[Imported malaria in Lombardia. A second review of hospitalized cases in 1981-1985].
We carried out a research on hospitalized cases of imported malaria in Lombardy in the period 1981-1985 to characterize the risk factors and the clinical features of this phenomenon and to identify its trend in comparison with the previous quinquennium (Carosi et al., 1983). 1) Prevalent factors of risk are: the P. falciparum etiology (68%), the african origin of the strains, the work motivated travelling (56%) and a long period of stay (56%) in the summer-autumnal season (62%). On the contrary, in the previous quinquennium, short periods of stay during winter season prevailed. 2) As far as the chemoprophylaxis is concerned, it has been adopted in 55% of the cases, but only in 14 cases it was correct. In 52% of the cases, symptoms were noted within 20 days of re-entry, and in 17% of the cases they started abroad. In 62% of the cases a correct diagnosis was made within 10 days from the onset of symptoms and in 72% fever disappeared within 48 hours after therapy. Data show an inversion of the trend of the previous quinquennium and evidentiate a wider use of chemoprophylaxis and a more effective therapeutic action by the Sanitary Structure in Lombardy. The Authors stress the need for improvement in malaria control programs by Italian industries working in Developing Countries (roads and dams construction) and the increasing prophylactic problems related to che widespread extent of chloroquine resistant P. falciparum strains in Africa. Our causistry shows the outcome of 14 falciparum malaria cases in spite of correct chloroquine chemoprophylaxis.


The current evidence base for the clinical care of suicidal patients: strengths and weaknesses.
To delineate the place of suicide as a public health problem, describe the methodology by which studies of care of suicidal persons have been assessed in this compendium of evaluative papers, and consider whether improved clinical care can reduce suicide. Systematic review according to the principles of evidence-based medicine. The limitations of the evidence are highlighted. There is evidence that optimal clinical care can make a difference and reduce suicide. There is no magic clinical bullet currently available that could replace excellent clinical care, which remains the centrepiece of treatment of suicidal persons.


The Importance of Advanced Imaging by Cardiac Magnetic Resonance Imaging in Diagnosing Congenital Left Ventricular Diverticulum.
The left ventricle diverticulum is a very rare congenital cardiac malformation that is usually present during childhood. However, we are reporting the case of an adult patient with a left ventricular diverticulum who presented with chest pain. This paper also highlights the importance of using advanced imaging modalities such as cardiac magnetic resonance, which was essential for diagnosing our case. Our management was conservative, as the patient's chest pain was very mild and resolved within a few days.


Comparison of Static and Dynamic Baseline Creatinine Surrogates for Defining Acute Kidney Injury.
"Dynamic" baseline serum creatinine (sCr), based on a rolling 48-h window, and a static baseline sCr (previous outpatient sCr) were used to define acute kidney injury (AKI). Retrospective cohort study of adult admissions to the University of Alabama (UAB) Health System hospitals for years 2016-2018. Included admissions had >1- and <180-day length of stay, >2 inpatient sCr measurements, and an averaged estimated glomerular filtration rate >15 mL/min/1.73 m2. The final cohort of 62,380 patients included 100,570 admissions, 3,509 inpatient deaths, and 1,916 admissions with inpatient dialysis. AKI was defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria and a static or dynamic baseline sCr. Discrimination was evaluated with area under receiver operator curves (AUC), logistic regression, and net reclassification improvement (NRI). Preadmission outpatient "static" sCr values were available for 43,433 admissions. The lowest sCr value during a rolling 48-h window before each inpatient sCr defined a "dynamic" baseline sCr. Using point-wise comparisons, the dynamic baseline sCr performed better than static baseline sCr for inpatient mortality (AUC [0.819 vs. 0.741; p < 0.001] and NRI ≥0.306 [p < 0.001]) and inpatient dialysis (AUC [0.903 vs. 0.864; p < 0.001] and NRI ≥0.317 [p < 0.001]). The dynamic baseline sCr is available without reference to preadmission sCr values and avoids confounding associated with missing outpatient sCr values. AKI defined with the dynamic baseline sCr significantly improved discrimination of risk for inpatient mortality and dialysis compared to static baseline sCr.


A Modified Single-Armed Suture Technique for Traumatic Cyclodialysis Cleft with Vitreoretinal Injury.
Our aim was to assess the therapeutic efficacy of a modified single-arm suture technique on traumatic cyclodialysis cleft with vitreoretinal injury. The procedure involved fixing a detached ciliary body using a single-armed 10-0 polypropylene suture under the assistance of a 29-gauge needle. Patients with a traumatic cyclodialysis cleft combined with an anterior and posterior segment injury who underwent modified internal cyclopexy together with vitreoretinal surgery were enrolled in this study. Ultrasound biomicroscopy (UBM) was used to diagnose and evaluate the cyclodialysis and anterior segment injury. B-scan ultrasonography was performed to assess the condition of the vitreous, retina and choroid. The surgical time and successful rate for repairing the cyclodialysis cleft were recorded. Preoperative and postoperative best-corrected visual acuity (BCVA), and intraocular pressure (IOP) were documented for assessment. The study included 20 eyes. The extent of the cyclodialysis cleft was from 30° to 360°. Besides a traumatic cyclodialysis cleft, the included cases also combined this with vitreous hemorrhages, retinal detachment, macular holes, choroid avulsion, and suprachoroidal hemorrhage. All the clefts were anatomically closed in one surgery. The average surgical time for fixing the cyclodialysis cleft was 2.68 ± 0.54 min/30° cleft. A significant improvement in LogMAR BCVA was observed from 2.94 ± 0.93 preoperatively to 1.81 ± 1.11 at the 6-month follow-up. IOP was elevated from 10.90 ± 6.18 mmHg preoperatively to 14.45 ± 2.35 mmHg at the 6-month follow-up. The modified single-armed suture technique was proved to be an effective method to fix the traumatic cyclodialysis cleft, which could facilitate the use of the procedure to repair chorioretinal disorders. It improved the BCVA and maintained the IOP with less postoperative complications.


Diverse ranking metamaterial inverse design based on contrastive and transfer learning.
Metamaterials, thoughtfully designed, have demonstrated remarkable success in the manipulation of electromagnetic waves. More recently, deep learning can advance the performance in the field of metamaterial inverse design. However, existing inverse design methods based on deep learning often overlook potential trade-offs of optimal design and outcome diversity. To address this issue, in this work we introduce contrastive learning to implement a simple but effective global ranking inverse design framework. Viewing inverse design as spectrum-guided ranking of the candidate structures, our method creates a resemblance relationship of the optical response and metamaterials, enabling the prediction of diverse structures of metamaterials based on the global ranking. Furthermore, we have combined transfer learning to enrich our framework, not limited in prediction of single metamaterial representation. Our work can offer inverse design evaluation and diverse outcomes. The proposed method may shrink the gap between flexibility and accuracy of on-demand design.


Synergistic bone marrow toxicity of pyrimethamine and zidovudine in murine in vivo and in vitro models: mechanism of toxicity.
Pyrimethamine (Pyr) is commonly used for treatment of toxoplasmic encephalitis in AIDS patients; however, in two clinical studies, an increased number of deaths were observed when Pyr was coadministered with zidovudine (ZDV). The BALB/c mouse was chosen as a model to study the mechanism underlying the unexpected toxicity from coadministration of these drugs. Daily administration by oral gavage of 60 mg/kg Pyr and 240 mg/kg ZDV resulted in 100% lethality after 30 days. These dose levels produced no effect when the drugs were given individually for the same period. Administration of combinations of Pyr and ZDV resulted in macrocytic anemia and leukopenia with synergistic decreases in lymphocyte and neutrophil numbers. To examine the mechanism of this hematotoxicity at the cellular level, mouse bone marrow colony-forming unit (mCFU) assays were employed. A combination of ZDV with various concentrations of Pyr resulted in synergistic decreases in numbers of erythroid and granulocyte-macrophage precursors (mCFU-E and mCFU-GM). mCFU-GM precursors appeared more sensitive than erythroid precursors to combinations of Pyr and ZDV. Incorporation of (14)C-ZDV into cellular DNA was increased in a dose-dependent manner in the presence of increasing concentrations of Pyr in the mCFU-GM assay. This suggested that inhibition of dihydrofolate reductase by Pyr and accompanying inhibition of dTTP synthesis allows preferential incorporation of ZDV into DNA, with resulting strand breakage and cell death. (14)C-ZDV incorporation was also observed when human GM cultures were analyzed, however, incorporation was less and required higher concentrations of Pyr.


The self and depression: Four psychological theories and their potential neural correlates.
We review theory and research pertaining to psychodynamic, social, humanistic, and ethological models of the self and depression and examine research into the neurobiological bases of the self and depression. We provide a narrative review of classic and recent empirical evidence pertaining to these four models of the relation of the self to depression as well as exemplar relevant neurobiological research. Evidence stemming from each of the four theories reviewed here shows a robust relationship between deficits in the sense of self and depressive symptoms, as well as increases in depressive symptoms over time. A smaller body of literature has linked one's sense of self to onsets of depressive episodes. A growing body of literature has linked self-relevant variables to functioning in various prefrontal and cortical midline brain regions as well as emotion and reward processing brain regions which have in turn been linked to depression. Evidence has therefore converged across all four theories and confirmed that a deficit in one's sense of self confers risk for depression and that there is substantial overlap in the brain areas associated with one's sense of self and depression.


Novel no-stop FLNA mutation causes multi-organ involvement in males.
Mutations in FLNA (Filamin A, OMIM 300017) cause X-linked periventricular nodular heterotopia (XL-PNH). XL-PNH-associated mutations are considered lethal in hemizygous males. However, a few males with unusual mutations (including distal truncating and hypomorphic missense mutations), and somatic mosaicism have been reported to survive past infancy. Two brothers had an atypical presentation with failure to thrive and distinct facial appearance including hypertelorism. Evaluations of these brothers and their affected cousin showed systemic involvement including severe intestinal malfunction, malrotation, congenital short bowel, PNH, pyloric stenosis, wandering spleen, patent ductus arteriosus, atrial septal defect, inguinal hernia, and vesicoureteral reflux. The unanticipated finding of PNH led to FLNA testing and subsequent identification of a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). Western blotting and qRT-PCR of patients' fibroblasts showed diminished levels of protein and mRNA. This FLNA mutation, the most distal reported so far, causes in females classical XL-PNH, but in males an unusual, multi-organ phenotype, providing a unique insight into the FLNA-associated phenotypes.


