- and 30-fold compared to the control parental cells, respectively. The radioiodide uptake ability of both the Ad-CMV-hNIS and Ad-hTERT-hNIS transduced cell lines were repressed 11-fold by sodium perchlorate (NaClO4). The subsequent in vitro clonogenic assay of the infected A549 cell line was further repressed to 23% (Ad-CMV-hNIS) and 30% (Ad-hTERT-hNIS) of the control group after receiving radioiodide for 7 hours (P < 0.001). Our preliminary study indicates that an adenovirus mediated transgene expression system of the hNIS under the control of hTERT promoter has the potential to become an effective wide-spectrum yet highly specific anti-cancer strategy.


High Prevalence of Abnormal General Movements in Hospitalized Very Low Birth Weight Infants.
Abnormal general movements (GMs) are predictive of later risk of motor impairments in preterm infants. The goals of this study are to (1) describe the implementation of the GM assessment (GMA) in a neonatal intensive care unit (NICU) and (2) investigate the prevalence and evolution of abnormal GMs in very low birth weight (VLBW) infants. Observational study of GMs in VLBW infants (gestational age [GA] <32 weeks and/or birth weight [BW] <1,500 g) following GMA implementation in a level-IV NICU. All VLBW infants admitted between November 2017 and April 2019 were eligible for the GMA. Infants were excluded if they required high-frequency ventilation or if they could not be unbundled for video acquisition. GMAs were scored weekly by at least 2 GMA-certified providers. The GMA was performed in 121 VLBW infants with a mean (standard deviation [SD]) GA of 28.3 (2.6) and BW of 1,113 (400 g). Only 28% of infants had normal GMs on initial assessment (32.9 ± 2.7 weeks' GA), while 61 and 11% had poor repertoire and cramped-synchronized GMs, respectively. At NICU discharge (37.6 ± 3.4 weeks corrected GA), 45 and 21% of infants were classified as having poor repertoire and cramped-synchronized GMs, respectively. Most infants with cramped-synchronized GMs on initial assessment had persistent abnormal GMs at discharge. In contrast, only one infant with normal GMs on first assessment developed cramped-synchronized GMs. Abnormal GMs are common in VLBW infants, including a high prevalence of the more concerning cramped-synchronized movement pattern. The GMA can be successfully performed in VLBW infants. The GMA may be helpful in identifying infants at increased risk of later motor impairments, as well as assisting clinicians, in the stratification of infants who may benefit from additional brain imaging and/or an intensive hospital-based interventions. · Abnormal GMs are common in VLBW infants.. · Poor repertoire in the most prevalent pattern observed.. · Infants at risk for abnormal motor outcomes can be identified in the NICU..


Difficulties in achieving arterial hypertension control.
Our study aims to examine the effectiveness of arterial hypertension treatment on arterial pressure values in a group of people, by gender and age. We performed an analytical prospective study, from 2007 to 2009, that included 2266 people; 674 subjects (397 women and 277 men) were diagnosed with essential systemic arterial hypertension, according to ESH (European Society of Hypertension) criteria. Medium age was 49 years. Therapy applied to all diagnosed patients consisted in: general measures (lifestyle modifications) and pharmacological treatment. Medication regimens implied: one agent (single drug therapy: inhibitors of angiotensin converting enzyme or angiotensin receptors blockers), two, three or more combined drugs (we used a combination of inhibitors of angiotensin converting enzyme or angiotensin receptors blockers and diuretics, beta-blockers, calcium channel blockers). Patients were followed up at 1 month, 3 and 6 month from the beginning of the study. Statistics used was EpiInfo6. Hypertension control was obtained for 33.38% of all patients; a better control was noticed for feminine gender (35.52%) over masculine gender (30.33%); distribution on age group showed the best control of the disease for the group aged 41 to 60 years old (19.92%) over those aged under 40 years (1.93%) and over 60 years (12.17%). Patient's poor compliance to treatment generates a suboptimal hypertension control, emphasizing that efforts for achieving goal blood pressure should continue.


