Protection from harm: the experience of adults after therapy with prolonged-speech.
It is well documented that adults can control stuttering if they use certain novel speech patterns referred to generically as prolonged-speech (PS). These speech patterns were refined in the 1960s and developed into behavioural treatment programmes. The bulk of available PS treatment research has focused on speech parameters thought to reflect favourable treatment outcome. Considering this, and that post-treatment relapse is known to be common, clinicians and researchers could be usefully informed by knowledge about the experiences of those who receive these treatments. Subsequently, they could use such information in attempts to control stuttering in their clients. Yet, at present, systematic research on this topic is scant. The continued development of PS treatments could be usefully informed by research into the experiences of those who use PS to control stuttering. Hence, that is the topic of the present report. The method used was phenomenology. Participants were a purposive sample of 10 people who had received PS treatment. During a 2-year period, a collaborative approach to the study of the topic was developed between the participants and interviewer. Interviews were from 1.5 to 2 hours, and a total of 34 interviews and discussions were undertaken with participants. Transcripts of these were used to generate text from which themes were identified using line-by-line, holistic and selective approaches. The main findings were that even after therapy with PS there is a continued risk of stuttering occurring, and although adults have the novel experience of controlling stuttering, they also continue to experience feeling different from those who do not stutter, which may be exacerbated after therapy. Given the negative consequences associated with stuttering and feeling different, the essence of the experience after therapy with PS is that adults use their own resources to integrate behavioural skills with existing experiences in order to protect themselves from the harm of stuttering as best they can. PS changes speech, but not the dynamic and often unpredictable communication situations of everyday life. Hence, the maximum benefits of PS are attained when clients use a strategic approach to control stuttered speech and daily communication. These findings are consistent with the results of existing outcome research as well as with other current research from the present group. Their implications are discussed in relation to the structure of PS treatments as well as in relation to future PS outcome research. The clinical implications of these findings are discussed in terms of informing prospective clients of the experiential consequences of PS, selecting clients who might benefit from PS and in terms of assisting clients to achieve optimal benefits from PS.


The role of health risk factors and disease on worker productivity.
The costs attributed to employee health problems are usually measured by employers in terms of direct health care costs, such as medical plan claims. Although it has been understood that employee health problems also produce indirect costs for employers, their measurement has been far less frequent. At best, studies have recorded one component of indirect health costs: the time lost to employee absenteeism and disability. The study presented here includes a measure of the actual decrease in the productivity of employees while they are on the job, in addition to measures of absenteeism and disability. These three measurements were combined to produce a Worker Productivity Index (WPI). The WPIs of 564 telephone customer-service agents were correlated with the employees' number and type of health risks, as measured by a Health Risk Appraisal. Additionally, the WPI was also examined across different disease states in the same population of employees. As the number of health risks increased, an employee's productivity decreased. The nature of the health risk may also differentially affect the pattern of the decrease. Finally, disease states were also associated with different patterns of productivity reduction.


Direct fourier reconstruction in fan-beam tomography.
We consider the problem of reconstructing tomographic imagery from fan-beam projections using the direct Fourier method (DFM). Previous DFM reconstructions from parallel-beam projections produced images of quality comparable to that of filtered convolution back-projection. Moreover, the number of operations using DFM in the parallel-beam case is proportional to N2 log N versus N3 for back projection [3]. The fan-beam case is more complicated because additional interpolation of the nonuniformly spaced rebinned data is required. We derive bounds on the detector spacing in fan-beam CT that enable direct Fourier reconstruction and describe the full algorithm necessary for processing the fan-beam data. The feasibility of the method is demonstrated with an example. A key result of this paper is that high-quality imagery can be reconstructed from fan-beam data using the DFM in 0 (N2 log N) operations.


VA nursing home residents with substance use disorders: Mental health comorbidities, functioning, and problem behaviors.
This research addresses whether residents with substance use disorders (SUDs) in VA nursing homes (VANHs) are distinctive in terms of their demographic characteristics, medical and mental health comorbidities, functioning, and problem behaviors. Residents over age 55 admitted to VANHs (n = 27,002) were identified in VA administrative files, and SUD and non-SUD residents were compared. Compared with other residents, the residents with SUDs (18% of admissions over age 55) were more likely to be younger, male, African-American, unmarried, have low income and a tobacco use disorder. Controlling for demographic factors and smoking, SUD residents were more likely to have mental health comorbidities (dementia, serious mental illness, depressive disorders, and post-traumatic stress disorder), as well as AIDS/hepatitis, pulmonary disease, gastro-intestinal disorders, and injuries. SUD residents were less likely to have cancer, diabetes, neurological disorders, heart failure, and renal failure. SUD residents were more independent in activities of daily living, such as mobility and toileting. They were more likely to engage in verbal disruption but not in other problem behaviors such as aggression. With demographic factors and comorbidities controlled, the functioning differences were diminished, and SUD and non-SUD residents did not differ in the levels of problem behaviors. VANH residents with SUDs have distinctive patterns of comorbidities and functioning. SUD appears to represent a separate risk factor for VANH admission. Residents with SUDs present challenges but may have good potential for positive discharge outcomes if their substance use problems and limited resources can be addressed.


Cyclin D1 overexpression enhances radiation-induced apoptosis and radiosensitivity in a breast tumor cell line.
Overexpression of cyclin D1, a G1 cell cycle regulator, is often found in many different tumor types, such as breast carcinoma and squamous cell carcinoma of the head and neck. The overexpression of this protein is, in several cases, associated with a poor prognosis. In this study, the effect of cyclin D1 on radiosensitivity was investigated in a breast tumor cell line, MCF7, containing a cyclin D1 gene construct under the control of a tetracycline-sensitive regulator. MCF7 cells cultured without tetracycline resulted in a 6-fold increase in the cyclin D1 protein. Cyclin D1-overexpressing MCF7 cells were more sensitive to ionizing radiation than the nonoverexpressing counterparts. The cyclin D1-overexpressing cells also exhibited a higher induction of apoptosis. Treatment with a dose of 5 Gy resulted in a rapid increase of p53 and p21 in the cyclin D1-overexpressing cells. Nonoverexpressing cells showed a more transient expression of these proteins after ionizing radiation. A pronounced G2-M block was observed in both cell lines. The cyclin D1-overexpressing cells were, however, released earlier from the block than the control cells. These data suggest that overexpression of cyclin D1 alters sensitivity toward ionizing radiation by modulating gamma-radiation-induced G2-M transition.


Genetic Profiling of Non-Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA.
Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually acquire resistance to these drugs. The identification of various resistance mechanisms for determination of subsequent treatment for these patients will require a method for simultaneous detection of multiple genetic alterations with high sensitivity. We performed cancer personalized profiling by deep sequencing (CAPP-Seq) with circulating tumor DNA obtained from patients with NSCLC who acquired resistance to first- or second-generation EGFR-TKIs. Plasma samples from 27 patients were analyzed, and 24 samples underwent CAPP-Seq successfully. Original activating EGFR mutations were detected in 23 patients, with the remaining patient showing MET amplification. With regard to known mechanisms of EGFR-TKI resistance, the T790M mutation of EGFR was detected in 17 of the 24 patients, MET amplification in 9 patients (6 of whom also harbored T790M), ERBB2 amplification in 2 patients (1 of whom also harbored T790M), and EGFR amplification in 4 patients (all of whom harbored T790M). Our results thus show that CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations in circulating tumor DNA obtained from patients with NSCLC at the time of disease progression during treatment with first- or second-generation EGFR-TKIs. Patients positive for the T790M mutation of EGFR were also found to constitute a molecularly heterogeneous population. KEY POINTS: CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations.The T790M mutation of EGFR is associated with amplification of MET, ERBB2, or EGFR in NSCLC patients resistant to EGFR-TKIs.T790M-positive patients are molecularly heterogeneous, and genetic alterations coexisting with T790M may differ between patients treated with first-generation or second-generation EGFR-TKIs.


Chronic edema of the lower extremities: international consensus recommendations for compression therapy clinical research trials.
Chronic edema is a multifactorial condition affecting patients with various diseases. Although the pathophysiology of edema varies, compression therapy is a basic tenant of treatment, vital to reducing swelling. Clinical trials are disparate or lacking regarding specific protocols and application recommendations for compression materials and methodology to enable optimal efficacy. Compression therapy is a basic treatment modality for chronic leg edema; however, the evidence base for the optimal application, duration and intensity of compression therapy is lacking. The aim of this document was to present the proceedings of a day-long international expert consensus group meeting that examined the current state of the science for the use of compression therapy in chronic edema. An expert consensus group met in Brighton, UK, in March 2010 to examine the current state of the science for compression therapy in chronic edema of the lower extremities. Panel discussions and open space discussions examined the current literature, clinical practice patterns, common materials and emerging technologies for the management of chronic edema. This document outlines a proposed clinical research agenda focusing on compression therapy in chronic edema. Future trials comparing different compression devices, materials, pressures and parameters for application are needed to enhance the evidence base for optimal chronic oedema management. Important outcomes measures and methods of pressure and oedema quantification are outlined. Future trials are encouraged to optimize compression therapy in chronic edema of the lower extremities.


Measures of trunk muscle strength and their measurement properties: a protocol for a systematic review and narrative synthesis of clinical measures.
Spinal musculoskeletal conditions, including low back and neck pain, are leading causes of disability globally. The trunk muscles, which comprise muscles in the thoracic and lumbar regions, are essential for functional activities, necessitating mobility, motor control and strength. To investigate the effectiveness of interventions directed at improving trunk muscle strength, it is essential to have valid, reliable and responsive performance-based outcome measures (PBOM). While isokinetic dynamometry is considered the gold-standard PBOM, the associated costs, size/weight and operational complexity of this equipment preclude its use in a clinical setting. There is, therefore, a need to evaluate the measurement properties of alternative accessible measures of trunk strength. This systematic review therefore aims to investigate the measurement properties of PBOM of trunk muscle strength measures appropriate for use in a clinical setting. This protocol has been designed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. CINAHL, Web of Science, Pedro, MEDLINE, EMBASE, SPORTDiscuss will be searched systematically from the database start date up to 16 April 2020, along with reference checking and the grey literature searching. Eligibility criteria include studies investigating measurement properties of PROM for trunk muscle strength for use in a clinical setting in adults with and without spinal musculoskeletal complaints. Two independent reviewers will determine the eligibility of the studies through screening process of titles, abstract and the full text. Both reviewers will assess the risk of bias using COnsensus-based Standards for the selection of health status Measurement Instruments risk-of-bias tool and then extract the data from included studies. The overall quality of the included studies will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. A narrative synthesis will be carried out if meta-analysis is not applicable. Findings from this systematic review will aid clinicians and practitioners working in the field for example, sport, in using the most appropriate PBOM to measure trunk muscle strength. No research ethics application is needed as there are no patient data in this study. The results of this study will be submitted to a peer reviewed journal and presented at conferences. CRD42020167464.