Confirmatory factor analysis of the antisocial process screening device with a clinical inpatient population.
Research linking psychopathic tendencies to childhood behavior problems is predicated on the assumption that the findings are based on using psychometrically sound measures of psychopathic tendencies. Although evaluated with community samples, the psychometric properties of such measures have not been evaluated with inpatient clinical populations thereby limiting conclusions. Hence, the goal of the present study was to evaluate the factor structure of a widely used measure-the Antisocial Process Screening Device (APSD)-with an inpatient population. Parents of 328 children (M age = 8.90 years) completed the APSD at the time of their child's admission for treatment. Although confirmatory factor analyses supported the three- and two-factor solutions proposed by the authors of the measure, the two-factor structure was more parsimonious. Factors of the two-factor model were also related to symptoms of childhood behavior disorders. The findings extend current research on the APSD's factor structure to an inpatient population.


Antinociceptive and anti-inflammatory activities of Bridelia retusa methanolic fruit extract in experimental animals.
Antinociceptive and anti-inflammatory potentials of methanolic extract of Bridelia retusa fruit (BRME) were evaluated against different animal models in rodents. Antinociceptive effects of BRME were assessed in mice using the acetic acid-induced writhing and formalin test. Anti-inflammatory effects of BRME in three different doses, namely, 100, 200, and 400 mg/kg, were evaluated by utilizing different animal models representing various changes associated with inflammation, namely, carrageenan-induced paw oedema, histamine and serotonin-induced paw oedema, arachidonic acid-induced paw oedema, formalin-induced paw oedema, TPA-induced ear oedema, acetic acid-induced vascular permeability, total WBC count in paw fluid, and myeloperoxidase assay. Also BRME was phytochemically evaluated using chromatographic method. The BRME did not exhibit any signs of toxicity up to a dose of 2000 mg/kg. The extract showed statistical significant inhibition of induced nociception and inflammation in dose dependent manner. The higher dose of extract significantly inhibited pain and inflammation against control (P < 0.001). HPLC results revealed the presence of gallic acid and ellagic acid as phytoconstituents in BRME and it was proven as anti-inflammatory agents. The present study scientifically demonstrated the antinociceptive and anti-inflammatory potential of fruit of B. retusa methanolic extract. These effects may be attributed to the presence of polyphenolic phytoconstituents in the extract.


Synovial cyst: an uncommon cause of back pain.
Synovial cyst is an uncommon cause of back pain and radiculopathy. This case report describes the magnetic resonance imaging findings of two lumbar synovial cysts with special emphasis on the differential diagnoses of other extradural cystic lesions.


From the Rodent Spinal Cord Injury Model to Human Application: Promises and Challenges.
Repair of the spinal cord and improvement of mobility after injury has been a matter of basic and clinical research for several decades. A number of repair approaches were performed in animals, mainly rodent models of spinal cord injury (SCI). Some of these experimental therapies resulted in significant regeneration of tract fibers, formation of new connections and circuits, and associated improvement of mobility. Some clinical trials aiming at translating these approaches to the human condition of an SCI are currently on-going. The present therapy, however, remains rehabiliation: Mobility of patients with an SCI can be improved to a limited extent by the exploition of neuroplasticity. In this article the present state of the art in the field of SCI research will be discussed. Studies dealing with the promotion of spinal cord repair and those directed to improve mobility by exploition of neuroplasticity will be summarized. The promises and challenges of translational basic research in rodent SCI models will be presented.


Epstein-Barr virus and Herpesvirus saimiri: sensitivity to interferons and interferon inducers.
The in vitro sensitivity of oncogenic herpesviruses, Epstein-Barr virus (EBV), and Herpesvirus saimiri (HVS) to human interferon produced by normal human leukocytes (Le), lymphoblastoid cell lines (LYI), and diploid fibroblasts (Fi) was studied. Four virus strains were used: HVS S295C, the highly oncogenic HVS S396-O, the transforming B95-8 strain of EBV, and the nontransforming P3HR1 strain of EBV. All interferons were active when applied to the cells after absorption of HVS and P3HR1-EBV, although different amounts were required to achieve 50% inhibition of HVS-induced cytopathic effect or EBV-induced early antigen (EA) expression. Transformation of human umbilical cord blood lymphocytes (HCBL) by the B95-8 strain of EBV was prevented only by Le and LYI. In these experiments, the most effective inhibitor of the oncogenic herpesviruses was Le, and the least effective was Fi. The effect of polynucleotides poly(I).poly(C) and the complex of poly(I).poly(C) with poly-L-lysine and carboxymethylcellulose on HVS and EBV was also studied. Their inhibitory action was proportionate to the ability of herpesvirus-infected cells to produce interferon. Thus owl monkey kidney cells, which produce relatively high levels of interferon, required nanogram quantities of polynucleotides to become resistant to HVS. Transformation of HCBL by B95-8-EBV was also prevented by poly(I).poly(C). In Raji cells superinfected with P3HR1-EBV, polynucleotides failed to stimulate interferon, and higher EBV-induced EA expression was observed. The percentage of P3HR1 and Raji cells spontaneously expressing EBV-associated antigens remained unchanged after exposure to either interferon or polynucleotides.


Syndesmotic screw placement: a biomechanical analysis.
At the present time, syndesmotic screw fixation is recommended when there is a tibiofibular diastasis, a Maisonneuve fracture, or syndesmotic instability after fixation of distal tibia-fibula fractures. The aim/purpose of this study was to demonstrate the optimal level of syndesmotic screw placement before creation of a Maisonneuve fracture. Legs of 17 embalmed cadavers underwent knee disarticulation. The legs were then dissected to expose the syndesmosis/interosseous membrane. The paired cadaver legs were tested in two groups. In group I (10 pairs), the left legs were tested without any syndesmotic fixation and the right legs were tested with the syndesmosis fixed at 2.0 cm above the tibiotalar joint. In group II (7 pairs), the syndesmosis in each left leg was fixed at 3.5 cm above the tibiotalar joint and the right leg syndesmosis was fixed at 2.0 cm above the tibiotalar joint. After ligament section and syndesmosis fixation, each leg was then jig mounted with transfixing wires through the proximal tibia and calcaneus. The ankle was placed in neutral with 15 degrees of pronation and a load of 150 pounds and a strain gauge anchored medially and laterally. The proximal tibia was internally rotated while the ankle was held fixed until syndesmotic, bony, or hardware failure occurred. Torsional force, the degree of rotation and the amount of syndesmotic widening were quantitated. Two-tailed t-test comparing no fixation with fixation at 2.0 cm indicated less syndesmotic widening with screw placed at 2.0 cm (P = 0.04). Two-tailed t-test comparing screw fixation at 2.0 cm and 3.5 cm indicated less syndesmotic widening with screw placed at 2.0 cm (P = 0.07). It would seem reasonable to place a syndesmotic screw at 2.0 cm above tibiotalar joint.


Developmental Origins and Nephron Endowment in Hypertension.
Primary hypertension continues to be one of the main risk factors for cardiovascular disease worldwide. A stable intrauterine environment is critical for the future development and health of the fetus. The developing kidney has been found to be especially vulnerable during this time period, and epidemiological studies have demonstrated that an adverse in utero environment is associated with an increased risk of hypertension and chronic kidney disease. Macro- and micronutrient deficiencies as well as exposure to tobacco, alcohol, and certain medications during gestation have been shown to negatively impact nephrogenesis and reduce one's nephron number. In 1988, Brenner et al. put forth the controversial hypothesis that a reduced nephron complement is a risk factor for hypertension and chronic kidney disease in adulthood. Since then numerous animal and human studies have confirmed this relationship demonstrating that there is an inverse association between blood pressure and nephron number. As our understanding of the developmental programming of hypertension and other non-communicable diseases improves, more effective preventive health measures can be developed in the future.


[The arterial blood gas change in anesthetized patients with apnea: disadvantage of hyperventilation before intubation].
We studied the arterial blood gas changes during 4 minute apnea period without using constant oxygen flow under anesthesia. Fifteen adult surgical patients (ASA PS 1 or 2, 21-49 years of age) were randomly divided into 3 groups by ETCO2 before the start of apnea (group I: 40 mmHg, group II: 30 mmHg, group III: 20 mmHg). In addition, each patient was monitored with pulse oximetry, ECG, blood pressure, FIO2 and ETCO2. The rate of rise of PaCO2 during the apnea showed no significant difference among these 3 groups. In the first minute of apnea, PaCO2 increased 9.8 +/- 1.9 mmHg, and then increased at a rate of 3.4-4.4 mmHg.min-1 thereafter. In conclusion, the rate of rise of PaCO2 in anesthetized patients with apnea was logarithmic and there was no correlation with pre-apnea ETCO2. The rate of SpO2 decrease was significant in hyperventilated group (III). Thus, hyperventilation applied before the endotracheal intubation is not of benefit to the oxygenation of healthy humans.


Imaging Accuracy in Preoperative Staging of T3-T4 Laryngeal Cancers.
Preoperative imaging impacts treatment planning and prognosis in laryngeal cancers. We investigated the accuracy of standard computed tomography (CT) in evaluating tumor invasions at critical glottic areas. CT scans of glottic cancers treated by partial or total laryngectomy between Jan 2015 and Aug 2019 were reviewed to assess levels of tumor invasion at critical glottic subsites. CT accuracy in the identification of tumor extensions was determined against the gold standard of histopathological analysis of surgical samples. This study included 64 patients. In the anterior commissure, CT showed high rates of false positives at all levels (sensitivity 56.2-70%, specificity 87.8-92.3%); in the anterior vocal fold, it overestimated the deep invasion (19.5% specificity, 90.3% sensitivity), while it underestimated the extralaryngeal spread (63.6% sensitivity, 98.1% specificity). In the posterior paraglottic space (pPGS), false negative results were more frequent for superficial extensions (25% sensitivity, 95.8% specificity) and deep invasions (58.8% sensitivity, 82.3% specificity). Shorter disease-specific and disease-free survivals were associated with pStage IV (p: 0.045 and 0.008) and with the pathological involvement of pPGS (p: 0.045 and 0.015). Negative prognostic correlation of pPGS involvement was confirmed on histopathological data. CT staging did not provide a satisfactory prognostic stratification and should be complemented with magnetic resonance imaging.