Prescribing antibiotics: the use of diagnostic tests in general practice. A register-based study.
To assess (i) the pattern of antibiotic prescribing in Danish general practice, (ii) the use of diagnostic tests [point-of-care (POC) and tests analysed at the hospital laboratory (laboratory tests)], and (iii) the frequency of diagnostic testing in relation to antibiotic prescriptions. Retrospective cross-sectional register-based study. General practice in a geographical area of Denmark covering 455,956 inhabitants. We studied redeemed antibiotic prescriptions and performed diagnostic tests in general practice from 2013 to 2017 among inhabitants in nine selected municipalities. Frequency of antibiotic courses. Frequency and type of diagnostic testing performed in relation to types of antibiotics. A total of 783,252 antibiotic courses were redeemed from general practice with an overall decrease of 19% during 2013-2017. Diagnostic testing increased by 6% during this period. POC tests comprised the majority of performed diagnostic tests (83%) with C-reactive protein (CRP) as the most frequently used test. A 27% increase in the use of laboratory tests was observed. Tests were performed in relation to 43% of all antibiotic courses; most in relation to prescriptions for sulphonamide and trimethoprim (57%) and rarely when prescribing tetracyclines (10%). Conflicting with national guidelines, Danish GPs prescribed fluoroquinolones without performing any kind of diagnostic testing in 48% of the cases. This study provides an overview of the use of diagnostic tests in relation to antibiotics and creates basis for further research into the variability between types of antibiotics. The study indicates that there is room for improvement to use diagnostic tests as an aid to promote prudent antibiotic use.KEY POINTSDiagnostic tests (point-of-care or tests analysed at the hospital laboratory), can increase diagnostic certainty and lead to a reduction in antibiotic use in general practice.A decrease in antibiotic courses in general practice in Denmark was observed during 2013-2017, while the use of diagnostic tests increased.A diagnostic test was performed in relation to 43% of antibiotic courses.Only 52% of prescribed fluoroquinolones was related to a diagnostic test, conflicting with national guidelines.


Comparing genomes within the species Mycobacterium tuberculosis.
The study of genetic variability within natural populations of pathogens may provide insight into their evolution and pathogenesis. We used a Mycobacterium tuberculosis high-density oligonucleotide microarray to detect small-scale genomic deletions among 19 clinically and epidemiologically well-characterized isolates of M. tuberculosis. The pattern of deletions detected was identical within mycobacterial clones but differed between different clones, suggesting that this is a suitable genotyping system for epidemiologic studies. An analysis of genomic deletions among an extant population of pathogenic bacteria provided a novel perspective on genomic organization and evolution. Deletions are likely to contain ancestral genes whose functions are no longer essential for the organism's survival, whereas genes that are never deleted constitute the minimal mycobacterial genome. As the amount of genomic deletion increased, the likelihood that the bacteria will cause pulmonary cavitation decreased, suggesting that the accumulation of mutations tends to diminish their pathogenicity. Array-based comparative genomics is a promising approach to exploring molecular epidemiology, microbial evolution, and pathogenesis.


Introduction to the PLOS ONE collection on 'Understanding and preventing suicide: Towards novel and inclusive approaches'.
More than 700,000 people lose their lives to suicide each year and evidence suggests that the current COVID-19 pandemic is leading to increases in risk factors for suicide and suicide-related behaviour, in particular among young people. It is widely documented that some sectors of the population are over-represented in the suicide statistics. It is also well established that the pathways that lead someone to a suicidal crisis are complex and differ across regions and sectors of the population; as such a multi-faceted approach to prevention is required. Many of us would also argue that novel approaches, that combine broad population-based strategies with individual interventions, and approaches that capitalise on new technologies and methodologies are also required. For these reasons, when bringing together this collection, we deliberately sought studies that focused upon those groups who are over-represented in the suicide statistics yet under-represented in research. We also called for studies that reported on novel approaches to suicide prevention and for studies that reflected the voices of people with lived experience of suicide, also often unheard in research efforts.


The Role of DNA Methylation in Genome Defense in Cnidaria and Other Invertebrates.
Considerable attention has recently been focused on the potential involvement of DNA methylation in regulating gene expression in cnidarians. Much of this work has been centered on corals, in the context of changes in methylation perhaps facilitating adaptation to higher seawater temperatures and other stressful conditions. Although first proposed more than 30 years ago, the possibility that DNA methylation systems function in protecting animal genomes against the harmful effects of transposon activity has largely been ignored since that time. Here, we show that transposons are specifically targeted by the DNA methylation system in cnidarians, and that the youngest transposons (i.e., those most likely to be active) are most highly methylated. Transposons in longer and highly active genes were preferentially methylated and, as transposons aged, methylation levels declined, reducing the potentially harmful side effects of CpG methylation. In Cnidaria and a range of other invertebrates, correlation between the overall extent of methylation and transposon content was strongly supported. Present transposon burden is the dominant factor in determining overall level of genomic methylation in a range of animals that diverged in or before the early Cambrian, suggesting that genome defense represents the ancestral role of CpG methylation.