Electrostatic assembly/disassembly of nanoscaled colloidosomes for light-triggered cargo release.
Colloidosome capsules possess the potential for the encapsulation and release of molecular and macromolecular cargos. However, the stabilization of the colloidosome shell usually requires an additional covalent crosslinking which irreversibly seals the capsules, and greatly limits their applications in large-cargos release. Herein we report nanoscaled colloidosomes designed by the electrostatic assembly of organosilica nanoparticles (NPs) with oppositely charged surfaces (rather than covalent bonds), arising from different contents of a bridged nitrophenylene-alkoxysilane [NB; 3-nitro-N-(3-(triethoxysilyl)propyl)-4-(((3-(triethoxysilyl)propyl)-amino)methyl)benzamid] derivative in the silica. The surface charge of the positively charged NPs was reversed by light irradiation because of a photoreaction in the NB moieties, which impacted the electrostatic interactions between NPs and disassembled the colloidosome nanosystems. This design was successfully applied for the encapsulation and light-triggered release of cargos.


Triiodothyronine (T3) suppression test. An aid in the diagnosis of mild hyperthyroidism in cats.
The purpose of this study was to develop a T3 suppression test to help in the diagnosis of mild hyperthyroidism in cats. We evaluated the response in circulating T4 concentrations to exogenous T3 (liothyronine) administration in 44 clinically normal cats, 77 cats with hyperthyroidism, and 22 cats with nonthyroidal disease. The test was performed by first collecting blood samples for basal serum T4 and T3 determinations, administering liothyronine at an oral dosage of 25 micrograms three times daily for seven doses, and, on the morning of the third day, again collecting serum samples for T4 and T3 determinations 2 to 4 hours after the seventh dose of liothyronine. The mean basal serum concentrations of T4 (53.1 nmol/L) and T3 (1.8 nmol/L) were significantly higher in the cats with hyperthyroidism than in the normal cats (T4 = 25.3 nmol/L, T3 = 1.3 nmol/L) and the cats with nonthyroidal disease (T4 = 29.5 nmol/L, T3 = 1.4 nmol/L); however, there was a great deal of overlap of basal values between the three groups of cats. Of the 77 cats with mild hyperthyroidism, 41 (53%) had serum T4 values and 55 (71%) had T3 values that were within the established normal ranges. After administration of liothyronine, mean serum T4 concentrations fell much more markedly in the normal cats and the cats with nonthyroidal disease than in the hyperthyroid cats.(ABSTRACT TRUNCATED AT 250 WORDS)


Invasive cane toads are unique in shape but overlap in ecological niche compared to Australian native frogs.
Invasive species are an important issue worldwide but predicting invasiveness, and the underlying mechanisms that cause it, is difficult. There are several primary hypotheses to explain invasion success. Two main hypothesis based on niche spaces stand out as alternative, although not exclusive. The empty niche hypothesis states that invaders occupy a vacant niche space in the recipient community, and the niche competition hypothesis states that invaders overlap with native species in niche space. Studies on trait similarity/dissimilarity between the invader and native species can provide information on their niche overlap. Here, we use the highly invasive and well-studied cane toad (Rhinella marina) to test these two hypotheses in Australia, and assess its degree of overlap with native species in several niche dimensions. We compare extensive morphological and environmental data of this successful invader to 235 species (97%) of native Australian frogs. Our study is the first to document the significant morphological differences between the invasive cane toad and a continent-wide frog radiation: despite significant environmental overlap, cane toads were distinct in body size and shape from most Australian frog species, suggesting that in addition to their previously documented phenotypic plasticity and wide environmental and trophic niche breadth, their unique shape also may have contributed to their success as an invasive species in Australia. Thus, the invasive success of cane toads in Australia may be explained through them successfully colonizing an empty niche among Australian anurans. Our results support that the cane toad's distinct morphology may have played a unique role in the invasiveness of this species in Australia, which coupled with a broad environmental niche breadth, would have boosted their ability to expand their distribution across Australia. We also propose RLLR (Relative limb length ratio) as a potentially useful measure of identifying morphological niche uniqueness and a potential measure of invasiveness potential in anuran amphibians.


A two-step centrifugation procedure for the purification of sheep erythrocyte antigen-binding cells.
A two-step centrifugation procedure has been developed to isolate greater quantities of highly purified sheep erythrocyte antigen-binding cells (ABC) than previously possible. The first step involves partially separating sheep erythrocyte rosettes from unrosetted lymphocytes by their difference in buoyant density on Ficoll-Hypaque. Subsequent passage through a linear 5 to 10% Ficoll gradient produces further purification of rosettes by sedimentation velocity. Approximately 4.5 X 10(6) ABC can be obtained at 50 to 100% purity from 10(9) immune spleen cells (5 days post-immunization) and 1 X 10(5) ABC at 20 to 40% purity from 10(9) nonimmune spleen cells. The purified ABC from 5-day immune animals are 80 to 90% B cells and 10 to 20% T cells, and represent between 30 and 40% of the original ABC in the spleen cell population. Less than 0.2% of the purified ABC are plaque-forming cells (PFC) and less than 2% have intracellular immunoglobulin (Ig) or J chain. The quantities of ABC obtained are sufficient for investigating biochemical parameters of antigen-induced lymphocyte activation and for direct analysis of the surface isotypes found on antigen-binding cells after immunization.


Long-distance control of origin choice and replication timing in the human beta-globin locus are independent of the locus control region.
DNA replication in the human beta-globin locus is subject to long-distance regulation. In murine and human erythroid cells, the human locus replicates in early S phase from a bidirectional origin located near the beta-globin gene. This Hispanic thalassemia deletion removes regulatory sequences located over 52 kb from the origin, resulting in replication of the locus from a different origin, a shift in replication timing to late S phase, adoption of a closed chromatin conformation, and silencing of globin gene expression in murine erythroid cells. The sequences deleted include nuclease-hypersensitive sites 2 to 5 (5'HS2-5) of the locus control region (LCR) plus an additional 27-kb upstream region. We tested a targeted deletion of 5'HS2-5 in the normal chromosomal context of the human beta-globin locus to determine the role of these elements in replication origin choice and replication timing. We demonstrate that the 5'HS2-5-deleted locus initiates replication at the appropriate origin and with normal timing in murine erythroid cells, and therefore we conclude that 5'HS2-5 in the classically defined LCR do not control replication in the human beta-globin locus. Recent studies also show that targeted deletion of 5'HS2-5 results in a locus that lacks globin gene expression yet retains an open chromatin conformation. Thus, the replication timing of the locus is closely correlated with nuclease sensitivity but not globin gene expression.


Generation of induced pluripotent stem cell line (ZZUi007-A) from a 52-year-old patient with a novel CHCHD2 gene mutation in Parkinson's disease.
CHCHD2 mutation has been reported as a potential cause of a rare form of familial Parkinson's disease. Recently, a novel CHCHD2 mutation was identified in a family with Parkinson's disease. The dermal fibroblasts of the patient were obtained and successfully transformed into induced pluripotent stem cells(iPSCs), employing episomal plasmids expressing OCT3/4, SOX2, KLF4, LIN28, and L-MYC. Our model may offer a good platform for further research on the pathomechanism, drug testing, and gene therapy of this disease. RESOURCE TABLE: RESOURCE UTILITY: CHCHD2 mutation has been shown to be associated with Parkinson's disease (PD) (Shi et al., 2016). Induced pluripotent stem cells (iPSCs), generated from a patient harboring a CHCHD2 mutation, may provide an ideal cell model for exploring the pathogenesis of this disease and aid in drug screening. RESOURCE DETAILS: Parkinson's disease (PD) is one of the most common neurodegenerative disorders, characterized by resting tremors, muscular rigidity, bradykinesia, and postural instability. Previous studies have revealed that parkinsonism can be caused by mutations in several genes including parkin, PTEN-induced putative kinase protein 1 (PINK1), parkinsonism-associated deglycase (DJ1), and ATPase 13A2 (ATP13A2) (Bonifati, 2014). In this study, a novel CHCHD2 mutation was identified in a family with Parkinson's disease (Shi et al., 2016), and the fibroblasts of the patient were successfully transformed into iPSCs. Episomal plasmids were used to generate the ZZUi007-A iPSC line (Fig. 1A). Pluripotency markers were examined via immunocytochemical staining using antibodies against human OCT-4, TRA-1-60 and Nanog (Fig. 1B). Flow cytometric analysis showed that more than 99% of the cells expressed OCT-4 and TRA-1-60 (Fig. 1C). The karyotype of CHCHD2-01 iPSCs was numerically and structurally normal (Fig. 1D). The mutation (c.182C > T; p.Thr61Ile) in CHCHD2 was confirmed by Sanger sequencing in the newly established iPSC line (Fig. 1E). Episomal plasmids were detected by polymerase chain reaction (PCR) using episomal plasmid-specific primers and disappeared from passage 15 (Fig. 1F). Furthermore, the iPSC line had the potential to differentiate into cells of all three germ layers in vivo (Fig. 1G).


