Evaluation of the safety and potential lipid-lowering effects of oral hydrogen-rich coral calcium (HRCC) capsules in patients with metabolic syndrome: a prospective case series study.
Metabolic syndrome is characterized by a cluster-like occurrence of conditions such as hypertension, hyperglycaemia, elevated low-density lipoprotein (LDL) cholesterol or triglycerides (TG) and high visceral fat. Metabolic syndrome is linked to the build-up of plaque within the artery, which leads to disorders of the circulatory, nervous and immune systems. A variety of treatments target the regulation of these conditions; nevertheless, they remain dominant risk factors for the development of type 2 diabetes (T2DM) and cardiovascular disease (CVD), which affect 26.9% of the US population. Management and intervention strategies for improving cholesterol and/or TG are worthwhile, and recent studies on hydrogen treatment are promising, particularly as molecular hydrogen is easily ingested. This study aimed to investigate the lipid-lowering effects and quality of life (QOL) improvement of hydrogen-rich coral calcium (HRCC) in patients with metabolic syndrome. The patients, all Taiwanese, were randomly assigned to 3 different doses (low, medium, and high) of HRCC capsules. The primary outcome was the adverse effects/symptoms during this 4-week use of HRCC capsules. The secondary outcome was lipid profile changes. Complete blood count, inflammatory biomarkers, and QOL were also measured before and after the course of HRCC. Sixteen patients with metabolic syndrome completed this study (7 males, 9 females; mean age: 62 years; range: 32-80). No obvious adverse effects were recorded. Only changes in blood TG reached significance. The baseline TG value was 193.19 μL (SD = 107.44), which decreased to 151.75 μL (SD = 45.27) after 4 weeks of HRCC (p = 0.04). QOL showed no significant changes. This study is the first human clinical trial evaluating HRCC capsules in patients with metabolic syndrome. Based on the safety and potential TG-lowering effects of short-term HRCC, further long-term investigations of HRCC are warranted. [ClinicalTrials.gov], identifier [NCT05196295].


The RoPE Score and Right-to-Left Shunt Severity by Transcranial Doppler in the CODICIA Study.
For patients with cryptogenic stroke (CS) and patent foramen ovale (PFO), it is unknown whether the magnitude of right-to-left shunt (RLSh) measured by contrast transcranial Doppler (c-TCD) is correlated with the likelihood an identified PFO is related to CS as determined by the Risk of Paradoxical Embolism (RoPE) score. Additionally, for patients with CS, it is unknown whether PFO assessment by c-TCD is more sensitive for identifying RLSh compared with transesophageal echocardiography (TEE). Our aim was to determine the significance of RLSh grade by c-TCD in patients with PFO and CS. We evaluated patients with CS who had RLSh quantified by c-TCD in the Multicenter Study into RLSh in Cryptogenic Stroke (CODICIA) to determine whether there is an association between c-TCD shunt grade and the RoPE Score. For patients who underwent c-TCD and TEE, we determined whether there is agreement in identifying and grading RLSh between these two modalities. The RoPE score predicted the presence versus the absence of RLSh documented by c-TCD (c-statistic = 0.66). For patients with documented RLSh by c-TCD, shunt severity was correlated with increasing RoPE score (rank correlation (r) = 0.15, p = 0.01). Among 293 patients who had both c-TCD and TEE performed, c-TCD was more sensitive (98.7%) for detecting RLSh. Of the 97 patients with no PFO identified on TEE, 28 (29%) had a large amount of RLSh seen on c-TCD. For patients with CS, severity of RLSh by c-TCD is positively correlated with the RoPE score, indicating that this technique for shunt grading identifies patients more likely to have pathogenic rather than incidental PFOs. c-TCD is also more sensitive in detecting RLSh than TEE. These findings suggest an important role for c-TCD in the evaluation of PFO in the setting of CS.


Effect of climatic conditions on epidemic patterns of influenza in Okinawa, Japan, during the pandemic of 2009: surveillance of rapid antigen test results.
Climatic conditions may have affected the incidence of influenza during the pandemic of 2009 as well as at other times. This study evaluated the effects of climatic conditions on influenza incidence in Okinawa, a subtropical region in Japan, during the 2009 pandemic using surveillance data from rapid antigen test (RAT) results. Weekly RAT results performed in four acute care hospitals in the Naha region of the Okinawa Islands from January 2007 to July 2011 were anonymously collected for surveillance of regional influenza prevalence. Intense epidemic peaks were noted in August 2009 and December 2009-January 2010 during the influenza pandemic of 2009. RAT positivity rates were lower during the pandemic period than during the pre- and post-pandemic periods. Lower ambient temperature was associated with higher influenza incidence during pre- and post-pandemic periods but not during the pandemic of 2009. Lower relative humidity was associated with higher influenza incidence during the pandemic as well as during the other two periods. The association of climatic conditions and influenza incidence was less prominent during the pandemic of 2009 than during pre- and post-pandemic periods.


Hypocaloric feeding: pros and cons.
Since the 1980s, hypocaloric feeding has been regularly proposed in the critically ill, although there is no clear definition available, nor evidence-based strategy to support it. We aim to define hypocaloric feeding based on indirect calorimetric data and to discuss patient-relevant clinical outcomes resulting from hypocaloric feeding. Overfeeding and underfeeding both have proven deleterious effects and should be avoided, which requires determination of the patient's total energy requirement. Indirect calorimetry appears as the only precise method to determine such requirements in clinical settings. We define hypocaloric feeding as the delivery of 0.5-0.9 times the resting energy expenditure, isocaloric feeding as 1.1-1.3 times the resting energy expenditure, whereas hypercaloric feeding delivers more than 1.5 times the resting energy expenditure. Whether the patients are lean or obese, all the available predictive equations of energy requirements are grossly inaccurate in more than 30% of cases. There is growing evidence that negative energy balances are associated with poor intensive-care-unit and hospital outcome. Using an evidence-based approach, hypocaloric feeding in the critically ill cannot be supported either. Whether the cutoff of tolerance for introducing feeding is 24 h or more is not yet defined and still awaits a prospective trial.