[Morphological and morphometric characteristics of the large-intestinal mucosa in Campylobacter infections].
Twenty-two biopsy specimens of colon mucosa were obtained from 16 patients with gastrointestinal campylobacteriosis histologically, histochemically and morphometrically. At the height of the disease colon mucosa of these patients showed a morphological picture of acute hemorrhagic and erosive--hemorrhagic colitis. When compared with such for other intestinal infections (shigellosis, salmonellosis, rotaviral gastroenteritis), the morphological features appeared to vary permitting a differential diagnosis with acute colitis due to above infections, but objective criteria to differentiate campylobacter-induced colitis from colitis in aggravation of nonspecific ulcerative one and Crohn's disease still remains to be found.


Internet Promotion of Direct Anterior Approach Total Hip Arthroplasty by Members of the American Association of Hip and Knee Surgeons.
The direct anterior approach (DAA) in total hip arthroplasty is of significant interest to both patients and surgeons, largely due to intense marketing. This study addressed the question, "What is the level of promotion of DAA total hip arthroplasty on the internet by American Association of Hip and Knee Surgeons (AAHKS) members?" An internet search was performed to identify surgeon-specific websites for each member of the AAHKS using the members' full name and a previously published set of criteria. Each website was evaluated utilizing a questionnaire to systematically identify claims made regarding proposed DAA-specific risks, benefits, as well as the presence/absence of supporting data. We identified 1855 qualified websites. The DAA was referenced on 22.8% (423/1855) of these websites. Claims regarding DAA-specific benefits included less invasive/muscle sparing (46.3%), quicker recovery (45.2%), decreased pain (28.1%), decreased hospital stay (22.0%), and decreased dislocation risk (16.3%). Potential DAA risks including lateral femoral cutaneous nerve injury, periprosthetic/greater trochanteric fracture, and wound complication/hematoma were addressed on only 4.7%, 3.1%, and 1.7% of websites, respectively. Supporting peer-reviewed literature was identified on only 3.6% of DAA websites. Over one-fifth of AAHKS members promoted the DAA on the internet. Member websites claimed DAA benefits such as faster recovery and decreased pain approximately 9 times more frequently than any potential risk of the procedure (P < .001). While AAHKS policy does not regulate member marketing, it is the responsibility of all orthopedic surgeons to disseminate accurate, validated information concerning the procedures we perform.


Seasonal variations in indoor resting Anopheles gambiae and Anopheles arabiensis in Kaduna, Nigeria.
A longitudinal study in a guinea savanna area in Northern Nigeria showed that indoor resting samples consisted almost entirely of An. gambiae in the wet season, characterized by relatively lower temperature and higher relative humidity, whereas An. arabiensis predominated in the dry season, characterized by relatively higher temperature and lower relative humidity. A significant change was also observed in the frequency of polymorphic chromosomal inversions in the population of An. gambiae. The inverted arrangements 2Rbc, 2Rd and 2La were found more frequent in the dry season samples as compared to the wet season ones.


Invasive Fungal Infections Complicating COVID-19: A Narrative Review.
Invasive fungal infections (IFIs) can complicate the clinical course of COVID-19 and are associated with a significant increase in mortality, especially in critically ill patients admitted to an intensive care unit (ICU). This narrative review concerns 4099 cases of IFIs in 58,784 COVID-19 patients involved in 168 studies. COVID-19-associated invasive pulmonary aspergillosis (CAPA) is a diagnostic challenge because its non-specific clinical/imaging features and the fact that the proposed clinically diagnostic algorithms do not really apply to COVID-19 patients. Forty-seven observational studies and 41 case reports have described a total of 478 CAPA cases that were mainly diagnosed on the basis of cultured respiratory specimens and/or biomarkers/molecular biology, usually without histopathological confirmation. Candidemia is a widely described secondary infection in critically ill patients undergoing prolonged hospitalisation, and the case reports and observational studies of 401 cases indicate high crude mortality rates of 56.1% and 74.8%, respectively. COVID-19 patients are often characterised by the presence of known risk factors for candidemia such as in-dwelling vascular catheters, mechanical ventilation, and broad-spectrum antibiotics. We also describe 3185 cases of mucormycosis (including 1549 cases of rhino-orbital mucormycosis (48.6%)), for which the main risk factor is a history of poorly controlled diabetes mellitus (>76%). Its diagnosis involves a histopathological examination of tissue biopsies, and its treatment requires anti-fungal therapy combined with aggressive surgical resection/debridement, but crude mortality rates are again high: 50.8% in case reports and 16% in observational studies. The presence of other secondary IFIs usually diagnosed in severely immunocompromised patients show that SARS-CoV-2 is capable of stunning the host immune system: 20 cases of Pneumocystis jirovecii pneumonia, 5 cases of cryptococcosis, 4 cases of histoplasmosis, 1 case of coccidioides infection, 1 case of pulmonary infection due to Fusarium spp., and 1 case of pulmonary infection due to Scedosporium.


