Licochalcone A induces cell cycle arrest and apoptosis via suppressing MAPK signaling pathway and the expression of FBXO5 in lung squamous cell cancer.
Lung squamous cell carcinoma (LSCC) is a highly heterogeneous malignancy with high mortality and few therapeutic options. Licochalcone A (LCA, PubChem ID: 5318998) is a chalcone extracted from licorice and possesses anticancer and anti‑inflammatory activities. The present study aimed to elucidate the anticancer effect of LCA on LSCC and explore the conceivable molecular mechanism. MTT assay revealed that LCA significantly inhibited the proliferation of LSCC cells with less cytotoxicity towards human bronchial epithelial cells. 5‑ethynyl‑2'‑deoxyuridine (EdU) assay demonstrated that LCA could reduce the proliferation rate of LSCC cells. The flow cytometric assays indicated that LCA increased the cell number of the G1 phase and induced the apoptosis of LSCC cells. LCA downregulated the protein expression of cyclin D1, cyclin E, CDK2 and CDK4. Meanwhile, LCA increased the expression level of Bax, cleaved poly(ADP‑ribose)polymerase‑1 (PARP1) and caspase 3, as well as downregulated the level of Bcl‑2. Proteomics assay demonstrated that LCA exerted its antitumor effects via inhibiting mitogen‑activated protein kinase (MAPK) signaling pathways and the expression of F‑box protein 5 (FBXO5). Western blot analysis showed that LCA decreased the expression of p‑ERK1/2, p‑p38MAPK and FBXO5. In the xenograft tumors of LSCC, LCA significantly inhibited the volumes and weight of tumors in nude mice with little toxicity in vital organs. Therefore, the present study demonstrated that LCA effectively inhibited cell proliferation and induced apoptosis in vitro, and suppressed xenograft tumor growth in vivo. LCA may serve as a future therapeutic candidate of LSCC.


Genome-driven cell engineering review: in vivo and in silico metabolic and genome engineering.
Producing 'designer cells' with specific functions is potentially feasible in the near future. Recent developments, including whole-cell models, genome design algorithms and gene editing tools, have advanced the possibility of combining biological research and mathematical modelling to further understand and better design cellular processes. In this review, we will explore computational and experimental approaches used for metabolic and genome design. We will highlight the relevance of modelling in this process, and challenges associated with the generation of quantitative predictions about cell behaviour as a whole: although many cellular processes are well understood at the subsystem level, it has proved a hugely complex task to integrate separate components together to model and study an entire cell. We explore these developments, highlighting where computational design algorithms compensate for missing cellular information and underlining where computational models can complement and reduce lab experimentation. We will examine issues and illuminate the next steps for genome engineering.


Agreement of findings of glaucoma screening between trained vision center technicians and glaucoma specialists at a tertiary hospital in South India.
To study the agreement of findings of glaucoma screening between trained vision center (VC) technicians and glaucoma specialists in patients referred from VC to the glaucoma services of a tertiary eye care hospital in south India. This was a retrospective study comparing the findings of the VC technicians and the specialists of the glaucoma services in the base hospital, in patients referred from 13 VCs between January and June 2019. Medical records of 277 referred patients (out of 533 referrals) who attended the glaucoma clinic were analyzed. Of the 277 patients, 111 (40%) were confirmed having glaucoma, 133 (48%) were suspects, 29 (10.4%) were normal, and four (1.4%) had other pathology. The mean age of the patients was 59.7 ± 13 years and 60.6% were females. There was no statistically significant difference between the mean intraocular pressure (IOP) measured (17 ± 7.2 mmHg at the VC and 18 ± 8.7 mmHg at the clinic, p = 0.16) and the cup-to-disc ratio (CDR) (0.7 ± 0.13 at the VC and 0.6 ± 0.18 at the clinic, p = 0.57). Bland-Altman plots with 95% limits of agreement supported that mean differences were close to zero, and the intraclass correlation coefficient at 95% CI showed good consistency between the measurement of IOP (0.78 [0.74 to 0.81]) and CDR (0.90 [0.88 to 0.92]) at the base hospital and vision center. There is good agreement between the findings of VC technicians and glaucoma specialists. VC technicians can help in detecting glaucoma in the community.


The Use of Mathematical Modelling for Improving the Tissue Engineering of Organs and Stem Cell Therapy.
Regenerative medicine is a multidisciplinary field where continued progress relies on the incorporation of a diverse set of technologies from a wide range of disciplines within medicine, science and engineering. This review describes how one such technique, mathematical modelling, can be utilised to improve the tissue engineering of organs and stem cell therapy. Several case studies, taken from research carried out by our group, ACTREM, demonstrate the utility of mechanistic mathematical models to help aid the design and optimisation of protocols in regenerative medicine.


Did Child Restraint Laws Globally Converge? Examining 40 Years of Policy Diffusion.
The objective of the current study is to determine what factors have been associated with the global adoption of mandatory child restraint laws (ChRLs) since 1975. In order to determine what factors explained the global adoption of mandatory ChRLs, Weibull models were analyzed. To carry out this analysis, 170 countries were considered and the time risk corresponded to 5,146 observations for the period 1957-2013. The dependent variable was first time to adopt a ChRL. Independent variables representing global factors were the World Health Organization (WHO) and World Bank's (WB) road safety global campaign; the Geneva Convention on Road Traffic; and the United Nation's (UN) 1958 Vehicle Agreement. Independent variables representing regional factors were the creation of the European Transport Safety Council and being a Commonwealth country. Independent variables representing national factors were population; gross domestic product (GDP) per capita; political violence; existence of road safety nongovernmental organizations (NGOs); and existence of road safety agencies. Urbanization served as a control variable. To examine regional dynamics, Weibull models for Africa, Asia, Europe, North America, Latin America, the Caribbean, and the Commonwealth were also carried out. Empirical estimates from full Weibull models suggest that 2 global factors and 2 national factors are significantly associated with the adoption of this measure. The global factors explaining adoption are the WHO and WB's road safety global campaign implemented after 2004 (P <.01), and the UN's 1958 Vehicle Agreement (P <.001). National factors were GDP (P <.01) and existence of road safety agencies (P <.05). The time parameter ρ for the full Weibull model was 1.425 (P <.001), suggesting that the likelihood of ChRL adoption increased over the observed period of time, confirming that the diffusion of this policy was global. Regional analysis showed that the UN's Convention on Road Traffic was significant in Asia, the creation of the European Transport Safety Council was significant in Europe and North America, and the global campaign was in Africa. In Commonwealth and European and North American countries, the existence of road safety agencies was also positively associated with ChRL adoption. Results of the world models suggest that the WHO and WB's global road safety campaign was effective in disseminating ChRLs after 2004. Furthermore, regions such as Asia and Europe and North America were early adopters since specific regional and national characteristics anticipated the introduction of this policy before 2004. In this particular case, the creation of the European Transport Safety Council was fundamental in promoting ChRLs. Thus, in order to introduce conditions to more rapidly diffuse road safety measures across lagging regions, the maintenance of global efforts and the creation of road safety regional organizations should be encouraged. Lastly, the case of ChRL convergence illustrates how mechanisms of global and regional diffusion need to be analytically differentiated in order better to assess the process of policy diffusion.


Facile synthesis of chitosan/ZnO bio-nanocomposite hydrogel beads as drug delivery systems.
ZnO nanoparticles were synthesized in situ during the formation of physically cross-linked chitosan hydrogel beads using sodium tripolyphosphate as the cross-linker. The aim of the study was to investigate whether these nanocomposite beads have the potential to be used in drug delivery applications. The formation of ZnO nanoparticles (ZnONPs) in the hydrogels was confirmed by X-ray diffraction and scanning electron microscopy studies. SEM micrographs revealed the formation of ZnONPs with size range of 10-25 nm within the hydrogel matrix. Furthermore, the swelling and drug release properties of the beads were studied. The prepared nanocomposite hydrogels showed a pH sensitive swelling behavior. The ZnO nanocomposite hydrogels have rather higher swelling ratio in different aqueous solutions in comparison with neat hydrogel. In vitro drug release test was carried out to prove the effectiveness of this novel type of nanocomposite beads as a controlled drug delivery system. A prolonged and more controlled drug releases were observed for ZnONPs containing chitosan beads, which increased by the increase in ZnONPs content.


Probing the Dynamics of a Superradiant Quantum Phase Transition with a Single Trapped Ion.
We demonstrate that the quantum phase transition (QPT) of the Rabi model and critical dynamics near the QPT can be probed in the setup of a single trapped ion. We first demonstrate that there exists equilibrium and nonequilibrium scaling functions of the Rabi model by finding a proper rescaling of the system parameters and observables, and show that those scaling functions are representative of the universality class to which the Rabi model belongs. We then propose a scheme that can faithfully realize the Rabi model in the limit of a large ratio of the effective atomic transition frequency to the oscillator frequency using a single trapped ion and, therefore, the QPT. It is demonstrated that the predicted universal functions can indeed be observed based on our scheme. Finally, the effects of realistic noise sources on probing the universal functions in experiments are examined.


Gene expression in melanoma cell lines and cultured melanocytes: correlation between levels of c-src-1, c-myc and p53.
The molecular genetics of melanoma is little understood and has concentrated largely on DNA analyses. We have examined mRNA levels of 21 different oncogenes, antioncogenes, growth factors and proteases in cultured melanocytes and 17 melanoma cell lines. C-mel, c-erb-B2, c-myc, c-src-1, p53, platelet derived growth factor A chain, gro, transforming growth factor alpha, epidermal growth factor receptor and tissue plasminogen activator were all expressed in at least some cell lines. Most striking was the finding that there are significant intercorrelations of c-myc, p53 and c-src-1 levels, and between p53 and c-erb-B2, which may be due to common regulatory control of these genes in cells of the melanocytic lineage.