Epidemiology of cutaneous melanoma and melanoma in situ: a 10-year nationwide retrospective cohort study in South Korea.
Numerous studies on the epidemiology of cutaneous melanoma (CM) have been reported for Caucasians, but rarely for Asian populations including Korea. The aim of this study was to investigate the epidemiology of CM and melanoma in situ (MIS) in the Korean population. We investigated a nationally representative sample cohort of over one million Koreans for patients diagnosed with CM and MIS. Annual and overall incidence rates, as well as the survival rate of CM during the study period (2004-2013), were estimated. Demographic factors associated with survival rates and other clinical features of CM and MIS were evaluated and compared with an age-matched, sex-matched, and income level-matched control group. The overall incidence was 1.09 (95% confidence interval, 0.87-1.41) per 100 000 person-years, which was low compared with Caucasians. The incidence rate had increased by 1.07-fold yearly during the 10-year follow-up period (P < 0.001). Five-year and 10-year survival rates of the melanoma patient group were 85.5 and 66.2%, respectively, and were also lower than those of the Caucasian population. The most frequently involved site was the lower limb, followed by the head and neck. Old age and diabetes were associated with an increased risk of melanoma-specific death, whereas surgical excision was a factor associated with decreased overall and melanoma-specific death rates irrespective of the stage of CM. Our data provide a better understanding of the characteristics of CM, especially in the Korean population, and warrant further study into the association between CM and other comorbid conditions.


[Application of molecular modeling to new therapeutic cancer approaches].
Recent progress in the experimental determination of protein structures allow to understand, at a very detailed level, the molecular recognition mechanisms that are at the basis of the living matter. This level of understanding makes it possible to design rational therapeutic approaches, in which effectors molecules are adapted or created de novo to perform a given function. An example of such an approach is drug design, were small inhibitory molecules are designed using in silico simulations and tested in vitro. In this article, we present a similar approach to rationally optimize the sequence of killer T lymphocytes receptors to make them more efficient against melanoma cells. The architecture of this translational research project is presented together with its implications both at the level of basic research as well as in the clinics.


An integrated transcriptomics and metabolomics analysis of the Cucurbita pepo nectary implicates key modules of primary metabolism involved in nectar synthesis and secretion.
Nectar is the main reward that flowers offer to pollinators to entice repeated visitation. Cucurbita pepo (squash) is an excellent model for studying nectar biology, as it has large nectaries that produce large volumes of nectar relative to most other species. Squash is also monoecious, having both female and male flowers on the same plant, which allows comparative analyses of nectary function in one individual. Here, we report the nectary transcriptomes from both female and male nectaries at four stages of floral maturation. Analysis of these transcriptomes and subsequent confirmatory experiments revealed a metabolic progression in nectaries leading from starch synthesis to starch degradation and to sucrose biosynthesis. These results are consistent with previously published models of nectar secretion and also suggest how a sucrose-rich nectar can be synthesized and secreted in the absence of active transport across the plasma membrane. Nontargeted metabolomic analyses of nectars also confidently identified 40 metabolites in both female and male nectars, with some displaying preferential accumulation in nectar of either male or female flowers. Cumulatively, this study identified gene targets for reverse genetics approaches to study nectary function, as well as previously unreported nectar metabolites that may function in plant-biotic interactions.


Impact of RNase E and RNase J on Global mRNA Metabolism in the Cyanobacterium Synechocystis PCC6803.
mRNA levels result from an equilibrium between transcription and degradation. Ribonucleases (RNases) facilitate the turnover of mRNA, which is an important way of controlling gene expression, allowing the cells to adjust transcript levels to a changing environment. In contrast to the heterotrophic model bacteria Escherichia coli and Bacillus subtilis, RNA decay has not been studied in detail in cyanobacteria. Synechocystis sp. PCC6803 encodes orthologs of both E. coli and B. subtilis RNases, including RNase E and RNase J, respectively. We show that in vitro Sy RNases E and J have an endonucleolytic cleavage specificity that is very similar between them and also compared to orthologous enzymes from E. coli, B. subtilis, and Chlamydomonas. Moreover, Sy RNase J displays a robust 5'-exoribonuclease activity similar to B. subtilis RNase J1, but unlike the evolutionarily related RNase J in chloroplasts. Both nucleases are essential and gene deletions could not be fully segregated in Synechocystis. We generated partially disrupted strains of Sy RNase E and J that were stable enough to allow for their growth and characterization. A transcriptome analysis of these strains partially depleted for RNases E and J, respectively, allowed to observe effects on specific transcripts. RNase E altered the expression of a larger number of chromosomal genes and antisense RNAs compared to RNase J, which rather affects endogenous plasmid encoded transcripts. Our results provide the first description of the main transcriptomic changes induced by the partial depletion of two essential ribonucleases in cyanobacteria.


Knee Septic Arthritis after Palm Tree Thorn Injury: A Case Report.
A monoarthritic painful knee may have multiple etiologies, of which septic arthritis is commonly considered to be one of the most deleterious pathologies. This type of acute symptom is, in the literature, for some rare cases, related to an inflammatory process secondary to a penetrating plant thorn, which was considered an aseptic process and therefore treated by removing the foreign body. This work reports a recent case falling into that diagnosis, which due to its infrequent nature, could have been misevaluated and consequently mistreated. Our goal is to bring to the attention of the orthopedic community that this type of deleterious pathology, which is today uncommon, must never be fully disregarded. We share a case of a 68-year-old male who was admitted 2 days after being injured by a palm tree (Arecaceae) thorn with acute inflammatory signs and effusion in the left knee. Although, ultrasound excluded pathway or intra-articular foreign bodies, in the arthroscopic procedure, a thorn was found and removed. Pantoea agglomerans was identified in the synovial fluid. Following the removal of the foreign body, empirical antibiotic treatment with coverage against Gram-negative pathogens was initiated and later on replaced by appropriate antibiotics, after susceptibility testing is obtained.


Treating the whole body in Huntington's disease.
Huntington's disease is a genetic neurodegenerative disorder with symptoms that are linked to the progressive dysfunction and neuronal death in corticostriatal circuits. The causative gene (mutated HTT) is widely expressed outside the CNS and several peripheral signs of disease, including weight loss and increased proinflammatory signalling, are often seen; however, their importance in the pathophysiology of Huntington's disease is not clear. Studies in animals have shown that features of the disease involving the CNS, including synapse loss and behavioural alterations, are susceptible to modulation by treatments that target tissues and organs outside the CNS. Links between peripheral biology and neurodegeneration have also been shown in other chronic neurodegenerative diseases, suggesting that modulation of these peripheral targets can offer new approaches to therapeutic development. Treatments targeted to tissues and organs outside the CNS might therefore substantially improve the quality of life of patients with Huntington's disease, even in the absence of disease-modifying effects.


New therapeutic strategies for renal cell carcinoma.
Treatment options for renal cell carcinoma have changed dramatically since 2005 when the U.S. Food and Drug Administration approved six new therapies. These agents inhibit pathways relevant in the pathogenesis of renal cell carcinoma, interfering with tumor angiogenesis, cell progression, and metastasis. Understanding the pharmacology of these agents is necessary for clinicians to provide appropriate patient education, assure adherence with the treatment plan, and facilitate early identification and intervention for side effects. These activities will provide positive clinical outcomes.


Discharge of older patients with chronic diseases: What nurses do and what they record. An observational study.
To describe which nursing activities are observed during the discharge of older patients with chronic diseases and to investigate the consistency between the nursing activities actually observed and those documented. The discharge from hospital of older patients with chronic diseases is a critical transition that can lead to dissatisfaction, delays in discharge, re-admission, adverse events and increased mortality. Although nurses' interventions during discharge are important for patient outcomes, little is known about the nursing activities actually performed as compared with those documented. An observational study of the nursing activities performed during patients' discharge and a retrospective audit of the nursing records of the same patients and nurses. Structured nonparticipant observations were conducted of the activities performed by nurses at discharge. A retrospective audit of the nursing records relating to patient discharge, including the nursing diary and the assessment of critical issues at hospital discharge, was also conducted. The STROBE guidelines were followed (See Supporting Information Appendix S2). During hospital discharge of 102 patients, 1,224 nursing activities were observed. The number of activities was not related to patients' age, gender and educational level, nor to nurses' postgraduate education. Statistically significant correlations emerged between the number of activities observed and the nurses' work experience. A predefined discharge plan guiding nurses' activities during discharge would enable them to respond better to the care needs of elderly patients. Results from the study could help clinical nurses to address care priorities of patients at discharge, by using appropriate plans and checklists and improving recording rates. Novice nurses should be supported when caring for elderly patients with chronic disease at discharge.


Distinguishing genomic homogenization from parapatric speciation in an elevationally replacing pair of Ramphocelus tanagers.
Geographically connected species pairs with weakly differentiated genomes could either represent cases of genomic homogenization in progress or of incipient parapatric speciation. Discriminating between these processes is difficult because intermediate stages of either may produce weakly differentiated genomes that diverge at few locations. We used coalescent modelling applied to a genome-wide sample of SNPs to discriminate between speciation with gene flow and genomic homogenization in two phenotypically distinct but genomically weakly diverged species of elevationally replacing Ramphocelus tanagers, forming a hybrid zone in the Andean foothills. We found overwhelming support for a model of genomic homogenization following secondary contact. Simulating under this model suggested that our species pair was differentiated (FST = 0.30) at secondary contact but that most of the genome has rapidly homogenized during 254 Ky of high gene flow towards the present (FST = 0.02). Despite extensive genome-wide homogenization, plumage remains distinctive with a narrower than expected geographic cline width, indicating divergent selection on colour. We found two SNPs significantly associated with plumage colour, which retain moderately high FST . We conclude that the majority of the genome has fused, but that divergent selection on select loci probably maintains the geographically structured colour differences between these incipient species.


