[The bulletin of Nariakira Shimazu].
In 1858, the sudden and fatal illness of Nariakira Shimazu, the feudal lord of the Satsuma clan, provoked suspicion as to the cause of his death. Nagahiro Kuroda, the feudal lord of the Fukuoka clan, sent a letter to Munenari Date, the feudal lord of the Uwajima clan, informing the results of his investigation, along with the bulletin on Nariakira written by Hoshu Tsuboi, a clan physician. While the author was emending the texts of the bulletin, he found that there are two series of historical materials; dated in August and dated on July 16th, the day Nariakira expired. After examination of those materials, the author also discovered that some corrections may have been made at the office on the original text of the bulletin for compilation of the Shimazu documents in the Meiji era. In the present communication, the author reports the process of the study and the contents of the bulletin.


Rab2 and Rab6 are Implicated in Acrosome Formation during Spermatogenesis in Eriocheir sinensis: Based on Sperm Proteome.
Rab proteins are GTP-dependent small proteins that function as regulators of intracellular vesicle transport, fusion, and localization. However, few studies have investigated their function in Decapoda reproduction. The Eriocheir sinensis sperm has no tail and the nuclei are uncondensed. With the acrosome forming the majority of the sperm mass, it provides an ideal model for studying acrosome formation. We firstly analyzed the sperm proteome using LC-MS/MS. To study the functions of Rab2 and Rab6, related to the Golgi apparatus, in the acrosome formation during spermatogenesis, the genes of Rab2 and Rab6 were cloned based on the testis transcriptome of E.sinensis and poly-clonal antibodies were prepared. The presence of 2 Rab proteins was confirmed in the testis and sperm by western blot. We further observed the characteristics of target 2 Rab proteins using immunofluorescence (IF). A total of 1247 proteins including 7 Rab proteins, Rab1, Rab2, Rab5, Rab6, Rab11, Rab14, and Rab18 were identified in the sperm proteome. The IF results showed that Rab2 co-localizes with GM130, a cis-Golgi matrix protein, in the spermatagonia and spermatocytes. In the early spermatids, Rab2 and Rab6 participate in the formation of pre-acrosomal vesicles. In maturing spermatids, both Rab2 and Rab6 settle on the acrosomal membrane but present different characteristics wrapping the pre-acrosome. In the mature sperm, Rab2 localizes in the perinuclear theca surrounding the nuclei cup, while Rab6 remains on the acrosomal membrane. Our research found 7 Rab proteins based on the analysis of the sperm proteome in E.sinensis, and confirmed the involvement of Rab2 and Rab6 in acrosome formation. These findings provide a foundation for studying the functions of Rab proteins during spermatogenesis in Decapoda animals.


Fetal gene transfer by intrauterine injection with microbubble-enhanced ultrasound.
Intrauterine injection of naked DNA expressing luciferase, green fluorescent protein (GFP), or beta-galactosidase (beta-gal) and fluorescein isothiocyanate-labeled oligodeoxynucleotide (FITC-ODN), in combination with microbubble-enhanced ultrasound (US), referred to as the "shotgun method" (SGM), produced high-level protein expression in fetal mice. With the SGM, luciferase expression increased approximately 10(3)-fold in comparison with expression after injection of naked DNA alone. Electron microscopic analysis demonstrated transient formation of pores on the skin surface after intraamniotic (i.a.) injection with the SGM. Widespread expression of GFP and beta-gal and delivery of FITC-ODN were observed in multiple fetal tissues adjacent to the injection points. PCR analysis indicated that germline transfection was only transient following intraperitoneal (i.p) injection, and there was no evidence of transfer of the reporter gene to the offspring. Thus, SGM might provide a useful means to clarify the molecular mechanisms of genetic diseases in utero, as well as a tool to develop gene therapies in utero.


Retaining the general practitioner workforce in England: what matters to GPs? A cross-sectional study.
The general practice (GP) workforce in England is in crisis, reflected in increasing rates of early retirement and intentions to reduce hours of working. This study aimed to investigate underlying factors and how these might be mitigated. GPs in central England were invited to participate in an on-line survey exploring career plans and views and experiences of work-related pressures. Quantitative data were analysed using logistic regression analysis and principal components analysis. Qualitative data were analysed using a thematic framework approach. Of 1,192 GPs who participated, 978 (82.0 %) stated that they intend to leave general practice, take a career break and/or reduce clinical hours of work within the next five years. This included 488 (41.9 %) who intend to leave practice, and almost a quarter (279; 23.2 %) intending to take a career break. Only 67 (5.6 %) planned to increase their hours of clinical work. For participants planning to leave practice, the issues that most influenced intentions were volume and intensity of workload, time spent on "unimportant tasks", introduction of seven-day working and lack of job satisfaction. Four hundred fifty five participants responded to open questions (39128 words in total). The main themes were the cumulative impact of work-related pressures, the changing and growing nature of the workload, and the consequent stress. Reducing workload intensity, workload volume, administrative activities, with increased time for patient care, no out-of-hour commitments, more flexible working conditions and greater clinical autonomy were identified as the most important requirements to address the workforce crisis. In addition, incentive payments, increased pay and protected time for education and training were also rated as important. New models of professionalism and organisational arrangements may be needed to address the issues described here. Without urgent action, the GP workforce crisis in England seems set to worsen.


Ultrastructural changes associated with retroviral replication in central nervous system capillary endothelial cells.
Widespread ultrastructural alterations in the vascular basal lamina were found in the central nervous system of symptomatic mice infected with three different neuropathogenic murine leukemia viruses. These changes appeared to progress in frequency and severity in parallel with the progression of spongiform lesions and clinical symptoms. Accumulations of pleomorphic, apparently degenerating, virions were frequently seen within areas that showed marked aberrations from the normal basal lamina ultrastructure. We suggest that the observed retrovirus-associated ultrastructural changes in the endothelial basal lamina may alter normal physiologic functions and thus play a primary role in the pathogenesis of retrovirus-induced spongiform disease.


Types and prevalence of coexisting spine lesions on whole spine sagittal MR images in surgical degenerative spinal diseases.
We investigated types and prevalence of coexisting lesions found on whole spine sagittal T2-weighted images (WSST2I) acquired from magnetic resonance imaging (MRI) and evaluated their clinical significance in surgical degenerative spinal diseases. Coexisting spinal lesions were investigated using WSST2I from 306 consecutive patients with surgical degenerative spinal diseases. Severity of coexisting lesions was classified into four grades (0-3). Lesions of grade 2 and 3 were defined as "meaningful coexisting spine lesions" (MCSL). Degenerative spinal diseases were classified into three pathologies: simple disc herniation, degenerative spinal stenosis, and ligament ossification disease. The relationships between MCSL, gender, age, and primary spine lesions were analyzed. MCSL were found in 95 patients: a prevalence of 31.1%. Five out of 95 MCSL were surgically managed. The most common types of MCSL were disc herniation with 13.1% prevalence, followed by degenerative stenosis (9.5%) and ligament ossification diseases (6.8%). Older patients (age >or= 40) showed a significantly higher prevalence of MCSL than younger patients. There was no significant difference between male and female patients. The prevalence of MCSL was significantly higher (52.4%) in ligament ossification diseases than in disc herniation or spinal stenosis. Degenerative spinal diseases showed a high prevalence of MCSL, especially in old ages and ligament ossification diseases. WSST2I is useful for diagnosing coexisting spinal diseases and to avoid missing a significant cord-compressing lesion.