Incidence of polyneuropathy in Utrecht, the Netherlands.
Ascertain the incidence of cryptogenic axonal polyneuropathy (CAP) and how this relates to the overall incidence of polyneuropathy. Electronic diagnostic registries of all hospital-based neurologic practices in the province of Utrecht (population 1,224,852 = 7.4% of the Dutch population) were consulted in 2010 to identify incident cases with polyneuropathy. Medical files were reviewed to specify the final diagnosis. Age-adjusted incidence rates for the Netherlands were calculated using national age-specific population figures. The overall incidence of polyneuropathy was 77.0/100,000 person-years (95% confidence interval 71.1-82.8) in persons aged 18 years and older. Diabetic polyneuropathy (32%), CAP (26%), toxic polyneuropathy (14%), and immune-mediated polyneuropathy (9%) were the most frequent diagnoses. The incidence of CAP was 31.6/100,000 person-years (95% confidence interval 27.0-36.3) in persons aged 40 years and older. The incidence of polyneuropathy increased with age, as well as the proportion of patients diagnosed with CAP: 12% (40-49 years), 20% (50-59 years), 28% (60-69 years), 32% (70-79 years), and 35% (≥80 years) (χ(2) test, p = 0.005). The chance of establishing an etiologic diagnosis in patients presenting with a polyneuropathy decreases with age. Given the aging population, polyneuropathy in general and CAP in particular will pose a growing health care problem.


Role of mitochondrial oxidative stress on lymphocyte homeostasis in patients diagnosed with extra-pulmonary tuberculosis.
Extra-pulmonary tuberculosis is often an underrated illness. Recent clinical studies have pointed out that lymphocyte homeostasis is dramatically disturbed as revealed through a series of signs and symptoms. Lymphocytes, the known effector cells of our immune system, play an important role in providing immunologic resistance against Mycobacterium infection. It is important to have quantitative insights into the lifespan of these cells; therefore, we aimed to study the precise effect of gastrointestinal tuberculosis infection on peripheral blood lymphocyte subpopulations and function. Our results indicated that gastrointestinal tuberculosis could increase mitochondrial oxidative stress, lower mitochondrial DNA copy number, promote nuclear DNA damage and repair response, decrease mitochondrial respiratory chain enzyme activities, and upregulate Bcl-2 and caspase-3 gene expression in lymphocytes. We further revealed that Mycobacterium infection induces autophagy for selective sequestration and subsequent degradation of the dysfunctional mitochondrion before activating cellular apoptosis in the peripheral lymphocyte pool. Together, these observations uncover a new role of mitochondrial-nuclear crosstalk that apparently contributes to lymphocyte homeostasis in gastrointestinal tuberculosis infection.


Fibroadenomas with stromal cellularity. A clinicopathologic study of 21 patients.
Data on clinical and pathologic features of tumors from 21 patients who had breast tumors compatible with juvenile (cellular) fibroadenomas (JCF) were reviewed. All patients were black females ranging in age at time of presentation from 10 to 39 years, with a median age of 15 years. Follow-up (median period, six years) was obtained for 20 patients. Patients were categorized into two groups; 13 had solitary lesions and eight had multiple and successive lesions. No histologic differences were observed between JCF occurring as solitary or multiple tumors or between lesions occurring in patients younger and older than age 20 years. The JCF was shown to be a fairly distinct clinicopathologic entity that characteristically occurred in adolescents, but which was occasionally seen in young adults. It had a benign course, characterized by synchronous and metachronous multicentricity, rather than local recurrence.


Oral midazolam with and without meperidine for management of the difficult young pediatric dental patient: a retrospective study.
The purpose of this retrospective study was to examine different dosages of midazolam used alone or in combination with different dosages of meperidine for managing difficult young pediatric dental patients. Patient records and sedation logs of 120 moderately to severely apprehensive/ uncooperative subjects, ages 24-48 mos, sedated in private practice setting, were reviewed. Subjects, divided into six groups of 20, received midazolam in doses of 0.7 or 1.0 mg/kg with and without meperidine in doses of 1.0 or 1.5 mg/kg. Ratings of the effectiveness of sedation, duration of action, need for restraint to accomplish treatment, and recovery times were made. Nitrous oxide was not used. When used alone, use of 0.7 mg/kg midazolam produced the most agitation, required restraint most frequently, and produced the shortest working time (P<0.001). Subjects receiving 1.0 mg/kg midazolam and meperidine were the most effective, completing 20/20 visits with no need for restraint, no loss of consciousness throughout appointments, and no adverse reactions (P<0.001). Use of lower dose midazolam and higher dose meperidine was reliable, permitting treatment to be completed without restraint in 18/20 patients. Combined higher doses of both agents demonstrated somnolence and oversedation. The addition of meperidine increased working time (P<0.05). The addition of meperidine appears to enhance the effectiveness and duration of action of midazolam for managing difficult young pediatric patients.


Packing properties of 1-alkanols and alkanes in a phospholipid membrane.
We have used vibrating tube densitometry to investigate the packing properties of four alkanes and a homologous series of ten alcohols in fluid-phase membranes of dimyristoyl phosphatidylcholine (DMPC). It was found that the volume change of transferring these compounds from their pure states into the membrane, DeltaV(m)(pure-->mem), was positive for small (C4-C6) 1-alkanols while it was negative for larger alcohols and all alkanes. The magnitude of DeltaV(m)(pure-->mem) ranged from about +4 cm3/mol for alcohols with an alkyl chain about half the length of the fatty acids of DMPC, to -10 to -15 cm3/mol for the alkanes and long chain alcohols. On the basis of these observations, previously published information on the structure of the membrane-solute complexes and the free volume properties of (pure) phospholipid membranes, we suggest that two effects dominate the packing properties of hydrophobic solutes in DMPC. First, perturbation of the tightly packed interfacial zone around the ester bonds and first few methylene groups of DMPC brings about a positive contribution to DeltaV(m)(pure-->mem). This effect dominates the volume behavior for alcohols like 1-butanol, 1-pentanol and 1-hexanol. More hydrophobic solutes penetrate into the membrane core, which is loosely packed. In this region, they partially occupy interstitial (or free-) volume, which bring about a denser molecular packing and generate a negative contribution to DeltaV(m)(pure-->mem).


Performance of Lynch syndrome predictive models in a multi-center US referral population.
Lynch syndrome is the most common cause of inherited colorectal cancer (CRC) and is due to germline mutations in mismatch repair (MMR) genes. Early Lynch syndrome diagnosis and appropriate CRC surveillance improves mortality. Traditional qualitative clinical criteria including Amsterdam and Bethesda guidelines may miss mutation carriers. Recently, quantitative predictive models including MMRPredict, PREMM(1,2,6), and MMRPro were developed to facilitate diagnosis. However, these models remain to be externally validated in the United States. Therefore, we evaluated the test characteristics of Lynch syndrome predictive models in a tertiary referral group at two US academic centers. We retrospectively collected data on 230 consecutive individuals who underwent genetic testing for MMR gene mutations at the University of Chicago and University of California at San Francisco's Cancer Risk Clinics. Each individual's risk of mutation was examined using MMRPredict, PREMM(1,2,6), and MMRPro. Amsterdam and Bethesda criteria were also determined. Testing characteristics were calculated for each of the models. We included 230 individuals in the combined cohort. In all, 113 (49%) probands were MMR mutation carriers. Areas under the receiver operator characteristic curves were 0.76, 0.78, and 0.82 for MMRPredict, PREMM(1,2,6), and MMRPro, respectively. While similar in overall performance, our study highlights unique test characteristics of these three quantitative models including comparisons of sensitivity and specificity. Moreover, we identify characteristics of mutation carriers who were missed by each model. Overall, all three Lynch syndrome predictive models performed comparably in our multi-center US referral population. These results suggest that Lynch syndrome predictive models can be used to screen for MMR mutation carriers and can provide improved test characteristics compared with traditional clinical criteria. Identification of MMR mutation carriers is paramount as appropriate screening can prevent CRC mortality in this high-risk group.


[Updates in osteogenesis imperfecta].
Osteogenesis Imperfecta, a heterogenous group of inherited disorders, is characterized by both bone fragility and low bone mass. Since the Sillence classification of the disease, significant progress has been made in understanding the molecular, histological and genetical pathogenesis of the disease, and it led to expanded nosology. The multidisciplinary approach including rehabilitation, medications and surgery, may significantly improve the quality of life and prolong life expectancy.


Radiation therapy failure in prostate cancer patients: risk factors and methods of detection.
Radiation therapy for clinically localized prostatic carcinoma remains one of the mainstays among therapeutic approaches; however, patients continue to fail radiation therapy at too high a rate. This article reviews the risk factors and methods of detection for prostate cancer recurrence. The relative merits of the three major pre-therapy prognostic indicators-TNM staging, Gleason score, and serum prostate-specific antigen (PSA) levels-are discussed. The use of staging and Gleason score, as well as digital rectal examination, transrectal ultrasound, and post-radiation prostate biopsies in detecting failure of radiation therapy is reviewed. Challenges relating to the use of serum PSA levels as an indicator of recurrence are examined. Finally, this article makes recommendations as to procedure for evaluating patients suspected of failing radiation therapy.


Analysis of 29 cases of pancreatic pseudocyst treated surgically.
Twenty-nine cases of pancreatic pseudocyst requiring operative management were reviewed to determine the method of diagnosis and to analyse the results of internal and external drainage. Pain and the presence of an intra-abdominal mass were the two most common clinical features in the 29 patients. Serum amylase values were elevated in 50%. Diagnosis was confirmed by barium contrast roentgenography and abdominal ultrasonography in 60% of cases. Endoscopic retrograde cholangiopancreatography was a valuable diagnotic technique in four problem cases. The most common form of surgical treatment was internal drainage of the pseudocyst (18 patients). Th mortality resulting from internal drainage was 6% and there was an overall complication rate of 44%. External drainage was carried out in seven patients (six required emergency operation). The mortality associated with external drainage was 43% and the overall complication rate 86%.


Adrenal insufficiency--an unusual cause of shock in postoperative patients.
To remind physicians that adrenal insufficiency can cause postoperative shock and that the manifestations are difficult to distinguish from those of sepsis. We present detailed case reports of three patients who had hyperdynamic shock in the surgical intensive-care unit and describe their response to the cosyntropin stimulation test. All three patients were diagnosed as having adrenal insufficiency with use of the cosyntropin stimulation test. Two of the three patients rapidly recovered; however, because of delay in the diagnosis of adrenal insufficiency, the third patient succumbed to multisystem organ failure. The cases presented highlight the need to exclude adrenal insufficiency as a possible cause of hyperdynamic circulatory shock, particularly when no clear-cut diagnosis exists. Early recognition of adrenal insufficiency is important and can result in reversal of shock and prevention of death. Adrenal insufficiency can be diagnosed through screening random cortisol levels and by use of the cosyntropin stimulation test. Patients in addisonian crisis often respond to the first dose of glucocorticoid with dramatic improvement in blood pressure and systemic vascular resistance. Administration of glucocorticoid can thus lead to improved organ perfusion and recovery of organ function. Delays in diagnosis and treatment of acute hypoadrenalism can have a fatal outcome.