TP53 and ATM mRNA expression in skin and skeletal muscle after low-level laser exposure.
Low-level lasers are widespread in regenerative medicine, but the molecular mechanisms involved in their biological effects are not fully understood, particularly those on DNA stability. Therefore, this study aimed to investigate mRNA expression of genes related to DNA genomic stability in skin and skeletal muscle tissue from Wistar rats exposed to low-level red and infrared lasers. For this, TP53 (Tumor Protein 53) and ATM (Ataxia Telangiectasia Mutated gene) mRNA expressions were evaluated by real-time quantitative PCR (RT-qPCR) technique 24 hours after low-level red and infrared laser exposure. Our data showed that relative TP53 mRNA expression was not significantly altered in both tissues exposed to lasers. For ATM, relative mRNA expression in skin tissue was not significantly altered, but in muscle tissue, laser exposure increased relative ATM mRNA expression. Low-level red and infrared laser radiations alter ATM mRNA expression related to DNA stability in skeletal muscle tissue.


Diagnosis of Pneumocystis carinii pneumonia.
Pneumocystis carinii pneumonia occurs at some point in the course of disease in approximately 85 per cent of patients with AIDS. Because of the frequency of P. carinii pneumonia and because it is readily treatable, prompt, accurate, and efficient diagnostic schemes are of extreme importance. The clinical presentation is generally characterized by fever, nonproductive cough, and shortness of breath. Such symptoms in a patient from a recognized HIV transmission category should prompt a diagnostic evaluation to identify P. carinii or other opportunistic infections. A chest radiograph usually provides an objective indication of lung disease. Pulmonary function tests, particularly the DLCO and lung imaging using 67Ga-citrate, are useful screening tests in patients with normal chest films. Examination of sputum induced by inhalation of a mist of hypertonic saline is a very useful means of identifying P. carinii. Bronchoalveolar lavage is nearly 100 per cent sensitive to the presence of P. carinii and should be performed in patients who have a nondiagnostic sputum examination. Transbronchial biopsy increases the overall yield for diagnoses other than P. carinii and should be performed in patients in whom bronchoalveolar lavage does not provide a diagnosis. Because of the effectiveness of sputum examinations and bronchoscopic procedures, open lung biopsy is rarely necessary. Measurements of circulating P. carinii antigen and antibodies are of no help in diagnosis.


FLASH is an essential component of Cajal bodies.
Cajal bodies are small nuclear organelles with a number of nuclear functions. Here we show that FLICE-associated huge protein (FLASH), originally described as a component of the apoptosis signaling pathway, is mainly localized in Cajal bodies and is essential for their structure. Reduction in FLASH expression by short hairpin RNA results in disruption of the normal architecture of the Cajal body and relocalization of its components. Because the function of FLASH in the apoptosis receptor signaling pathway has been strongly questioned, we have now identified a clear function for this protein.


A comparison of two single-headed and two multi-headed allergen skin test devices.
Given the potential differences in performance of skin test devices, the purpose of this study was to prospectively assess the performance of two single-headed and two multiheaded devices for allergy skin testing in terms of wheal size, sensitivity, specificity, intradevice variability, and pain level. Two single-headed devices (Greer Pick, Duotip-Test) and two multiheaded devices (Multi-Test II, OMNI) were tested in 15 subjects in a prospective partially blind fashion looking at wheal reactions and pain using histamine and glycerol-saline on the arms and back. Differences among devices in wheal size and pain were noted. Sensitivity, specificity, and intradevice variability were calculated. Differences between corner and interior heads in multiheaded devices were analyzed. No significant differences were observed in wheal size between Greer Pick (7.1+/-1.4 mm) and Duotip-Test (7.2+/-1.6 mm). Multiheaded devices were significantly different in wheal size compared with each other and to the single-headed devices (Multi-Test II, 5.4+/-1.7 mm; OMNI, 3.3+/-1.2 mm). Single-headed devices were more sensitive (100% each, 95% CI of 92-100%) than the multiheaded devices. Multi-Test II was significantly more sensitive (83%, 95% CI of 78-87%) than OMNI (57%, 95% CI of 51-62%). There was significant intradevice variability for the multiheaded devices with corner heads being significantly more sensitive than interior heads. Specificities for all devices were equally good (-97%). Pain was greater for multiheaded devices than single-headed devices but was generally mild. In conclusion, this study supports the idea that single-headed devices may be more sensitive and consistent than multiheaded devices. Multi-Test II is more sensitive than OMNI. In multiheaded devices, corner heads are more sensitive than interior heads.


Reduced body sizes in climate-impacted Borneo moth assemblages are primarily explained by range shifts.
Both community composition changes due to species redistribution and within-species size shifts may alter body-size structures under climate warming. Here we assess the relative contribution of these processes in community-level body-size changes in tropical moth assemblages that moved uphill during a period of warming. Based on resurvey data for seven assemblages of geometrid moths (>8000 individuals) on Mt. Kinabalu, Borneo, in 1965 and 2007, we show significant wing-length reduction (mean shrinkage of 1.3% per species). Range shifts explain most size restructuring, due to uphill shifts of relatively small species, especially at high elevations. Overall, mean forewing length shrank by ca. 5%, much of which is accounted for by species range boundary shifts (3.9%), followed by within-boundary distribution changes (0.5%), and within-species size shrinkage (0.6%). We conclude that the effects of range shifting predominate, but considering species physiological responses is also important for understanding community size reorganization under climate warming.


Improving web site performance using commercially available analytical tools.
It is easy to accurately measure web site usage and to quantify key parameters such as page views, site visits, and more complex variables using commercially available tools that analyze web site log files and search engine use. This information can be used strategically to guide the design or redesign of a web site (templates, look-and-feel, and navigation infrastructure) to improve overall usability. The data can also be used tactically to assess the popularity and use of new pages and modules that are added and to rectify problems that surface. This paper describes software tools used to: (1) inventory search terms that lead to available content; (2) propose synonyms for commonly used search terms; (3) evaluate the effectiveness of calls to action; (4) conduct path analyses to targeted content. The American Academy of Orthopaedic Surgeons (AAOS) uses SurfRay's Behavior Tracking software (Santa Clara CA, USA, and Copenhagen, Denmark) to capture and archive the search terms that have been entered into the site's Google Mini search engine. The AAOS also uses Unica's NetInsight program to analyze its web site log files. These tools provide the AAOS with information that quantifies how well its web sites are operating and insights for making improvements to them. Although it is easy to quantify many aspects of an association's web presence, it also takes human involvement to analyze the results and then recommend changes. Without a dedicated resource to do this, the work often is accomplished only sporadically and on an ad hoc basis.


Exosomes-mediated transfer of long noncoding RNA LINC01133 represses bladder cancer progression via regulating the Wnt signaling pathway.
Bladder cancer (BC), as one of the most common malignant cancers of the urinary system, has a high incidence and mortality rates. Recently, increasing studies have indicated that exosomes can mediate cellular communication in assorted cancers, including BC. Long noncoding RNAs (lncRNAs) have also been confirmed to take part in the regulation of many cancers. Long intergenic non-protein coding RNA 1133 (LINC01133) is an lncRNA and its roles in several cancers have been revealed. However, the functions of exosomes and LINC01133 in BC are still not elucidated. In our research, functional assays were conducted to evaluate the function of LINC01133, as well as the influence of exosomes and LINC01133 on BC cells. Western blot assay, immunofluorescence assay, electron microscope, and nanoparticle tracking analysis were applied for detecting the characteristics of exosomes. Bioinformatics tools and quantitative reverse-transcription polymerase chain reaction were performed to test the expression of LINC01133 in BC cells and exosomes of the immortalized human uroepithelial cell line (SV-HUC-1). Luciferase reporter assay was performed to measure the activity of the Wnt pathway. We discovered that LINC01133 expression was high in exosomes of SV-HUC-1 and low in that of BC cells. Additionally, exosomes restrained cell viability, proliferation, migration, and invasion. Similarly, LINC01133 exerted the same function on BC cells. In addition, the Wnt signaling pathway could be inactivated by LINC01133. Finally, in vivo experiments demonstrated that cell growth could be suppressed by overexpressed LINC01133. In short, exosomes-mediated transfer of lncRNA LINC01133 repressed BC progression via regulating the Wnt signaling pathway.


Variation in intron length in caffeic acid O-methyltransferase (COMT) in Vanilla species (Orchidaceae).
Variation in intron length in caffeic acid O-methyltransferase (COMT) in Vanilla was studied and demonstrated that COMT genes in Vanilla are organized with four exons and three introns. At least two to four different versions (either allelic or paralogous) of the COMT multigenic family in the genus Vanilla (in terms of intron sizes) were detected. The three introns were differentially variable, with intron-1 being the most length-polymorphic. Patterns of variations were in accordance with known phylogenetic relationships in the genus obtained with neutral markers. In particular, the genus displayed a strong Old World versus New World differentiation with American fragrant species being characterized by a specific 99bp intron-1 size-variant and a unique 226bp intron-3 variant. Conversely, leafless species of the genus displayed unexpected variations in intron lengths. Due to their role in primary (lignin) and secondary (phenolics, e.g., vanillin, alkaloids) metabolisms, COMT genes might not be neutral markers, and represent candidate functional markers for resistance, aromatic or medicinal properties of Vanilla species. Investigating the orthologous/paralogous status of the different genes revealed (in terms of intron size) will allow the evolution of the COMT genes to be studied.