The VerIFAST: an integrated method for cell isolation and extracellular/intracellular staining.
Isolation and characterization of a specific subset of cells from a large heterogeneous population is necessary for studying rare subpopulations of cells. Existing methods require transfer or wash steps that risk causing loss of the rare cell population of interest. Integrated methods reduce loss, making these methods especially useful for reliable isolation of rare cell populations. In this report, we demonstrate the VerIFAST, a device that builds upon the simplified workflow of the Immiscible Filtration Assisted by Surface Tension (IFAST) to integrate a method for cellular isolation with methods for extra- and intracellular staining. First, a front-end purification step allows cells and unwanted particulates to passively settle out of the operational path of the paramagnetic particles, resulting in good efficiency of capture (>80%) and purity (>70%) with a single virtual wall traverse. Second, a Sieve Chamber is used downstream of the isolation chamber that removes excess unbound paramagnetic particles (PMPs) and performs complex multi-step washing procedures without centrifugation or transfer steps. Further, cellular staining can be performed in the device and is demonstrated for extracellular epithelial cell adhesion molecule (EpCAM), intracellular pan-cytokeratins, and Ki-67.


Mast cell heterogeneity in higher animals: a comparison of the properties of autologous lung and intestinal mast cells from nonhuman primates.
The issue of mast cell heterogeneity has been investigated in nonhuman primates by a comparative examination of lung and intestinal mast cells. These cells were obtained in parallel from the respective tissues of individual monkeys by an identical enzymatic dispersion technique. Mast cells derived from the lungs differed from those derived from the intestine in that the majority of the former cell type could be stained with toluidine blue at pH 4 to 5, whereas the intestinal mast cells in the dispersed preparations required a more acidic pH (less than 1) to display metachromasia. In addition, the lung cells exhibited an increased content of the mast cell mediator histamine. Nonhuman primate lung mast cells were also quantitatively more responsive to an immunologic challenge than their intestinal counterparts in that they released a higher percentage of cellular histamine and generated more leukotriene C4 on stimulation. Considerable inter-animal variation was observed between the magnitude of mediator release from both mast cell types after anaphylactic activation, but evidence for the presence in nonhuman primates of the phenomenon of releasability was not obtained. The responsiveness of both cell types to a range of potential nonimmunologic secretagogues and anti-allergic agents, including compound 48/80, substance P, theophylline, and isoprenaline, was essentially similar. We conclude that mast cell heterogeneity in higher animals may be reflected more by cytochemical rather than by functional differences between mast cell classes.


Relaxation of guinea-pig stomach by bradykinin.
Intraluminal pressure changes were recorded from guinea-pig stomachs in vitro. Bradykinin (Bk) (0.4-9.6 nM) was generally found to produce a biphasic response (relaxation followed by contraction) in bathing solutions containing 1.1 mM calcium chloride. In bathing solutions containing 5.2 mM calcium chloride a relaxation without contraction was the most common observation. Relaxations to Bk were unaffected by selective concentrations of tetrodotoxin (5.6 microM), phentolamine (5.0-50.0 microM) and propranolol (5.0-50.0 microM). During virtually complete desensitization to Bk produced by 3 cumulative doses of 6.4 nM, relaxations to vagal stimulation were only reduced by 24.2% and those to adrenaline (2.0 microM) by 25.9%, indicating that Bk is unlikely to be the inhibitory transmitter released during vagal stimulation. Relaxations to ATP (10 microM) were reduced by 89.4% suggesting that Bk and ATP share a common step in the production of relaxation.


Matrix-dependent gene expression of egr-1 and PDGF A regulate angiotensin II-induced proliferation in human vascular smooth muscle cells.
We have previously shown, in a neonatal rat cell line, that angiotensin II (Ang II)-induced proliferation in vascular smooth muscle cells is extracellular matrix (ECM) dependent. We hypothesized that such an effect might be mediated via differences in Ang II-induced increases in the transcriptional factor early growth response-1 (Egr-1) gene and, consequently, in platelet-derived growth factor (PDGF). Cultured human newborn aortic smooth muscle cells were studied on 4 different surfaces: (1) plastic, (2) laminin, (3) collagen, and (4) fibronectin. Ang II-induced increases in DNA synthesis were significantly greater on collagen (2.0+/-0.3-fold) and fibronectin (1.9+/-0.3-fold) than on laminin (1.0+/-0.2-fold) or plastic (1.4+/-0.2-fold). As with DNA synthesis, at 48 and 72 hours, Ang II-induced increases in cell numbers occurred only in cells grown on collagen and fibronectin culture plates and were blocked by an antagonist to the angiotensin type 1 (losartan, 10 micromol/L) but not the angiotensin type 2 (PD 123319, 10 micromol/L) receptor. Anti-PDGF AA antibody (6 microg/mL) blocked the increase in DNA synthesis by 60% to 64% in cells on collagen or fibronectin cultures but not on plastic cultures. When PDGF-AA (10 ng/mL) and Ang II were added together, DNA synthesis increased 2-fold and did not differ on the various ECM proteins. Increases in PDGF A-chain mRNA were observed only in cells grown on collagen (3.21+/-0.65-fold) and fibronectin (2.86+/-0.49-fold) plates 2 to 8 hours after the addition of Ang II and were blocked by losartan but not PD 123319. Expression of Egr-1, an early growth response gene, increased at 15 minutes, peaked at 30 minutes, and returned to normal after 2 hours with Ang II treatment. Ang II-induced increases in Egr-1 mRNA were greater on collagen (4. 82+/-0.66-fold at maximum) and fibronectin (4.01+/-0.56-fold) than on laminin (2.74+/-0.45-fold) or plastic (2.53+/-0.40-fold) and were blocked by losartan but not PD 123319. Thus, in human vascular smooth muscle cells in culture, Ang II-induced proliferation is mediated via the angiotensin type 1 receptor, dependent on ECM proteins, and regulated by differential gene expression of Egr-1 and PDGF-1.


The science on front-of-package food labels.
The U.S. Food and Drug Administration and Institute of Medicine are currently investigating front-of-package (FOP) food labelling systems to provide science-based guidance to the food industry. The present paper reviews the literature on FOP labelling and supermarket shelf-labelling systems published or under review by February 2011 to inform current investigations and identify areas of future research. A structured search was undertaken of research studies on consumer use, understanding of, preference for, perception of and behaviours relating to FOP/shelf labelling published between January 2004 and February 2011. Twenty-eight studies from a structured search met inclusion criteria. Reviewed studies examined consumer preferences, understanding and use of different labelling systems as well as label impact on purchasing patterns and industry product reformulation. The findings indicate that the Multiple Traffic Light system has most consistently helped consumers identify healthier products; however, additional research on different labelling systems' abilities to influence consumer behaviour is needed.


Canadian Association of Radiologists Musculoskeletal System Diagnostic Imaging Referral Guideline.
The Canadian Association of Radiologists (CAR) Musculoskeletal System Expert Panel consists of musculoskeletal radiologists, a family physician, a sports and exercise medicine physician, emergency medicine physicians, a patient advisor, and an epidemiologist/guideline methodologist. After developing a list of 25 musculoskeletal clinical/diagnostic scenarios, a systematic rapid scoping review was undertaken to identify systematically produced referral guidelines that provide recommendations for 1 or more of these clinical/diagnostic scenarios. Recommendations from 41 guidelines (50 publications) and contextualization criteria in the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) for guidelines framework were used to develop 124 recommendation statements across the 25 scenarios related to the evaluation of the musculoskeletal system. This guideline presents the methods of development and the recommendations for imaging in the context of musculoskeletal pain, infection, tumors, arthropathies, metabolic bone disease, stress injuries, orthopedic hardware, avascular necrosis/bone infarction, and complex regional pain syndrome.


Effect of heat treatment on stainless steel lingual arch appliances.
This study evaluated the effect of heat treatment on 0.036" diameter stainless steel wire. Forty wires were bent into arch forms (20 experimental and 20 control). The arch width changes were measured and the forces generated were determined over an eight week period. Heat treatment resulted in immediate and significant expansion (p < 0.001) followed by stabilization of arch width. The control wires continued to expand throughout the study. The force generated by the control group and experimental group expansion was capable of producing tooth movement.


Blockchain-Based Authentication and Trust Management Mechanism for Smart Cities.
Security has always been the main concern for the internet of things (IoT)-based systems. Blockchain, with its decentralized and distributed design, prevents the risks of the existing centralized methodologies. Conventional security and privacy architectures are inapplicable in the spectrum of IoT due to its resource constraints. To overcome this problem, this paper presents a Blockchain-based security mechanism that enables secure authorized access to smart city resources. The presented mechanism comprises the ACE (Authentication and Authorization for Constrained Environments) framework-based authorization Blockchain and the OSCAR (Object Security Architecture for the Internet of Things) object security model. The Blockchain lays out a flexible and trustless authorization mechanism, while OSCAR makes use of a public ledger to structure multicast groups for authorized clients. Moreover, a meteor-based application is developed to provide a user-friendly interface for heterogeneous technologies belonging to the smart city. The users would be able to interact with and control their smart city resources such as traffic lights, smart electric meters, surveillance cameras, etc., through this application. To evaluate the performance and feasibility of the proposed mechanism, the authorization Blockchain is implemented on top of the Ethereum network. The authentication mechanism is developed in the node.js server and a smart city is simulated with the help of Raspberry Pi B+. Furthermore, mocha and chai frameworks are used to assess the performance of the system. Experimental results reveal that the authentication response time is less than 100 ms even if the average hand-shaking time increases with the number of clients.


[Involvement of ATP in radiation-induced bystander effect as a signaling molecule].
We previously reported that low doses (0.25-0.5 Gy) of γ-rays induce intracellular antioxidant, radioresistant, DNA damage repair, and so on. Meanwhile, we have recently reported that ATP is released from the cells exposed to low-dose γ-rays. Here, it was investigated whether or not γ-radiation-induced release of extracellular ATP contributes to various radiation effects, in paricular, focusing on the inductions of intracellular antioxidant and DNA damage repair. Irradiation with γ-rays or exogenously added ATP increased expression of intracellular antioxidants such as thioredoxin and the increases were blocked by pretreatment with an ecto-nucleotidase in both cases. Moreover, release of ATP and autocrine/paracrine positive feedback through P2Y receptors serve to amplify the cellular repair response to radiation-induced DNA damage. To sum up, it would be suggested that ATP signaling is important for the effective induction of radiation stress response, such as protection of the body from the radiation and DNA damage repair. In addition, the possibility that this signaling is involved in the radiation resistance of cancer cells and beneficial effect on the organism of low-dose radiation and radiation adaptive response, would be further suggested.