Epidemiologic studies of cancer in agricultural workers.
The incidence of cancer in agricultural workers is generally low, in part due to the low prevalence of cigarette smoking in this group. However, agricultural workers have elevated risks for several specific cancer types including leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and cancers of the lip, stomach, prostate, brain, and connective tissue. Two major groups of risk factors have been proposed as causes of hematologic malignancies in agricultural workers. The first group includes various agricultural chemicals. In particular, several studies have found increased risks of malignant lymphoma and soft tissue sarcoma in persons exposed to phenoxy herbicides. However, the evidence is inconsistent and there is a wide variation in relative risk estimates. The second group of risk factors includes various animal viruses. There is currently little evidence concerning the zoonotic nature or human carcinogenicity of these viruses. However, leads have been suggested by recent evidence of increased risks of hematologic malignancies in abattoir workers, veterinarians, and meat inspectors. A third hypothesis, for which little evidence is currently available, is that agricultural work may involve prolonged antigenic stimulus leading to lymphoproliferation. The factors responsible for the increased risks for cancers other than hematologic malignancies are not well understood but may also involve exposure to chemicals or viruses.


Tumor markers in stage P1 bladder cancer.
The infiltration of muscularis mucosa in superficial bladder cancer has been reported to be predictive of an unfavourable course of the disease. We studied immunohistochemically Ki-67, PCNA and p53 tumour markers in 68 P1a and Pib bladder tumours. A statistically significant difference (p = 0.01) was found in the distribution of grades between stages P1a and P1b, with more grade 3 and less grade 2 tumours in the latter category. Univariate analysis revealed a strong association of Ki-67 (p = 0.001) and PCNA (p = 0.032) only with stage. P53 protein expression did not have any significant association with either stage or grade. In 60 patients entered into the multivariate analysis a clearly predominant, significant effect of stage on Ki-67 (p = 0.000) was shown. Increased proliferative activity when compared to P1a is present in P1b bladder tumours, as detected by the increased expression of Ki-67 proliferating antigen. The immunohistochemical study of Ki-67 antigen may help in predicting stage P1 tumours' behaviour, even in cases where pathological distinction of P1a and P1b substages is difficult.


Toward an ecotoxicological risk assessment of microplastics: Comparison of available hazard and exposure data in freshwaters.
Microplastics have been detected in freshwaters all over the world in almost all samples, and ecotoxicological studies have shown adverse effects of microplastics on organisms. However, no risk assessment of microplastics has been performed specifically in freshwater so far. The aim of the present study was therefore to review all exposure and ecotoxicity data available for microplastics in freshwaters and to perform a preliminary probabilistic risk assessment. The exposure probability distribution was based on 391 concentrations measured in Asia, Europe, and North America. Because exposure data are mainly available in particle number-based metrics but results from hazard studies are mostly mass-based, the hazard results were converted into particle number concentrations. A statistical analysis of the hazard data showed that there was no significant influence of particle shape or type of polymer on the no-observed-effect concentration. The predicted-no-effect concentration (PNEC) was calculated as the fifth percentile of the probabilistic species sensitivity distribution, based on 53 values from 14 freshwater species, to have a mode of 7.4 × 105 particles · m-3 (25th and 75th quantiles of 6.1 × 105 and 1.3 × 106 particles · m-3 , respectively). The exposure probability distribution was divided by the PNEC probability distribution to calculate risk characterization ratios (RCRs), with modes of 1.3 × 10-6 in North America, 3.3 × 10-6 in Europe, and 4.6 × 10-3 in Asia. Probability distributions associated with the RCRs showed that ecological risks cannot be entirely excluded in Asia, where 0.4% of the RCR values were above 1. Environ Toxicol Chem 2019;38:436-447. © 2018 SETAC.