Behavior of ewes and lambs subjected to restraint fostering.
The objective of this study was to investigate the development of maternal-filial social attachments between ewes and alien lambs using the technique of "restraint fostering." Forty-eight to 72 h after parturition, 22 Targhee -type ewes were separated from their natural lambs, placed in restraining devices ( stanchions ) and each exposed to a single alien lamb. After a period of 1 or 4 d of restraint, the ewes were subjected to five 10-min lamb acceptance tests over a 48-h period. The observer recorded butts and butt attempts by the ewe and successful and unsuccessful suckle attempts by the lamb. The ewe-lamb pairs were then housed in pens with other groups of ewes and lambs and observed intermittently for acceptance behaviors. Six of the 14 ewes restrained for 4 d and none of the eight ewes restrained for 24 h met the criterion for successful adoption within 48 h. After being housed in group pens, adoptions were achieved by three ewes in the 1-d group and an additional four ewes in the group restrained for 4 d. Ewes restrained for 24 h were significantly more aggressive toward fostered young than ewes restrained for 4 d. In addition, the proportion of successful suckling attempts was significantly lower for lambs fostered on ewes in the 1-d group. Both groups showed a decline in butts and butt attempts over successive acceptance tests, but while the proportion of successful suckling attempts declined for lambs housed with 1-d ewes, they increased over time for lambs fostered on ewes restrained for 4 d.(ABSTRACT TRUNCATED AT 250 WORDS)


Design and Implementation of Data Exchange Formats for Molecular Detection of Drug-Resistant Tuberculosis.
Drug-resistant tuberculosis (TB) remains a public health threat to the United States and worldwide control of TB. Rapid and reliable drug susceptibility testing (DST) is essential for aiding clinicians in selecting an optimal treatment regimen for TB patients and to prevent ongoing transmission. Growth-based DST results for culture-confirmed cases are routinely reported to the U.S. Centers for Disease Control and Prevention through the National TB Surveillance System (NTSS). However, the NTSS currently lacks the capacity and functionality to accept laboratory results from advanced molecular methods that detect mutations associated with drug resistance. The objective of this study is to design and implement novel comprehensive data exchange formats that utilize the Health Level Seven (HL7) version 2.5.1 messaging hierarchy to capture, store, and monitor molecular DST data, thereby, improving the quality of data, specifications and exchange formats within the NTSS as well as ensuring full reporting of drug-resistant TB.


Neonatal diagnosis, treatment and related factors of congenital dislocation of the hip.
The unstable hip can be diagnosed in newborns with acceptable accuracy. The following factors are associated with the newborn unstable hip: female preponderance, breech presentations, cesarean section deliveries, first borns, left hip involvement, the Caucasian race, and increased birth weight. These findings suggest that the newborn unstable hip is determined prior to delivery, possibly within the last 4 weeks of intrauterine life. Diagnosed at birth, treatment in the average case is relatively short-term, effective, and without complication.


Astragaloside IV ameliorates fat metabolism in the liver of ageing mice through targeting mitochondrial activity.
Astragaloside IV (AST) is a major bioactive compound of Radix Astragali with medical and health benefits. Previous studies have found that AST can reduce the body weights of high-fat diet fed mice. However, the effect of AST on fat metabolism of ageing mice is unclear. In this study, naturally ageing mice were administered intragastrically with AST at 30 mg/kg/day (ageing + AST-L group) and 90 mg/kg/day (ageing + AST-H group) for 16-20 months. Adult (4 months old) and ageing mice were given 1% sodium carboxyl methylcellulose as vehicle. Energy metabolism-related biological parameters of living mice were examined. Moreover, mRNA and protein levels of key enzymes/proteins involved in triglyceride (TG) lipolysis, fatty acid β-oxidation (FAO), ketone body (KB) production and mitochondrial respiratory chain were also examined after sacrifice. Results demonstrated that treatment with AST significantly reduced body weight, white fat and liver/body weight ratio of ageing mice, significantly reduced serum/hepatic TG levels, respiratory quotient, promoted fatty acid mobilization in white adipose tissue, mitochondrial FAO and KB production and mitochondrial biosynthesis/functions in the liver of ageing mice. AST also up-regulated the expression of phosphorylated AMP-activated protein kinase, acetyl-CoA carboxylase, acetyl-coenzyme A synthetase, carnitine palmitoyltransferase 1a/1b, enoyl coenzyme A hydratase-short chain, acyl-CoA dehydrogenase medium chain and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase-2 involved in fat metabolism. These results indicated that mitochondrial activity could be the target of AST to treat abnormal fat metabolism during ageing.


Decentralized Learning Framework of Meta-Survival Analysis for Developing Robust Prognostic Signatures.
A significant hurdle in developing reliable gene expression-based prognostic models has been the limited sample size, which can cause overfitting and false discovery. Combining data from multiple studies can enhance statistical power and reduce spurious findings, but how to address the biologic heterogeneity across different datasets remains a major challenge. Better meta-survival analysis approaches are needed. We presented a decentralized learning framework for meta-survival analysis without the need for data aggregation. Our method consisted of a series of proposals that together alleviated the influence of data heterogeneity and improved the performance of survival prediction. First, we transformed the gene expression profile of every sample into normalized percentile ranks to obtain platform-agnostic features. Second, we used Stouffer's meta-z approach in combination with Harrell's concordance index to prioritize and select genes to be included in the model. Third, we used survival discordance as a scale-independent model loss function. Instead of generating a merged dataset and training the model therein, we avoided comparing patients across datasets and individually evaluated the loss function on each dataset. Finally, we optimized the model by minimizing the joint loss function. Through comprehensive evaluation on 31 public microarray datasets containing 6,724 samples of several cancer types, we demonstrated that the proposed method has outperformed (1) single prognostic genes identified using conventional meta-analysis, (2) multigene signatures trained on single datasets, (3) multigene signatures trained on merged datasets as well as by other existing meta-analysis methods, and (4) clinically applicable, established multigene signatures. The decentralized learning approach can be used to effectively perform meta-analysis of gene expression data and to develop robust multigene prognostic signatures.


Thiosugars: new perspectives regarding availability and potential biochemical and medicinal applications.
Thiosugars, containing a sulfur atom as heteroatom or a disaccharide linked via a sulfur bridge, possess unique physicochemical properties such as water solubility, which differs from conventional functionalized monosaccharides. The differences in biological activities between thiosugars and their oxygen analogs depend on geometric, conformational, and flexibility differences. They depend also on their electronic differences, the sulfide function being less electronegative and more polarizable than the ethereal moiety. Many functionalized thiosugars occur naturally and are potential targets for the development of carbohydrate-based therapeutics. Among the few new examples of the potential new targets are salacinol and kotalanol, tagetitoxin, thiolactomycin and analogues, mycothiol and analogues, and S-nitrosothiols. These new developments and representative examples of functionalized thiosugar prototypes as potential new targets are presented in this mini review.


Efficacy of Carotid Artery Stenting Performed under General Anesthesia with Somatosensory Evoked Potential Monitoring.
During carotid artery stenting (CAS), hemodynamics may be affected by the carotid sinus reflex in some cases. Although general anesthesia has been reported to stabilize intraoperative hemodynamics, the patient's neurological condition must be assessed indirectly. Therefore, we investigated the changes in intraoperative hemodynamics and perioperative complications of CAS under general anesthesia and evaluated the efficacy of somatosensory evoked potential (SEP) monitoring in detecting a reduction in perfusion during CAS. From April 2011 to August 2016,57 consecutive patients who underwent CAS under general anesthesia were evaluated. The follow-up period ranged from 3 to 8 years. During CAS, anesthesiologists monitored and managed the hemodynamics. SEP monitoring was performed during the CAS procedure in all patients. Intraoperative hypotension (systolic blood pressure ≤ 100 mmHg) was evident in 16 patients (28.1%), and 13 patients (22.8%) experienced intraoperative bradycardia; however, all of these cases were promptly managed under general anesthesia. None of the patients showed systolic blood pressure < 50 mmHg from baseline. Regarding perioperative complications, none of the patients exhibited myocardial infarction or postoperative hyperperfusion symptoms, and there was no mortality. Among 21 patients (36.8%) with a decrease in the intraoperative SEP, 3 (5.3%) exhibited transient ischemic symptoms and 1 (1.8%) had postoperative infarction. CAS under general anesthesia is a safe and effective management option in terms of intraoperative hemodynamic stability. In addition, our findings indicate that SEP monitoring could be helpful in evaluating transient postoperative cerebral ischemia or cerebral infarction after CAS.


First-phase insulin secretion restoration and differential response to glucose load depending on the route of administration in type 2 diabetic subjects after bariatric surgery.
The purpose of this study was to elucidate the mechanisms of diabetes reversibility after malabsorptive bariatric surgery. Peripheral insulin sensitivity and beta-cell function after either intravenous (IVGTT) or oral glucose tolerance (OGTT) tests and minimal model analysis were assessed in nine obese, type 2 diabetic subjects before and 1 month after biliopancreatic diversion and compared with those in six normal-weight control subjects. Insulin-dependent whole-body glucose disposal was measured by the euglycemic clamp, and glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were also measured. The first phase of insulin secretion after the IVGTT was fully normalized after the operation. The disposition index from OGTT data was increased about 10-fold and became similar to the values found in control subjects, and the disposition index from IVGTT data increased about 3.5-fold, similarly to what happened after the euglycemic clamp. The area under the curve (AUC) for GIP decreased about four times (from 3,000 +/- 816 to 577 +/- 155 pmol x l(-1) x min, P < 0.05). On the contrary, the AUC for GLP1 almost tripled (from 150.4 +/- 24.4 to 424.4 +/- 64.3 pmol x l(-1) . min, P < 0.001). No significant correlation was found between GIP or GLP1 percent changes and modification of the sensitivity indexes independently of the route of glucose administration. Restoration of the first-phase insulin secretion and normalization of insulin sensitivity in type 2 diabetic subjects after malabsorptive bariatric surgery seem to be related to the reduction of the effect of some intestinal factor(s) resulting from intestinal bypass.


Human Papilloma Virus Associated Squamous Cell Carcinoma of the Head and Neck.
Oral cancer is one of the commonest causes for mortality and morbidity with squamous cell carcinoma being the sixth most frequent malignant tumour worldwide. In addition to tobacco and alcohol, human papilloma virus (HPV) is associated with a proportion of head and neck cancers. As in cervical cancers, HPV types 16 and 18 are the cause of malignant transformation. HPV-positive cancers of head and neck have unique characteristics such as occurrence in a younger age group, distinct clinical and molecular features, and better prognosis as compared to HPV-negative carcinomas. They also possess the potential for prevention by using vaccination. The present review describes in detail the salient features of HPV associated oral squamous cell carcinoma (OSCC), its differences from HPV-negative OSCC, diagnostic features, and recent strategies in prevention and management.