Integration of participatory approaches into surveillance systems.
Animal health surveillance is essential for protecting public health, enhancing access to international markets for animals and their products, and improving animal health, production and welfare. It is of vital importance for protecting and improving the livelihoods of diverse groups of livestock keepers and stakeholders in livestock value chains. Surveillance systems consist of sets of complementary components which generate information to inform risk assessment, decision-making and policy formulation for both national programmes and international trade. Participatory approaches have the potential to add value to surveillance systems by enhancing their performance, especially their sensitivity and timeliness, and encouraging the inclusion of marginalised groups. This paper summarises key considerations in the assessment and design of animal health surveillance and discusses how participatory approaches can be integrated into comprehensive surveillance systems, leading to a more effective overall outcome for both domestic and international purposes.


[Effect of Raw Materials and Preparing Process on the Composition of Lime-Ash].
As the saying goes that "no ash, no glaze", lime-ash has been the core material widely used to prepare glaze in ancient China. Among all the lime-ashes, those made in Jingdezhen are the most influential and representative ones. Not only did lime-ash contribute greatly to the prosperity of porcelain making of Jingdezhen in Song, Yuan, Ming and Qing Dynasty, but also it has a complicated, rigorous and a touch of "mysterious" in its preparation process, technical principle and glaze mechanism. Therefore, the research of the lime-ash has been an important subject in exploring the "secret" of ancient Chinese porcelain production by Chinese and foreign researchers. In this paper, four representative firewood and two lime stones as the raw materials were collected for the comparative studies, and three kinds of lime-ash with different smolder times were collected from one of the only two traditional lime-ash workshops in Shou'an town nearby Jingdezhen urban area. The chemical composition and phase composition of the raw materials and lime-ash with different smolder times made in Jingdezhen were discussed by testing with the Energy Dispersive X Ray Fluorescence (EDXRF) and X-Ray Diffraction (XRD). The results showed that Fe(2)O(3), MnO contents reaches 1.41% and 1.52% respectively, but the P(2)O(5) content is just 0.54% of Langqi grass which is lower than other firewood that is not only benefited to form the characteristic of "Green in the white" in Jingdezhen traditional glaze, but also is favor to enhance the transparency of glaze and promote the coloration of traditional under-glazed color painted porcelain, such as the blue and white porcelain. The CaO content of grey lime stone is lower than that of the black lime stone with MgO content of 35.79%.This could be the main reason why the craftsmen prefer to use black lime stone to prepare lime-ash. In addition, the EDXRF results show that the K(2)O, P(2)O(5), MnO and Fe(2)O(3) contents have increased as the time of smoldering increases. In the meanwhile, the calcium carbonate (CaCO(3)) phase has also increased, but the calcium hydroxide (Ca(OH)(2)) phase has decreased. The study helps Jingdezhen porcelain "look like jade" and is also good to avoid the "thickness" of glaze when there is a certain amount of Ca(OH)(2) in glaze. So it could be concluded that the unique raw materials and smolder technology of the lime-ash which have provided the technical support for the development of lime-ash glaze are the unique features of ancient Jingdezhen ash glaze.


Biomechanical characteristics of human ankle ligaments.
The purpose of this study was to define the biomechanical characteristics of the isolated, individual bone-ligament-bone complexes of the human ankle. Twenty human ankles were dissected of all soft tissues to leave only the tibia, fibula, talus, and calcaneus with their intact anterior talofibular, calcaneofibular, posterior talofibular, and deep deltoid ligaments. Specimens were mounted and tested in a Minneapolis Testing System. Protocol consisted of cyclic loading of each isolated bone-ligament-bone preparation, followed by several constant velocity load-deflection tests at varying deflection rates, followed by a final, extremely rapid load to failure test. All ligaments exhibited nonlinearity and strain rate dependence in their load-deflection data. These properties were correlated with ligament function and trauma. The anterior talofibular ligament, the most commonly injured ankle ligament, had the lowest mean maximum load of the specimens tested, whereas the deep deltoid ligament, the least frequently completely disrupted ankle ligament, had the highest load to failure.


Nidogen 1 and 2 gene promoters are aberrantly methylated in human gastrointestinal cancer.
Nidogens are highly conserved proteins of basement membranes. Two nidogen proteins, nidogen 1 and nidogen 2, are known in mammals. We show that CpG islands of both NID1 and NID2 genes are aberrantly methylated in human cancer samples and cancer cell lines. For both genes, methylation was correlated with loss of gene transcription in human cell lines. Furthermore, demethylation of the NID1 and NID2 promoters restored gene transcription, demonstrating that methylation was responsible for silencing nidogen genes. In primary tumors, we detected NID1 promoter methylation in 67% of colon cancer samples and in 90% of gastric cancers. NID2 promoter was methylated in 29% of colon and 95% of gastric cancers. Immuno-staining for nidogen-2 confirmed the correlation between aberrant methylation and loss of nidogen expression also in primary tumors, implying that aberrant methylation was a mechanism for inhibiting nidogens expression in human gastrointestinal tumors. These results suggest that loss of nidogens expression has a potential pathogenetic role in colon and stomach tumorigenesis. Nidogens are believed to connect laminin and collagen IV networks, hence stabilizing the basement membrane structure. Nidogens are also important for cell adhesion, as they establish contacts with various cellular integrins. Loss of nidogen expression may favor invasion and metastasis of cancer cells by loosening cell interaction with basal membrane and by weakening the strength of the basement membrane itself, first barrier from the connective vascularized matrix.