Three-dimensional measurement of wedged scoliotic vertebrae and intervertebral disks.
Idiopathic scoliosis involves complex spinal intrinsic deformations such as the wedging of vertebral bodies (VB) and intervertebral disks (ID), and it is obvious that the clinical evaluation obtained by the spinal projections on the two-dimensional (2D) radiographic planes do not give a full and accurate interpretation of scoliotic deformities. This paper presents a method that allows reconstruction in 3D of the vertebral body endplates and measurement of the 3D wedging angles. This approach was also used to verify whether 2D radiographic measurements could lead to a biased evaluation of scoliotic spine wedging. The 3D reconstruction of VB contours was done using calibrated biplanar X-rays and an iterative projection computer procedure that fits 3D oriented ellipses of adequate diameters onto the 3D endplate contours. "3D wedging angles" of the VB and ID (representing the maximum angle between adjacent vertebrae) as well as their angular locations with respect to the vertebral frontal planes were computed by finding the positions of the shortest and longest distances between consecutive endplates along their contour. This method was extensively validated using several approaches: (1) by comparing the 3D reconstructed endplates of a cadaveric functional unit (T8-T9) with precise 3D measurements obtained using a coordinate measuring machine for 11 different combinations of vertebral angular positions; (2) by a sensitivity study on 400 different vertebral segments mathematically generated, with errors randomly introduced on the digitized points (standard deviations of 0.5, 1, 2, and 3 mm); (3) by comparing the clinical wedging measurements (on postero-anterior and lateral radiographs) at the thoracic apical level of 34 scoliotic patients (15 degrees < Cobb < 45 degrees) to the computed values. Mean errors for the 11 vertebral positions were 0.5 +/- 0.4 mm for VB thickness, less than 2.2 degrees for endplate orientation, and about 11 degrees (3 mm) for the location of the maximum 3D wedging angle along the endplate contour. The errors below 2 mm (introduced on the digitized points) slightly affected the 3D wedging angle (< 2 degrees) and its location (< 4 degrees) for the ID. As for the clinical evaluation, average angular errors were less than 0.4 degrees in the radiographic frontal and lateral planes. The mean 3D wedged angles were about 4.9 degrees +/- 1.9 degrees for the VB and 6.0 degrees +/- 1.7 degrees for the ID. Linear relations were found between the 2D and the 3D angles, but the 3D angles were located on diagonal planes statistically different than the radiographic ones (between 100 degrees and 221 degrees). There was no statistical relation between the 2D radiographic angles and the locations of the 3D intervertebral wedging angles. These results clearly indicate that VB and ID endplates are wedged in 3D, and that measurements on plain radiographs allow incomplete evaluation of spinal wedging. Clinicians should be aware of these limitations while using wedging measurements from plain radiographs for diagnosis and/or research on scoliotic deformities.


B‑cell translocation gene 1 serves as a novel prognostic indicator of hepatocellular carcinoma.
Although the B‑cell translocation gene 1 (BTG1) plays an important role in apoptosis and negatively regulates cell proliferation, BTG1 expression in hepatocellular carcinoma (HCC) has not been evaluated. In this study expression analysis of BTG1 was conducted to clarify the role of BTG1 in the initiation of HCC carcinogenesis and progression. BTG1 mRNA expression levels were determined for HCC cell lines and 151 surgical specimen pairs using quantitative real‑time reverse transcription polymerase chain reaction (RT‑qPCR) assay. The mutational and methylation status of HCC cell lines were analyzed via high resolution melting (HRM) analysis and direct sequencing analysis to elucidate the regulatory mechanisms of BTG1 expression. The expression and distribution of the BTG1 protein in liver tissues were evaluated using immunohistochemistry (IHC). Decreased expression of BTG1 mRNA was confirmed in the majority of HCC cell lines (89%) and clinical HCC tissues (85%) compared with non‑cancerous liver tissues. Mutations or promoter hypermethylation were not identified in HCC cell lines. BTG1 mRNA expression levels were not influenced by background liver status. The pattern of BTG1 protein expression was consistent with that of BTG1 mRNA. Downregulation of BTG1 mRNA in HCC was significantly associated with shorter disease‑specific and recurrence‑free survival rates. Multivariate analysis of disease‑specific survival rates identified BTG1 mRNA downregulation as an independent prognostic factor for HCC (hazard ratio 2.12, 95% confidence interval 1.12‑4.04, P=0.022). Our results indicate that altered BTG1 expression might affect hepatocarcinogenesis and may represent a novel biomarker for HCC carcinogenesis and progression.


A novel KCND3 mutation associated with early-onset lone atrial fibrillation.
Atrial fibrillation (AF) is the most common arrhythmia in the clinic. While previous studies have identified AF-associated mutations in several genes, the genetic basis for AF remains unclear. Here, we identified a novel T361S missense mutation in potassium voltage-gated channel, shal-related subfamily, member 3 (KCND3) from a Chinese Han family ancestor with lone AF. The wild-type (WT) or mutant T361S of Kv4.3 protein (encoded by KCND3) were co-expressed with the auxiliary subunit K+ channel-Interacting Protein (KChIP2) in HEK293 cells, and transient outward potassium current (Ito) were recorded using patch-clamp methods, and the surface or total protein levels of Kv4.3 were analyzed by western blot. Ito density, measured at 60 mV, for T361S was significantly higher than that for WT. Both the steady-state activation and inactivation curves showed a remarkable hyperpolarizing shift in T361S. Moreover, recovery from inactivation after a 500-ms depolarizing pulse was significantly delayed for T361S compared with that for WT. Mechanistically, the gain of function of Ito elicited by T361S was associated with the increased expression of cell surface and total cell protein of Kv4.3. The computer stimulation revealed that the T361S mutation shortened the action potential duration through an increased Itoin Human Atrial Model. In conclusion, we identified a novel T361S mutation in KCND3 associated with AF in the Chinese Han family. The T361S mutant result in the changes in channel kinetics as well as the up-regulation of Kv4.3 protein, which may be a critical driver for lone AF as observed in the patient.


Capillary-dominated electrified jets of a viscous leaky dielectric liquid.
The capillary-dominated regime of dynamics of electrified jets of a viscous leaky dielectric liquid is studied numerically. In this regime the effective force in the direction of an applied field due to tangential electric stresses is balanced by the gradient of liquid pressure governed by the surface-tension stresses. As is characteristic of this regime, the electric current and the characteristic jet radius are dependent on the surface-tension coefficient and not on viscosity. In the scope of this work, the conditions of the existence of this regime are determined. A qualitative order-of-magnitude analysis gives the power-law dependences of the jet radius and electric current on the parameters of the problem (conductivity, applied electric field, flow rate, and surface-tension coefficient). Numerical results are obtained for low conductive liquids for a large range of the dimensionless flow rate (capillary number, Ca). The order-of-magnitude estimations of electric current are in agreement with the numerical results given a small Ca. The corresponding numerically obtained jet shapes are discussed and explained.