Multiresolution GPC-Structured Control of a Single-Loop Cold-Flow Chemical Looping Testbed.
Chemical looping is a near-zero emission process for generating power from coal. It is based on a multi-phase gas-solid flow and has extremely challenging nonlinear, multi-scale dynamics with jumps, producing large dynamic model uncertainty, which renders traditional robust control techniques, such as linear parameter varying H ∞ design, largely inapplicable. This process complexity is addressed in the present work through the temporal and the spatiotemporal multiresolution modeling along with the corresponding model-based control laws. Namely, the nonlinear autoregressive with exogenous input model structure, nonlinear in the wavelet basis, but linear in parameters, is used to identify the dominant temporal chemical looping process dynamics. The control inputs and the wavelet model parameters are calculated by optimizing a quadratic cost function using a gradient descent method. The respective identification and tracking error convergence of the proposed self-tuning identification and control schemes, the latter using the unconstrained generalized predictive control structure, is separately ascertained through the Lyapunov stability theorem. The rate constraint on the control signal in the temporal control law is then imposed and the control topology is augmented by an additional control loop with self-tuning deadbeat controller which uses the spatiotemporal wavelet riser dynamics representation. The novelty of this work is three-fold: (1) developing the self-tuning controller design methodology that consists in embedding the real-time tunable temporal highly nonlinear, but linearly parametrizable, multiresolution system representations into the classical rate-constrained generalized predictive quadratic optimal control structure, (2) augmenting the temporal multiresolution loop by a more complex spatiotemporal multiresolution self-tuning deadbeat control loop, and (3) demonstrating the effectiveness of the proposed methodology in producing fast recursive real-time algorithms for controlling highly uncertain nonlinear multiscale processes. The latter is shown through the data from the implemented temporal and augmented spatiotemporal solutions of a difficult chemical looping cold flow tracking control problem.


Porphyromonas gingivalis suppresses oral squamous cell carcinoma progression by inhibiting MUC1 expression and remodeling the tumor microenvironment.
Bacteria are the causative agents of various infectious diseases; however, the anti-tumor effect of some bacterial species has attracted the attention of many scientists. The human oral cavity is inhabited by abundant and diverse bacterial communities and some of these bacterial communities could play a role in tumor suppression. Therefore, it is crucial to find oral bacterial species that show anti-tumor activity on oral cancers. In the present study, we found that a high abundance of Porphyromonas gingivalis, an anaerobic periodontal pathogen, in the tumor microenvironment (TME) was positively associated with the longer survival of patients with oral squamous cell carcinoma (OSCC). An in vitro assay confirmed that P. gingivalis accelerated the death of OSCC cells by inducing cell cycle arrest at the G2/M phase, thus exerting its anti-tumor effect. We also found that P. gingivalis significantly decreased tumor growth in a 4-nitroquinoline-1-oxide-induced in situ OSCC mouse model. The transcriptomics data demonstrated that P. gingivalis suppressed the biosynthesis of mucin O-glycan and other O-glycans, as well as the expression of chemokines. Validation experiments further confirmed the downregulation of mucin-1 (MUC1) and C-X-C motif chemokine 17 (CXCL17) expression by P. gingivalis treatment. Flow cytometry analysis showed that P. gingivalis successfully reversed the immunosuppressive TME, thereby suppressing OSCC growth. In summary, the findings of the present study indicated that the rational use of P. gingivalis could serve as a promising therapeutic strategy for OSCC.


Effect of thyroid function on LDL oxidation in hypothyroidism and hyperthyroidism.
Oxidized low-density lipoproteins (LDL) are highly suspected of initiating the atherosclerosis process. Hypothyroidism is frequently associated with hypercholesterolemia and carries increased risk for atherosclerosis. In contrast to hypothyroidism, hyperthyroidism is not associated with increased LDL cholesterol, but is associated with increased oxidized LDL. This study was designed to evaluate the changes in LDL oxidation in subjects with hypothyroidism or hyperthyroidism, and to reveal the effects of treatment in hypothyroidism and hyperthyroidism on LDL oxidation and lipid profiles. Thirty-two patients with hypothyroidism and 16 patients with hyperthyroidism were studied before the therapy and thereafter, when they were euthyroid with appropriate treatment. Plasma lipids and lipoproteins, and the oxidizability of LDL by determining the levels of malonaldehyde bis (dimethyacetyl) (MDA) and diene conjugation, were determined at baseline and after the patients were rendered euthyroid. The actual content of dienes in LDL particles was increased in hypothyroidism, with a decrease after T4 supplementation (p < .001). Dienes in LDL particles were increased in hyperthyroidism, with a decrease after treatment (p < .05). In hypothyroid patients, the lag phase was shorter in the pretreatment period than in the euthyroid period (p > .05). The lag phase of hyperthyroid patients was shorter in the pretreatment period than in the euthyroid period and hypothyroid state (p < .001). The Cu2+-catalyzed dienes of LDL and MDA oxidation in the hypothyroid state and the subsequent euthyroid states were decreased (p < .001). The Cu2+-catalyzed dienes of LDL (p < .01) and MDA oxidation (p < .001) in hyperthyroid patients after treatment were decreased. The enhanced LDL oxidation may play a role in the cardiac disease process in both hypothyroidism and hyperthyroidism.


The incubation period of Buruli ulcer (Mycobacterium ulcerans infection) in Victoria, Australia - Remains similar despite changing geographic distribution of disease.
Buruli ulcer (BU) is a geographically-restricted infection caused by Mycobacterium ulcerans; contact with an endemic region is the primary risk factor for disease acquisition. Globally, efforts to estimate the incubation period of BU are often hindered as most patients reside permanently in endemic areas. However, in the south-eastern Australian state of Victoria, a significant proportion of people who acquire BU are visitors to endemic regions. During a sustained outbreak of BU on the Bellarine peninsula we estimated a mean incubation period of 4.5 months. Since then cases on the Bellarine peninsula have declined but a new endemic area has developed centred on the Mornington peninsula. Retrospective review of 443 cases of BU notified in Victoria between 2013 and 2016. Telephone interviews were performed to identify all cases with a single visit to an endemic region, or multiple visits within a one month period. The incubation period was defined as the time between exposure to an endemic region and symptom onset. Data were subsequently combined with those from our earlier study incorporating cases from 2002 to 2012. Among the 20 new cases identified in short-term visitors, the mean incubation period was 143 days (4.8 months), very similar to the previous estimate of 135 days (4.5 months). This was despite the predominant exposure location shifting from the Bellarine peninsula to the Mornington peninsula. We found no association between incubation period and age, sex, location of exposure, duration of exposure to an endemic region or location of BU lesion. Our study confirms the mean incubation period of BU in Victoria to be between 4 and 5 months. This knowledge can guide clinicians and suggests that the mode of transmission of BU is similar in different geographic regions in Victoria.


Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye.
This study seeks to determine the intraocular pharmacokinetics of molecules and particles injected into the suprachoroidal space of the rabbit eye in vivo using a hollow microneedle. Suprachoroidal injections of fluorescein and fluorescently tagged dextrans (40 and 250 kDa), bevacizumab, and polymeric particles (20 nm to 10 μm in diameter) were performed using microneedles in New Zealand white rabbits. The fluorescence intensity within the eye was monitored in each animal using an ocular fluorophotometer to determine the distribution of the injected material in the eye over time as compared with intravitreal injection of fluorescein. Fundus photography and histology were performed as well. Molecules and particles injected near the limbus using a microneedle flowed circumferentially around the eye within the suprachoroidal space. By targeting the suprachoroidal space, the concentration of injected materials was at least 10-fold higher in the back of the eye tissues than in anterior tissues. In contrast, intravitreal injection of fluorescein targeted the vitreous humor with no significant selectivity for posterior versus anterior segment tissues. Half-lives in the suprachoroidal space for molecules of molecular weight from 0.3 to 250 kDa ranged from 1.2 to 7.9 hours. In contrast, particles ranging in size from 20 nm to 10 μm remained primarily in the suprachoroidal space and choroid for a period of months and did not clear the eye. No adverse effects of injection into the suprachoroidal space were observed. Injection into the suprachoroidal space using a microneedle offers a simple and minimally invasive way to target the delivery of drugs to the choroid and retina.


Estrogen receptor agonists/antagonists in breast cancer therapy: A critical review.
Estrogens display intriguing tissue selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer. There are also strong evidences to show that both endogenous and exogenous estrogens are involved in the pathogenesis of breast cancer. Tamoxifen has been the only drug of choice for more than 30years to treat patients with estrogen related (ER) positive breast tumors. There is a need therefore, for identifying newer, potential and novel candidates for breast cancer. Keeping this in view, the present review focuses on selective estrogen receptor modulators and estrogen antagonists such as sulfatase and aromatase inhibitors involved in breast cancer therapy. A succinct and critical overview of the structure of estrogen receptors, their signaling and involvement in breast carcinogenesis are herein described.


Agronomic Performance and Economics of Yield Loss Associated With Angular Leaf Spot Disease of Common Bean in the Southern Highlands of Tanzania.
Angular leaf spot (ALS) caused by Pseudocercospora griseola is among the devastating diseases of common bean (Phaseolus vulgaris L.) in the Southern Highlands of Tanzania (SHT). This study was conducted to assess the agronomic performance and economics of yield loss associated with the disease on five bean cultivars that are widely grown by farmers. The cultivars were evaluated in a split plot design with a randomized complete block arrangement during 2012/2013 and 2013/2014. The main plots were two rates of fungicide and a control whereas the subplots consisted of cultivars. Data were collected on disease severity, yield, and yield components. Analysis of variance was done and marginal rate of returns determined using partial budget. Results indicated significant decrease in yields, number of pods, seeds, and seed weight at P < 0.05 for untreated plots. Decreases in yield were associated with ALS disease severity that in turn was influenced by cultivar and rate of fungicide used. Higher grain yield losses of as much as 61% and the lowest marginal rate of returns were recorded for unsprayed plots during heavy rains. Fungicide usage at the recommended rates should be considered during heavy rains and breeding for resistance should be taken as an economical and sustainable strategy for managing the disease.