Kinematics and Kinetics of Taekwon-do Side Kick.
The aim of the paper is to present an analysis of the influence of selected kinematic factors on the side kick technique. This issue is especially important in the traditional version of taekwon-do, in which a single strike may reveal the winner. Six taekwon-do (International Taekwon-do Federation) athletes were asked to participate in this case study. Generally accepted criteria of sports technique biomechanical analysis were adhered to. The athletes executed a side kick three times (in Taekwon-do terminology referred to as yop chagi) in a way which they use the kick in board breaking. The obtained data were used to determine the mean velocity changes in the function of relative extension length of the kicking leg. The maximum knee and foot velocities in the Cartesian coordinate system were determined. The leg lifting time and the duration of kick execution as well as the maximum force which the standing foot exerted on the ground were also determined. On the basis of the obtained values, mean values and standard deviations were calculated. The correlation dependence (r=0.72) shows that greater knee velocity affects the velocity which the foot develops as well as the fact that the total time of kick execution depends on the velocity which the knee (r = -0.59) and the foot (r = - 0.86) develop in the leg lifting phase. The average maximum speed was obtained at the length of the leg equal to 82% of the maximum length of the fully extended leg. This length can be considered the optimum value for achieving the maximum dynamics of the kick.


Zerumbone Alleviates Neuropathic Pain through the Involvement of l-Arginine-Nitric Oxide-cGMP-K⁺ ATP Channel Pathways in Chronic Constriction Injury in Mice Model.
The present study investigates the involvement of the l-arginine-Nitric Oxide-cGMP-K⁺ ATP pathways responsible for the action of anti-allodynic and antihyperalgesic activities of zerumbone in chronic constriction injury (CCI) induced neuropathic pain in mice. The role of l-arginine-NO-cGMP-K⁺ was assessed by the von Frey and the Randall-Selitto tests. Both allodynia and hyperalgesia assessments were carried out on the 14th day post CCI, 30 min after treatments were given for each respective pathway. Anti-allodynic and antihyperalgesic effects of zerumbone (10 mg/kg, i.p) were significantly reversed by the pre-treatment of l-arginine (10 mg/kg), 1H [1,2,4]Oxadiazole[4,3a]quinoxalin-1-one (ODQ), a soluble guanosyl cyclase blocker (2 mg/kg i.p.) and glibenclamide (ATP-sensitive potassium channel blocker) (10 mg/kg i.p.) (p < 0.05). Taken together, these results indicate that systemic administration of zerumbone produces significant anti-allodynic and antihyperalgesic activities in neuropathic pain in mice possibly due to involvement of the l-arginine-NO-cGMP-PKG-K⁺ ATP channel pathways in CCI model.


Pyruvate metabolism by aminopterin-inhibited Aerobacter aerogenes.
1. The synthesis and utilization of both alanine (by reductive amination, oxidative deamination and transamination) and valine (by transamination only) in Aerobacter aerogenes are unaffected by aminopterin. These amino acids, which accumulate in aminopterin-treated cultures of this organism, are therefore considered to be formed as secondary products from the excess of pyruvate that also accumulates. 2. Oxidative metabolism of pyruvate and the synthesis of acetylmethylcarbinol by A. aerogenes cells are unaltered by growth in the presence of aminopterin. 3. Cells from static and anaerobic cultures that have been treated with the folic acid antagonist in the early exponential phase have a decreased ability to cleave pyruvate to acetate and formate, and to effect the exchange of formate with the carboxyl group of pyruvate. 4. 3-Methyl-2-oxobutanoate, the keto acid precursor of valine, cannot replace pyruvate as substrate in either the phosphoroclastic or the exchange reaction.


Identifying older inpatients at high risk of unintentional medication discrepancies: a classification tree analysis.
Unintentional medication discrepancies at admission are differences between the best possible medication history and the prescribed treatment at admission, and are associated with adverse outcomes, particularly in older people. This study aimed to identify the clinical profiles of geriatric inpatients with unintentional medication discrepancies at hospital admission. A classification tree Chi-square Automatic Interaction Detector (CHAID) analysis was conducted to assess those patients' profiles and characteristics that were associated with a higher risk of unintentional medication discrepancies. One-hundred and thirty consecutive older patients admitted to acute care (87 ± 5 years old; 61.8% women) were assessed. The CHAID analysis retrieved 5 clinical profiles of older inpatients with a risk of up to 94.4% for unintentional medication discrepancies. These profiles were determined based on combinations of three characteristics: use of eye drops, frequent falls (≥ 1/year), and admission due to urgent hospitalization. These easily measurable clinical characteristics may be helpful as a supportive measure to improve pharmacological care.