Chylomicron remnant-vitamin A metabolism by the human hepatoma cell line HepG2.
The binding and metabolism of [3H]vitamin A-containing chylomicron (CM) remnants by the human hepatoma cell line HepG2 were studied. Mesenteric lymph chylomicrons were collected from [3H]retinol-fed rats and incubated with lipoprotein lipase to obtain CM remnants. At 4 degrees C, specific CM remnant binding was inhibited by an excess of unlabeled CM remnants. Specific binding predominated at low concentrations and approached saturation while total binding continued to increase over an extensive concentration range (0.45-32 microgram triglyceride/ml). CM remnant uptake at 37 degrees C was greater than that of CM and at least 70 times more efficient than the pinocytosis of sucrose. CM remnant binding increased with the extent of lipolysis. Addition of human apolipoprotein E enhanced both CM remnant and CM binding. After internalization, HepG2 cells hydrolyzed CM remnant-[3H]retinyl esters, and radiolabeled metabolites accumulated. As a function of the concentration of [3H]retinoid initially bound to cells, retinol and retinyl esters accumulated as the major cell-associated metabolites. In contrast, retinol was the major metabolite in the medium only at low retinoid concentrations; other more polar metabolites accumulated at higher concentrations (greater than 110 pmol retinoid/mg cell protein). The accumulation in the medium of labeled metabolites derived from CM remnant-retinoid was reduced when cells were preincubated in unlabeled retinol-supplemented media. The specific activity of retinol in the medium indicated that CM remnant-vitamin A had mixed with the cellular store prior to its secretion as retinol. These results indicate that HepG2 cells internalize CM remnants in part by specific binding sites, and that the metabolism of CM remnant-retinoids by the HepG2 cell involves retinyl ester hydrolysis and the secretion of retinol and other more polar metabolites. These processes were regulated in part by the concentration of retinoid delivered by the CM remnant and by the initial retinoid content of the cell.


The use of theory in the development and evaluation of behaviour change interventions to improve antimicrobial prescribing: a systematic review.
This systematic review (SR) reviews the evidence on use of theory in developing and evaluating behaviour change interventions (BCIs) to improve clinicians' antimicrobial prescribing (AP). The SR protocol was registered with PROSPERO. Eleven databases were searched from inception to October 2018 for peer-reviewed, English-language, primary literature in any healthcare setting and for any medical condition. This included research on changing behavioural intentions (e.g. in simulated scenarios) and research measuring actual AP. All study designs/methodologies were included. Excluded were: grey literature and/or those which did not state a theory. Two reviewers independently extracted and quality assessed the data. The Theory Coding Scheme (TCS) evaluated the extent of the use of theory. Searches found 4227 potentially relevant papers after removal of duplicates. Screening of titles/abstracts led to dual assessment of 38 full-text papers. Ten (five quantitative, three qualitative and two mixed-methods) met the inclusion criteria. Studies were conducted in the UK (n = 8), Canada (n = 1) and Sweden (n = 1), most in primary care settings (n = 9), targeting respiratory tract infections (n = 8), and medical doctors (n = 10). The most common theories used were Theory of Planned Behaviour (n = 7), Social Cognitive Theory (n = 5) and Operant Learning Theory (n = 5). The use of theory to inform the design and choice of intervention varied, with no optimal use as recommended in the TCS. This SR is the first to investigate theoretically based BCIs around AP. Few studies were identified; most were suboptimal in theory use. There is a need to consider how theory is used and reported and the systematic use of the TCS could help.


Hypothesis and Theory: A Pathophysiological Concept of Stroke-Induced Acute Phase Response and Increased Intestinal Permeability Leading to Secondary Brain Damage.
Gut integrity impairment leading to increased intestinal permeability (IP) is hypothesized to be a trigger of critically illness. Approximately 15-20% of human ischemic stroke (IS) victims require intensive care, including patients with impaired level of consciousness or a high risk for developing life-threatening cerebral edema. Local and systemic inflammatory reactions are a major component of the IS pathophysiology and can significantly aggravate brain tissue damage. Intracerebral inflammatory processes following IS have been well studied. Until now, less is known about systemic inflammatory responses and IS consequences apart from a frequently observed post-IS immunosuppression. Here, we provide a hypothesis of a crosstalk between systemic acute phase response (APR), IP and potential secondary brain damage during acute and subacute IS stages supported by preliminary experimental data. Alterations of the acute phase proteins (APPs) C-reactive protein and lipopolysaccharide-binding protein and serum level changes of antibodies directed against Escherichia coli-cell extract antigen (IgA-, IgM-, and IgG-anti-E. coli) were investigated at 1, 2, and 7 days following IS in ten male sheep. We found an increase of both APPs as well as a decrease of all anti-E. coli antibodies within 48 h following IS. This may indicate an early systemic APR and increased IP, and underlines the importance of the increasingly recognized gut-brain axis and of intestinal antigen release for systemic immune responses in acute and subacute stroke stages.


Enrichment of open reading frames presented on bacteriophage M13 using hyperphage.
The enrichment of open reading frames (ORFs) from large gene libraries and the presentation of the corresponding polypeptides on filamentous phage M13 (phage display) is frequently used to identify binding partners of unknown ORFs. In particular phage display is a valuable tool for the identification of pathogen-related antigens and a first step for the development of new diagnostics and therapeutics. Here, we introduce a significant improvement of phage-based ORF enrichment by using Hyperphage, a helperphage with a truncated gIII. The methods allow both the enrichment of ORFs from cDNA libraries and the display of the corresponding polypeptides on phage, thus combining ORF enrichment with a screening for binding in one step without any further subcloning steps. We demonstrated the benefits of the method by isolating the sequences encoding two predicted immunogenic epitopes of the outer membrane protein D encoding gene (ompD) of Salmonella typhimurium. Here, we showed that when using a mixture of three constructs with only one containing an ORF solely this correct construct could be reisolated in phage particles. Further; both epitopes were detected by enzyme-linked immunosorbent assay (ELISA), demonstrating correct translation of fusion proteins. Furthermore, the enrichment system was evaluated by the enrichment of ORFs from total cDNA of lymphocytes. Here, we could show that 60% of the phage contained ORFs, which is an increase of an order of magnitude compared with conventional phage expression system. Together these data show that the Hyperphage-based enrichment system significantly improves the enrichment of ORFs and directly allows the display of the corresponding polypeptide on bacteriophage M13.


Efficacy of live attenuated influenza A/Scotland/74 (H3N2) virus vaccine against challenge with influenza A/Victoria/3/75 (H3N2) virus.
For evaluation of heterologous protection by live attenuated influenza virus vaccine, 42 healthy volunteers with low titers of or no antibody to A/Scotland/74 (H3N2) and A/Victoria/3/75 (H3N2) influenza viruses were given live attenuated A/Scotland/74 (H3N2) virus vaccine or placebo by the intranasal route with no resultant vaccine-related illness. Seventeen of 21 vaccine recipients and none of 21 placebo recipients developed antibody conversion. Thirty-seven days after administration of vaccine or placebo, all subjects were challenged intranasally with wild-type A/Victoria/3/75 influenza virus. Five placebo recipients and no vaccine recipients developed moderately severe illness, whereas 10 vaccine recipients and three placebo recipients developed no illness (p less than 0.025). Although 16 of 21 vaccine recipients fulfilled criteria of infection with the challenge virus, shedding of virus was significantly less frequent, less prolonged, and of significantly lower magnitude than that in the placebo recipients. Thus, live attenuated influenza virus vaccine showed a significant protective effect against illness following challenge with heterologous wild-type virus. The protective effect and the negligible side effects of this vaccine merit consideration of its use in a large-scale field trial.