The benefits of values-based recruitment.
Sam Foster, Chief Nurse at Heart of England NHS Foundation Trust, discusses using values-based recruitment when interviewing prospective staff for the NHS.


Catalytic Site Constraints in the P450s Mediating Loganic Acid (7DLH) and Secologanic Acid Synthesis (SLAS) in Camptotheca.
Terpene indole alkaloids (TIAs) are plant-derived natural products synthesized in low levels in medicinal plants such as Catharanthus roseus and Camptotheca acuminata. TIA pathways species utilize several CYP72A subfamily members to form loganic acid from 7-deoxyloganic acid (a simple hydroxylation) as well as secologanin and secologanic acid from loganin and loganic acid (a C-C bond scission). Divergences in the specificities of these P450s have allowed Camptotheca secologanic acid synthases (SLASs) to become bifunctional enzymes capable of performing both reactions. In contrast, Catharanthus 7-deoxyloganic acid hydroxylase (7DLH) and secologanin synthase (SLS) have remained monofunctional enzymes capable either of monooxygenation or C-C bond scission. Our in vitro reconstitutions have now demonstrated that Camptotheca also contains a monofunctional 7DLH capable only of hydroxylating 7-deoxyloganic acid. Mutageneses aimed at evaluating residues important for the tight specificity of Camptotheca 7DLH (CYP72A729) and the broad specificity of SLAS (CYP72A564) have identified several residues where reciprocal switches substantially affect their activities: Lys128His in 7DLH increases hydroxylation of 7-deoxyloganic acid, and His132Lys in SLAS decreases this hydroxylation and C-C bond scissions of loganic acid and loganin; Gly321Ser in 7DLH does not affect hydroxylation of 7-deoxyloganic acid, whereas Ser324Gly in SLAS significantly increases C-C bond scission of loganic acid; Asp332Glu in the acid-alcohol pair of 7DLH increases hydroxylation of 7-deoxyloganic acid, whereas Glu335Asp in SLAS completely eliminates both of its activities. These mutations that enhance or eliminate these respective activities have significant potential to aid engineering efforts aimed at increasing TIA production in cell cultures, microbial systems, and/or other plants.


A Feasibility Study of Pain Neuroscience Education and Exercise for Community-Dwelling Older Adults With Chronic Pain.
Pain prevalence in older adults is high and greatly impacts their functioning. The primary aim of this study was to determine the feasibility of an intervention consisting of pain neuroscience education (PNE) plus exercise for community-dwelling older adults attending primary care, by assessing recruitment rates (inclusion, refusal, and exclusion rates), adverse events, and acceptability of the intervention. Secondary aims were to establish suitable procedures for delivering the intervention and assess the feasibility of data collection for psychosocial and physical functioning. A mixed-methods feasibility study with 2 groups was conducted. One group received 8 weekly 75-minute sessions of PNE plus exercise (PNE+E) and the other received usual care (UC), which consisted of appointments with the general practitioner. Inclusion, refusal, exclusion, and retention rates, dropouts, and adverse events were assessed. The Brief Pain Inventory, the Pain Catastrophizing Scale, the Tampa Scale, the Geriatric Depression Scale, the World Health Organization Disability Assessment Schedule, the 4-meter walk gait speed test and the 5 times sit-to-stand tests were used for assessment. A focus group interview was conducted with participants from the PNE+E group. Descriptive statistics were used for quantitative data and thematic analysis for qualitative data. Of 61 participants recruited, 33 (PNE+E = 22; UC = 11) entered the study, and 24 completed the intervention (PNE+E = 15; UC = 9). The inclusion rate was 54%, the refusal rate was 21%, the exclusion rate was 35%, the dropout rate was 32% in the PNE+E and 18% in the UC, and the retention rate was 68% in the PNE+E group and 82% in the UC group. No adverse events were reported and the intervention was well accepted by participants. Data collection for the clinical outcomes was feasible and results suggested higher improvements in the PNE+E group than in the UC group. PNE+E is possible to implement, safe, and well accepted by community-dwelling older adults independent of their education level. This study informs future studies on practical and methodological strategies that should be considered when designing a PNE+E intervention for older adults, such as adapting the language of the PNE to participants, using relatable metaphors, and encouraging written and exercise homework.


Validation of a measure of excessive drinking: frequency per year that BAL exceeds 0.08%.
Although self-report data are generally evaluated as reliable, validity estimates for self-reported drinking behavior are not as favorable. A new method of measurement addressing problems currently associated with the questionable validity of self-report drinking information is introduced. Study 1 tests the correspondence between the new measure (occasions per year blood alcohol level exceeded 0.08%), traditional self-report measures, and laboratory alcohol consumption. The novel measure correlated most strongly with volume of alcohol consumed in the laboratory compared to the traditional measures. In Study 2 the novel measure was favored over a traditional measure when discriminating between the presence and absence of problem-drinking symptoms.


Glial fibrillary acidic protein is expressed in the aged rat olfactory epithelium.
Our findings suggest that the aging process induces changes in the phenotype of olfactory supporting cells in the rat. To investigate age-related changes in the expression of astroglial intermediate filament proteins in the olfactory supporting cells of the rat. The expression of nestin and glial fibrillary acidic protein (GFAP) in the olfactory epithelium (OE) of young (3 months) and aged (25 months) Sprague-Dawley rats was compared using Western blotting and immunohistochemistry. Western blot analysis showed nestin expression only in the young OE, whereas GFAP was detected only in the aged OE. Immunohistochemistry showed that GFAP was localized in the olfactory supporting cells of the aged OE, with regional differences.


CD301b/MGL2+ Mononuclear Phagocytes Orchestrate Autoimmune Cardiac Valve Inflammation and Fibrosis.
Valvular heart disease is common and affects the mitral valve (MV) most frequently. Despite the prevalence of MV disease (MVD), the cellular and molecular pathways that initiate and perpetuate it are not well understood. K/B.g7 T-cell receptor transgenic mice spontaneously develop systemic autoantibody-associated autoimmunity, leading to fully penetrant fibroinflammatory MVD and arthritis. We used multiparameter flow cytometry, intracellular cytokine staining, and immunofluorescent staining to characterize the cells in inflamed K/B.g7 MVs. We used genetic approaches to study the contribution of mononuclear phagocytes (MNPs) to MVD in this model. Specifically, we generated K/B.g7 mice in which either CX3CR1 or CD301b/macrophage galactose N-acetylgalactosamine-specific lectin 2 (MGL2)-expressing MNPs were ablated. Using K/B.g7 mice expressing Cx3Cr1-Cre, we conditionally deleted critical inflammatory molecules from MNPs, including the Fc-receptor signal-transducing tyrosine kinase Syk and the cell adhesion molecule very late antigen-4. We performed complementary studies using monoclonal antibodies to block key inflammatory molecules. We generated bone marrow chimeric mice to define the origin of the inflammatory cells present in the MV and to determine which valve cells respond to the proinflammatory cytokine tumor necrosis factor (TNF). Finally, we examined specimens from patients with rheumatic heart disease to correlate our findings to human pathology. MNPs comprised the vast majority of MV-infiltrating cells; these MNPs expressed CX3CR1 and CD301b/MGL2. Analogous cells were present in human rheumatic heart disease valves. K/B.g7 mice lacking CX3CR1 or in which CD301b/MGL2-expressing MNPs were ablated were protected from MVD. The valve-infiltrating CD301b/MGL2+ MNPs expressed tissue-reparative molecules including arginase-1 and resistin-like molecule α. These MNPs also expressed the proinflammatory cytokines TNF and interleukin-6, and antibody blockade of these cytokines prevented MVD. Deleting Syk from CX3CR1-expressing MNPs reduced their TNF and interleukin-6 production and also prevented MVD. TNF acted through TNF receptor-1 expressed on valve-resident cells to increase the expression of vascular cell adhesion molecule-1. Conditionally deleting the vascular cell adhesion molecule-1 ligand very late antigen-4 from CX3CR1-expressing MNPs prevented MVD. CD301b/MGL2+ MNPs are key drivers of autoimmune MVD in K/B.g7 mice and are also present in human rheumatic heart disease. We define key inflammatory molecules that drive MVD in this model, including Syk, TNF, interleukin-6, very late antigen-4, and vascular cell adhesion molecule-1.


Myelolipoma of the adrenal gland: sonographic and CT features.
The radiologic findings in 13 patients with pathologically proved adrenal myelolipomas were reviewed. All lesions involved the right adrenal gland; they ranged from 2 to 9 cm in diameter. Sonograms showed hyperechoic tumors in 11 cases (five homogeneous, six heterogeneous). Two myelolipomas composed primarily of myeloid tissue were hypoechoic. A propagation speed artifact was seen in seven lesions, all of which were composed primarily of fat and larger than 4 cm. CT identified fat-density tissues in all lesions. Contrast-enhanced CT showed positive attenuation values in the two predominantly myeloid tumors. CT appears to be sensitive for the diagnosis of adrenal myelolipomas. However, precontrast images are required to avoid errors.


Mechanism of RhoA/Rho kinase activation in endothelin-1- induced contraction in rabbit basilar artery.
This study was undertaken to demonstrate the role of the RhoA/Rho kinase pathway in endothelin-1 (ET-1)-induced contraction of the rabbit basilar artery. Isometric tension and Western blot were used to examine ET-1-induced contraction and RhoA activation. The upstream effect on ET-1-induced RhoA activity was determined by using ET(A) and ET(B) receptor antagonists, protein kinase C (PKC), tyrosine kinase, and phosphatidylinositol-3 kinase inhibitors. The downstream effect of ET-1-induced contraction and RhoA activity was studied in the presence of the Rho kinase inhibitor Y-27632. The effect of Rho kinase inhibitor on ET-1-induced myosin light chain (MLC) phosphorylation was investigated by using urea-glycerol-PAGE immunoblotting. We found 1) ET-1 increased RhoA activity (membrane binding RhoA) in a concentration-dependent manner; 2) ET(A), but not ET(B), receptor antagonist abolished the effect of ET-1 on RhoA activation; 3) phosphodylinositol-3 kinase inhibitor, but not PKC and tyrosine kinase inhibitors, reduced ET-1-induced RhoA activation; 4) Rho kinase inhibitor Y-27632 (10 microM) inhibited ET-1-induced contraction; and 5) ET-1 increased the level of MLC phosphorylation. Rho kinase inhibitor Y-27632 reduced the effect of ET-1 on MLC phosphorylation. This study demonstrated that RhoA/Rho kinase activation is involved in ET-1-induced contraction in the rabbit basilar artery. Phosphodylinositol-3 kinase and MLC might be the upstream and downstream factors of RhoA activation.