Transoral robotic thyroidectomy: lessons learned from an initial consecutive series of 24 patients.
Transoral thyroid surgery is an ideal method for minimally invasive thyroidectomy, as there is less flap dissection during the procedure and no postoperative scars. Nonetheless, technical obstacles have precluded the wide dissemination of this procedure. We present the surgical procedures and outcomes of transoral robotic thyroidectomy (TORT). From September 2012 to June 2016, we performed TORT at Korea University Hospital. We used three intraoral ports and a single axillary port for the system's four robotic arms. The surgical outcomes were retrospectively reviewed. Twenty-four female patients (mean age 39.6 ± 11.6 years; mean tumor size 1.0 ± 1.3 cm) underwent unilateral thyroid lobectomies with or without ipsilateral central neck dissection. Twenty patients had papillary thyroid carcinomas (PTC), three had benign nodules, and one had a follicular thyroid carcinoma. The mean surgical time was 232 ± 41 min; the mean hospital stay was 3.3 ± 0.8 days. The number of retrieved central lymph nodes in the PTC patients was 4.7 ± 3.2. There were no reports of transient or permanent vocal cord palsy, recurrence, or mortality during the median follow-up period of 16.8 months. Paresthesia of the lower lip and the chin due to mental nerve injury was observed in nine of the first 12 patients (six transient, three permanent), but no further reports of paresthesia were recorded after patient 12, when the locations of the intraoral incisions were modified. TORT is feasible and safe for selected patients after technical refinements, and can be a potential alternative approach for scarless thyroid surgery.


Maize defense elicitor, 12-oxo-phytodienoic acid, prolongs aphid salivation.
12-Oxo-phytodienoic acid (OPDA), an intermediate in the jasmonic acid (JA) biosynthesis pathway, regulates diverse signaling functions in plants, including enhanced resistance to insect pests. We previously demonstrated that OPDA promoted enhanced callose accumulation and heightened resistance to corn leaf aphid (CLA; Rhopalosiphum maidis), a phloem sap-sucking insect pest of maize (Zea mays). In this study, we used the electrical penetration graph (EPG) technique to monitor and quantify the different CLA feeding patterns on the maize JA-deficient 12-oxo-phytodienoic acid reductase (opr7opr8) plants. CLA feeding behavior was unaffected on B73, opr7opr8 control plants (- OPDA), and opr7opr8 plants that were pretreated with OPDA (+ OPDA). However, exogenous application of OPDA on opr7opr8 plants prolonged aphid salivation, a hallmark of aphids' ability to suppress the plant defense responses. Collectively, our results indicate that CLA utilizes its salivary secretions to suppress or unplug the OPDA-mediated sieve element occlusions in maize.


Myths and Facts about Food Intolerance: A Narrative Review.
Most adverse reactions to food are patient self-reported and not based on validated tests but nevertheless lead to dietary restrictions, with patients believing that these restrictions will improve their symptoms and quality of life. We aimed to clarify the myths and reality of common food intolerances, giving clinicians a guide on diagnosing and treating these cases. We performed a narrative review of the latest evidence on the widespread food intolerances reported by our patients, giving indications on the clinical presentations, possible tests, and dietary suggestions, and underlining the myths and reality. While lactose intolerance and hereditary fructose intolerance are based on well-defined mechanisms and have validated diagnostic tests, non-coeliac gluten sensitivity and fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) intolerance are mainly based on patients' reports. Others, like non-hereditary fructose, sorbitol, and histamine intolerance, still need more evidence and often cause unnecessary dietary restrictions. Finally, the main outcome of the present review is that the medical community should work to reduce the spread of unvalidated tests, the leading cause of the problematic management of our patients.


[Advisory report from the Health Council of the Netherlands to include human papillomavirus vaccination in the national immunisation programme for the prevention of cervical cancer].
The Health Council of the Netherlands has advised the Minister of Health, Welfare and Sport to include vaccination against Human papillomavirus (HPV) for girls aged 12 years as part of the National Immunisation Programme. A catch-up vaccination is proposed for girls aged 13-16 years. High-risk HPV infections cause cervical cancer. Approximately 70% of these infections are attributed to HPV-16 and HPV-18. Vaccination was shown to prevent these infections and subsequent precursor lesions. Its efficacy in preventing cervical cancer has not yet been proven but is highly plausible. Protection lasts for more than so years. A booster may be needed after so years. The efficacy and safety of the two available vaccines are comparable. State-mandated vaccination is effective and ensures equal treatment regardless of economic status. Maintenance of the population screening programme for cervical cancer is important, and this must be communicated to the public properly. Careful monitoring is necessary for surveillance of effects, side effects, response rates and participation rates in cervical cancer screening. Guidelines are needed to aid physicians in determining whether to provide individual vaccination.


Electrospinning adipose tissue-derived extracellular matrix for adipose stem cell culture.
Basement membrane-rich extracellular matrices, particularly murine sarcoma-derived Matrigel, play important roles in regenerative medicine research, exhibiting marked cellular responses in vitro and in vivo, although with limited clinical applications. We find that a human-derived matrix from lipoaspirate fat, a tissue rich in basement membrane components, can be fabricated by electrospinning and used to support cell culture. We describe practical applications and purification of extracellular matrix (ECM) from adipose tissue (At-ECM) and its use in electrospinning scaffolds and adipose stem cell (ASC) culture. The matrix composition of this purified and electrospun At-ECM was assessed histochemically for basement membrane, connective tissue, collagen, elastic fibers/elastin, glycoprotein, and proteoglycans. Each histochemical stain was positive in fat tissue, purified At-ECM, and electrospun At-ECM, and to some extent positive in a 10:90 blend with polydioxanone (PDO). We also show that electrospun At-ECM, alone and blended with PDO, supports ASC attachment and growth, suggesting that electrospun At-ECM scaffolds support ASC cultivation. These studies show that At-ECM can be isolated and electrospun as a basement membrane-rich tissue engineering matrix capable of supporting stem cells, providing the groundwork for an array of future regenerative medicine advances.