Acute otitis media associated bilateral sudden hearing loss: case report and literature review.
Sudden sensorineural hearing loss is a rare otological condition with potential for dire outcomes including permanent hearing loss. Although the majority of cases are deemed idiopathic, bilateral sudden sensorineural hearing loss represents a rare subset typically related to systemic conditions, with higher morbidity and mortality. A controversial association with acute otitis media has been reported, with few bilateral cases published in the literature. A very rare case of bilateral sudden sensorineural hearing loss associated with acute otitis media is described, with a review of the literature. The limited evidence available suggests that acute otitis media with tinnitus and/or bacterial pathology may have an increased risk of sudden sensorineural hearing loss, which is consistent with the case described. Although there is no sufficiently powered published evidence to provide definitive treatment guidelines, the literature reviewed suggests that early myringotomy and antibiotics may greatly improve treatment outcomes.


Efficiency of Orexin-A for Inflammatory Flare and Mucosal Healing in Experimental Colitis: Comparison with the Anti-TNF Alpha Infliximab.
Inflammatory bowel diseases are chronic inflammation of the intestinal mucosa characterized by relapsing-remitting cycle periods of variable duration. Infliximab (IFX) was the first monoclonal antibody used for the treatment of Crohn's disease and ulcerative colitis (UC). High variability between treated patients and loss of IFX efficiency over time support the further development of drug therapy. An innovative approach has been suggested based on the presence of orexin receptor (OX1R) in the inflamed human epithelium of UC patients. In that context, the aim of this study was to compare, in a mouse model of chemically induced colitis, the efficacy of IFX compared to the hypothalamic peptide orexin-A (OxA). C57BL/6 mice received 3.5% dextran sodium sulfate (DSS) in drinking water for 5 days. Since the inflammatory flare was maximal at day 7, IFX or OxA was administered based on a curative perspective at that time for 4 days using intraperitoneal injection. Treatment with OxA promoted mucosal healing and decreased colonic myeloperoxidase activity, circulating concentrations of lipopolysaccharide-binding protein, IL-6 and tumor necrosis factor alpha (TNFα) and decreased expression of genes encoding cytokines in colonic tissues with better efficacy than IFX allowing for more rapid re-epithelization. This study demonstrates the comparable anti-inflammatory properties of OxA and IFX and shows that OxA is efficient in promoting mucosal healing, suggesting that OxA treatment is a promising new biotherapy.


Imidazolium-based ionic liquids used as additives in the nanolubrication of silicon surfaces.
In recent years, with the development of micro/nanoelectromechanical systems (MEMS/NEMS), the demand for efficient lubricants of silicon surfaces intensified. Although the use of ionic liquids (ILs) as additives to base oils in the lubrication of steel/steel or other types of metal/ metal tribological pairs has been investigated, the number of studies involving Si is very low. In this work, we tested imidazolium-based ILs as additives to the base oil polyethylene glycol (PEG) to lubricate Si surfaces. The friction coefficients were measured in a nanotribometer. The viscosity of the PEG + IL mixtures as well as their contact angles on the Si surface were measured. The topography and chemical composition of the substrates surfaces were determined with atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS), respectively. Due to the hygroscopic properties of PEG, the first step was to assess the effect of the presence of water. Then, a series of ILs based on the cations 1-ethyl-3-methylimidazolium [EMIM], 1-butyl-3-methylimidazolium [BMIM], 1-ethyl-3-vinylimidazolium [EVIM], 1-(2-hydroxyethyl)-3-methylimidazolium [C2OHMIM] and 1-allyl-3-methylimidazolium [AMIM] combined with the anions dicyanamide [DCA], trifluoromethanesulfonate [TfO], and ethylsulfate [EtSO4] were added to dry PEG. All additives (2 wt %) led to a decrease in friction coefficient as well as an increase in viscosity (with the exception of [AMIM][TfO]) and improved the Si wettability. The additives based on the anion [EtSO4] exhibited the most promising tribological behavior, which was attributed to the strong interaction with the Si surface ensuring the formation of a stable surface layer, which hinders the contact between the sliding surfaces.


Papillary muscle repair surgery in ischemic mitral valve patients.
Ischemic mitral regurgitation (MR), when ischemia/infarction has resulted in fibrotic degeneration and elongation of papillary muscles, carries a high risk for the patient and a technical challenge for the surgeon. We have developed a papillary-shortening plasty for this specific pathology. Papillary muscle repair was performed in 88 patients (7.2%) where degenerated and fibrotic elongated papillary muscles were found, which resulted in a prolapse of one or more parts of the mitral valve leaflets (MR III-IV). All patients had a papillary muscle-shortening plasty using a pericardium pledged-reinforced polytetrafluoroethylene suture and a ring annuloplasty. Because the cause of regurgitation in this specific group of patients was ischemic, concomitant coronary bypass grafting was required in all patients, with 2.2 grafts/patient. There were five hospital deaths (5.7%). Postoperative mitral valve function was satisfactory in all patients: no residual mitral regurgitation (MR 0) was found in 80 patients (90.9%), mild regurgitation (MR I) in 5 patients (5.7%), and moderate regurgitation (MR I-II) was observed in 3 patients (3.4%). Within a short mean follow-up period of 18.6 months (3 to 40 months), there was one late death (1.2%). The actuarial freedom from reoperation and thromboembolic complications was 100%, but there were two anticoagulation-induced gastric bleeding complications (2.3%). All patients were in New York Heart Association functional class I or II at the time of follow-up. Our data show that careful assessment of papillary muscle pathology is mandatory, and that a papillary muscle-shortening plasty is a simple but valuable surgical tool to repair the mitral valve in this specific group of high-risk patients with ischemic mitral regurgitation.


Tobacco control: an issue twinned with oral cancer control.
Oral cancer is a silent crisis in India. Thirty per cent of all cancers are oral cancer, and approximately 17% of all cancers in men and 10.5% of all cancers in women are oral cancer. Approximately 70,000 new cases are reported annually and 46,000 oral cancer-related deaths occur each year in India; furthermore, the number of cases is rapidly increasing. With this crescendo there may be an estimated 100,000 new cases by 2020, which is insurmountable, especially in emerging economies like India. This astronomical increase is a direct result of tobacco usage. The Global Adult Tobacco Survey performed in 2010 (GATS-2010) reported that approximately 274.5 million people in India use tobacco in various forms. Increasing use of smokeless tobacco, especially by women and children, is of major concern. The World Health Organisation has identified tobacco control and oral cancer control measures as a health priority. However, prevention of tobacco use in India is a great challenge owing to low overall literacy rates and to greater prevalence among people in lower socio-economic strata. Addressing this problem requires a multidisciplinary approach. This paper presents a situational analysis of oral cancer in India and the role of tobacco in making it the epicentre of the disease, and focuses on the role of dental care-givers in influencing and promoting tobacco-control programmes and early detection of oral cancer.


Impaired recruitment of Grk6 and beta-Arrestin 2 causes delayed internalization and desensitization of a WHIM syndrome-associated CXCR4 mutant receptor.
WHIM (warts, hypogammaglobulinemia, infections, and myelokatexis) syndrome is a rare immunodeficiency syndrome linked to heterozygous mutations of the chemokine receptor CXCR4 resulting in truncations of its cytoplasmic tail. Leukocytes from patients with WHIM syndrome display impaired CXCR4 internalization and enhanced chemotaxis in response to its unique ligand SDF-1/CXCL12, which likely contribute to the clinical manifestations. Here, we investigated the biochemical mechanisms underlying CXCR4 deficiency in WHIM syndrome. We report that after ligand activation, WHIM-associated mutant CXCR4 receptors lacking the carboxy-terminal 19 residues internalize and activate Erk 1/2 slower than wild-type (WT) receptors, while utilizing the same trafficking endocytic pathway. Recruitment of beta-Arrestin 2, but not beta-Arrestin 1, to the active WHIM-mutant receptor is delayed compared to the WT CXCR4 receptor. In addition, while both kinases Grk3 and Grk6 bind to WT CXCR4 and are critical to its trafficking to the lysosomes, Grk6 fails to associate with the WHIM-mutant receptor whereas Grk3 associates normally. Since beta-Arrestins and Grks play critical roles in phosphorylation and internalization of agonist-activated G protein-coupled receptors, these results provide a molecular basis for CXCR4 dysfunction in WHIM syndrome.


Effects of extraocular muscle tenotomy on congenital nystagmus in macaque monkeys.
Extraocular muscle tenotomy has been reported to damp congenital nystagmus in an achiasmatic sheepdog. We performed extraocular muscle tenotomy to evaluate its effects on congenital nystagmus in primates. Magnetic search coil eye movement recordings were used to document the presence of horizontal congenital nystagmus in 2 adult macaque monkeys that also had naturally occurring infantile strabismus. Extraocular muscle tenotomy was performed by operating on all 4 horizontal recti, surgically detaching the muscles from the globe and suturing them back to their original insertions without resection or recession. Eye movement recordings were repeated 4 months after the procedure, comparing the waveform, amplitude, retinal slip velocity, and intensity (frequency x amplitude) of the nystagmus before and after tenotomy. Visual acuity was also measured before and after surgery in 1 animal. Preoperatively, a disconjugate, pendular nystagmus was evident in 1 monkey, and the other had a conjugate pendular-jerk nystagmus damped by convergence. After tenotomy, nystagmus mean amplitude decreased 18% to 52% in 1 monkey but increased 14% in the other (t test, P <.002). Retinal slip velocity and nystagmus intensity increased in both monkeys. After tenotomy, mean velocity increased 22% to 218%, while mean intensity increased 40% to 208% (t test, P <.002). Visual acuity measured after tenotomy decreased an average of 20% ( approximately 2.0 cycles per degree) in each eye. Tenotomy had no noteworthy effects on eye alignment or other aspects of visual behavior other than the congenital nystagmus. Nystagmus velocity and intensity increased after extraocular muscle tenotomy in 2 monkeys. Further studies are required to establish the clinical value of this procedure as a treatment for various subtypes of congenital nystagmus in humans.