Low abundance of telomerase in yeast: implications for telomerase haploinsufficiency.
Telomerase is an RNA-dependent reverse transcriptase that maintains telomeric DNA at a species-specific equilibrium length. To determine an upper limit for the number of telomerase molecules in a Saccharomyces cerevisiae cell, we have established real-time RT-PCR assays to quantify the noncoding telomerase RNA, TLC1. We find that the number of TLC1 molecules in a haploid yeast cell is approximately 29, less than the number of chromosome ends (64) in late S-phase. Wild-type diploid cells contain approximately 37 telomerase RNAs, while diploids heterozygous for a null tlc1 allele have half the wild-type amount, approximately 19 TLC1 molecules. For comparison, there are approximately 480 molecules of the U2 snRNA per haploid cell. We show that a biological consequence of this low level of telomerase is haploinsufficiency: A TLC1/tlc1Delta heterozygote maintains shorter telomeres. A dominant-negative telomerase RNA, with a deletion of the template for telomeric DNA synthesis, further demonstrates that yeast telomere length is sensitive to telomerase dosage. Sixfold overexpression of tlc1Deltatemplate establishes a new telomere length set point, approximately 160 bp shorter than wild type. Removing telomerase protein-interaction sites from the tlc1Deltatemplate RNA mitigates the dominant-negative effect, suggesting that the tlc1Deltatemplate RNA competes with wild-type TLC1 for a limited supply of telomerase proteins or for telomeres. Because yeast telomerase is tethered at chromosome ends, the finding that it may be outnumbered by its telomeric DNA substrates provides a new perspective for interpreting the results of telomere maintenance studies.


Possibilities for load reductions using garment leg protectors for motorcyclists -- a technical, medical and biomechanical approach.
This study has considered demands placed on protective clothes for motorcyclists together with observed benefits and limitations for absorbing loads and preventing injuries. In this study, 1933 accidents involving injured motorcyclists, collected by an in-depth investigation team at ARU-MUH, were analysed to find the detailed injury patterns comparing persons with and without protective clothes. The parameters influencing the force reduction are discussed comparing impact speed, elasticity coefficient and thickness of the materials used in special protectors. Additionally, post mortem human tests were carried out to find the effectiveness of such protector devices for load reductions in the lower leg. This study showed that loads, and the subsequent risk of fractures, can be reduced efficiently by foam-plate systems. Benefits were established for using a laminate of hard and soft materials for protection against soft tissue injuries both in the accident analysis and experimental tests.


BW373U86, a delta-opioid receptor agonist, reverses bradykinin-induced thermal allodynia in rhesus monkeys.
The synthetic delta-opioid receptor agonist BW373U86 (0.18-0.56 mg/kg s.c.) was studied in rhesus monkeys with a warm-water, tail-withdrawal assay, designed to detect bradykinin (0.1 microgram) and prostaglandin E2 (5-15.8 micrograms)-induced thermal allodynia. BW373U86 dose-dependently reversed bradykinin allodynia, but was ineffective against prostaglandin E2 allodynia. The BW373U86 dose-effect curve was shifted to the right by the delta-opioid receptor-selective antagonist naltrindole (1.0 mg/kg) but not by the mu-opioid receptor-selective antagonist quadazocine (0.1 mg/kg). The present findings add to the conditions in which delta-opioid receptor-mediated behavioral effects have been detected in primates, and suggest that delta-opioid agonists may be of therapeutic interest in the treatment of some types of hyperalgesic conditions.


[Sonography of jugular vein thrombosis].
Based on a case report, angiographic and sonographic findings of jugular venous thrombosis are discussed. On the strength of the sonographic demarcation of anatomical and functional soft tissue structures of the neck ultrasound should rank first in the diagnostic hierarchy after clinical investigation.


Restoration of the glycogen-forming function of hepatocytes in rats with liver cirrhosis is facilitated by a high-carbohydrate diet.
Using cytofluorimetric and biochemical methods, the content of glycogen and its labile and stable fractions, as well as activities of glucose-6-phosphatase (EC 188.8.131.52), glycogen phosphorylase (EC 220.127.116.11) and glycogen synthase (EC 18.104.22.168) were determined in the rat liver for 6 months after chronic poisoning of the animals with CCl4 and then at 1, 3, and 6 months after the end of the poisoning. One group of rats was given a standard diet, the other, a high-carbohydrate diet. The 6-month long chronic intoxication with CCl4 was shown to produce development of typical liver cirrhosis characterized by a 2.8-fold increase in the total glycogen content in hepatocytes as compared with normal cells, by a fall in the glycogen labile fraction (from 85 to 53% of the total glycogen) as well as by decreases in the activities of glycogen phosphorylase and glucose-6-phosphatase by 25 and 82% respectively. The structural rehabilitation occurred faster and more completely at the cellular level than at the tissue level. Functional variables of the cirrhotic liver tissue also recovered, after cessation of poisoning, faster and more completely than the liver structure at the tissue level: glycogen levels in hepatocytes fell dramatically, the labile: stable glycogen fraction ratio recovered completely, and the activity of glycogen phosphorylase rose to the level characteristic of the normal liver. Use of the high-carbohydrate diet promoted a somewhat faster and more complete recovery of hepatic structure and function.