Targeting of porous hybrid silica nanoparticles to cancer cells.
Mesoporous silica nanoparticles functionalized by surface hyperbranching polymerization of poly(ethylene imine), PEI, were further modified by introducing both fluorescent and targeting moieties, with the aim of specifically targeting cancer cells. Owing to the high abundance of folate receptors in many cancer cells as compared to normal cells, folic acid was used as the targeting ligand. The internalization of the particles in cell lines expressing different levels of folate receptors was studied. Flow cytometry was used to quantify the mean number of nanoparticles internalized per cell. Five times more particles were internalized by cancer cells expressing folate receptors as compared to the normal cells expressing low levels of the receptor. Not only the number of nanoparticles internalized per cell, but also the fraction of cells that had internalized nanoparticles was higher. The total number of particles internalized by the cancer cells was, therefore, about an order of magnitude higher than the total number of particles internalized by normal cells, a difference high enough to be of significant biological importance. In addition, the biospecifically tagged hybrid PEI-silica particles were shown to be noncytotoxic and able to specifically target folate receptor-expressing cancer cells also under coculture conditions.


Sin Nombre virus mRNA synthesis.
Sin Nombre (SN) virus is the major etiologic agent of hantavirus pulmonary syndrome, a severe respiratory disease with high mortality. Like other hantaviruses, SN virus causes an inapparent chronic infection of the natural rodent reservoir and tends to grow slowly and produce little cytopathic effect even in highly susceptible Vero E6 tissue culture cells. An electrochemiluminescent quantitative PCR approach was developed to allow examination of SN virus RNA transcription in synchronously infected cells. Although virion particles contain equimolar ratios of the three negative-strand genome RNA segments (S, M, and L), rates and levels of accumulation of the corresponding N, GPC, and L viral mRNAs varied. The smallest mRNA (N) was detectable earliest and plateaued at the highest level, where as the largest mRNA (L) appeared latest and at the lowest plateau level. In addition, all three mRNAs were found to share a common 5' capped primer initiation mechanism, but appeared to have different mRNA termination mechanisms. The N mRNA 3' terminus mapped to position 1435 on the S segment, in close proximity to a CCC-rich suspected transcription termination motif. The GPC mRNA 3' terminus contained a poly(A) tall and mapped to a U8 transcription termination-polyadenylation motif reminiscent of those seen in other negative-strand RNA viruses. Finally, the L mRNA 3' terminus appeared identical to the L segment antigenome 3' terminus.


[Activation analysis with reactor and 14 MeV neutrons in an experimental study of oxoplatinum].
The authors described a procedure of the instrumental neutron activation analysis of biomedical material on reactor and 14 MeV neutrons for determination of the platinum, silicon, chlorine, phosphorus, sodium and zinc content using the anticompton system of detection together with a programmed analyser and an automatic sample changer. The procedure was tested on rat small intestinal samples within the interval of 10 min-30 days after a single i. v. administration of oxoplatinum (15 mg per 1 kg of the animal body mass). Platinum redistribution with relative concentration maximum on the 15th day was noted. Changes in the phosphorus, chlorine, sodium and silicon content within the interval of 3-30 days were suggestive of a possible toxic effect of oxoplatinum metabolites during this period. In a clinical application of oxoplatinum one should take into account a possible toxic effect of metabolites in a long-term period after repeated administration of the agent.


Flow effects in balanced steady state free precession imaging.
An analysis of the effect of flow on 2D fully balanced steady state free precession (SSFP) imaging is presented. Transient and steady-state SSFP signal intensities in the presence of steady and pulsatile flow were simulated using a matrix formalism based on the Bloch equations. Various through-plane flow waveforms and rates were modeled numerically considering factors such as the excitation slice profile and both in- and out-flow effects. Phantom measurements in an experimental setup that allowed the assessment of SSFP signal properties as a function of frequency offset and flow rate demonstrated that the computer simulations provided a suitable description of the effects of flow in SSFP imaging. A volunteer scan was performed to provide in vivo validations. For accurate modeling of SSFP signal intensities it is crucial to include effects such as imperfect slice profiles and, more importantly, "out-of-slice" contributions to the signal. Both simulations and experiments show that there can be considerably large-frequency offset dependent-signal contributions from flowing spins that have already left the imaging slice but still add to the SSFP signal. Although spins leaving the slice do not experience additional RF-excitation, gradient activity is not confined to the region of excitations and the balanced nature of the SSFP imaging gradients allows "out-of-slice" transverse magnetization to contribute to the total SSFP signal, effectively by broadening the slice thickness for flowing spins. This results in a frequency dependence of in-flow related signal enhancement and flow artifacts.


Committee opinion no. 625: management of women with dense breasts diagnosed by mammography.
Women with dense breasts have a modestly increased risk of breast cancer and experience reduced sensitivity of mammography to detect breast cancer. However, evidence is lacking to advocate for additional testing until there are clinically validated data that indicate improved screening outcomes. Currently, screening mammography remains the most useful tool for breast cancer detection and consistently has demonstrated a reduction in breast cancer mortality. The American College of Obstetricians and Gynecologists does not recommend routine use of alternative or adjunctive tests to screening mammography in women with dense breasts who are asymptomatic and have no additional risk factors. The American College of Obstetricians and Gynecologists recommends that health care providers comply with state laws that may require disclosure to women of their breast density as recorded in a mammogram report.


Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide.
In this direct colorimetric procedure, serum triglycerides are hydrolyzed by lipase, and the released glycerol is assayed in a reaction catalyzed by glycerol kinase and L-alpha-glycerol-phosphate oxidase in a system that generates hydrogen peroxide. The hydrogen peroxide is monitored in the presence of horseradish peroxidase with 3,5-dichloro-2-hydroxybenzenesulfonic acid/4-aminophenazone as the chromogenic system. The high absorbance of this chromogen system at 510 nm affords useful results with a sample/reagent volume ratio as low as 1:150, and a blank sample measurement is not needed. A single, stable working reagent is used; the reaction is complete in 15 min at room temperature. The standard curve is linear for triglyceride concentrations as great as 13.6 mmol/L. Average analytical recovery of triglycerides in human sera is 100.1%, and within-run and between-run precision studies showed CVs of less than or equal to 1.6 and less than or equal to 3.0%, respectively. The method is suitable for automation.


Ethanol feeding selectively impairs the spreading of rat perivenous hepatocytes on extracellular matrix substrates.
Hepatocytes require attachment and subsequent spreading on an extracellular matrix for their proper growth, function and survival. Our previous studies have shown that ethanol feeding selectively impairs perivenule hepatocyte attachment to various extracellular matrices. This study was undertaken to determine whether zonal differences in hepatocyte spreading in response to ethanol feeding occurs and to ascertain the influence of ethanol consumption on the zonal expression of the beta1 subunit of integrins, which are the major surface receptors responsible for matrix binding and subsequent interactions. Hepatocytes from the perivenous and periportal regions of the liver were isolated by digitonin/collagenase perfusion from rats that were pair-fed for 2 to 3 weeks with a liquid diet containing either ethanol or isocaloric carbohydrate. The ability of perivenous and periportal hepatocytes to spread on plates coated with either type IV collagen, laminin, fibronectin or polylysine was determined. In addition, the isolated cells were used for the analysis of total cellular and surface beta1 integrin expression. With all of the matrix substrates tested, the spreading of perivenous hepatocytes isolated from the ethanol-fed animals was markedly impaired, while the spreading of periportal hepatocytes was essentially unaffected by ethanol feeding. Both the total cellular as well as the surface expression of the beta1 integrin subunit in perivenous cells from the ethanol-fed rats were significantly higher than from the perivenous control cells, whereas the total and surface expression of the beta1 integrin in periportal cells isolated from ethanol-fed and control rats were not significantly different. The results indicated that in addition to impairing hepatocyte attachment, ethanol feeding also impairs another critical step of the adhesion process, that of hepatocyte spreading on extracellular matrix substrates. This defect occurred preferentially in perivenous cells and not periportal cells and was associated with an increase in beta1 integrin expression, suggesting that a compensatory mechanism occurs as an attempt by the perivenous cells to overcome impaired cell-matrix interactions caused by ethanol. Overall, these alterations in extracellular matrix-hepatocyte interactions could lead to alterations of hepatocyte structure and function and potentially play a role in alcoholic liver injury.


BIRD ATTACK OCULAR INJURIES.
To report 30 patients with bird attack-related eye injuries. This study was performed among patients coming to Farabi Eye Hospital, Tehran, Iran, from 2010 to 2015 with a history of bird attack causing eye injury. The inclusion criteria were a history of bird attack by pecking causing eye injury and having treatment and follow-up record for at least 6 months after treatment. The primary eye examinations included a full ophthalmic examination including evaluation of uncorrected visual acuity and best-corrected visual acuity (BCVA), anterior segment slit lamp biomicroscopy, and photography. For all patients with penetrating injury, primary repair was undertaken. Thirty patients (10 females and 20 males) with a mean age of 23.3 ± 18.5 years entered the study. The most common zone of injury was zone 1 (P < 0.001), and lensectomy was not needed in majority of patients (P < 0.001). The most common bird causing the injury was mynah (P < 0.001). Those patients with baseline BCVA of less than 20/200 or those with endophthalmitis had statistically worse final BCVA after treatment. Patients attacked by mynah bird had significantly better pretreatment uncorrected visual acuity and BCVA. The most common bird causing the eye injury among the sample of patients from Iran was mynah, which differs with previous studies indicating the rooster attack as the most common cause of eye injury. The authors also found that the most common zone of injury was zone 1, and the presence of endophthalmitis and lower baseline BCVA were significant risk factors for worse visual outcomes.


Identification of multiple cancer/testis antigens by allogeneic antibody screening of a melanoma cell line library.
Cancer/testis (CT) antigens-immunogenic protein antigens that are expressed in testis and a proportion of diverse human cancer types-are promising targets for cancer vaccines. To identify new CT antigens, we constructed an expression cDNA library from a melanoma cell line that expresses a wide range of CT antigens and screened the library with an allogeneic melanoma patient serum known to contain antibodies against two CT antigens, MAGE-1 and NY-ESO-1. cDNA clones isolated from this library identified four CT antigen genes: MAGE-4a, NY-ESO-1, LAGE-1, and CT7. Of these four, only MAGE-4a and NY-ESO-1 proteins had been shown to be immunogenic. LAGE-1 is a member of the NY-ESO-1 gene family, and CT7 is a newly defined gene with partial sequence homology to the MAGE family at its carboxyl terminus. The predicted CT7 protein, however, contains a distinct repetitive sequence at the 5' end and is much larger than MAGE proteins. Our findings document the immunogenicity of LAGE-1 and CT7 and emphasize the power of serological analysis of cDNA expression libraries in identifying new human tumor antigens.