Ex vivo gene therapy and vision.
Ex vivo gene therapy, a technique where genetic manipulation of cells is undertaken remotely and more safely since it is outside the body, is an emerging therapeutic strategy particularly well suited to targeting a specific organ rather than for treating a whole organism. The eye and visual pathways therefore make an attractive target for this approach. With blindness still so prevalent worldwide, new approaches to treatment would also be widely applicable and a significant advance in improving quality of life. Despite being a relatively new approach, ex vivo gene therapy has already achieved significant advances in the treatment of blindness in pre-clinical trials. In particular, advances are being achieved in corneal disease, glaucoma, retinal degeneration, stroke and multiple sclerosis through genetic re-programming of cells to replace degenerate cells and through more refined neuroprotection, modulation of inflammation and replacement of deficient protein. In this review we discuss the latest developments in ex vivo gene therapy relevant to the visual pathways and highlight the challenges that need to be overcome for progress into clinical trials.


Epidural corticosteroid injections for lumbosacral radicular pain.
Lumbosacral radicular pain (commonly called sciatica) is a syndrome involving patients who report radiating leg pain. Epidural corticosteroid injections deliver a corticosteroid dose into the epidural space, with the aim of reducing the local inflammatory process and, consequently, relieving the symptoms of lumbosacral radicular pain. This Cochrane Review is an update of a review published in Annals of Internal Medicine in 2012. Some placebo-controlled trials have been published recently, which highlights the importance of updating the previous review. To investigate the efficacy and safety of epidural corticosteroid injections compared with placebo injection on pain and disability in patients with lumbosacral radicular pain. We searched the following databases without language limitations up to 25 September 2019: Cochrane Back and Neck group trial register, CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, International Pharmaceutical Abstracts, and two trial registers. We also performed citation tracking of included studies and relevant systematic reviews in the field. We included studies that compared epidural corticosteroid injections of any corticosteroid drug to placebo injections in patients with lumbosacral radicular pain. We accepted all three anatomical approaches (caudal, interlaminar, and transforaminal) to delivering corticosteroids into the epidural space. We considered trials that included a placebo treatment as delivery of an inert substance (i.e. one with no pharmacologic activity), an innocuous substance (e.g. normal saline solution), or a pharmacologically active substance but not one considered to provide sustained benefit (e.g. local anaesthetic), either into the epidural space (i.e. to mimic epidural corticosteroid injection) or adjacent spinal tissue (i.e. subcutaneous, intramuscular, or interspinous tissue). We also included trials in which a local anaesthetic with a short duration of action was used as a placebo and injected together with corticosteroid in the intervention group. Two authors independently performed the screening, data extraction, and 'Risk of bias' assessments. In case of insufficient information, we contacted the authors of the original studies or estimated the data. We grouped the outcome data into four time points of assessment: immediate (≤ 2 weeks), short term (> 2 weeks but ≤ 3 months), intermediate term (> 3 months but < 12 months), and long term (≥ 12 months). We assessed the overall quality of evidence for each outcome and time point using the GRADE approach. We included 25 clinical trials (from 29 publications) investigating the effects of epidural corticosteroid injections compared to placebo in patients with lumbosacral radicular pain. The included studies provided data for a total of 2470 participants with a mean age ranging from 37.3 to 52.8 years. Seventeen studies included participants with lumbosacral radicular pain with a diagnosis based on clinical assessment and 15 studies included participants with mixed duration of symptoms. The included studies were conducted mainly in North America and Europe. Fifteen studies did not report funding sources, five studies reported not receiving funding, and five reported receiving funding from a non-profit or government source. Eight trials reported data on pain intensity, 12 reported data on disability, and eight studies reported data on adverse events. The duration of the follow-up assessments ranged from 12 hours to 1 year. We considered eight trials to be of high quality because we judged them as having low risk of bias in four out of the five bias domains. We identified one ongoing trial in a trial registry. Epidural corticosteroid injections were probably slightly more effective compared to placebo in reducing leg pain at short-term follow-up (mean difference (MD) -4.93, 95% confidence interval (CI) -8.77 to -1.09 on a 0 to 100 scale; 8 trials, n = 949; moderate-quality evidence (downgraded for risk of bias)). For disability, epidural corticosteroid injections were probably slightly more effective compared to placebo in reducing disability at short-term follow-up (MD -4.18, 95% CI -6.04 to -2.17, on a 0 to 100 scale; 12 trials, n = 1367; moderate-quality evidence (downgraded for risk of bias)). The treatment effects are small, however, and may not be considered clinically important by patients and clinicians (i.e. MD lower than 10%). Most trials provided insufficient information on how or when adverse events were assessed (immediate or short-term follow-up) and only reported adverse drug reactions - that is, adverse events that the trialists attributed to the study treatment. We are very uncertain that epidural corticosteroid injections make no difference compared to placebo injection in the frequency of minor adverse events (risk ratio (RR) 1.14, 95% CI 0.91 to 1.42; 8 trials, n = 877; very low quality evidence (downgraded for risk of bias, inconsistency and imprecision)). Minor adverse events included increased pain during or after the injection, non-specific headache, post-dural puncture headache, irregular periods, accidental dural puncture, thoracic pain, non-local rash, sinusitis, vasovagal response, hypotension, nausea, and tinnitus. One study reported a major drug reaction for one patient on anticoagulant therapy who had a retroperitoneal haematoma as a complication of the corticosteroid injection. This study found that epidural corticosteroid injections probably slightly reduced leg pain and disability at short-term follow-up in people with lumbosacral radicular pain. In addition, no minor or major adverse events were reported at short-term follow-up after epidural corticosteroid injections or placebo injection. Although the current review identified additional clinical trials, the available evidence still provides only limited support for the use of epidural corticosteroid injections in people with lumbosacral radicular pain as the treatment effects are small, mainly evident at short-term follow-up and may not be considered clinically important by patients and clinicians (i.e. mean difference lower than 10%). According to GRADE, the quality of the evidence ranged from very low to moderate, suggesting that further studies are likely to play an important role in clarifying the efficacy and tolerability of this treatment. We recommend that further trials should attend to methodological features such as appropriate allocation concealment and blinding of care providers to minimise the potential for biased estimates of treatment and harmful effects.


Skin-fat-graft: a simple tool for reconstruction of small deep defects of the nose.
Small deep defects of the nose after resection of benign or malignant skin tumors are a common challenge in facial plastic surgery daily routine. The use of local flaps has several disadvantages for what reason they are a minor or no option especially in certain localizations in the lower third of the nose. Many elder patients suffer from comorbidities where complex more-staged reconstructional procedures drop out. We present a technique of nasal defect closure with a skin-fat composite graft. Between April 2010 and July 2013, we treated 42 patients with a total of 46 skin-fat-grafts to the nose. We reevaluated the esthetic and functional outcome in a retrospective analysis. In 80% of the cases, the results were rated excellent to satisfactory, 20% fair to poor. Reasons for worse validation were color and contour differences of grafts and surrounding tissue as well as alar retraction in very few cases. Nevertheless, we consider skin-fat-grafts to be a useful tool in single-layer nasal reconstruction in defects of smaller size.


Salivary nerve growth factor reactivity to acute psychosocial stress: a new frontier for stress research.
Neurotrophins such as nerve growth factor (NGF) may represent a stress-responsive system complementing the better known neuroendocrine (hypothalamic-pituitary-adrenal axis) and autonomic nervous system, but there is little evidence for NGF response to acute stress in humans because noninvasive measures have not been available. We investigated salivary NGF (sNGF) in 40 healthy young adults confronting a romantic conflict stressor. Five saliva samples-two collected before and three after the conflict-were assayed for sNGF, cortisol (hypothalamic-pituitary-adrenal marker), and α-amylase (sAA; ANS marker). In addition, a control group (n = 20) gave saliva samples at the same time intervals to determine whether sNGF changes were specific to the conflict stressor. sNGF showed significant reactivity from entry to the first poststress sample among study participants (β = .13, p = .001), with nonsignificant change across poststress samples. Control participants showed no change in sNGF across the same period. Within-person changes in sNGF were generally aligned with both cortisol (β = .17, p = .003) and sAA (β = .17, p = .021) responses. Preconflict negative emotion predicted lower sNGF reactivity (β = -.08, p = .009) and less alignment with sAA (β = -.09, p = .040), whereas positive emotion predicted less alignment with cortisol (β = -.10, p = .019). This study is the first to document sNGF as a marker that responds to stress in humans.


RNA regulatory processes in RNA virus biology.
Numerous post-transcriptional RNA processes play a major role in regulating the quantity, quality and diversity of gene expression in the cell. These include RNA processing events such as capping, splicing, polyadenylation and modification, but also aspects such as RNA localization, decay, translation, and non-coding RNA-associated regulation. The interface between the transcripts of RNA viruses and the various RNA regulatory processes in the cell, therefore, has high potential to significantly impact virus gene expression, regulation, cytopathology and pathogenesis. Furthermore, understanding RNA biology from the perspective of an RNA virus can shed considerable light on the broad impact of these post-transcriptional processes in cell biology. Thus the goal of this article is to provide an overview of the richness of cellular RNA biology and how RNA viruses use, usurp and/or avoid the associated machinery to impact the outcome of infection. This article is categorized under: RNA in Disease and Development > RNA in Disease.


Healthy City Project: An application of data envelopment analysis.
The importance of Korea's Healthy City Project has recently increased due to the growth of the elderly population and chronic diseases. Consequently, local governments are expanding the project to manage health at the local level; however, because local government resources are limited, efficient business operation is required. Thus, the purpose of this study is to present a plan for effective project management by developing a strategy for a Healthy City Project that is suitable for the scale of local governments. For efficiency analysis, data were collected from the homepages of 90 local governments that are implementing the Healthy City Project in Korea, and data envelopment analysis (DEA) was conducted using both the CCR model and the BCC model. The input variables for the DEA included budget, manpower, organization, planned projects, and research education. In addition, we selected program, network, and project performance as output variables. Analysis results indicated that the CCR model identified 22 (out of 90) municipalities in which Healthy City Projects are implemented efficiently, while 68 are inefficient. The BCC model identified many more efficient regions than the CCR model; however, the difference was insignificant. Thus, the budget, manpower, planned projects, and network must be increased to improve efficiency. First, to improve the efficiency of the Healthy City Project, a sufficient budget must be secured during its implementation. Second, long- and short-term plans are needed to expand the Healthy City Program. Third, networks must be created for local governments to benchmark Healthy City Projects.