Interview with David Tauben: University of Washington, Chief of the Division of Pain Medicine.
Dr Tauben is Clinical Professor jointly appointed in the Departments of Medicine and Anesthesia & Pain Medicine, and is the Hughes M & Katherine G Blake Endowed Professor, board certified in both Internal Medicine and Pain Medicine. He is also University of Washington (UW) Director of Medical Student and Resident Education in Pain Medicine, and Medical Director of UW TelePain, a tele-video-conferencing program intended to provide innovative pain education and consultative support to a five-state northwest regional primary care providers. He served as a member of the NIH National Pain Strategy task force on pain education and is principal investigator for the UW's prestigious NIH Pain Consortium Center of Excellence for Pain Education, leading curriculum development to extend the pain proficiency qualifications of interprofessional primary care providers. Dr Tauben is a member of the American Pain Society and the International Association for the Study of Pain special interest study groups on Pain Education. He is a founding member of the State of Washington Agency Medical Directors panel of medical experts developing opioid prescription guidelines for the state, and a regular clinical and content expert for regulatory and legislative bodies involved in public policy regarding pain medicine practice and standards. He speaks as a clinical expert in medical management of chronic pain, especially as it applies to primary care practices. Dr Tauben served as an expert for several US Centers for Disease Control clinical outreach programs and policy reviews advising primary care providers on how to prescribe opioids for chronic noncancer pain. He is annually recognized by his peers as recipient of regional awards in care of pain patients, and brings decades of clinical experience of best practice medication management of acute and chronic pain. Dr Tauben received his bachelors degree in philosophy from Yale University, medical degree from Tufts University School of Medicine and completed his residency training at the UW, in Seattle. He is a fellow of the American College of Physicians.


Restoring pistil-side self-incompatibility factors recapitulates an interspecific reproductive barrier between tomato species.
Interspecific reproductive barriers are poorly understood, but are central to the biological species concept. The pre-zygotic barriers between red- and green-fruited species in the tomato clade of the genus Solanum provide a model to better understand these barriers in plants. Compatibility usually follows the SI x SC rule: pollen from self-compatible (SC) red-fruited species is rejected on pistils of the predominantly self-incompatible (SI) green-fruited species, but the reciprocal crosses are compatible. This suggests that the interspecific reproductive barrier may be linked to the intraspecific SI mechanism. However, pollen from the SC red-fruited species is also rejected by SC accessions of green-fruited species that lack S-RNase, a key protein expressed in pistils of SI Solanum species. Thus, multiple mechanisms may contribute to the barrier between red- and green-fruited species. We tested whether an S-RNase-dependent barrier is sufficient for rejection of pollen from red-fruited species by introducing functional S-RNase, HT-A and HT-B genes from SI species into Solanum lycopersicum (cultivated tomato). We found that expressing S-RNase in combination with either HT-A or HT-B in the pistil is sufficient to cause rejection of pollen from all four red-fruited species. Thus, redundant mechanisms must operate side by side to prevent crosses between red- and green-fruited species in the clade, underlining the complexity of interspecific pollination barriers. Our results also have implications for mating system transitions. We suggest that these transitions must occur in a specific sequence, and that the transition from SI to SC also affects interspecific compatibility.


Radiation Exposure of Patients and Interventional Radiologists during Prostatic Artery Embolization: A Prospective Single-Operator Study.
To prospectively analyze the radiation exposure of patients and interventional radiologists during prostatic artery embolization (PAE). Twenty-five consecutive PAE procedures performed with an Artis zee system in a single center by an interventional radiologist were prospectively monitored. The mean age, weight, and prostate volume of the patients were 65.7 year (range, 43-85 y), 71.4 kg (range, 54-88 kg), and 79 cm3 (range, 36-157 cm3), respectively. In addition to Digital Imaging and Communications in Medicine radiation data, direct measures were also obtained. Radiochromic film was used to evaluate peak skin dose (PSD). The radiologist wore a protective apron and a thyroid collar, and a ceiling-suspended screen and a table curtain were used. To estimate the absorbed doses, nine pairs of dosimeters were attached to the operator's body. The average fluoroscopy time was 30.9 minutes (range, 15.5-48.3 min). The mean total dose-area product (DAP) was 450.7 Gy·cm2 (range, 248.3-791.73 Gy·cm2) per procedure. Digital subtraction angiography was responsible for 71.5% of the total DAP, followed by fluoroscopy and cone-beam computed tomography. The mean PSD was 2,420.3 mGy (range, 1,390-3,616 mGy). The average effective dose for the interventional radiologist was 17 μSv (range, 4-47 μSv); values for the eyes, hands, and feet were obtained, and were all greater on the left side. PAE may lead to high x-ray exposures to patients and interventional radiologists.


Two additional glutaredoxins exist in Escherichia coli: glutaredoxin 3 is a hydrogen donor for ribonucleotide reductase in a thioredoxin/glutaredoxin 1 double mutant.
Thioredoxin (Trx) and glutaredoxin (Grx1) are hydrogen donors for ribonucleotide reductase, the key enzyme for deoxyribonucleotide biosynthesis. The viability of a double mutant lacking both Trx and Grx1 implies the presence of a third, unknown hydrogen donor. This paper reports the purification and characterization of two proteins with glutaredoxin activity (using hydroxyethyl disulfide as a substrate) from an Escherichia coli mutant lacking Trx and Grx1 (delta trxA, grx::kan). Affinity chromatography was used to bind glutaredoxin on a glutathione-containing thiol-Sepharose column. The molecular weight of Grx2, 27,000, was atypical for glutaredoxins, whereas Grx3 had a molecular weight of 10,000. Amino acid sequence analysis revealed novel structures with putative active sites typical of glutaredoxins: Cys-Pro-Tyr-Cys. The proteins are therefore referred to as Grx2 and Grx3. The low hydrogen donor activity for ribonucleotide reductase in the crude extract was recovered in the purification of Grx3, whereas Grx2 was inactive. As a hydrogen donor for E. coli ribonucleotide reductase, Grx3 showed approximately the same Km value (0.35 microM) as Grx1, whereas its Vmax value was only 5% that of Grx1. The combination of the Grx3 hydrogen donor activity and a 25-fold induction of ribonucleotide reductase activity in a delta trxA, grx double mutant provides an explanation for its viability and deoxyribonucleotide biosynthesis. The physiological functions of Grx2 and Grx3 remain to be determined.


Antitumor Effect of Docetaxel in Osteosarcoma by the Inhibition of Wnt Signal Channel.
Osteosarcoma (OS) is the most common type of malignant bone tumor in adults and children. Despite the great strides in biology and medicine, the survival rate of patients with metastatic disease remains very poor. This rate has been staggering with recurrence and metastasis. In the present study, we proposed Wnt/β-catenin pathway as a key biological target for the effective treatment in OS. Wnt signaling has been reported to play important roles in osteoblastogenesis. We hypothesized that docetaxel (DTX) will effectively arrest the osteosarcoma progression by suppressing the Wnt/β-catenin pathway in OS cells. Our results show that DTX significantly inhibited the cell proliferation of U2OS and SaOS-2 cancer cells in a time-dependent and dose-dependent manner. DTX inhibited the intrinsic transcriptional activity of β-catenin/Tcf in U2OS cancer cells and SaOS-2 cancer cells. GSK-3βinhibitor (SB216763) treatment remarkably increased the β-catenin/Tcf transcriptional activities. The transcriptional activities have been increased by around ~200% due to the decrease in the degradation of β-catenin mediated through GSK-3β. Summarizing, present study clearly showed that DTX inhibited Wnt/β-catenin signalling pathways and significantly reduced the matrix metallopeptodase 9 (MMP-9) protein expressions and its activity. Taken together, our findings provide novel insight on the effect of anticancer small molecules to improve the outcomes in osteosarcoma.


Therapeutic potential of nuclear receptor agonists in Alzheimer's disease.
Alzheimer's disease (AD) is characterized by an extensive accumulation of amyloid-β (Aβ) peptide, which triggers a set of deleterious processes, including synaptic dysfunction, inflammation, and neuronal injury, leading to neuronal loss and cognitive impairment. A large body of evidence supports that nuclear receptor (NR) activation could be a promising therapeutic approach for AD. NRs are ligand-activated transcription factors that regulate gene expression and have cell type-specific effects. In this review, we discuss the mechanisms that underlie the beneficial effects of NRs in AD. Moreover, we summarize studies reported in the last 10-15 years and their major outcomes arising from the pharmacological targeting of NRs in AD animal models. The dissection of the pathways regulated by NRs in the context of AD is of importance in identifying novel and effective therapeutic strategies.