Effects of Activity Tracker Use With Health Professional Support or Telephone Counseling on Maintenance of Physical Activity and Health Outcomes in Older Adults: Randomized Controlled Trial.
Despite a range of efforts to increase physical activity participation in Australia, inactivity levels in older adults have remained high over recent decades, contributing to increased rates of chronic health conditions. Lifestyle interventions, including telephone counseling (TC), improve physical activity participation and associated health outcomes over the short term; however, ongoing feedback and support is required to maintain these changes. Newer technologies such as wearable activity trackers (ATs) may offer an alternative method for providing ongoing support. This study aims to investigate whether newer technologies such as wearable ATs assist in providing ongoing support to maintain physical activity levels and health outcomes. Older adults aged >60 years who had just completed a 12-week face-to-face individualized community exercise program in Tasmania, Australia, participated in the study. They were randomized to receive AT, TC, or usual care (UC). All groups received a home exercise program and an optional referral to a community-based exercise program. The AT group also received an AT and text message feedback from an accredited exercise physiologist (AEP). The TC group received phone calls from an AEP throughout the 12-month intervention. The primary outcome was daily steps measured by an ActivPAL (TM) accelerometer at baseline and at 3, 6, and 12 months. Secondary outcome measures included body composition, blood pressure, 10-time sit-to-stand (TTSTS) test, timed up and go test, and cardiorespiratory fitness. This trial was approved by the Tasmanian Health and Medical Human Research Ethics Committee (H0014713). A total of 117 participants were randomized to the study (AT, n=37; TC, n=38; UC, n=42). At baseline, the participants (75/117, 64.1% female; mean age 72.4 years, SD 6.4) completed an average of 6136 steps (SD 2985) per day. Although there were no significant differences between groups, the TC and AT groups maintained daily step counts (mean difference [MD] -79 steps, 95% CI -823 to 663 steps; P=.81; and MD -588 steps, 95% CI -1359 to 182 steps; P=.09), and UC showed a reduction in daily steps (MD 981 steps, 95% CI -1668 to -294 steps; P=.003) during the 12-month period. Diastolic blood pressure was significantly higher after AT than after UC (MD 5.62 mm Hg, 95% CI 1.30 to 9.94 mm Hg; P=.01), and TTSTS was significantly slower on TC compared with UC (MD 2.36 seconds, 95% CI -0.14 to 4.87 seconds; P=.03). The use of an AT with AEP support or TC is effective at maintaining daily step count in older adults over a 12-month period, suggesting that wearable ATs are as effective as TC. Further research to investigate which option is more cost-effective would be beneficial. Australian New Zealand Clinical Trial Registry ACTRN12615001104549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=369118.


Inter-familial and intra-familial phenotypic variability in three Sicilian families with Anderson-Fabry disease.
Anderson-Fabry disease (AFD) is an inborn lysosomal enzymopathy resulting from the deficient or absent activity of the lysosomal exogalactohydrolase, α-galactosidase A. This deficiency, results in the altered metabolism of glycosphingolipids which leads to their accumulation in lysosomes, thus to cellular and vascular dysfunction. To date, numerous mutations (according to recent data more than 1000 mutations) have been reported in the GLA intronic and exonic mutations. Traditionally, clinical manifestations are more severe in affected hemizygous males than in females. Nevertheless, recent studies have described severe organ dysfunction in women. This study reports clinical, biochemical, and molecular findings of the members of three Sicilian families. The clinical history of these patients highlights a remarkable interfamilial and intrafamilial phenotypic variability which characterizes Fabry disease relative to target organs and severity of clinical manifestations. Our findings, in agreement with previous data, report a little genotype-phenotype correlation for the disease, suggesting that the wide phenotypic variability of Anderson-Fabry disease is not completely ascribable to different gene mutations but other factors and mechanisms seem to be involved in the pathogenesis and clinical expression of the disease. Moreover, this study emphasies the importance of pedigree analysis in the family of each proband for identifying other possibly affected relatives.


Evaluation of denaturing gradient gel electrophoresis for the detection of mycobacterial species and their potential association with waterborne pathogens.
The versatility of denaturing gradient gel electrophoresis (DGGE) protocol provides enough grounds for its wide application over an array of microorganisms. This work was designed to evaluate DGGE for the detection and confirmation of mycobacteria and their association, if any, with waterborne pathogens. A total of 76 samples comprising raw untreated water, schmutzdecke, floccules and final treated water obtained from a common water source, and two water treatment works (WTW1 and WTW2), were analysed. Thirty-five species were identified from the overall samples, with 7% (5/76), 13% (10/76) and 26% (20/76) from the common raw water source, WTW1 and WTW2 respectively. The majority of the species were Cyanobacteria, with high dominance in the raw water entering WTW2. In the final treated water of WTW1 Eutreptiella braarudii was found, and that of WTW2 contained Anabaena nereformis, Anabaena torulosa and Podocarpus nerrifolius. Furthermore, one Mycobacterium species was found in the raw water of WTW1 aside from the detection of Mycobacterium avium ssp. paratuberculosis by the technique. No association between mycobacteria and the other species was observed. This implies DGGE may be employed to study the diversity of other akin mycobacterial species from various sources, and not as a direct means of elucidating microbial associations.


Combinatorial process for extracellular matrix influences on gene expression: a hypothesis.
The extracellular matrix (ECM) has a number of influences on gene expression during growth and development. Cellular and tissue interactions among similar and dissimilar cell types result in the production of complex and fascinating extracellular matrices throughout development. This paper presents a hypothesis that will emphasize those examples in which the extracellular matrix mediates de novo gene expression termed "determination" of a unique phenotype. It will be found that a number of gene families within the eucaryotic genome can be preferentially activated during the course of differentiation-specific protein expression. Results from a number of laboratories illustrate that close-range and/or short-range cell-cell interactions invoke preferential differentiation-specific protein synthesis and accumulation during embryogenesis. This discussion will highlight how the extracellular matrix microenvironment of a particular population of cells invokes irreversible, differentiation-specific gene expression. Recent advances in the isolation and characterization of a large number of different extracellular matrix macromolecules (eg various types of collagens, fibronectin, chondronectin, osteonectin, laminin, proteoglycans, enamel protein) now suggest a renewed interest in this problem area, and also the promise for significant breakthroughs in the near future. The combinatorial hypothesis for extracellular matrix influences on gene expression states that changing, rearranging, or altering the macromolecular constituents within ECM results in a myriad diversity in developmental instructions. The hypothesis predicts that no individual morphogen is required.