Variables involved in the discordance between HbA1c and fructosamine: the glycation gap revisited.
Glycation gap (GG) is defined as the difference between the measured level of HbA1c and the level that would be predicted from its regression on the fructosamine level. The aims of the study were: 1) To determine the reproducibility and consistency of GC; 2) To discover factors related to GG value. Given that metformin might increase glucose transport through the erythrocyte membrane, this treatment was also considered in the analyses of the results. GG was calculated in two blood samples separated 30.6 (SD 7.3) weeks, obtained in 508 type 2 diabetic patients. The following variables were considered: HbA1c, fructosamine, glucose, creatinine, hematological parameters and treatment with metformin. Multivariate and logistic regression analyses were performed to explore the variables independently related to CG. GG was reproducible and consistent over time. Creatinine, mean corpuscular hemoglobin concentration (MCHC), and glycemia (inverse relationship); and HbA1c and treatment with metformin (direct relationship) were independently related to GG. Patients treated with metformin showed higher HbA1c values, despite similar fructosamine concentrations, than patients not treated with the drug. GG is independently related to serum levels of creatinine, MCHC and treatment with metformin. The spurious effect of metformin on Hb glycation could have serious clinical implications and should be considered when interpreting the results of clinical trials.


Transcriptome analysis reveals determinant stages controlling human embryonic stem cell commitment to neuronal cells.
Proper neural commitment is essential for ensuring the appropriate development of the human brain and for preventing neurodevelopmental diseases such as autism spectrum disorders, schizophrenia, and intellectual disorders. However, the molecular mechanisms underlying the neural commitment in humans remain elusive. Here, we report the establishment of a neural differentiation system based on human embryonic stem cells (hESCs) and on comprehensive RNA sequencing analysis of transcriptome dynamics during early hESC differentiation. Using weighted gene co-expression network analysis, we reveal that the hESC neurodevelopmental trajectory has five stages: pluripotency (day 0); differentiation initiation (days 2, 4, and 6); neural commitment (days 8-10); neural progenitor cell proliferation (days 12, 14, and 16); and neuronal differentiation (days 18, 20, and 22). These stages were characterized by unique module genes, which may recapitulate the early human cortical development. Moreover, a comparison of our RNA-sequencing data with several other transcriptome profiling datasets from mice and humans indicated that Module 3 associated with the day 8-10 stage is a critical window of fate switch from the pluripotency to the neural lineage. Interestingly, at this stage, no key extrinsic signals were activated. In contrast, using CRISPR/Cas9-mediated gene knockouts, we also found that intrinsic hub transcription factors, including the schizophrenia-associated SIX3 gene and septo-optic dysplasia-related HESX1 gene, are required to program hESC neural determination. Our results improve the understanding of the mechanism of neural commitment in the human brain and may help elucidate the etiology of human mental disorders and advance therapies for managing these conditions.


Immunoselection of tumor variants resistant to antibody-mediated cytotoxicity. Their immunologic and metastatic characterization.
The immunological characteristics of two series of metastatic variants of restricted genetic origin were related to their lung-colony-forming potential. A series of metastatic variants was isolated from a tumor-cell population in which heterogeneity appeared following short-term in vivo passage, while a second series of variants were immunoselected in vitro for resistance to antibody-complement-mediated cell lysis. In the case of the first series, the sensitivity of the individual variants to cell-mediated and antibody-complement-mediated cytotoxicity appeared to be partly determined by the number and rate of loss of antibody-binding sites on the cell surface. These characteristics also correlated with the efficiency of experimental metastasis in the animal. We compared the results reported herein with our previous studies of nonimmune parameters for this series of metastatic variants, and we conclude that immunological differences can be important to the efficiency of lung-colony formation. However, in the case of the second series of variants, despite selection in vitro for resistance to antibody-complement-mediated cell lysis, the behavior of these variants in the lung colony assay could not be predicted by the immunologic parameters examined.


S-100 and MATH-1 Protein Expressions Can Be Useful for the Prediction of Clinical Outcome in Neuroblastoma Patients.
Neuroblastoma (NB) is the most frequent extracranial solid tumor of childhood, remarkable for its broad spectrum of clinical behavior. This diversity in behavior correlates closely with defined clinical and biological features and combinations of prognostic variables are used for risk-group assignment. S-100 proteins have roles in differentiation and were shown to be frequently dysregulated in NB. MATH-1 protein plays role in neuronal cell differentiation through development. However, up to date, there are no studies evaluating the relationship between MATH-1 and NB. Grb2-associated binding (Gab) proteins have roles in the regulation of cell growth and differentiation. Gab1 was reported to be related to poor survival of high-risk NB patients. The aim of this study was to investigate the relationship between differentiation-related S-100, MATH-1, and Gab1 proteins and risk group and/or stages of NB. A significant relation was found between S-100 and early stages of NB. This study also revealed a significant association between MATH-1 and low-risk groups. S-100 and MATH-1 were also shown to provide survival advantages among stages and risk groups. The findings of this study support the assumption that S-100 and MATH-1 can be potential prognostic biomarkers for staging and risk-group assignment of NB patients. These proteins can be useful tools for clinicians to guide through treatment options, especially for the evaluation of tumor differentiation.


Summary of the comparative effectiveness review on off-label use of atypical antipsychotics.
Conventional and atypical antipsychotic medications are approved by the FDA for treatment of schizophrenia and bipolar disorder. Over many decades, the widespread use of conventional antipsychotics produced various side effects requiring additional medications, such as the atypical antipsychotics. Beginning in 2006, 9 atypical antipsychotic drugs have been approved by the FDA for indications that were previously off-label uses: aripiprazole (as augmentation for major depressive disorder [MDD] and for autism spectrum disorders), asenapine, clozapine, iloperidone, olanzapine (in combination with fluoxetine for MDD and bipolar depression), paliperidone, quetiapine (quetiapine and quetiapine XR [extended release] as monotherapy in bipolar depression and quetiapine XR as augmentation for MDD), risperidone (for autism spectrum disorders), and ziprasidone. In 2006, the Agency for Healthcare Research and Quality (AHRQ) published a systematic review on the comparative effectiveness of off-label uses of atypical antipsychotics. Since that time, numerous studies have been published evaluating these therapies in various new off-label uses; new or increased adverse effects have been observed with off-label uses; new atypical antipsychotics have been approved; and previously off-label uses have been approved for some atypical antipsychotics. Hence, AHRQ published an updated review in September 2011 that summarized the benefits and harms of atypical antipsychotics in the treatment of attention-deficit hyperactivity disorder/attention deficit disorder (ADHD), anxiety, behavioral disturbances of dementia and severe geriatric agitation, depression, eating disorders, insomnia, obsessive-compulsive disorder (OCD), personality disorder, post-traumatic stress disorder (PTSD), substance use and dependence disorders, and Tourette's syndrome. The new report also investigated topics for which data in the previous report were found to be insufficient to make conclusions, including subpopulations (i.e., race/ethnicity, gender) that would benefit most from atypical antipsychotics, appropriate dose, and time needed to see clinical improvement. The 2011 review included the following atypical antipsychotics: aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone; no clinical trials were found for off-label use of the 3 most recently FDA-approved atypical antipsychotics (asenapine, iloperidone, and paliperidone). To (a) familiarize health care professionals with the methods and findings from AHRQ's 2011 Comparative Effectiveness Review (CER) of off-label use of atypical antipsychotics, (b) encourage consideration of the clinical and managed care applications of the review findings, and (c) identify limitations and gaps in the existing research with respect to the benefits and risks of off-label use of atypical antipsychotics. Antipsychotic medications are FDA approved for the treatment of schizophrenia and bipolar disorder. Conventional antipsychotics have been widely used for decades and spurred the development of the atypical antipsychotics. Atypical antipsychotics were produced and are now being used for patients who may have experienced various side effects while using conventional antipsychotics.In 2006, an AHRQ study reviewed off-label uses of atypical antipsychotics (excluding clozapine because of its association with potentially fatal bone marrow suppression and the requirement for frequent blood tests for safety monitoring). Findings indicated that the most common off-label uses of these drugs included depression, OCD, PTSD, personality disorders, Tourette's syndrome, autism, and agitation in dementia. The reviewers concluded in 2006 that overall there was not sufficiently high strength of evidence of efficacy for any off-label use of atypical antipsychotics. There was, however, strong evidence for an increased risk of adverse events with off-label use, including significant weight gain and sedation and increased mortality among the elderly.Since the 2006 review, significant developments occurred in the use of atypical antipsychotics, including FDA approval of the atypical antipsychotics asenapine, iloperidone, and paliperidone and FDA approval of previous off-label uses: (a) quetiapine and quetiapine XR as monotherapy in bipolar depression; (b) quetiapine XR as augmentation therapy for MDD; (c) aripiprazole as augmentation therapy for MDD; (d) olanzapine/fluoxetine combination for MDD; (e) olanzapine/fluoxetine combination for bipolar depression; and (f) risperidone and aripiprazole for autism spectrum disorders. Additional studies have been published for new off-label uses, and there have been reports of new or increased adverse effects for off-label uses.Further review of previously insufficient information was warranted on subpopulations where treatment modification such as dosing may increase efficacy. The 2006 review did not have sufficient information to make conclusions regarding subpopulations (i.e., race/ethnicity, gender) that would benefit most from atypical antipsychotics, appropriate dosing, and the duration of treatment needed to see clinical improvement. The updated AHRQ report in 2011 reviewed off-label uses of atypical antipsychotic medications in anxiety, ADHD, behavioral disturbances of dementia and severe geriatric agitation, MDD, eating disorders, insomnia, OCD, PTSD, personality disorders, substance abuse, and Tourette's syndrome; autism was included in the 2006 review but is now reviewed in a separate report of the comparative effectiveness of antipsychotics for on-label uses. The significant findings in the updated review include (a) small but statistically significant benefits for olanzapine, aripiprazole, and risperidone for elderly patients with dementia; (b) quetiapine appears superior to placebo for general anxiety disorder (GAD); (c) risperidone was associated with benefits in the treatment of OCD; and (d) adverse events are common. Atypical antipsychotics were not effective in the treatment of eating disorders or personality disorder. The evidence did not support the use of atypical antipsychotics in the treatment of substance abuse, and data were inconclusive for the use of these medications for insomnia. The number needed to harm (NNH) was calculated for adverse events in elderly patients, including risk of death (NNH = 87), stroke (NNH = 53 for risperidone), extrapyramidal symptoms (NNH = 10 for olanzapine and NNH = 20 for risperidone), and urinary symptoms (NNH = 16 to 36). Adverse events in nonelderly adults included weight gain (particularly with olanzapine), fatigue, sedation, akathisia (with aripiprazole), and extrapyramidal symptoms.