SPRING: an RCT study of probiotics in the prevention of gestational diabetes mellitus in overweight and obese women.
Obesity is increasing in the child-bearing population as are the rates of gestational diabetes. Gestational diabetes is associated with higher rates of Cesarean Section for the mother and increased risks of macrosomia, higher body fat mass, respiratory distress and hypoglycemia for the infant. Prevention of gestational diabetes through life style intervention has proven to be difficult. A Finnish study showed that ingestion of specific probiotics altered the composition of the gut microbiome and thereby metabolism from early gestation and decreased rates of gestational diabetes in normal weight women. In SPRING (the Study of Probiotics IN the prevention of Gestational diabetes), the effectiveness of probiotics ingestion for the prevention of gestational diabetes will be assessed in overweight and obese women. SPRING is a multi-center, prospective, double-blind randomized controlled trial run at two tertiary maternity hospitals in Brisbane, Australia. Five hundred and forty (540) women with a BMI > 25.0 kg/m(2) will be recruited over 2 years and receive either probiotics or placebo capsules from 16 weeks gestation until delivery. The probiotics capsules contain > 1x10(9) cfu each of Lactobacillus rhamnosus GG and Bifidobacterium lactis BB-12 per capsule. The primary outcome is diagnosis of gestational diabetes at 28 weeks gestation. Secondary outcomes include rates of other pregnancy complications, gestational weight gain, mode of delivery, change in gut microbiome, preterm birth, macrosomia, and infant body composition. The trial has 80% power at a 5% 2-sided significance level to detect a >50% change in the rates of gestational diabetes in this high-risk group of pregnant women. SPRING will show if probiotics can be used as an easily implementable method of preventing gestational diabetes in the high-risk group of overweight and obese pregnant women.


Mitigation of Single-Event Effects in SiGe-HBT Current-Mode Logic Circuits.
It has been known that negative feedback loops (internal and external) in a SiGe heterojunction bipolar transistors (HBT) DC current mirrors improve single-event transient (SET) response; both the peak transient current and the settling time significantly decrease. In the present work, we demonstrate how radiation hardening by design (RHBD) techniques utilized in DC bias blocks only (current mirrors) can also improve the SET response in AC signal paths of switching circuits (e.g., current-mode logic, CML) without any additional hardening in those AC signal paths. Four CML circuits both with and without RHBD current mirrors were fabricated in 130 nm SiGe HBT technology. Two existing RHBD techniques were employed separately in the current mirrors of the CML circuits: (1) applying internal negative feedback and (2) adding a large capacitor in a sensitive node. In addition, these methods are also combined to analyze the overall SET performance. The single-event transients of the fabricated circuits were captured under the two-photon-absorption laser-induced single-event environment. The measurement data clearly show significant improvements in SET response in the AC signal paths of the CML circuits by using the two radiation hardening techniques applied only in DC current mirrors. The peak output transient current is notably reduced, and the settling time upon a laser strike is shortened significantly.


A new method for estimating nonsynonymous substitutions and its applications to detecting positive selection.
The standard methods for computing the number of nonsynonymous substitutions (Ka) lump all amino acid changes into one single class, even though their rates of substitution vary by at least 10-fold (Tang et al., 2004). Classifying these changes by their physicochemical properties has not been suitably effective in isolating the fastest evolving classes of changes. We now propose to use the Universal index U of Tang et al. (2004) to classify the 75 elementary amino acid changes (codons differing by 1 bp) by their evolutionary exchangeability. Let Ki denote the Ka value of each class (i = 1, ..., 75 from the most to the least exchangeable). The cumulative Ki for the top 10 classes, denoted Kh (for high-exchangeability types), has two important properties: (1) Kh usually accounts for 25%-30% of total amino acid changes and (2) when the observed number of amino acid substitutions is large, Kh is predictably twice the value of Ka. This shall be referred to as the twofold approximation. The new method for estimating Kh is applied to the comparisons between human and macaque and between mouse and rat. The twofold approximation holds well in these data sets, and the signature of positive selection can be more easily discerned using the Kh statistic than using Ka. Many genes with Ka/Ks > 0.5 can now be shown to have Kh/Ks > 1 and to have evolved adaptively, at least for the high-exchangeability group of amino acid changes.


[Studies on rubella vaccination in adult females. I: Clinical and laboratory studies on clinical reactions].
More than 1,000 young females were screened for rubella HI antibodies. Clinico-laboratory studies were carried out in 272 seronegative healthy adult women who received Japanese licensed rubella vaccine, TO-336 or MEQ11 vaccine. Clinical reactions were observed in 51 (29.7%) of 172 vaccinees, aged 18-30 years (mean age; 20. 8 year), who received TO-336 vaccine, whereas only 4 cases (4.0%) had clinical reactions in 100 vaccinees, aged 18-26 years (mean age; 19.1 year), who received MEQ11 vaccine. The most troublesome and common clinical reaction was arthralgia, particularly in women received TO-336 vaccine. Joint symptoms, especially the knee, hand and finger joint, were observed in 41 of 51 cases with clinical reactions after TO-336 vaccination. On the other hand, vaccinees who received TO-336 vaccine gave a more satisfactory seroconversion response than vaccinees who received MEQ11 vaccine (100% vs 97%). This difference was also reflected in the geometric mean titers (1: 58 vs 1: 31). These results suggested strongly that MEQ11 vaccine might be a more attenuated rubella vaccine than TO-336 vaccine, according to the clinical reactions and antibody response. Associations of host factors to clinical reactions were examined. There was not a significant difference of antibody response between vaccinees who developed clinical reactions and those who did not. But vaccinees with HLA-B 15 responded well and high against two rubella vaccines. There was no specific association between HLA types and clinical reactions.


Reality of dental implant surface modification: a short literature review.
Screw-shaped endosseous implants that have a turned surface of commercially pure titanium have a disadvantage of requiring a long time for osseointegration while those implants have shown long-term clinical success in single and multiple restorations. Titanium implant surfaces have been modified in various ways to improve biocompatibility and accelerate osseointegration, which results in a shorter edentulous period for a patient. This article reviewed some important modified titanium surfaces, exploring the in vitro, in vivo and clinical results that numerous comparison studies reported. Several methods are widely used to modify the topography or chemistry of titanium surface, including blasting, acid etching, anodic oxidation, fluoride treatment, and calcium phosphate coating. Such modified surfaces demonstrate faster and stronger osseointegration than the turned commercially pure titanium surface. However, there have been many studies finding no significant differences in in vivo bone responses among the modified surfaces. Considering those in vivo results, physical properties like roughening by sandblasting and acid etching may be major contributors to favorable bone response in biological environments over chemical properties obtained from various modifications including fluoride treatment and calcium phosphate application. Recently, hydrophilic properties added to the roughened surfaces or some osteogenic peptides coated on the surfaces have shown higher biocompatibility and have induced faster osseointegration, compared to the existing modified surfaces. However, the long-term clinical studies about those innovative surfaces are still lacking.