A new economic loss assessment system for urban severe rainfall and flooding disasters based on big data fusion.
and Purpose: Increasingly frequent meteorological disasters have brought severe challenges that should be urgently handled in the sustainable development. However, meteorological data, loss data, social economic data and so forth relating to meteorological disasters rarely be effectively fused, failing to generate, rapidly and efficiently, economic losses and thus hindering the emergency management of disasters. A new economic losses evaluation information system has been developed for monitoring severe rainfall and flooding disasters in cities. The data mining method, econometric regression model and input-output model are implemented in the system, on the basis of multi-source data including hourly rainfall, geographical conditions, historical and real-time disaster information, socioeconomic data, and defense countermeasure. Combined with the weather forecast information, this system can has the capability for reporting the real-time direct and indirect economic losses incurred by urban heavy rainfall and flooding disasters, automatically generating defense countermeasure reports for typical rainstorm and flooding points, and providing the spatial distribution of disasters. Finally, the system is conducive to improving the ability to manage disaster emergencies and eventually reducing the economic losses from the disaster.


Polarizable Force Field with a σ-Hole for Liquid and Aqueous Bromomethane.
Bromomethane (CH3Br) is an acutely toxic environmental pollutant that contributes to ozone depletion. Molecular simulation could be a valuable tool for studying its partitioning and transport in the environment if an accurate molecular model was available. The generalized Amber force field (GAFF), OPLS (optimized potentials for liquid simulations) force field, and CHARMM general force field (CGenFF) were tested for their ability to model the physical properties of liquid bromomethane. The OPLS force field was in fairly good agreement with experiment, while CGenFF and GAFF were significantly in error. The Br Lennard-Jones parameters of the GAFF and CGenFF models were reparameterized, but their radial distribution functions still have significant deviations from those calculated by ab initio molecular dynamics (AIMD). A Drude polarizable force field for bromomethane was parametrized with an off-center positively charged site to represent the C-Br σ-hole. This model is in good agreement with the bulk physical properties and the AIMD RDFs. The modest solubility of bromomethane was reproduced by this model, with dispersion interactions being the dominant water-solute interaction. The water-solute electrostatic interactions are a smaller factor in solubility. This model predicts bromomethane to have a 13 kJ mol(-1) surface excess potential at the water-vapor interface.


Insulin action in the brain regulates mitochondrial stress responses and reduces diet-induced weight gain.
Insulin action in the brain controls metabolism and brain function, which is linked to proper mitochondrial function. Conversely, brain insulin resistance associates with mitochondrial stress and metabolic and neurodegenerative diseases. In the present study, we aimed to decipher the impact of hypothalamic insulin action on mitochondrial stress responses, function and metabolism. To investigate the crosstalk of insulin action and mitochondrial stress responses (MSR), namely the mitochondrial unfolded protein response (UPRmt) and integrated stress response (ISR), qPCR, western blotting, and mitochondrial activity assays were performed. These methods were used to analyze the hypothalamic cell line CLU183 treated with insulin in the presence or absence of the insulin receptor as well as in mice fed a high fat diet (HFD) for three days and STZ-treated mice without or with insulin therapy. Intranasal insulin treatment was used to investigate the effect of acute brain insulin action on metabolism and mitochondrial stress responses. Acute HFD feeding reduces hypothalamic mitochondrial stress responsive gene expression of Atf4, Chop, Hsp60, Hsp10, ClpP, and Lonp1 in C57BL/6N mice. We show that insulin via ERK activation increases the expression of MSR genes in vitro as well as in the hypothalamus of streptozotocin-treated mice. This regulation propagates mitochondrial function by controlling mitochondrial proteostasis and prevents excessive autophagy under serum deprivation. Finally, short-term intranasal insulin treatment activates MSR gene expression in the hypothalamus of HFD-fed C57BL/6N mice and reduces food intake and body weight development. We define hypothalamic insulin action as a novel master regulator of MSR, ensuring proper mitochondrial function by controlling mitochondrial proteostasis and regulating metabolism.


In vitro and in vivo evaluations of dihydroquinoline- and dihydroisoquinoline-based targetor moieties for brain-specific chemical delivery systems.
Brain-targeted delivery of various drugs can be successfully achieved by chemical delivery systems (CDS) that contain a 1,4-dihydropyridine-based redox targetor moiety and undergo a sequential metabolism. However, the susceptibility of this moiety toward hydration in acidic media may limit the shelf-life of such compounds in aqueous formulation. Here, a systematic investigation of the chemical stability toward oxidation and hydration of ester and amide derivatives of 3-substituted 1,4-dihydropyridine, 1,4-dihydroquinoline, and 4-substituted 1,2-dihydroisoquinoline is reported, together with the in vitro stability and in vivo (rat) distribution of isoquinoline-based testosterone and hydrocortisone chemical delivery systems, which were selected as having the most suitable acid-resistant targetor moieties.


Advances in Imaging and Automated Quantification of Malignant Pulmonary Diseases: A State-of-the-Art Review.
Quantitative imaging in lung cancer is a rapidly evolving modality in radiology that is changing clinical practice from a qualitative analysis of imaging features to a more dynamic, spatial, and phenotypical characterization of suspected lesions. Some quantitative parameters, such as the use of 18F-FDG PET/CT-derived standard uptake values (SUV), have already been incorporated into current practice as it provides important information for diagnosis, staging, and treatment response of patients with lung cancer. A growing body of evidence is emerging to support the use of quantitative parameters from other modalities. CT-derived volumetric assessment, CT and MRI lung perfusion scans, and diffusion-weighted MRI are some of the examples. Software-assisted technologies are the future of quantitative analyses in order to decrease intra- and inter-observer variability. In the era of "big data", widespread incorporation of radiomics (extracting quantitative information from medical images by converting them into minable high-dimensional data) will allow medical imaging to surpass its current status quo and provide more accurate histological correlations and prognostic value in lung cancer. This is a comprehensive review of some of the quantitative image methods and computer-aided systems to the diagnosis and follow-up of patients with lung cancer.


Antioxidant activities and phenolics profiling of different parts of Carica papaya by LCMS-MS.
This article deals with the comparison of the antioxidant activity of aqueous extracts of various parts of Carica papaya L. The evaluation of total phenolic content and total flavonoid content revealed high antioxidant potential of the seeds and fruits. The free radical-scavenging potential of the aqueous extracts indicated the seeds to have better DPPH-scavenging activity than fruits. The results were augmented by the FRAP activity as well. The phenolics present in the extracts were separated and identified as 5-hydroxy feruloyl quinic acid, acetyl p-coumaryl quinic acid, quercetin-3-O-rhamnoside, syringic acid hexoside, 5-hydroxy caffeic quinic acid, peonidin-3-O-glucoside, sinapic acid-O-hexoside, cyaniding-3-O-glucose and methyl feruloyl glycoside by LCMS-MS technique.


HMGB1 siRNA can reduce damage to retinal cells induced by high glucose in vitro and in vivo.
Diabetic retinopathy (DR), one of the most common complications of late-phase diabetes, is associated with many risk factors, among which continuous low-grade inflammation is one of the principal ones. As such, lowering inflammation levels and maintain the viability of human retinal endothelial cells (HRECs) are critical for DR therapy. HMGB1 is a well-known proinflammatory cytokine. However, whether HMGB1 small interfering RNA (siRNA) can protect retina cells under a high-glucose environment from morphological changes and functional abnormalities remain undetermined. We aimed to investigate the effect of HMGB1 siRNA on retinal cells in DR. A total of 80 adult Wistar rats were randomly divided into four groups (n=20 each): normal control, diabetes mellitus (DM), scrambled (Scr) siRNA, and HMGB1 siRNA. Rats in the DM, Scr siRNA, and siRNA groups were established by intraperitoneal injection of streptozotocin. At 16 weeks after injection, rats in the siRNA and Scr-siRNA groups were intravitreally injected with 2 μL HMGB1 siRNA and 2 μL Scr-siRNA, while rats in the control and DM groups were intravitreally injected with the same dose of sterile saline. At 1 week after injections, we performed the following experiments. Immunohistochemical staining and real-time quantitative polymerase chain reaction were performed to test HMGB1 protein and messenger RNA expression in retinas. We performed TUNEL assays to detect retinal cell apoptosis and electroretinography to detect retinal function. In HRECs treated with high glucose, proliferation, morphology, apoptosis, super-oxide dismutase (SOD), and reactive oxygen species production were detected. Western blot was applied to determine the expressions of HMGB1 and its related protein and apoptosis protein. Intravitreal injection of HMGB1 siRNA reduced protein and messenger RNA expression of HMGB1 (both P<0.05). Intravitreal injection of HMGB1 siRNA reduced apoptosis of retinal cells (P<0.05), protected morphological changes in the retina, and improved the function of the retina (P<0.05). In HRECs treated with high glucose, HMGB1 siRNA pretreatment increased cell viability, reduced cell apoptosis, and reduced oxidative damage to cells (all P<0.05). Western blot detection found that HMGB1 siRNA pretreatment can inhibit the expression of cleaved caspase 3 and improve the expression of BCL2 (P<0.05). HMGB1 and NFκB expression increased in a time-dependent manner in the high-glucose environment and IKKβ and NFκB protein expression decreased significantly after HMGB1 silencing. As a therapeutic target, HMGB1 siRNA can reduce retinal cell damage induced by high glucose in vitro and in vivo and delay DR progress through the HMGB1-IKKβ-NFκB signaling pathway.