Update on lactose malabsorption and intolerance: pathogenesis, diagnosis and clinical management.
Lactose is the main source of calories in milk, an essential nutriedigestion, patients with visceral hypersensitivity nt in infancy and a key part of the diet in populations that maintain the ability to digest this disaccharide in adulthood. Lactase deficiency (LD) is the failure to express the enzyme that hydrolyses lactose into galactose and glucose in the small intestine. The genetic mechanism of lactase persistence in adult Caucasians is mediated by a single C→T nucleotide polymorphism at the LCTbo -13'910 locus on chromosome-2. Lactose malabsorption (LM) refers to any cause of failure to digest and/or absorb lactose in the small intestine. This includes primary genetic and also secondary LD due to infection or other conditions that affect the mucosal integrity of the small bowel. Lactose intolerance (LI) is defined as the onset of abdominal symptoms such as abdominal pain, bloating and diarrhoea after lactose ingestion by an individual with LM. The likelihood of LI depends on the lactose dose, lactase expression and the intestinal microbiome. Independent of lactose digestion, patients with visceral hypersensitivity associated with anxiety or the Irritable Bowel Syndrome (IBS) are at increased risk of the condition. Diagnostic investigations available to diagnose LM and LI include genetic, endoscopic and physiological tests. The association between self-reported LI, objective findings and clinical outcome of dietary intervention is variable. Treatment of LI can include low-lactose diet, lactase supplementation and, potentially, colonic adaptation by prebiotics. The clinical outcome of these treatments is modest, because lactose is just one of a number of poorly absorbed carbohydrates which can cause symptoms by similar mechanisms.


Adult epiglottitis in a Canadian setting.
The objective of this study was to determine stable estimates of the incidence, case fatality, and epidemiologic features of adult epiglottitis, and risk factors for intubation. The authors designed a retrospective cohort combined with a nested case-control study, followed by detailed analysis of cases from two tertiary care institutions. Among 813 cases, the incidence was 2.02 cases/10(5) population per year. Ten recorded deaths constituted a case fatality rate of 1.2% (95% confidence interval [CI]: 0.5% to 1.9%). The eight fully documented deaths indicated no sudden episodes of catastrophic upper airway obstructions without previous dyspnea. A detailed review of 51 cases revealed that 18% of patients underwent expeditious intubation. Patients managed without initially requiring intubation did not need emergency airway interventions. Only the presence of dyspnea (noted in 29% of patients) at the time of admission (P < 0.001) predicted the need for intubation. A low case fatality rate in a conservatively managed cohort and the absence of sudden upper airway catastrophes in patients without dyspnea suggest that prophylactic intubation and intensive care unit monitoring is not warranted in all patients. An early complaint of dyspnea may safely discriminate between patients requiring invasive airway management and close observation.


The carbohydrate structure of DEFB126, the major component of the cynomolgus Macaque sperm plasma membrane glycocalyx.
Based on the amino-acid sequence of the macaque epididymal secretory protein, ESP 13.2 (Q9BEE3/AJ236909), it has now been classified as beta-defensin DEFB126. DEFB126 is one of the five beta-defensins with genes that are clustered along chromosome 20pl3, and all five proteins have an extended carboxy terminus that continues beyond the 6-cysteine beta-defensin core region. This 60-amino acid carboxyl tail extension of the DEFB126 molecule is extraordinarily rich in threonine and serine (40%), many of which appear to be likely candidates for having O-glycosylation. DEFB126 has been shown to coat the entire surface of cynomolgus macaque sperm as they move through the corpus/caudal region of the epididymis. It is a major glycocalyx barrier to the external environment and is retained until the completion of capacitation. Sperm exposed to fluorescein-conjugated poly-L-lysine or Alexa488-histone showed a very uniform fluorescent labeling pattern over the entire sperm surface, almost identical to that observed with anti-DEFB126 Ig label. Sperm surface components that were released following treatment with caffeine/cAMP (in vitro capacitation) were blotted and probed with three different lectins which are known to recognize terminal sialic acid residues, and all three recognized the 35 kDa DEFB126 band. Neuraminidase treatment of sperm shifted the molecular weight of DEFB126 from 34-36 kDa to approximately 38-40 kDa and removed or greatly inhibited sialic acid-specific lectin recognition. O-Glycanase treatment alone was ineffective at removal of the oligosaccharides, but prior treatment with neuraminidase was sufficient to enable the O-glycanase treatment to effectively change the apparent molecular weight to 10 kDa, confirming that a major portion of the molecular mass is associated with the carbohydrate portion. Western blots of neuraminidase-treated DEFB126 showed strong recognition with a number of lectins that identify beta-galactose and also lectins that recognize the N-acetylgalactosamine-serine/threonine, the proposed connection site of O-glycosylation. All of the lectins that recognized DEFB126 on Western blots were used to fluorescently probe sperm. The fluorescent patterns that were observed with poly-L-lysine, Alexa488-histone, sialic acid-specific lectins, and galactose-specific lectins showed even distributions over the entire sperm surface and the patterns were identical to sperm labeled with anti-DEFB126 Ig, and all but the antibody did not recognize neuraminidase-treated sperm.


Glycosyltransferase 8 domain-containing protein 1 (GLT8D1) is a UDP-dependent galactosyltransferase.
Glycosyltransferases (GTs) are enzymes that catalyze the formation of glycosidic bonds and hundreds of GTs have been identified so far in humans. Glycosyltransferase 8 domain-containing protein 1 (GLT8D1) has been associated with central nervous system diseases and cancer. However, evidence on its enzymatic properties, including its substrates, has been scarcely described. In this paper, we have produced and purified recombinant secretory GLT8D1. The enzyme was found to be N-glycosylated. Differential scanning fluorimetry was employed to analyze the stabilization of GLT8D1 by Mn2+ and nucleotides, revealing UDP as the most stabilizing nucleotide scaffold. GLT8D1 displayed glycosyltransferase activity from UDP-galactose onto N-acetylgalactosamine but with a low efficiency. Modeling of the structure revealed similarities with other GT-A fold enzymes in CAZy family GT8 and glycosyltransferases in other families with galactosyl-, glucosyl-, and xylosyltransferase activities, each with retaining catalytic mechanisms. Our study provides novel structural and functional insights into the properties of GLT8D1 with implications in pathological processes.


Mucormycosis: a rare fungal infection in tornado victims.
This article reviews four immunocompetent patients who developed a rare fungal infection, mucormycosis, secondary to multiple traumatic injuries sustained during an EF-5 tornado in Joplin, MO. Commonly found in soil and decaying organic matter, mucorales are fungi associated with soft tissue and cutaneous infections. Onset of this fungal infection can occur without clinical signs, presenting several days to several weeks after injury, delaying diagnosis. A multidisciplinary treatment approach including aggressive antifungal therapy and aggressive surgical debridement is critical. This diagnosis should be considered in all patients presenting with injuries sustained from high-velocity embedment of debris such as natural disasters or explosions. We present four cases of mucormycosis, species Apophysomyces trapeziformis. Data reported includes predisposing factors, number of days between injury and diagnosis of mucormycosis, surgical treatment, antifungal therapy, outcomes, and potential risk factors that may have contributed to the development of mucormycosis.


The treatment of mild hypertension study. A randomized, placebo-controlled trial of a nutritional-hygienic regimen along with various drug monotherapies. The Treatment of Mild Hypertension Research Group.
There is no consensus for the optimal treatment program for individuals with mild hypertension, including whether treatment should emphasize life-style changes alone, such as weight loss, reduction of sodium and alcohol intake, and increased physical activity, or whether it should also include a pharmacologic component. The dilemma is accentuated by the availability of many drugs from different classes to lower blood pressure. To study the relative efficacy and safety of a combination of pharmacologic and nutritional-hygienic intervention compared with nutritional-hygienic intervention alone, a double-blind, controlled clinical trial was initiated. Nine hundred two men and women with mild hypertension (average blood pressure, 140/91 mm Hg) were randomized to receive nutritional-hygienic intervention plus one of six treatments: (1) placebo; (2) diuretic (chlorthalidone); (3) beta-blocker (acebutolol); (4) alpha 1-antagonist (doxazosin mesylate); (5) calcium antagonist (amlodipine maleate); or (6) angiotensin-converting enzyme inhibitor (enalapril maleate). After 12 months, weight loss averaged 4.5 kg, urinary sodium excretion was reduced by 23%, and reported leisure-time physical activity was nearly doubled. Systolic and diastolic blood pressure in the group given nutritional-hygienic intervention alone (placebo) were reduced by 10.6 and 8.1 mm Hg, respectively. For participants in the five groups receiving antihypertensive medication in addition to nutritional-hygienic treatment, blood pressure reductions were significantly greater than those achieved with nutritional-hygienic treatment alone (range, 16 to 22 mm Hg for systolic and 12 to 14 mm Hg for diastolic blood pressure). Although differences among treatment groups in certain dimensions of quality of life, self-reported side effects, plasma lipid levels, and biochemical measures were observed, no consistent pattern in the differences was noted. Nutritional-hygienic therapy is an effective first-step treatment for persons with mild hypertension, and significant additional blood pressure lowering with minimal short-term side effects can be achieved by adding one of five different classes of antihypertensive agents.