Viral degradasome hijacks mitochondria to suppress innate immunity.
The balance between the innate immunity of the host and the ability of a pathogen to evade it strongly influences pathogenesis and virulence. The two nonstructural (NS) proteins, NS1 and NS2, of respiratory syncytial virus (RSV) are critically required for RSV virulence. Together, they strongly suppress the type I interferon (IFN)-mediated innate immunity of the host cells by degrading or inhibiting multiple cellular factors required for either IFN induction or response pathways, including RIG-I, IRF3, IRF7, TBK1 and STAT2. Here, we provide evidence for the existence of a large and heterogeneous degradative complex assembled by the NS proteins, which we named "NS-degradasome" (NSD). The NSD is roughly ∼300-750 kD in size, and its degradative activity was enhanced by the addition of purified mitochondria in vitro. Inside the cell, the majority of the NS proteins and the substrates of the NSD translocated to the mitochondria upon RSV infection. Genetic and pharmacological evidence shows that optimal suppression of innate immunity requires mitochondrial MAVS and mitochondrial motility. Together, we propose a novel paradigm in which the mitochondria, known to be important for the innate immune activation of the host, are also important for viral suppression of the innate immunity.


Safety and effectiveness of high-power thulium laser enucleation of the prostate in patients with glands larger than 80 mL.
The efficacy of thulium laser prostate enucleation (ThuLEP) for large prostates is unclear. This study aimed to explore the expanded utility of 150-200-W ThuLEP by studying patients with a large prostate (> 80 mL). We retrospectively reviewed records of 125 patients with large prostate glands (> 80 mL) who underwent ThuLEP performed by a single surgeon from June 2012 to June 2016. The ThuLEP data from our previous pilot study were used as the control. Operative variables, patient profiles, preoperative and postoperative urine flow rates, prostate volume, and the international prostate symptom score (IPSS) were recorded and analyzed using Student's t-test, the z-test, and logistic regression analysis. Of 366 patients who underwent ThuLEP, 125 (34.15%) were enrolled. The ages and estimated prostate volumes were compared with those of the control. Overall, 39.2% underwent Foley placement and 4% received an anticoagulant agent preoperatively. Maximum urinary flow rates before and 3 and 12 months postoperatively were 9.93, 23.20, and 19.00 mL/s, respectively, which were generally equal to those of the control groups (P = 0.68, 0.18, 0.98, respectively). Preoperative and postoperative IPSSs were 27.09 and 7.35, respectively. The postoperative prostate-specific antigen was reduced by 85.59% in comparison to the preoperative level. The estimated prostate size was reduced by 74.17% postoperatively. The modified Clavien-Dindo classification system was used to identify the overall rate of complications, which was approximately 22.4%. The mortality rate was 0.8%. High-power ThuLEP is safe and effective for patients with large prostate glands (> 80 mL). Prostate enucleation using a high-power thulium laser is feasible for patients who exhibit contraindications for surgery.


An investigation of the forces used by clinicians to open spaces with coil springs.
To determine the forces applied by coil springs used to open spaces for blocked out lateral incisors, and to compare the actual forces used with clinicans' concepts of an 'ideal' force. Twelve postgraduate orthodontic students (7M, 5F) and 12 orthodontic tutors (9M, 3F) participated in this study. They were asked to state what they considered was an ideal orthodontic force, and then to cut appropriate lengths of stainless steel and nickel titanium open coil springs to open spaces for blocked out maxillary and mandibular permanent lateral incisors on a typodont set-up. The forces generated by the open coil springs were measured and compared to the stated ideal forces. The mean ideal force was 76.75 g (Range: 25-200 g). The mean applied force was 314 g (Range: 21-519 g). There were no significant differences in the forces used by the male and female postgraduates, but the male tutors used a significantly higher force than the male postgraduate students (p = 0.007) and the female tutors (p < 0.001). The female tutors used a significantly lower force than the female postgraduates (p = 0.024) and the male postgraduates (p = 0.003). Higher forces were produced by the stainless steel coil springs in both arches (Maxillary arch: p = 0.007; Mandibular arch: p < 0.005). The clinicians could not agree on an ideal force to open spaces for blocked out lateral incisors. There were substantial differences between the forces applied by the coil springs and the forces considered by the clinicians to be ideal. There were large differences in the forces used by the different groups of orthodontists.


Obesity as a risk and severity factor in rheumatic diseases (autoimmune chronic inflammatory diseases).
The growing body of evidence recognizing the adipose tissue (AT) as an active endocrine organ secreting bioactive mediators involved in metabolic and inflammatory disorders, together with the global epidemic of overweight and obesity, rise obesity as a hot topic of current research. The chronic state of low-grade inflammation present in the obese condition and the multiple pleiotropic effects of adipokines on the immune system has been implicated in the pathogenesis of several inflammatory conditions including rheumatic autoimmune and inflammatory diseases. We will discuss the main relevant evidences on the role of the AT on immune and inflammatory networks and the more recent evidences regarding the effects of obesity on the incidence and outcomes of the major autoimmune chronic inflammatory diseases.


Social attainment in physically well-functioning long-term survivors of pediatric brain tumour; the role of executive dysfunction, fatigue, and psychological and emotional symptoms.
The purpose of this cross-sectional study was to investigate long-term social attainment in physically well-functioning adult survivors of pediatric brain tumour (PBT) and identify demographic, medical, and psychological factors related to poor social outcomes, with a special focus on the significance of executive dysfunction. One hundred and fourteen PBT survivors and a healthy control group provided personal data on social outcomes, i.e., education, work, and government benefits, and completed questionnaires on executive function (EF), psychological and emotional difficulties, and fatigue. A significantly higher number of survivors compared to healthy controls reported having received educational adjustments and substantial government benefits, and significantly more survivors than controls were currently not engaged in regular employment/training. PBT survivors and healthy controls did not differ on educational level or living situation. The factors most strongly associated with poor social outcomes were self-reported executive dysfunction, difficulties with adaptive functioning, and fatigue. The findings show that physically well-functioning PBT survivors are at risk of poorer social outcomes and financial dependence in adulthood compared to their healthy peers, and underline the importance of investigating EF in short- and long-term follow-ups. Future rehabilitation efforts should focus more on compensatory strategies for executive dysfunction and improving EF skills.


Molecular cloning of a tyrosine kinase gene from the marine sponge Geodia cydonium: a new member belonging to the receptor tyrosine kinase class II family.
We have isolated and characterized a cDNA from the marine sponge Geodia cydonium coding for a new member of the tyrosine protein kinase (TK) family. The cDNA encodes a protein of M(r) = 68,710, termed GCTK, which is homologous to class II receptor tyrosine kinases (RTKs). GCTK contains conserved amino acids (aa) characteristic of all protein kinases, and the sequences DLATRN and PIRWMATE which are highly specific for TKs. Furthermore, the sequence N-L-Y-x(3)-Y-Y-R is highly homologous to the sequence D-[LIV]-Y-x(3)-Y-Y-R found only in class II RTKs. The sponge TK, when compared with mammalian class II RTKs, shows maximum 31% homology in the TK domain indicating that this the oldest member of class II RTK started to diverge from the common ancestral protein kinase approximately 650 million years ago. Using GCTK as a probe we identified three mRNA signals ranging from 2.6 to 0.6 kb. Kinase activity was localized only in the cell membranes from G. cydonium (M(r) = 65,000), and was not detected in the cytosol of this organism. Antibodies raised against a synthetic peptide, corresponding to the aa residues within the catalytic domain of the sponge TK, recognized strongly two proteins of M(r) = 65,000; these proteins, present in membrane fractions, also bound to the antiphosphotyrosine antibody. These data suggest that the TK cloned from the sponge is a membrane-associated 65 kDa protein. Moreover these results demonstrate that RTKs are present from the lowest group of multicellular eukaryotes, sponges, to mammals, and may suggest that RTKs are involved in a signal transduction pathway.