Effect of nitric oxide synthase inhibitors and molsidomine on the anticonvulsant activity of some antiepileptic drugs.
The present study examined effects of the two nitric oxide synthase (NOS) inhibitors, N-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), as well as of the NO donor molsidomine on the anticonvulsant activity of conventional antiepileptic drugs (diphenylhydantoin and carbamazepine) and competitive (CGP 37,849) and non-competitive (dizocilpine) NMDA receptor antagonists against the maximal electroshock in mice. It was found that L-NAME (25 and 50 mg/kg) did not affect the anticonvulsant activity of either drug, having had no influence on their anticonvulsive ED50 values. 7-NI (50 and 100 mg/kg) reduced the anticonvulsive ED50 (augmentation of the anticonvulsant activity) of CGP 37,849 and dizocilpine, raised the anticonvulsive ED50 (attenuation of the anticonvulsant activity) of diphenylhydantoin and had no influence on the anticonvulsant effect of carbamazepine. At the same time, augmentation of the anticonvulsant activity (reduction of the ED50 values) of diphenylhydantoin, carbamazepine and CGP 37,849, but not of dizocilpine, was observed after molsidomine (100-150 mg/kg). Moreover, 7-NI (100 mg/kg) and molsidomine (100 and 150 mg/kg), but not L-NAME (25 and 50 mg/kg), raised the threshold for electroconvulsions. The obtained results indicate that alterations in the anticonvulsant activity of the investigated drugs evoked by 7-NI and mosidomine, may result from non-specific effects of the NOS inhibitor and the NO donor, having no connection with the brain NO pathway.


Oxygen-Defective Ultrathin BiVO4 Nanosheets for Enhanced Gas Sensing.
BiVO4 nanomaterials are potentially applicable in gas sensing, but the sensing performance is limited by the less active sites on the BiVO4 surface. In this work, we propose a strategy to improve the gas-sensing performance of BiVO4 by forming ultrathin nanosheets and introducing oxygen vacancies, which increase the surface active sites. Two-dimensional (2D) BiVO4 nanosheets with oxygen vacancies are prepared through a colloidal method with the assistance of nitric acid. Gas sensors based on the oxygen-defective 2D ultrathin BiVO4 nanosheets exhibit an enhanced sensing response, which is 3.4 times higher than those of the sensors based on oxygen-abundant BiVO4 nanosheets. The density functional theory calculation is employed to uncover the promoting effects of oxygen vacancies on enhancing the O2 adsorption capability of BiVO4 nanosheets. This work is not only expected to build a wide range of 2D metal oxide semiconductors with a high gas-sensing performance but also gives an insight into the mechanism of the enhanced response induced by the oxygen vacancies, which will be a guideline for further designing high-performance sensing materials.


Experimental investigation of pulsatile flows in tubes.
Based on cam-piston-valve arrangement, a mechanical pulsatile flow generator is designed to investigate sinusoidal flow and other types of pulsatile flow in straight rigid tube. Measurement reveals the relation between pressure gradient and flow rate. Numerical simulation using the k-epsilon turbulence model are carried out to compare the pulsatile flow produced by the generator with a sinusoidal flow and a physiological flow in a rigid tube. The results show that the pulsatile flow generated has similar dynamic properties to the physiological flow. Hence, the present setup can be used for in-vitro investigation of biofluid phenomena.


Primary epithelioid hemangioendothelioma of the eyelid: A case report.
Eyelid epithelioid hemangioendothelioma (EHE) is uncommon. The present study reports the clinical, histopathological and immunohistochemical characteristics of a 10-year-old girl with EHE and reviews the related literature. The patient was admitted with a painless red mass on the left eyelid, which had been present for 6 months. Under the microscope, tumor cells from the surgical specimen were composed of epithelioid cells (70%) and spindle cells (30%). The cytoplasm was eosinophilic, and some areas of the cytoplasm showed signet ring-like or vacuolization changes. The presence of red blood cells could be seen in the luminal part of the primary blood vessel. Immunohistochemical results showed that the tumor cells were positive for CD34 and CD31, and the Ki-67 proliferation index was 3%. As the first resection margin was positive, recurrence occurred 3 months after surgery, Therefore, patients with such tumors should undergo full resections to ensure a negative margin to prevent recurrence.


Cross-Feeding between Members of Thauera spp. and Rhodococcus spp. Drives Quinoline-Denitrifying Degradation in a Hypoxic Bioreactor.
The complex bacterial community in a quinoline-degrading denitrifying bioreactor is predominated by several taxa, such as Thauera and Rhodococcus However, it remains unclear how the interactions between the different bacteria mediate quinoline metabolism under denitrifying conditions. In this study, we designed a sequence-specific amplification strategy to isolate the most predominant bacteria and obtained four strains of Thauera aminoaromatica, a representative of a key member in the bioreactor. Tests on these isolates demonstrated that all were unable to degrade quinoline but efficiently degraded 2-hydroxyquinoline, the hypothesized primary intermediate of quinoline catabolism, under nitrate-reducing conditions. However, another isolate, Rhodococcus sp. YF3, corresponding to the second most abundant taxon in the same bioreactor, was found to degrade quinoline via 2-hydroxyquinoline. The end products and removal rate of quinoline by isolate YF3 largely varied according to the quantity of available oxygen. Specifically, quinoline could be converted only to 2-hydroxyquinoline without further transformation under insufficient oxygen conditions, e.g., less than 0.5% initial oxygen in the vials. However, resting YF3 cells aerobically precultured in medium with quinoline could anaerobically convert quinoline to 2-hydroxyquinoline. A two-strain consortium constructed with isolates from Thauera (R2) and Rhodococcus (YF3) demonstrated efficient denitrifying degradation of quinoline. Thus, we experimentally verified that the metabolic interaction based on 2-hydroxyquinoline cross-feeding between two predominant bacteria constitutes the main quinoline degradation mechanism. This work uncovers the mechanism of quinoline removal by two cooperative bacterial species existing in denitrifying bioreactors.IMPORTANCE We experimentally verified that the second most abundant taxon, Rhodococcus, played a role in degrading quinoline to 2-hydroxyquinoline, while the most abundant taxon, Thauera, degraded 2-hydroxyquinoline. Metabolites from Thauera further served to provide metabolites for Rhodococcus Hence, an ecological guild composed of two isolates was assembled, revealing the different roles that keystone organisms play in the microbial community. This report, to the best of our knowledge, is the first on cross-feeding between the initial quinoline degrader and a second bacterium. Specifically, the quinoline degrader (Rhodococcus) did not benefit metabolically from quinoline degradation to 2-hydroxyquinoline but instead benefited from the metabolites produced by the second bacterium (Thauera) when Thauera degraded the 2-hydroxyquinoline. These results could be a significant step forward in the elucidation of the microbial mechanism underlying quinoline-denitrifying degradation.


Unfolding spatiotemporal dynamics through symmetry reduction based on orbit topology.
Understanding key patterns in a spatially extended system is an essential task of modern physics of complex systems. Just like in low-dimensional nonlinear systems, here we show that orbit topology plays a critical role even for the investigation of spatiotemporal dynamics. First, we design a new scheme to reduce possible continuous symmetries that are prevailing in these systems based on topological consideration. The scheme is successfully demonstrated in the well-known pattern formation systems. Interesting bifurcation routes to chaos are conveniently revealed after symmetry reduction. In particular, we find that near the onset of turbulent dynamics, with an increase of instability, local phase chaos with the same spatial topological index may merge into more complex ones, while those with different indices induce defect chaos necessarily through connections docked with defects. The topological argument is so strong that the scenario presented here should be omnipresent in diverse systems.


"I'm not just a heart, I'm a whole person here": a qualitative study to improve sexual outcomes in women with myocardial infarction.
Little is known about recovery of female sexual function following an acute myocardial infarction (MI). Interventions to improve sexual outcomes in women are limited. Semistructured, qualitative telephone interviews were conducted with 17 partnered women (aged 43 to 75 years) purposively selected from the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status Registry to deepen knowledge of recovery of female sexual function following an acute myocardial infarction (MI) and to improve sexual outcomes in women. Sixteen women had a monogamous relationship with a male spouse; 1 had a long-term female partner. Most women resumed sexual activity within 4 weeks of their MI. Sexual problems and concerns were prevalent, including patient and/or partner fear of "causing another heart attack." Few women received counseling about sexual concerns or the safety of returning to sex. Most women who discussed sex with a physician initiated the discussion themselves. Inquiry about strategies to improve sexual outcomes elicited key themes: need for privacy, patient-centeredness, and information about the timing and safe resumption of sexual activity. In addition, respondents felt that counseling should be initiated by the treating cardiologist, who "knows whether your heart is safe," and then reinforced by the care team throughout the rehabilitation period. Partnered women commonly resume sexual activity soon after an MI with fear but without directed counseling from their physicians. Proactive attention to women's concerns related to sexual function and the safety of sexual activity following an MI could improve post-MI outcomes for women and their partners.


Analysis of anesthesia-controlled operating room time after propofol-based total intravenous anesthesia compared with desflurane anesthesia in functional endoscopic sinus surgery.
Anesthesia technique may contribute to the improvement of operation room (OR) efficiency by reducing anesthesia-controlled time. We compared the difference between propofol-based total intravenous anesthesia (TIVA) and desflurane anesthesia (DES) for functional endoscopic sinus surgery (FESS) undergoing general anesthesiaWe performed a retrospective study using data collected in our hospital to compare the anesthesia-controlled time of FESS using either TIVA via target-controlled infusion with propofol/fentanyl or DES/fentanyl-based anesthesia between January 2010 and December 2011. The various time intervals (surgical time, anesthesia time, extubation time, total OR stay time, post anesthesia care unit [PACU] stay time) and the percentage of prolonged extubation were compared between the 2 anesthetic techniques.We included data from 717 patients, with 305 patients receiving TIVA and 412 patients receiving DES. An emergence time >15 minutes is defined as prolonged extubation. The extubation time was faster (8.8 [3.5] vs. 9.6 [4.0] minutes; P = .03), and the percentage of prolonged extubation was lower (7.5% vs. 13.6%, risk difference 6.1%, P < .001) in the TIVA group than in the DES group. However, there was no significant difference between ACT, total OR stay time, and PACU stay time.In our hospital, propofol-based TIVA by target-controlled infusion provide faster emergence and lower chance of prolonged extubation compared with DES anesthesia in FESS. However, the reduction in extubation time may not improve OR efficiency.


Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages.
Tuberculosis, caused by the intracellular pathogen Mycobacterium tuberculosis, remains the world's deadliest infectious disease. Sterilizing chemotherapy requires at least 6 months of multidrug therapy. Difficulty visualizing the subcellular localization of antibiotics in infected host cells means that it is unclear whether antibiotics penetrate all mycobacteria-containing compartments in the cell. Here, we combined correlated light, electron, and ion microscopy to image the distribution of bedaquiline in infected human macrophages at submicrometer resolution. Bedaquiline accumulated primarily in host cell lipid droplets, but heterogeneously in mycobacteria within a variety of intracellular compartments. Furthermore, lipid droplets did not sequester antibiotic but constituted a transferable reservoir that enhanced antibacterial efficacy. Thus, strong lipid binding facilitated drug trafficking by host organelles to an intracellular target during antimicrobial treatment.