Diffuse reflectance spectroscopy for colorectal cancer surgical guidance: towards real-time tissue characterization and new biomarkers.
Colorectal cancer (CRC) is the third most common and second most deadly type of cancer worldwide, representing 11.3% of the diagnosed cancer cases and resulting in 10.2% (0.88 million) of the cancer related deaths in 2020. CRCs are typically detected at the late stage, which leads to high mortality and morbidity. Mortality and poor prognosis are partially caused by cancer recurrence and postoperative complications. Patient survival could be increased by improving precision in surgical resection using accurate surgical guidance tools based on diffuse reflectance spectroscopy (DRS). DRS enables real-time tissue identification for potential cancer margin delineation through determination of the circumferential resection margin (CRM), while also supporting non-invasive and label-free approaches for laparoscopic surgery to avoid short-term complications of open surgery as suitable. In this study, we have estimated the scattering properties and chromophore concentrations based on 2949 DRS measurements of freshly excised ex vivo specimens of 47 patients, and used this estimation to classify normal colorectal wall (CW), fat and tumor tissues. DRS measurements were performed with fiber-optic probes of 630 μm source-detector distance (SDD; probe 1) and 2500 μm SDD (probe 2) to measure tissue layers ∼0.5-1 mm and ∼0.5-2 mm deep, respectively. By using the 5-fold cross-validation of machine learning models generated with the classification and regression tree (CART) algorithm, we achieved 95.9 ± 0.7% sensitivity, 98.9 ± 0.3% specificity, 90.2 ± 0.4% accuracy, and 95.5 ± 0.3% AUC for probe 1. Similarly, we achieved 96.9 ± 0.8% sensitivity, 98.9 ± 0.2% specificity, 94.0 ± 0.4% accuracy, and 96.7 ± 0.4% AUC for probe 2.


The histopathology of experimentally infected hamsters with the Lyme disease spirochete, Borrelia burgdorferi.
Seven hamsters, experimentally infected with Borrelia burgdorferi, were examined by both cultural and histological techniques at 1 to 9 months postinfection. Spirochetes were detected in the spleen, kidney, or eye of all animals by culture and in the spleen, kidney, eye, liver, or heart blood of five of seven animals by histological examination. Two animals showed nonspecific hepatic portal lymphocytic infiltration, while five of the hamsters displayed no significant histologic signs of inflammation or granuloma formation in the major organ systems. Synovitis and arthropathy did not occur. All animals showed some degree of follicular lymphoid hyperplasia of the spleen. Spirochetes were predominantly extracellular with a rare organism appearing to be partially within a macrophage.


Retroperitoneal lymphocele after anterior spinal surgery.
Case report; Review of Literature. To present an uncommon complication after anterior lumbar surgery as well as a treatment option and a review of the literature. A number of complications have been reported after anterior lumbar surgery. Common complications include vascular, ureteral, and neurologic injuries. The development of a retroperitoneal lymphocele has been previously been described, but details regarding evaluation, diagnosis, and treatment options are lacking in the literature. The case of a single patient with a postoperative retroperitoneal lymphocele was identified and retrospectively reviewed. Permission was obtained from the patient to review and publish this information. A review of literature on lymphoceles and anterior lumbar complications was also performed using PubMed and Ovid databases. A 76-year-old woman underwent anterior interbody fusion from L2-L3-L4-L5, followed by posterior T11-L5 fusion for degenerative scoliosis and spinal stenosis. Six weeks after surgery, she presented with severe abdominal pain, nausea, and emesis. Examination revealed a retroperitoneal lymphocele, which was confirmed after aspiration. The patient was treated with a laparoscopic marsupialization procedure without recurrence. At 12 months, the patient had no further abdominal symptoms, noted improvements in back and leg pain scores, and had stable radiographic findings. Retroperitoneal lymphocele is a rare complication after anterior lumbar interbody fusion. The different diagnosis should include infectious abscess, ureteral injury with urinoma, pancreatic injury with pseudocyst formation, and spinal fluid leak with pseudomeningocele. Diagnosis can be guided by serum and cyst fluid analysis. Although treatment options exist, surgical treatment may provide the most reliable results.


Myoepithelial-Rich and Infiltrative Giant Vascular Eccrine Spiradenoma: A Unique Presentation of a Rare Adnexal Tumor.
A rare variant of the eccrine spiradenoma, the giant vascular eccrine spiradenoma, has been characterized as a large circumscribed and sometimes hemorrhagic solitary tumor occurring in adults older than 50 years. Histopathologically, the lesion is comprised of distinct cell populations and cystic hemorrhagic glandular spaces. We present a 68-year-old Bengali man with a giant vascular eccrine spiradenoma and describe immunohistochemical features of this tumor. In addition, we highlight unique aspects of this case, including a rich myoepithelial component and focal pseudocapsular infiltration.


Vanadate ingestion increases the gain in wound breaking strength and leads to better organized collagen fibers in rats during healing.
Repair of incision wounds closed by suturing is evaluated by the progressive gain in wound breaking strength. Previously the closure of open wounds in rats ingesting vanadate, an inhibitor of tyrosine phosphate phosphatases, was shown to occur with deposition of more uniformly organized collagen fiber bundles. The hypothesis of this study was that deposition of more uniformly organized collagen fibers would enhance the gain in wound breaking strength of incisional wounds. Six adult rats received vanadate-supplemented saline drinking water for 1 week before placement of two 6-cm, parallel, suture-closed wounds on their backs. Six control rats received identical wounds and were given saline drinking water. The drinking water regimen was continued for 1 week after wounding, and then wound strength was tested with a tensiometer and tissue samples were obtained for histologic evaluation. Wound breaking strength doubled in vanadate-treated rats compared with controls. Bright-field and polarized light microscopy showed that the connective tissue matrix of granulation tissue from control rats was oriented perpendicular to the surface of the skin. In contrast, the connective tissue matrix of granulation tissue from vanadate-treated rats was oriented parallel to the skin surface. The gap in granulation tissue between the edges of the wounds in the vanadate-treated rats was greater than that in controls. Electron microscopy showed that wounds in the vanadate-treated contained uniform collagen fibers that were 20 percent greater in diameter and more evenly spaced than they were in controls. It is proposed that these changes in the organization of collagen fibers within incisional wounds were responsible for the increased wound breaking strength observed in rats ingesting vanadate.


Melanoma patients with additional primary cancers: a single-center retrospective analysis.
Background: Recent progress in the diagnosis and treatment of primary and metastatic cutaneous melanoma (CM) has led to a significant increase in the patients` expectancy of life. The development of additional primary tumors (APT) other than CM represents an important survival issue. Results: Of a total of 1764 CM patients, 80 (4.5%) patients developed APT. For tumors diagnosed after CM, there was a 2.7 fold excess risk for APT compared to the swiss german population. A significantly increased risk was noted for female breast (SIR, 2.46), male larynx (SIR, 76.92), male multiple myeloma (SIR, 11.2), male oesophagus (SIR, 10.8) and thyroid on males (SIR, 58.8) and females (SIR, 38.1). All thyroid cancer cases had a common papillary histological subtype and a high rate of BRAFV600E mutation. Melanoma was the primary cause of death in the vast majority of patients. Methods: We used the cancer registry from the Comprehensive Cancer Center Zurich (CCCZ) and retrospectively analyzed patients with CM and APT between 2008 and 2018. We calculated the risk of APT compared to the swiss german population using the standardized incidence ratio (SIR). Conclusions: Patients with CM have an increased risk for hematologic and solid APT. Long-term follow-up is indicated.


A retained wood penetrating the superior orbital fissure in a neurologically intact child.
Transorbital intracranial injuries due to a wooden foreign body traversing superior orbital fissure is an extremely rare condition. A 9-year-old boy was struck by a tree branch in the left eye while playing in the garden two months ago. On physical examination, the patient had only a hypertrophic scar on his medial side of left upper eyelid at the admission. A history of recurrent cutaneous fistula from the puncture site due to a retained foreign body was suspected, and the patient was hospitalized to evaluate and remove the object to prevent severe infection. Afterwards, the child was operated successfully via the left transcranial route to detect and remove the foreign body. The authors described an unusual case of wooden foreign body that traversed the superior orbital fissure yet caused no deficit and was associated with no fracture. Even if symptoms are absent, removal of a wooden foreign body should be immediately performed to prevent sight-threatening and life-threatening complications.


Early antibiotic treatment may prevent complete development of Lemierre's syndrome: experience from 2 cases.
Lemierre's syndrome is a rare fulminant condition caused by an acute oropharyngeal infection, with secondary septic thrombophlebitis of the internal jugular vein complicated by multiple metastatic infections. Herein we report 2 patients with internal jugular vein thrombosis secondary to oropharyngeal infection, whose clinical course was indolent, and who were asymptomatic shortly after antibiotic therapy was begun. Careful examination of the neck in patients presenting with sore throat could help identify the typical 'cord sign'. In such cases, intravenous antibiotic treatment should be started as soon as possible to prevent development of metastatic infections and septicaemia characterizing Lemierre's syndrome.


Crystallization of the bovine ADP/ATP carrier is critically dependent upon the detergent-to-protein ratio.
The ADP/ATP carrier is an integral membrane protein located in the mitochondrial inner membrane. It mediates the exchange of cytosolic ADP for ATP generated in the mitochondrial matrix. Here, the purification and crystallization of the bovine ADP/ATP carrier in complex with the inhibitor carboxyatractyloside in the presence of LAPAO, an aminoxide detergent, is reported. High-quality crystals were only obtained when excess detergent was removed to reach a controlled detergent-to-protein ratio.


ARF-like protein 16 (ARL16) inhibits RIG-I by binding with its C-terminal domain in a GTP-dependent manner.
Retinoic acid-inducible gene I (RIG-I) recognizes RNA virus-derived nucleic acids, which leads to the production of type I interferon (IFN) in most cell types. Tight regulation of RIG-I activity is important to prevent ultra-immune responses. In this study, we identified an ARF-like (ARL) family member, ARL16, as a protein that interacts with RIG-I. Overexpression of ARL16, but not its homologous proteins ARL1 and ARF1, inhibited RIG-I-mediated downstream signaling and antiviral activity. Knockdown of endogenous ARL16 by RNAi potentiated Sendai virus-induced IFN-β expression and vesicular stomatitis virus replication. ARL16 interacted with the C-terminal domain (CTD) of RIG-I to suppress the association between RIG-I and RNA. ARL16 (T37N) and ARL16Δ45-54, which were restricted to the GTP-disassociated form, did not interact with RIG-I and also lost the inhibitory function. Furthermore, we suggest that endogenous ARL16 changes to GTP binding status upon viral infection and binds with the RIG-I CTD to negatively control its signaling activity. These findings suggested a novel innate immune function for an ARL family member, and a GTP-dependent model in which RIG-I is regulated.