Multidisciplinary Management of Neuroendocrine Neoplasia: A Real-World Experience from a Referral Center.
Multidisciplinary approach is widely advised for an effective care of patients with neuroendocrine neoplasia (NEN). Since data on efficacy of multidisciplinary management of NENs patients in referral centers are scanty, this study aimed at analyzing the modality of presentation and clinical outcome of patients with NENs managed by a dedicated multidisciplinary team. In this prospective observational study, we included all consecutive new patients visiting the Sant'Andrea Hospital in Rome (ENETS-Center of Excellence) between January 2014 and June 2018. A total of 195 patients were evaluated. The most frequent sites were pancreas (38.5%), small bowel (22%), and lung (9.7%). Median Ki67 was 3%. After the first visit at the center, additional radiological and/or nuclear medicine procedures were requested in 163 patients (83.6%), whereas histological data revision was advised in 84 patients (43.1%) (revision of histological slides: 27.7%, new bioptic sampling: 15.4%). After that, disease imaging staging and grading was modified in 30.7% and 17.9% of patients, respectively. Overall, a change in therapeutic management was proposed in 98 patients (50.3%). Multidisciplinary approach in a dedicated team may lead to change of disease imaging staging and grading in a significant proportion of patients. Enhancing referral routes to dedicated-NEN center should be promoted, since it may improve patients' clinical outcome.


MHY451 induces cell cycle arrest and apoptosis by ROS generation in HCT116 human colorectal cancer cells.
Colorectal cancer (CRC) is the third most frequently diagnosed cancer and cause of cancer-related deaths. Despite advancements in conventional therapeutic approaches to CRC, most patients with CRC die of their disease. There is a need to develop novel therapeutic agents for this malignancy. Therefore, the present study aimed to examine the anticancer effects and elucidate the underlying mechanism of MHY451 in HCT116 human colorectal cancer cells. Treatment with MHY451 inhibited cell growth in a time- and concentration-dependent manner. MHY451 increased the accumulation of cell cycle progression at the G2/M phase. This agent decreased the protein level of cyclin B1 and its activating partners, Cdc25c and Cdc2, whereas it increased the cell cycle inhibitor p21WAF/CIP. The induction of apoptosis was observed by decreased viability, cleavage of poly(ADP-ribose) polymerase (PARP), alteration in the ratio of Bax/Bcl-2 protein expression and reduction of procaspase-8 and -9. Pretreatment with Z-VAD-FMK, a pan-caspase inhibitor, inhibited MHY451-induced apoptosis, indicating that apoptotic cell death by MHY451 was mediated through caspases. Moreover, the apoptotic effect of MHY451 was reactive oxygen species (ROS)-dependent, evidenced by the inhibition of MHY451-induced PARP cleavage and ROS generation by N-acetylcysteine-induced ROS scavenging. Taken together, these results demonstrate that MHY451 exerts anticancer effects by regulating the cell cycle, inducing apoptosis through caspase activation and generating ROS. These results suggest that MHY451 has considerable potential for chemoprevention or treatment of CRC or both.


An online global survey and follow-up expert groups on the scope and needs related to training, research, and mentorship among early-career addiction medicine professionals.
Addiction medicine is a rapidly growing field with many young professionals seeking careers in this field. However, early-career professionals (ECPs) face challenges such as a lack of competency-based training due to a shortage of trainers, limited resources, limited mentorship opportunities, and establishment of suitable research areas. The International Society of Addiction Medicine (ISAM) New Professionals Exploration, Training & Education (NExT) committee, a global platform for early-career addiction medicine professionals (ECAMPs), conducted a two-phase online survey using a modified Delphi-based approach among ECAMPs across 56 countries to assess the need for standardized training, research opportunities, and mentorship. A total of 110 respondents participated in Phase I (online key informant survey), and 28 respondents participated in Phase II (online expert group discussions on three themes identified in Phase I). The survey found that there is a lack of standardized training, structured mentorship programs, research funding, and research opportunities in addiction medicine for ECAMPs. There is a need for standardized training programs, improving research opportunities, and effective mentorship programs to promote the next generation of addiction medicine professionals and further development in the entire field. The efforts of ISAM NExT are well-received and give a template of how this gap can be addressed.


Trichromatic color vision in primates.
Trichromatic color vision is rare among mammals, occurring only in some primates. Recent work has elucidated the adaptive behavioral significance of trichromacy as well as its underlying genetic and neurophysiological mechanisms. These studies reveal a complex neural system whose design and operation apparently does not conform to rigid deterministic principles.


Continuous electrochemical exfoliation of micrometer-sized graphene using synergistic ion intercalations and organic solvents.
A novel top-down electrochemical method is demonstrated to prepare gram quantities of few-layer graphene in a single-step, one-pot process. Potential-controlled cathodic reduction is used to intercalate graphite electrodes with alkali-substituted, ammonium- and dimethyl sulfoxide-solvated cations. In situ decomposition of the intercalated compounds breaks the π-π stacking of the graphene layers along the c axis of the graphite gallery, producing 1-20-μm-diameter few-layer graphene sheets, without the need for defect-inducing oxidative or sonication treatments. With a slight modification of the electrodes' configuration, the process can run in a continuous manner, presenting a potentially scalable approach for few-layer graphene production.


Chronic Pain in the Elderly with Cognitive Decline: A Narrative Review.
The presence of pain in elderly persons with cognitive decline is often neglected, under-reported, underestimated, misdiagnosed and not adequately treated, with consequences that have a strong impact on health, independence in activities of daily living and quality of life. There is no empirical evidence that people with dementia experience less pain; therefore, in patients with severe cognitive impairment the progression of cognitive decline dramatically affects the ability to verbalize the presence of pain. Self-assessment scales are considered the "gold standard" for pain assessment, but the presence of cognitive impairment is likely to reduce the reliability of these measures. Treatment of pain in elderly with cognitive decline or dementia is based on non-pharmacological and pharmacological strategies. Pharmacological treatment should consider physiological changes, high comorbidity and drug interactions that occur frequently in the elderly. This narrative review aims to describe current knowledge, methods of detection and treatment approaches for chronic pain in elderly persons with cognitive deficits.


Dietary Interventions and Changes in Cardio-Metabolic Parameters in Metabolically Healthy Obese Subjects: A Systematic Review with Meta-Analysis.
The aim of this systematic review was to assess the effect of diet on changes in parameters describing the body size phenotype of metabolically healthy obese subjects. The databases Medline, Scopus, Web of Knowledge and Embase were searched for clinical studies carried out between 1958 and June 2016 that reported the effect of dietary intervention on BMI, blood pressure, concentration of fasting triglyceride (TG), high density lipoprotein cholesterol (HDL-C), fasting glucose level, the homoeostatic model assessment of insulin resistance (HOMA-IR) and high sensitivity C-Reactive Protein (hsCRP) in metabolically healthy, obese subjects. Twelve clinical studies met inclusion criteria. The combined analyzed population consists of 1827 subjects aged 34.4 to 61.1 with a BMI > 30 kg/m². Time of intervention ranged from eight to 104 weeks. The baseline characteristics related to lipid profile were more favorable for metabolically healthy obese than for metabolically unhealthy obese. The meta-analyses revealed a significant associations between restricted energy diet and BMI (95% confidence interval (CI): -0.88, -0.19), blood pressure (systolic blood pressure (SBP): -4.73 mmHg; 95% CI: -7.12, -2.33; and diastolic blood pressure (DBP): -2.75 mmHg; 95% CI: -4.30, -1.21) and TG (-0.11 mmol/l; 95% CI: -0.16, -0.06). Changes in fasting glucose, HOMA-IR and hsCRP did not show significant changes. Sufficient evidence was not found to support the use of specific diets in metabolically healthy obese subjects. This analysis suggests that the effect of caloric restriction exerts its effects through a reduction in BMI, blood pressure and triglycerides in metabolically healthy obese (MHO) patients.