Conservative treatment of cervical pregnancy by curettage and local prostaglandin injection.
Recently, various conservative regimens for the treatment of cervical pregnancy have been introduced to preserve fertility in young women, with methotrexate being one of the most widely used drugs. The success of conservative treatment depends on early preoperative diagnosis. We report three cases of first trimester cervical pregnancy, successfully treated by curettage to evacuate the conceptus, followed by local prostaglandin instillation to prevent severe haemorrhage. In one patient, intra-amniotic instillation of hyperosmolar glucose was necessary to terminate fetal cardiac activity. beta-Human chorionic gonadotrophin returned to normal within 3 weeks in one patient and within 7 weeks in another, both of whom became pregnant again within 1 year, resulting in term deliveries. The third patient was lost to follow-up after 1 week. The advantage of prostaglandin and curettage is the absence of major side-effects to the mother or the fetus of a subsequent pregnancy. The management strategies used in the treatment of cervical pregnancies and the results obtained since the introduction of methotrexate in 1989 are discussed in the context of previously published literature. The incidence of subsequent pregnancies among women treated medically versus women treated surgically is reported.


Cancer disparities among Alaska native people, 1970-2011.
Cancer is the leading cause of death among Alaska Native people. The objective of this study was to examine cancer incidence data for 2007-2011, age-specific rates for a 15-year period, incidence trends for 1970-2011, and mortality trends for 1990-2011. US data were from the Surveillance, Epidemiology, and End Results (SEER) Program SEER*Stat database and from the SEER Alaska Native Tumor Registry. Age-adjusted cancer incidence rates among Alaska Native people and US whites were compared using rate ratios. Trend analyses were performed using the Joinpoint Regression Program. Mortality data were from National Center for Health Statistics. During 2007-2011 the cancer incidence rate among Alaska Native women was 16% higher than the rate among US white women and was similar among Alaska Native men and US white men. Incidence rates among Alaska Native people exceeded rates among US whites for nasopharyngeal, stomach, colorectal, lung, and kidney cancer. A downward trend in colorectal cancer incidence among Alaska Native people occurred from 1999 to 2011. Significant declines in rates were not observed for other frequently diagnosed cancers or for all sites combined. Cancer mortality rates among Alaska Native people during 2 periods, 1990-2000 and 2001-2011, did not decline. Cancer mortality rates among Alaska Native people exceeded rates among US whites for all cancers combined; for cancers of the lung, stomach, pancreas, kidney, and cervix; and for colorectal cancer. Increases in colorectal screening among Alaska Native people may be responsible for current declines in colorectal cancer incidence; however; improvements in treatment of colon and rectal cancers may also be contributing factors.


Sleep-disordered breathing as presenting manifestation of Chiari type I malformation: a case report.
Chiari Type I malformation (CM-I) is a rare disorder with displaced cerebellar tonsils through foramen magnum. Here we present a 30-year-old man with severe central and obstructive sleep apneas as presenting manifestations of CM-I. The patient underwent neurosurgery and the follow-up polysomnography revealed the resolution of central apnea while obstructive apnea remained unchanged. Central sleep apnea (CSA) could be associated with an underlying pathology; thus, further investigation is recommended in affected subjects.


Correlation between patient and visitor violence and workload among public healthcare workers in China: a cross-sectional study.
We studied the characteristics of patient and visitor violence (PVV) and the workload of doctors and nurses, and identified the correlation between the incidence of PVV and healthcare worker (HCW) workload in China. Cross-sectional study. 288 public health institutions in a city in northern China. Data on 87 998 HCWs were extracted from the 2015 database of the Medical Quality and Safety Notification System. The data included characteristics of the healthcare institution, types of services provided, information about each complaint and reported PVV incidents by hospital level. Pearson correlation analysis and multiple linear regression modelling were used to identify the correlation between the incidence of PVV and HCW workload. Three types of institutions were identified as being at particularly high risk for PVV: tertiary hospitals, specialised hospitals and institutions in a downtown district. Incidence rates of PVV at tertiary hospitals, specialised hospitals and institutions in a downtown district were 16.6%, 17.6% and 22.8%, respectively. All three types of institutions had a high inpatient workload (admissions per doctor per day): 0.15, 0.17 and 0.12, respectively. After controlling for scale, type and location, it was found that the overall incidence rate of PVV increased with increasing outpatient workload (β=0.236, p<0.01). PVV poses a significant challenge to public health institutions in China, and the high workload of HCWs likely contributes to higher risk of PVV. Prevention and intervention of PVV may be targeted to HCWs at specific institutions. The patient complaint notification system needs improvement and could be, for example, a better source of PVV information for future interventions.


Levels of serum biomarkers from a two-year multicentre trial are associated with treatment response on knee osteoarthritis cartilage loss as assessed by magnetic resonance imaging: an exploratory study.
There is an obvious need to identify biomarkers that could predict patient response to an osteoarthritis (OA) treatment. This post hoc study explored in a 2-year randomized controlled trial in patients with knee OA, the likelihood of some serum biomarkers to be associated with a better response to chondroitin sulfate in reducing cartilage volume loss. Eight biomarkers were studied: hyaluronic acid (HA), C reactive protein (CRP), adipsin, leptin, N-terminal propeptide of collagen IIα (PIIANP), C-terminal crosslinked telopeptide of type I collagen (CTX-1), matrix metalloproteinase-1 (MMP-1), and MMP-3. Patients were treated with chondroitin sulfate (1200 mg/day; n = 57) or celecoxib (200 mg/day; n = 62). Serum biomarkers were measured at baseline. The cartilage volume at baseline and its loss at 2 years were assessed by quantitative magnetic resonance imaging (MRI). Statistical analysis included analysis of covariance. As data from the original MOSAIC trial showed no differences in cartilage volume and loss in the lateral compartment of the knee joint between the two treatment groups in any comparison, only the medial compartment and its subregions were studied. Stratification according to the median biomarker levels was used to discriminate treatment effect. In patients with levels of biomarkers of inflammation (HA, leptin and adipsin) lower than the median, those treated with chondroitin sulfate demonstrated less cartilage volume loss in the medial compartment, condyle, and plateau (p ≤ 0.047). In contrast, patients treated with chondroitin sulfate with higher levels of MMP-1 and MMP-3, biomarkers of cartilage catabolism, had less cartilage volume loss in the medial compartment, condyle, and plateau (p ≤ 0.050). Patients with higher levels of PIIANP and CTX-1, biomarkers related to collagen anabolism and bone catabolism, respectively, had reduced cartilage volume loss in the medial condyle (p ≤ 0.026) in the chondroitin sulfate group. This study is suggestive of a potentially greater response to chondroitin sulfate treatment on cartilage volume loss in patients with knee OA with low level of inflammation and/or greater level of cartilage catabolism. This is a post hoc study. Original trial registration: ClinicalTrials.gov, NCT01354145 . Registered on 13 May 2011.


The age discrimination in employment act: a review of court decisions.
Over 600 federal court cases filed between 1970 and 1986 were reviewed in an attempt to discover the major themes and issues. Over all personnel decisions the employer was consistently favored (65%). Performance evidence was central to all cases reviewed. Subjective appraisals were often presented by management and were not considered suspect by the courts. Evidence of management's concern over the age of the workforce (e.g., economic costs and stereotypic beliefs) was also probative. Statistical evidence was presented in a majority of cases. However, inaccurate data and inappropriate comparisons negated its value. Most cases involved a termination or reduction in workforce decision (54%), but the most controversial area involved BFOQ's. A three-part sequential inquiry was proposed that would attempt to clear up these issues. Recent legal refinements may ease the plaintiff's burden in establishing a prima facie case of discrimination. Current techniques from the fields of industrial gerontology and industrial psychology may help clarify inconsistencies in court decisions.


Advances in the Development of PET Ligands Targeting Histone Deacetylases for the Assessment of Neurodegenerative Diseases.
Epigenetic alterations of gene expression have emerged as a key factor in several neurodegenerative diseases. In particular, inhibitors targeting histone deacetylases (HDACs), which are enzymes responsible for deacetylation of histones and other proteins, show therapeutic effects in animal neurodegenerative disease models. However, the details of the interaction between changes in HDAC levels in the brain and disease progression remain unknown. In this review, we focus on recent advances in development of radioligands for HDAC imaging in the brain with positron emission tomography (PET). We summarize the results of radiosynthesis and biological evaluation of the HDAC ligands to identify their successful results and challenges. Since 2006, several small molecules that are radiolabeled with a radioisotope such as carbon-11 or fluorine-18 have been developed and evaluated using various assays including in vitro HDAC binding assays and PET imaging in rodents and non-human primates. Although most compounds do not readily cross the blood-brain barrier, adamantane-conjugated radioligands tend to show good brain uptake. Until now, only one HDAC radioligand has been tested clinically in a brain PET study. Further PET imaging studies to clarify age-related and disease-related changes in HDACs in disease models and humans will increase our understanding of the roles of HDACs in neurodegenerative diseases.


Exploration of the growth process of ultrathin silica shells on the surface of gold nanorods by the localized surface plasmon resonance.
Ultrathin silica coating (UTSC) has emerged as an effective way to improve the compatibility and stability of nanoparticles without attenuating their intrinsic optical properties. Exploration strategies to probe the growth process of ultrathin silica shells on the surface of nanoparticles would represent a valuable innovation that would benefit the development of ultrathin silica coated nanoparticles and their relevant applications. In this work, we report a unique, very effective and straightforward strategy for probing the growth of ultrathin silica shells on the surface of gold nanorods (Au NRs), which exploits the localized surface plasmon resonance (LSPR) as a reporting signal. The thickness of the ultrathin silica shells on the surface of Au NRs can be quantitatively measured and predicted in the range of 0.5-3.5 nm. It is demonstrated that the LSPR shift accurately reflects the real-time change in the thickness of the ultrathin silica shells on Au NRs during the growth process. By using the developed strategy, we further analyze the growth of UTSC on the surface of Au NRs via feeding of Na2SiO3 in a stepwise manner. The responsiveness analysis of LSPR also provides important insight into the shielding effect of UTSC on the surface of Au NRs that is not accessible with conventional strategies. This LSPR-based strategy permits exploration of the surface-mediated sol-gel reactions of silica from a new point of view.