Real-time fiber-optic anemometer based on a laser-heated few-layer graphene in an aligned graded-index fiber.
A real-time all-fiber anemometer based on laser-heated few-layer graphene in aligned graded-index fibers has been proposed and experimentally demonstrated. The proposed fiber-optic anemometer was composed of a pair of all-fiber collimators by using aligned graded-index fibers that was coated with the few-layer graphene. The few-layer graphene was heated through a heating light from a 532-nm laser, which changed the optical transmittance of signal light with the wavelength of 1550 nm. The wind speed can be measured through the transmission power of the signal light based on the wind cooling effects on the heated few-layer graphene, acting as a "hot-wire" anemometer. The experimental results show that the maximum sensitivity of the anemometer reaches -22.03 μW/(m/s), and a fast response time of as 0.064 s can be achieved. The proposed fiber sensor can be used for the real-time measurement of wind speed in the fields of environmental monitoring, oil exploration, oceanography research, etc.


[Mercury pollution in selected food products in Poland in the context of their health safety].
Mercury is a silvery-white chemically active transition metal without known physiological role. It is also a toxin accumulated in living organisms--especially in the aquatic creatures (fish and shellfish). Mercury compounds are involved in biogeochemical cycles (especially atmospheric and hydrobiologic), and thus they become contaminants of food. Such process is facilitated by the increasing environmental chemization. Toxic effects of mercury compounds result from their high affinity to sulfur (sulfhydryl groups of amino acids), accumulation in parenchymal organs, metallic mercury lipophilicity as well as long biological half-life period. In Poland the major sources of mercury exposure in diet are fish products and mushrooms. The role of mercury in human toxicology was presented in the work, along with a review of the literature concerning mercury content in selected food products in Poland. In general, most of foods do not pose a threat to consumers' health. Some restrictions in the amount of predatory fish and mushrooms consumed by pregnant and breastfeeding women as well as small children should be however recommended.


Highly ordered hollow oxide nanostructures: the Kirkendall effect at the nanoscale.
Highly ordered ultra-long oxide nanotubes are fabricated by a simple two-step strategy involving the growth of copper nanowires on nanopatterned template substrates by magnetron sputtering, followed by thermal annealing in air. The formation of such tubular nanostructures is explained according to the nanoscale Kirkendall effect. The concept of this new fabrication route is also extendable to create periodic zero-dimensional hollow nanostructures.


Fragile sites in cancer: more than meets the eye.
Ever since initial suggestions that instability at common fragile sites (CFSs) could be responsible for chromosome rearrangements in cancers, CFSs and associated genes have been the subject of numerous studies, leading to questions and controversies about their role and importance in cancer. It is now clear that CFSs are not frequently involved in translocations or other cancer-associated recurrent gross chromosome rearrangements. However, recent studies have provided new insights into the mechanisms of CFS instability, their effect on genome instability, and their role in generating focal copy number alterations that affect the genomic landscape of many cancers.


The pharmacology of antibiotic therapy in hidradenitis suppurativa.
Hidradenitis suppurativa (HS) is a chronic, inflammatory, and debilitating skin disease. Several pharmacologic agents have been described to reduce lesion activity and inflammation in HS. In this study, we have reviewed the available antibiotic therapies for HS, analyzing the pharmacologic aspects of these kind of treatments. The role of bacteria, infections, and superinfections in HS is still debated and controversial. Antibiotics are recognized as first-line treatments for hidradenitis suppurativa, but the data on their efficacy are limited. Antibiotics should not be replaced by new biological therapies and it is not necessary to make an efficacy classification: it is important for dermatologists to recognize the right patient and the right moment to prescribe an antibiotic therapy, together or in a rotational way with other therapeutic options. The HS treatment process for the physicians is often complicated by the disease's severity and several comorbidities. Fortunately, a better understanding of HS pathogenesis has been used to improve treatment strategies. Antibiotic therapy is an effective treatment of patients with HS but probably, in the next five years, many therapeutic options will be available, which will change the way we manage the disease, especially the moderate-to-severe forms of HS.


Helmet noninvasive ventilation compared to facemask noninvasive ventilation and high-flow nasal cannula in acute respiratory failure: a systematic review and meta-analysis.
Although small randomised controlled trials (RCTs) and observational studies have examined helmet noninvasive ventilation (NIV), uncertainty remains regarding its role. We conducted a systematic review and meta-analysis to examine the effect of helmet NIV compared to facemask NIV or high-flow nasal cannula (HFNC) in acute respiratory failure. We searched multiple databases to identify RCTs and observational studies reporting on at least one of mortality, intubation, intensive care unit (ICU) length of stay, NIV duration, complications or comfort with NIV therapy. We assessed study risk of bias using the Cochrane Risk of Bias 2 tool for RCTs and the Ottawa-Newcastle Scale for observational studies, and rated certainty of pooled evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) framework. We separately pooled data from 16 RCTs (n=949) and eight observational studies (n=396). Compared to facemask NIV, based on low certainty of evidence, helmet NIV may reduce mortality (relative risk 0.56, 95% CI 0.33-0.95) and intubation (relative risk 0.35, 95% CI 0.22-0.56) in both hypoxic and hypercapnic respiratory failure, but may have no effect on duration of NIV. There was an uncertain effect of helmet NIV on ICU length of stay and development of pressure sores. Data from observational studies were consistent with the foregoing findings but of lower certainty. Based on low and very low certainty data, helmet NIV may reduce intubation compared to HFNC, but its effect on mortality is uncertain. Compared to facemask NIV, helmet NIV may reduce mortality and intubation; however, the effect of helmet NIV compared to HFNC remains uncertain.


KF-1 monoclonal antibody defines a specific basement membrane antigen defect in dystrophic forms of epidermolysis bullosa.
The monoclonal antibody, KF-1, identifies a noncollagenous constituent of the lamina densa of the basement membrane zone (BMZ) of skin. In order to determine whether this BMZ constituent is affected in epidermolysis bullosa (EB), a mechanobullous skin disease often resulting in marked disfigurement, we have examined skin from patients with various forms of this disease for binding by KF-1 as well as for binding by polyclonal antibodies to laminin, type IV collagen, and bullous pemphigoid antigen, three other known BMZ components of normal skin. In all specimens from patients with simplex and junctional forms of EB, all four antibodies bound normally. In contrast, absent or diminished KF-1 binding was noted in all skin specimens from patients with dystrophic EB; antibodies directed against the other BMZ constituents, however, bound normally. This suggests that KF-1 may play a role in the structural integrity of normal skin and its absence or diminution may be important in the pathogenesis of lesion formation in dystrophic EB.


Phosphorylation by SR kinases regulates the binding of PTB-associated splicing factor (PSF) to the pre-mRNA polypyrimidine tract.
PSF (PTB-associated splicing factor) is a multi-functional protein that participates in transcription and RNA processing. While phosphorylation of PSF has been shown to be important for some functions, the sites and the kinases involved are not well understood. Although PSF does not contain a typical RS domain, we report here that PSF is phosphorylated in vivo to generate an epitope(s) that can be recognized by a monoclonal antibody specific for phosphorylated RS motifs within SR proteins. PSF can be phosphorylated by human and yeast SR kinases in vivo and in vitro at an isolated RS motif within its N terminus. A functional consequence of SR phosphorylation of PSF is to inhibit its binding to the 3' polypyrimidine tract of pre-mRNA. These results indicate that PSF is a substrate of SR kinases whose phosphorylation regulates its RNA binding capacity and ultimate biological function.


Intragastric Safflower Yellow Alleviates HFD Induced Metabolic Dysfunction-Associated Fatty Liver Disease in Mice through Regulating Gut Microbiota and Liver Endoplasmic Reticulum Stress.
The gut microbiota was reported to play a significant role in the progression of the metabolic associated fatty liver disease (MAFLD). Our recent study suggested that gastrointestinal tract and liver were important targets mediating the anti-obesity effects of intragastric safflower yellow (SY). Therefore, our present study aims to investigate the effect of intragastric SY on MAFLD and possible mechanism. DIO mice were treated with 125 mg/kg/d SY for 12 weeks by gavage. We found intragastric SY significantly slowed weight gain of body, reduced the food intake and liver weight, improved hepatic steatosis, liver function and glucose metabolism in DIO mice. The comparison between OGTT and IPGTT illustrated OGTT produced a better improvement of glucose tolerance after SY treatment. We also found intragastric SY significantly increased the energy expenditure and locomotor activity of DIO mice. SY obviously decreased the expression of lipogenesis-associated and ERS-related genes in liver of DIO mice and PA-induced MAFLD hepatocyte model. Gut microbiota analysis demonstrated intragastric SY apparently changed the diversity and composition of gut microbiota of DIO mice. Further function prediction analysis indicated that gut microbiotas in SY-treated mice was positively related with energy metabolism, lipid metabolism and endocrine system. Intragastric SY has a significant therapeutic effect on MAFLD, which is mediated partly by modulating gut microbiota and improving liver ERS.


The relationship of MacAndrew alcoholism scale scores to MMPI profile type and degree of elevation.
Collected MMPI data for 38 Caucasian males who were hospitalized in a Veterans Administration alcoholism treatment program. On the basis of a Q-factor analysis, three prototypic profiles were derived, which adequately described 92% of the sample. These profiles were labeled: Type I (scales 1 and 2), Type II (F-K, Scales 4 and 9), and Type III (Scales K, 3 and 4). Type II was found to be correlated positively with scores on the MacAndrew Alcoholism Scale. No relationship was found between MacAndrew Alcoholism Scale scores and magnitude of psychological distress, as measured by mean T scores.


Parvocellular neurosecretory neurons: converging inputs after saphenous nerve and hypovolemic stimulations in the rat.
Effects of saphenous nerve stimulation and hemorrhage on discharge activity of parvocellular neurosecretory (PC) cells of the paraventricular hypothalamic nucleus (PVN) were studied in anesthetized rats. The PC cells were identified in the PVN with the criteria that units recorded in the PVN showed an antidromically conducted spike after median eminence but not after posterior pituitary stimulation of 0.45 mA intensity and were demonstrated histologically to be located in the parvocellular regions of the PVN. Saphenous nerve stimulation at 4 Hz repetition and of 3 mA intensity increased the discharge rate of 13 of the 52 PC cells tested. These excited cells exhibited a synaptically mediated excitation during post-stimulus period on peristimulus time histograms constructed during 1 Hz stimulation. Hemorrhage (4 ml/kg b.w.) activated 7 of the 10 PC cells tested which had been excited by saphenous nerve stimulation. Both saphenous nerve stimulation and hemorrhage increased immunoreactive adrenocorticotropic hormone (ACTH) in the plasma in the anesthetized rats. These data support the view that synergistic potentiation of ACTH secretion reported to occur after noxious and hypovolemic stimuli depends at least in part on the interaction between afferent neural signals originating from noxious and cardiovascular receptors on their way up to corticotropin-releasing factor (CRF)-secreting PVN neurons.