The association between anxiety and the degree of illness in mild obstructive sleep apnoea.
Obstructive sleep apnoea (OSA) has been reported to associate with anxiety, but earlier observations are scarce and the role of the persistence of anxiety in this connection is unclear. To examine the associations between OSA and anxiety, and in particular clarify the observations regarding the role of the persistence of anxiety in this connection. A total of 61 overweight patients with mild OSA participated in a 12-month lifestyle modification study and reported the presence of anxiety both at baseline and on 12-month follow up. They were divided into three groups (no anxiety, n = 25; past anxiety, n = 13; persistent anxiety, n = 23), and the degree of illness was assessed with the apnoea-hypopnea index (AHI). The persistence of anxiety was linearly associated with the AHI (P = 0.025), which was highest in individuals with persistent anxiety. The likelihood of belonging to the group with persistent anxiety increased 18% for each one-unit increase in the AHI in a model adjusted for age, gender and bodyfat % (odds ratio 1.18, 95% confidence interval 1.03-1.34, P = 0.014). Further adjustments for daytime sleepiness and the effect of participating in the lifestyle modification intervention did not alter this finding. Our observations suggest that the persistence of anxiety is independently associated with elevated levels of sleep-disordered breathing and that lifestyle modification interventions with a focus on diet and exercise alone may not be sufficient to treat OSA in individuals with simultaneous persistent anxiety.


Comparing traditional and novel injury scoring systems in a US level-I trauma center: an opportunity for improved injury surveillance in low- and middle-income countries.
In most low- and middle-income countries (LMICs), the resources to accurately quantify injury severity using traditional injury scoring systems are limited. Novel injury scoring systems appear to have adequate discrimination for mortality in LMIC contexts, but they have not been rigorously compared where traditional injury scores can be accurately calculated. To determine whether novel injury scoring systems perform as well as traditional ones in a HIC with complete and comprehensive data collection. Data from an American level-I trauma registry collected 2008-2013 were used to compare three traditional injury scoring systems: Injury Severity Score (ISS); Revised Trauma Score (RTS); and Trauma Injury Severity Score (TRISS); and three novel injury scoring systems: Kampala Trauma Score (KTS); Mechanism, GCS, Age and Pressure (MGAP) score; and GCS, Age and Pressure (GAP) score. Logistic regression was used to assess the association between each scoring system and mortality. Standardized regression coefficients (β2), Akaike information criteria, area under the receiver operating characteristics curve, and the calibration line intercept and slope were used to evaluate the discrimination and calibration of each model. Among 18,746 patients, all six scores were associated with hospital mortality. GAP had the highest effect size, and KTS had the lowest median Akaike information criteria. Although TRISS discriminated best, the discrimination of KTS approached that of TRISS and outperformed GAP, MGAP, RTS, and ISS. MGAP was best calibrated, and KTS was better calibrated than RTS, GAP, ISS, or TRISS. The novel injury scoring systems (KTS, MGAP, and GAP), which are more feasible to calculate in low-resource settings, discriminated hospital mortality as well as traditional injury scoring systems (ISS and RTS) and approached the discrimination of a sophisticated, data-intensive injury scoring system (TRISS) in a high-resource setting. Two novel injury scoring systems (KTS and MGAP) surpassed the calibration of TRISS. These novel injury scoring systems should be considered when clinicians and researchers wish to accurately account for injury severity. Implementation of these resource-appropriate tools in LMICs can improve injury surveillance, guiding quality improvement efforts, and supporting advocacy for resource allocation commensurate with the volume and severity of trauma.


The Denver prescreening developmental questionnaire (PDQ).
To facilitate periodic developmental screening of all children, a Prescreening Developmental Questionnaire (PDQ) was created to identify those children who require a more thorough screening with the Denver developmental Screening Test (DDST). Children positive on the DDST screen are then referred for a diagnostic assessment. To devise the PDQ, 97 of 105 standard DDST items were formulated into questions. Ten age-appropriate questions were answered by 1,155 parents with subsequent evaluation of their children with the DDST. Agreement between parental responses for individual items and the score for their children's corresponding DDST item varied from 68% to 100% (mean, 93.3%). When the PDQ was positive, 31.2% of the children were referred for a DDST screen. These referrals included 86.7% of abnormal and 53.8% of questionable DDSTs among the 1,155 children screened. The predictive value of a referral was 23.3%. The predictive value of a referral did not differ significantly whether the PDQ was answered by a parent or by day care center staff personnel. A subsequent field trial of 1,027 PDQs in private physicians' offices and public health clinics yielded a similar predictive value (24.7%) for a referral. The parents liked the PDQ which took them only about five minutes to answer and the physicians liked the PDQ since it decreased by almost 69% the number of DDSTs they felt obliged to administer.


Effects of Indole-3-Acetic Acid (IAA), a Plant Hormone, on the Ryegrass Yield and the Removal of Fluoranthene from Soil.
A soil culture experiment was conducted to determine whether a plant hormone, indole-3-acetic acid (IAA), could influence fluoranthene (Flu) removal from soil. Four treatments were utilized: (i) unplanted soil (CK), (ii) soil planted with ryegrass (P), (iii) soil planted with ryegrass and treated with 0.24 mg kg(-1) IAA (P+0.24), (iv) soil planted with ryegrass and treated with 2.4 mg kg(-1) IAA (P+2.4). The Flu initial concentration was 200 mg kg(-1). After 3 months, the percentage of Flu removal and plant root biomass were significantly increased under the P+2.4 and the removal rate was 35.68%. The total Flu content in plants was higher than that in the other treatments. The Flu concentration was significantly increased in the shoots, but not significantly altered in the roots. The highest translocation factor was observed in the P+2.4. Increase in number of bacteria, actinomycetes and fungi were observed in the planted treatments, and the amount of fungi was significantly increased in P+2.4. Flu removal was related to the Flu in ryegrass, and was insignificantly correlated with the stimulation of soil microflora, which suggesting that IAA may work mainly on improving plant growth, the Flu uptake, and eventually leading to enhanced remediation of Flu polluted soil.


Occurrence of mcr-mediated colistin resistance in Salmonella clinical isolates in Thailand.
Nontyphoidal Salmonella, an important zoonotic pathogen and a major cause of foodborne illnesses, could be a potential reservoir of plasmids harbouring mobile colistin resistance gene (mcr). This study reported, for the first time, a high rate of mcr-carrying Salmonella clinical isolates (3.3%, 24/724) in Thailand, associated with mcr-3 gene (3.0%, 22/724) in S. 4,[5],12:i:-(15.4%, 4/26), S. Typhimurium (8.8%, 5/57), and S. Choleraesuis (5.6%, 13/231). Remarkably, the increasing trends of colistin and extended-spectrum cephalosporin resistances have displayed a high agreement over the years, with a dramatic rise in the mcr-carrying Salmonella from 1.1% (6/563) during 2005-2007 to 11.2% (18/161) during 2014-2018 when CTX-M-55 became abundant. Clonal and plasmid analysis revealed that the self-transferable IncA/C and a novel hybrid IncA/C-FIIs MDR plasmids were the major vehicles to disseminate both mcr-3 and blaCTX-M55 genes among diverse Salmonella strains, from as early as 2007. To our knowledge the occurrence of mcr-3 and the co-existence of it with blaCTX-M-55 in S. Choleraesuis are reported here for the first time, leading to clinical concern over the treatment of the invasive salmonellosis. This study provides evidence of the potential reservoirs and vectors in the dissemination of the mcr and highlights the co-selection by colistin and/or cephalosporins.