Chronic treatment with electroconvulsive shock may modulate the immune function of macrophages.
To determine the effect of single and chronic electroconvulsive shock (ECS) administration on the immunoregulatory functions of macrophages. Male Wistar rats received single or chronic treatment with ECS (150 mA, 50 Hz, 0.5 seconds) delivered through ear clips, once a day for 10 consecutive days, or sham ECS administered likewise. The rats were killed 24 hours after the last treatment, and peritoneal macrophages were cultured in vitro for 3 or 36 hours for a subsequent determination of their metabolic activity. The ability of macrophages to reduce Alamar Blue, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), and nitrotetrazolium blue chloride and pinocytosis, adherence, and vitality, as well as synthesis of nitric oxide and arginase activity, was assessed. We found statistically significant changes in the biological properties of macrophages which occurred after 36 hours of incubation, especially in cultures stimulated with lipopolysaccharide; in contrast, no differences were observed between groups assessed after 3 hours of incubation. Rats receiving chronic 10-fold ECS showed a substantial increase in the metabolic activity of macrophages, reflected as their ability to reduce Alamar Blue and MTT and to increase arginase activity, accompanied with a marked but statistically insignificant decrease in nitric oxide synthesis compared with respective controls. Our results suggest that chronic treatment with ECS may induce long-lasting changes in the activity of peritoneal macrophages. Attenuation of their proinflammatory properties indicates that ECS can change the primarily immunoregulatory functions of macrophages.


Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families.
Spinocerebellar ataxia type 15 (SCA15) is a progressive neurodegenerative disorder characterized by pure cerebellar ataxia, very slow progression, and distinct cerebellar atrophy. The locus for SCA15 was first mapped to 3p24.2-3pter in an Australian family. We have subsequently mapped two Japanese families presenting with ataxia and postural tremor of the head, arm, or trunk to the SCA15 locus. Recently, partial deletions involving both the type 1 inositol 1,4,5-triphosphate receptor (ITPR1) and sulfatase modifying factor 1 (SUMF1) genes have been identified in Australian and British families with SCA15. We conducted fine haplotype analysis on the region including ITPR1. To identify the deletion, we conducted gene dosage analysis and array-based comparative genomic hybridization (aCGH) analysis. Gene expression analysis was performed using quantitative real-time reverse transcription PCR. Mutational analyses of ITPR1 and SUMF1 were also performed. We have identified a 414-kb deletion including the entire ITPR1 and exon 1 of SUMF1 in patients in family A. The expression levels of ITPR1 and SUMF1 mRNAs of the patient were half those of the normal control. Furthermore, in family B, we have identified a C-to-T substitution at position 8581 of ITPR1, resulting in the amino acid substitution of leucine for proline at codon 1059, which is highly conserved among species. Our results strongly confirm that ITPR1 is the causative gene for SCA15 and suggest that we need to investigate the point mutation in ITPR1 in the patients with autosomal dominant cerebellar ataxia and tremor.


Cell type-selective targeted delivery of a recombinant lysosomal enzyme for enzyme therapies.
Lysosomal diseases are a class of genetic disorders predominantly caused by loss of lysosomal hydrolases, leading to lysosomal and cellular dysfunction. Enzyme replacement therapy (ERT), where recombinant enzyme is given intravenously, internalized by cells, and trafficked to the lysosome, has been applied to treat several lysosomal diseases. However, current ERT regimens do not correct disease phenotypes in all affected organs because the biodistribution of enzyme uptake does not match that of the affected cells that require the enzyme. We present here targeted ERT, an approach that utilizes antibody-enzyme fusion proteins to target the enzyme to specific cell types. The antibody moiety recognizes transmembrane proteins involved in lysosomal trafficking and that are also preferentially expressed in those cells most affected in disease. Using Pompe disease (PD) as an example, we show that targeted ERT is superior to ERT in treating the skeletal muscle phenotypes of PD mice both as a protein replacement therapeutic and as a gene therapy.


[Hypertension and arteriopathy].
High blood pressure as other factors of atherosclerosis is a well-known risk factor for development of peripheral arterial disease. A patient characterized by an isolated systolic hypertension and a low ankle/arm systolic blood pressure ratio very often presents coronary heart disease. Practising exercise (such as walking), stoping smoking and following an adapted diet are recommended. Hypertension treatment must be considered as a secondary prevention approach with a blood pressure normalisation as a target. All the different classes of antihypertensive drugs can be used, but with a marked preference for angiotensin converting enzyme (with caution for the renal artery stenosis risk) and for betablockers to improve the potential coronary heart disease (care is needed in the presence of severe peripheral arterial disease).


Wheat Alkylresorcinols Modulate Glucose Homeostasis through Improving GLP-1 Secretion in High-Fat-Diet-Induced Obese Mice.
Wheat alkylresorcinols (ARs) consumption has been evidenced to improve obesity and its associated insulin resistance. However, the effect of ARs on glucagon-like peptide 1 (GLP-1) secretion and the underlying mechanism of action are still unclear. In this study, C57BL/6J mice were fed low-fat diet (LFD), high-fat diet (HFD), and HFD supplemented with 0.4% (w/w) ARs separately for 9 weeks. The results showed that ARs intervention significantly improved glucose homeostasis and restored the serum level of GLP-1 compared with the HFD control group. Moreover, ARs treatment alleviated HFD-induced ileal epithelium damage according to TUNEL staining, immunofluorescence, and transmission electron microscopy observation. The alleviative effect was further verified by apoptosis analysis and mitochondrial function evaluation. Furthermore, palmitic acid (PA) was administered to the intestinal secretin tumor cell line (STC-1) to clarify the protective effect of ARs on GLP-1 secretion in vitro. In consistence with the results of animal studies, ARs treatment could significantly improve GLP-1 secretion in STC-1 cells compared with PA treatment alone in a dose-dependent manner, accompanied by a reduction in apoptosis and mitochondrial dysfunction. In addition, ARs treatment notably enhanced the abundance of SCFA (short-chain fatty acid)-producing bacteria, such as Bacteroides, Bifidobacterium, and Akkermansia. The increased levels of intestinal SCFAs, such as acetic acid, propionic acid, and butyric acid, improved the expression of short-chain fatty acid receptors (FFAR3) and glucagon-like peptide-1 receptor (GLP-1R), enhancing the secretion of the intestinal hormones GLP-1. Thus, this study provides potential clinical implications of whole wheat as a dietary strategy to improve glucose homeostasis for obese populations.


Control models of cell cycle transit, exit, and arrest.
Several distinct cycles mediate the events which occur between one cell division and the next. In micro-organisms there are generally two cycles. One governs biomass growth, the other DNA synthesis and cell division. In higher eukaryotes there can be as many as four distinct cycles, with growth, DNA synthesis, cell division, and nuclear division each possessing its own functional sequence of events. These cycles are controlled and coordinated by several different regulatory mechanisms. Restriction points are specific steps in the cycle whose completion is governed by external regulatory agents. One set of restriction points requires nutrients and growth hormones for step completion. Another set serves as receptors for differentiating factors which cause cycle arrest and initiate cellular differentiation. There is currently a debate as to whether restriction point inhibition involves permanent arrest or temporary arrest with a stochastic arrested-state residence time controlled by a transition probability mechanism. Tissue sizing is a process of negative feedback inhibition mediated by intercellular communication via cell surface contact and the extracellular matrix. Sizers commonly operate throughout broad portions of the cycle and appear to cause a slowing of cycle transit velocity rather than arrest. Sizers are probably the major regulatory mechanism for cell growth under conditions of nutrient and growth factor excess. They also generate compensatory proliferation following wounding or cell death. A growing body of evidence suggests that both the transit velocity, with which cells move through their several cycles, and the coordination of the cycles are controlled by intracellular regulatory mechanisms which behave as biological oscillators. These oscillators trigger complex sequences of events such as DNA synthesis and cell division.


The effects of two different periods of weight-reduction on selected performance parameters in elite lightweight oarswomen.
Six successful members of the British Women's Lightweight Rowing Team were assessed before and after two-month (1990) and four-month (1991) periods of weight-reduction controlled by reduced caloric intake, while engaged in their normal physical training. Fat free mass (FFM) was calculated from body weight (BW) by utilising total body potassium measurements. Maximal oxygen intake (VO2max), respiratory anaerobic threshold (Tvent), upper body anaerobic peak power (PP) and mean power (MP) outputs, and knee flexor (KF) and extensor (KE) isokinetic peak torques were among the physiological parameters assessed. No statistical differences were noted between the data obtained prior to the two weight-reduction periods, and both periods resulted in lower BW (p < 0.001) and FFM (p < 0.05); approximately 50% of the lost BW was FFM. At the end of the two-month weight-reduction period Tvent (p < 0.02) and KF (p < 0.02) decreased. In contrast, a similar BW loss during the four-month period was associated with higher VO2max (p < 0.01) and PP (p < 0.05) compared with values prior to weight reduction. Comparisons between the percentage changes pre to post BW loss showed that the longer weight-reduction period was associated with significantly improved VO2max (p < 0.01), Tvent (p < 0.005), PP (p < 0.05) and KF (p < 0.05). We conclude: a) the proportion (50%) of weight lost as FFM in the present elite rowers is higher than the suggested optimal figure of 22%, and b) compared to four months, 6-7% of BW loss over two months may adversely influence fitness-related parameters in international lightweight oarswomen.


Characteristics of lipids imbalance in patients with tick-borne encephalitis.
Using a novel approach, we have analyzed 30 parameters characterizing detailed spectrum and fractional content of LPs in plasma of patients with tick-borne encephalitis (TBE). The blood plasma of all TBE patients (30 patients), as compared with that of healthy individuals (120 patients), is characterized by decreased concentrations of many LP subfractions and of the total concentration of all plasma LPs (hypolipoproteinemia). The observed difference in some parameters was statistically significant. Using computer-assisted factor analysis, we have shown that according to these 30 parameters TBE patients are similar to patients with multiple sclerosis and systemic lupus erythematosus. The results provide grounds for using data on blood plasma LPs as additional criteria for diagnosis of TBE.