Remote Charge Effects on the Oxygen-Atom-Transfer Reactivity and Their Relationship to Molybdenum Enzymes.
We report the syntheses, crystal structures, and characterization of the novel cis-dioxomolybdenum(VI) complexes [Tpm*MoVIO2Cl](MoO2Cl3) (1) and [Tpm*MoVIO2Cl](ClO4) (2), which are supported by the charge-neutral tris(3,5-dimethyl-1-pyrazolyl)methane (Tpm*) ligand. A comparison between isostructural [Tpm*MoVIO2Cl]+ and Tp*MoVIO2Cl [Tp* = hydrotris(3,5-dimethyl-1-pyrazolyl)borate] reveals the effects of one unit of overall charge difference on their spectroscopic and electrochemical properties, geometric and electronic structures, and O-atom-transfer (OAT) reactivities, providing new insight into pyranopterin molybdoenzyme OAT reactivity. Computational studies of these molecules indicate that the delocalized positive charge lowers the lowest unoccupied molecular orbital (LUMO) energy of cationic [Tpm*MoO2Cl]+ relative to Tp*MoO2Cl. Despite their virtually identical geometric structures revealed by crystal structures, the MoVI/MoV redox potential of 2 is increased by 350 mV relative to that of Tp*MoVIO2Cl. This LUMO stabilization also contributes to an increased effective electrophilicity of [Tpm*MoO2Cl]+ relative to that of Tp*MoO2Cl, resulting in a more favorable resonant interaction between the molydenum complex LUMO and the highest occupied molecular orbital (HOMO) of the PPh3 substrate. This leads to a greater thermodynamic driving force, an earlier transition state, and a lowered activation barrier for the orbitally controlled first step of the OAT reaction in the Tpm* system relative to the Tp* system. An Eyring plot analysis shows that this initial step yields an O≡MoIV-OPPh3 intermediate via an associative transition state, and the reaction is ∼500-fold faster for 2 than for Tp*MoO2Cl. The second step of the OAT reaction entails solvolysis of the O≡MoIV-OPPh3 intermediate to afford the solvent-substituted MoIV product and is 750-fold faster for the Tpm* system at -15 °C compared to the Tp* system. The observed rate enhancement for the second step is ascribed to a switch of the reaction mechanism from a dissociative pathway for the Tp* system to an alternative associative pathway for the Tpm* system. This is due to a more Lewis acidic MoIV center in the Tpm* system.


Regulation of human profilaggrin promoter activity in cultured epithelial cells by retinoic acid and glucocorticoids.
Vitamin A and other retinoids profoundly inhibit both morphological and biochemical aspects of epidermal differentiation in vitro. Profilaggrin, like most other markers of keratinocyte differentiation, is negatively regulated by retinoic acid in vitro, both at the level of mRNA synthesis and by inhibiting the activity of endoproteases that convert profilaggrin to filaggrin. Profilaggrin is an abundant component of keratohyalin granules and forms the precursor of filaggrin, the keratin associated protein of the stratum corneum. In this report, we identify a region of the human profilaggrin promoter that is involved in the transcriptional regulation of expression by retinoic acid (RA). A series of promoter deletions linked to the chloramphenicol acetyl transferase (CAT) reporter gene were prepared and analyzed by transfection into Hela cells and keratinocytes. We also cotransfected vectors expressing retinoic acid receptor and cultured the transfected cells in the presence and absence of ligand. The region responsive to retinoic acid was localized to a 53 bp sequence between -1109 and -1056 (relative to the mRNA start site at +1) that contains a cluster of five retinoic acid response elements with variable spacing and orientation. In vitro gel shift analysis demonstrated that nuclear retinoid receptors do not bind directly to the identified sequence, suggesting that the mode of regulation by RA may be indirect or that binding requires another cofactor in addition to retinoid receptors. Whereas in keratin genes retinoic acid and glucocorticoid responsive sequences frequently coincide, the glucocorticoid response element in the profilaggrin promoter was located downstream of the RARE cluster between -965 and -951. These studies demonstrate that RA and glucocorticoids regulate profilaggrin expression at least in part by transcriptional mechanisms, via a region of the promoter that contains both retinoid and glucocorticoid responsive elements.


Endotypes in allergic diseases.
The precision medicine concept is both appealing and challenging. We review here the recent findings in the endotype-driven approach for major allergic diseases. Stratified medicine for different allergic diseases can identify patients who are more likely to benefit or experience an adverse reaction in response to a given therapy and anticipate their long-term outcome and vital risk. In addition, this approach potentially facilitates drug development and prevention strategies. The endotype-driven approach in allergic diseases has tremendous potential, but there are notable barriers in reaching the new world of precision medicine. Multidimensional endotyping integrating visible properties with multiple biomarkers is recommended for both type 2 and nontype 2 allergic diseases to provide evidence that a certain pathway is the key driver for a given patient. Significant healthcare system changes are required to achieve the expected targets.


Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study.
Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805-15. ©2018 AACR.


Switching of colony morphology and adhesion activity of Trichosporon asahii clinical isolates.
Trichosporon asahii is a pathogenic yeast that causes trichosporonosis, a deep-seated infection, in immunocompromised hosts. Pathogenic factors involved in this infection have not been investigated in detail, but morphological phenotype switching is thought to be important for T. asahii pathogenesis. Therefore, we analyzed adhesion, which may be a key early step in T. asahii infection, after morphological phenotype switching. T. asahii clinical isolates show several colony morphologies. In this study, colonies showing white-farinose (W), off-white-smooth (O), off-white-rugose (OR), smooth (S), and yellowish-white (Y) morphologies were obtained from three isolates and compared in an adhesion assay performed in cell culture dishes. At least one type of colony morphology from each clinical isolate adhered strongly to the culture dish surface, although the colony type that displayed strong adherence varied among the strains. Thus, morphological phenotype switching altered the adhesion of T. asahii strains.


Molecular template for a voltage sensor in a novel K+ channel. III. Functional reconstitution of a sensorless pore module from a prokaryotic Kv channel.
KvLm is a prokaryotic voltage-gated K(+) (Kv) channel from Listeria monocytogenes. The sequence of the voltage-sensing module (transmembrane segments S1-S4) of KvLm is atypical in that it contains only three of the eight conserved charged residues known to be deterministic for voltage sensing in eukaryotic Kv's. In contrast, the pore module (PM), including the S4-S5 linker and cytoplasmic tail (linker-S5-P-S6-C-terminus) of KvLm, is highly conserved. Here, the full-length (FL)-KvLm and the KvLm-PM only proteins were expressed, purified, and reconstituted into giant liposomes. The properties of the reconstituted FL-KvLm mirror well the characteristics of the heterologously expressed channel in Escherichia coli spheroplasts: a right-shifted voltage of activation, micromolar tetrabutylammonium-blocking affinity, and a single-channel conductance comparable to that of eukaryotic Kv's. Conversely, ionic currents through the PM recapitulate both the conductance and blocking properties of the FL-KvLm, yet the KvLm-PM exhibits only rudimentary voltage dependence. Given that the KvLm-PM displays many of the conduction properties of FL-KvLm and of other eukaryotic Kv's, including strict ion selectivity, we conclude that self-assembly of the PM subunits in lipid bilayers, in the absence of the voltage-sensing module, generates a conductive oligomer akin to that of the native KvLm, and that the structural independence of voltage sensing and PMs observed in eukaryotic Kv channels was initially implemented by nature in the design of prokaryotic Kv channels. Collectively, the results indicate that this robust functional module will prove valuable as a molecular template for coupling new sensors and to elucidate PM residue-specific contributions to Kv conduction properties.


[Morphologic feature and cochlear implant surgical approach for cochlear modiolus deficiency].
To review the classification of cochlear modiolus deficiency and decision on surgical approach for above case,in order to provide mastery for cochlear implant (CI) indication. Basing on temporal bone HRCT pre-operation, CI subjects with modiolus deficiency were defined as following groups: (1) deficiency caused by cochlear dysplasia (Mondini malformation); (2) deficiency caused by dysplasia of cochlear and vestibule (Common cavity malformation); (3) deficiency caused by absence of internal acoustic meatus fundus (IP-III malformation). Three types of surgical approach were utilized: type I, electrode array was introduced through facial recess, enlarged the round window, type II, opened the surface of chchlea, electrode array was introduced through facial recess, fenestration on posterior promontory and then inserted around lateral wall of inner-cochlear cavity. type III, electrode array was introduce through fenestration of lateral semicircular canal and then placed close to the bony wall of common cavity. One hundred and sixty-six cochlear modiolus deficiency cases were identified into 3 groups as following: 135 Mondini malformation cases into group a, 18 common cavity malformation cases into group b, and 13 IP-III malformation cases into group c. Surgical approach: type I were used in 136 cases (123 Mondini cases and 13 IP-III cases), while approach type II in 12 cases (12 Mondini cases), and approach type III in 18 cases (18 common cavity cases). Income post-operation of CI: For group a (Mondini malformation), post-activation mean hearing threshold in sound field was 65 dB, speech recognition score is 95% (single finals test) and 25% (signal initials test), while it was 80 dB, 60% and 0 for group b (Conmon cavity malformation), and it was 55 dB, 100% and 45% for group c (IP-III malformation). The income of speech recognition score for cochlear modiolus deficiency was relatively poor, group b was worst and group c was best, while group a moderate.


Exercise during pregnancy.
Routine exercise has become an accepted component of a healthy lifestyle, and many women want to continue exercising during pregnancy. In most cases, pregnant women can maintain previous levels of activity, while sedentary women can undertake new activities gradually.