Reverse endoventricular artificial obturator in tricuspid valve position. Experimental feasibility research study.
The concept of vena contracta space reduction in tricuspid valve position was tested in an animal model. Feasibility of specific artificial obturator body (REMOT) fixed to the right ventricular apex and interacting with tricuspid valve leaflets was evaluated in three different animal studies. Catheter-based technique was used in three series of experiment in 7 sheep. First acute study was designed for evaluation if the screwing mode of guide wire anchoring to the right ventricular apex is feasible for the whole REMOT body fixing. Longer study was aimed to evaluate stability of the REMOT body in desired position when fixing the screwing wire on its both ends (to the right ventricular apex and to the skin in the neck area). X-ray methods and various morphological methods were used. The third acute study was intended to the REMOT body deployment without any fixing wire. In all of 7 sheep the REMOT was successfully inserted into the right heart cavities and then fixed to the right ventricular apex area. When the REMOT was left in situ more than 6 months it was stable, induced adhesion to the tricuspid valve leaflet and was associated with a specific cell invasion. Releasing of the REMOT from the guiding tools was also successfully verified. Deployment of the obturator body in the aim to reduce the tricuspid valve orifice is feasible and well tolerated in the short and longer term animal model. Specific cell colonization including neovascularization of the obturator body was observed.


The clinical significance of the effects of cigarette smoking on drug disposition.
Cigarette smoking is one of a number of environmental factors that contribute to interindividual variations in response to an administered drug. Polycyclic aromatic hydrocarbons present in cigarette smoke induce hepatic aryl hydrocarbon hydroxylase and cytochrome P448 and increased levels of these enzymes are responsible for a higher metabolic clearance of drugs which are substrates for these enzymes. The clinical significance of this induction is greatest for those drugs with a low therapeutic index such as theophylline. In some cases a modification of the normal therapeutic dose is justified to maintain adequate control. The magnitude of the effect of cigarette smoking on the induction of hepatic metabolic activity has been linked with age for a number of drugs including theophylline, some benzodiazepines and propranolol. Generally, the inductive effect is smaller in the elderly but, as there is no direct correlation between chronological age and physiological age, it is imperative that age and smoking habits be treated as individual sources of intersubject variation in pharmacokinetics and that this be borne in mind in the evaluation of new drugs and the safe clinical use of existing ones.


Toward a monophyletic Cheilanthes: The resurrection and recircumscription of Myriopteris (Pteridaceae).
The fern genus Cheilanthes (Pteridaceae) has perplexed taxonomists for more than two centuries. Complex patterns of evolution involving rampant morphological convergence, polyploidy, hybridization, and apomixis have made the taxonomy of this group especially difficult. Fortunately, recent phylogenetic analyses have helped to clarify relationships among cheilanthoid taxa. Based on these findings, we here formalize an updated taxonomy for one monophyletic clade comprising 47 primarily North and Central American taxa usually included in Cheilanthes. Because the type species of Cheilanthes (Cheilanthes micropteris) is only distantly related to this clade, we resurrect the genus Myriopteris to accommodate these taxa, and present a revised circumscription for the group, including 36 new combinations.


Comparison of MicroRNAs Mediated in Reactivation of the γ-Globin in β-Thalassemia Patients, Responders and Non-Responders to Hydroxyurea.
Drug induction of Hb F seems to be an ideal therapy for patients with hemoglobin (Hb) disorders, and many efforts have been made to reveal the mechanism behind it. Thus, we examined in vivo expression of some microRNAs (miRNAs) that are thought to be involved in this process. Among β-thalassemia (β-thal) patients who were undergoing hydroxyurea (HU) therapy in the past 3 months and five healthy individuals, five responders and five non-responders, were also included in the study. Erythroid progenitors were isolated by magnetic activated cell sorting (MACS) and miRNA expression analyzed using reverse transcription-polymerase chain reaction (RT-PCR). We showed that γ-globin, miR-210 and miR-486-3p had higher levels in the responders than the non-responders group. Moreover, miR-150 and miR-320 had higher levels in the healthy group than both non-responders and responders groups, but the expression of miR-96 did not show any significant difference between the study groups. To the best of our knowledge, this is the first study proposing that 'induction of cellular hypoxic condition by Hb F inducing agents' could be the milestone of possible mechanisms that explain why responders are able to reactivate γ-globin genes and subsequently, more production of Hb F, in response to these agents in comparison to non-responders. However, further investigations need to be performed to verify this hypothesis.


Theoretical investigations of the EPR g factors and the local structure for Er3+ in BaWO4.
The electron paramagnetic resonance (EPR) parameters g factors g(parallel) and g(perpendicular) as well as the local structure for Er3+ in scheelite-type BaWO4 are theoretically investigated by using the perturbation formulas of the EPR parameters for a 4f11 ion under tetragonal symmetry. In these formulas, the contributions to the EPR parameters arising from the second-order perturbation terms and the admixture of different states are included. It is found that the impurity-ligand bonding angles (or the polar angles) related to the fourfold axis in the tetragonal Er3+ center are about 1.5 degrees smaller than those in pure crystal. The calculated EPR parameters are in agreement with the observed values. The validity of the results is discussed.


Evidence For Cannabidiol Modulation of Serotonergic Transmission in a Model of Osteoarthritis via in vivo PET Imaging and Behavioral Assessment.
Preclinical studies indicate that cannabidiol (CBD), the primary nonaddictive component of cannabis, has a wide range of reported pharmacological effects such as analgesic and anxiolytic actions; however, the exact mechanisms of action for these effects have not been examined in chronic osteoarthritis (OA). Similar to other chronic pain syndromes, OA pain can have a significant affective component characterized by mood changes. Serotonin (5-HT) is a neurotransmitter implicated in pain, depression, and anxiety. Pain is often in comorbidity with mood and anxiety disorders in patients with OA. Since primary actions of CBD are analgesic and anxiolytic, in this first in vivo positron emission tomography (PET) imaging study, we investigate the interaction of CBD with serotonin 5-HT1A receptor via a combination of in vivo neuroimaging and behavioral studies in a well-validated OA animal model. The first aim of this study was to evaluate the target involvement, including the evaluation of modulation by acute administration of CBD, or a specific target antagonist/agonist intervention, in control animals. The brain 5-HT1A activity/availability was assessed via in vivo dynamic PET imaging (up to 60 min) using a selective 5-HT1A radioligand ([18F]MeFWAY). Tracer bindings of 17 ROIs were evaluated based on averaged SUVR values over the last 10 min using CB as the reference region. We subsequently examined the neurochemical and behavioral alterations in OA animals (induction with monosodium iodoacetate (MIA) injection), as compared to control animals, via neuroimaging and behavioral assessment. Further, we examined the effects of repeated low-dose CBD treatment on mechanical allodynia (von Frey tests) and anxiety-like (light/dark box tests, L/D), depressive-like (forced swim tests, FST) behaviors in OA animals, as compared to after vehicle treatment. The tracer binding was significantly reduced in control animals after an acute dose of CBD administered intravenously (1.0 mg/kg, i.v.), as compared to that for baseline. This binding specificity to 5-HT1A was further confirmed by a similar reduction of tracer binding when a specific 5-HT1A antagonist WAY1006235 was used (0.3 mg/kg, i.v.). Mice subjected to the MIA-induced OA for 13-20 days showed a decreased 5-HT1A tracer binding (25% to 41%), consistent with the notion that 5-HT1A plays a role in the modulation of pain in OA. Repeated treatment with CBD administered subcutaneously (5 mg/kg/day, s.c., for 16 days after OA induction) increased 5-HT1A tracer binding, while no significant improvement was observed after vehicle. A trend of increased anxiety or depressive-like behavior in the light/dark box or forced swim tests after OA induction, and a decrease in those behaviors after repeated low-dose CBD treatment, are consistent with the anxiolytic action of CBD through 5HT1A receptor activation. There appeared to be a sex difference: females seem to be less responsive at the baseline towards pain stimuli, while being more sensitive to CBD treatment. This first in vivo PET imaging study in an OA animal model has provided evidence for the interaction of CBD with the serotonin 5-HT1A receptor. Behavioral studies with more pharmacological interventions to support the target involvement are needed to further confirm these critical findings.


Recombinant vitronectin is a functionally defined substrate that supports human embryonic stem cell self-renewal via alphavbeta5 integrin.
Defined growth conditions are essential for many applications of human embryonic stem cells (hESC). Most defined media are presently used in combination with Matrigel, a partially defined extracellular matrix (ECM) extract from mouse sarcoma. Here, we defined ECM requirements of hESC by analyzing integrin expression and ECM production and determined integrin function using blocking antibodies. hESC expressed all major ECM proteins and corresponding integrins. We then systematically replaced Matrigel with defined medium supplements and ECM proteins. Cells attached efficiently to natural human vitronectin, fibronectin, and Matrigel but poorly to laminin + entactin and collagen IV. Integrin-blocking antibodies demonstrated that alphaVbeta5 integrins mediated adhesion to vitronectin, alpha5beta1 mediated adhesion to fibronectin, and alpha6beta1 mediated adhesion to laminin + entactin. Fibronectin in feeder cell-conditioned medium partially supported growth on all natural matrices, but in defined, nonconditioned medium only Matrigel or (natural and recombinant) vitronectin was effective. Recombinant vitronectin was the only defined functional alternative to Matrigel, supporting sustained self-renewal and pluripotency in three independent hESC lines.


[Diagnosing neck mass in adults].
Doctors are frequently presented to patients with a neck mass, and the condition might cause diagnostic challenges. In younger adults, a neck mass can typically be explained by congenital, inflammatory or infectious causes. The highest probability of neoplasms is found in patients above 40 years of age. When a malignant neoplasm in the neck is suspected, patients should be referred to an ear, nose and throat specialist. In cases of suspect signs of malignancy as defined by the Danish Health and Medicines Authority, patients should be referred to the integrated national cancer pathways.


Endothelial dysfunction by flow-mediated dilation assessed ultrasonically in patients with Kawasaki Disease.
Kawasaki Disease (KD) is a febrile disorder seen in infants and young children. One of the most serious complications of the disease is coronary aneurysm. Endothelial dysfunction is considered to underlie the etiopathology of coronary aneurysm. Flow-mediated dilation (FMD), as assessed ultrasonically, is used to observe the endothelial function. The current paper summarizes, by providing a systematic review, the clinical studies that have examined endothelial dysfunction by determining the FMD ultrasonically in patients with KD. A PubMed-based search found eight articles published until 2013. Six studies reported the FMD level to be significantly lower in the patients with KD compared to controls, while two studies reported no significant difference in the FMD level between those with and without KD. Although patients with KD appeared to have endothelial dysfunction in the current summary, most reports have been associated with limitations, such as a small size and no prospective design for vascular outcomes. Further studies are therefore needed to draw definite conclusions regarding whether patients with KD suffer from endothelial dysfunction as determined by the FMD and/or whether this determination can be useful for understanding and managing vascular complications in these patients.