Risk factors for breast cancer among Chinese women: a 10-year nationwide multicenter cross-sectional study.
The characteristics of established risk factors for breast cancer may vary among countries. A better understanding of local characteristics of risk factors may help in devising effective prevention strategies for breast cancer. Information on exposures to risk factors was collected from the medical charts of 4211 women with breast cancer diagnosed during 1999-2008. The distributions of these exposures among regions, and by menopausal status and birth period, were compared with the χ(2) test. Crude associations between the selected factors and breast cancer were estimated using the cases in the present study and a representative control population, which was selected from qualified published studies. As compared with cases from less developed regions, those from more developed regions were significantly more likely to be nulliparous, had fewer childbirths (P < 0.05), and were less likely to have breastfed (P = 0.08). As compared with premenopausal cases, postmenopausal cases were more likely to be overweight and to have breastfed and had more childbirths (P < 0.05). The number of live births and rate of breastfeeding decreased in relation to birth period (P for trends <0.001). Overweight, late menopause, and family history of breast cancer were significantly associated with breast cancer among Chinese women. Breast cancer incidence was associated with nulliparity and history of breastfeeding. Population attributable risks should be assessed, especially for more developed areas and young women. The effects of body mass index, age at menopause, and family history of breast cancer should be given priority during assessment of breast cancer risk among Chinese women.


A simple technique for defatting morsellised bone graft in revision hip arthroplasty.
A method for producing fat-free, non-saline laden morsellised bone graft for use in revision hip arthroplasty is described. The method is easily performed, requires inexpensive and readily available equipment and, we believe, reduces loss of bone graft compared with alternative techniques. (Hip International 2002; 4: 403-4).


Application of Teflon-AF thin films for bio-patterning of neural cell adhesion.
Teflon AF, an amorphous copolymer of polytetrafluoroethylene (PTFE) with 2,2-bis(triflouromethyl)-4,5-difluoro-1, 3-dioxole, has been receiving widespread attention in the opto-electronics industries and elsewhere for its superior optical and dielectric properties. The objective of the present study was to investigate surface parameters that may be required for the application of thin films of Teflon AF in the fields of biomaterials and bioelectronics. Using standard microelectronics procedures, micro-patterned thin films of Teflon-AF were fabricated, and their surface properties monitored and optimized with the aid of highly surface sensitive spectrometric techniques. Finally, their capability to inhibit or bio-pattern cell adhesion was tested with various neural cell lines.


Early Use of Tocilizumab May Prevent Clinical Deterioration in Select COVID-19 Patients: A Case Series.
Coronavirus disease 2019 (COVID-19) is a respiratory viral illness caused by the novel severe acute respiratory syndrome coronavirus 2. It is known to cause severe illness in certain patients, who develop acute respiratory distress syndrome (ARDS) often requiring intubation and mechanical ventilation adding to significant morbidity and mortality. Tocilizumab is an interleukin-6 inhibitor that has shown promise in improving outcomes in patients with COVID-19. It is usually administered to patients with severe COVID-19 who develop ARDS. We present three cases of COVID-19 where the patients were admitted to the hospital for observation and were found to be worsening clinically. They were believed to be developing ARDS, and intubation and mechanical ventilation were anticipated. Tocilizumab was administered in the early phase of the disease before intubation. Patients improved clinically and ultimately did not require intubation. Our findings suggest that early use of tocilizumab might be beneficial in preventing clinical deterioration and intubation in select COVID-19 patients.


Matrix metalloproteinase 7 mediates mammary epithelial cell tumorigenesis through the ErbB4 receptor.
To delineate the role of matrix metalloproteinase 7 (MMP7) in mammary tumorigenesis, MMP7 was expressed in the normal murine mammary gland cell line, c57MG. MMP7 markedly enhanced the growth rate of the c57MG cells in three-dimensional culture and promoted tumor formation in vivo. Subsequent investigation showed that MMP7 (a) up-regulated ErbB4 receptor levels, (b) solubilized the ErbB4 receptor cognate ligand heparin-bound epidermal growth factor, and (c) mediated the proteolytic processing of ErbB4 to yield a soluble intracellular domain (ICD) that localized to the cytoplasm and the nucleus. Furthermore, overexpression of the ErbB4 ICD in the c57MG cell line recapitulated the proliferative effects of MMP7 in vitro and in vivo. These data indicate a novel mechanism for mammary epithelial cell transformation by MMP7.


The effect of extended refrigerated storage on the physicochemical, structural, and microbial quality of sous vide cooked biceps femoris treated with ginger powder (zingibain).
The aim of the study was to investigate quality and shelf life of beef meat cooked under sous vide conditions then extended refrigerated storage for 10 weeks. Biceps femoris (n = 6) from six to seven year old cows were treated with 2 g/L ginger powder (GP) containing zingibain or control (no injection) and were then cooked in sous vide conditions at 65 °C for 1 h or 8 h. Cooked samples were evaluated for physicochemical (pH, total water content, cooking loss, Warner-Bratzler shear force (WBSF), texture profile analysis (TPA), L*, a*, b* properties and thiobarbituric acid reactive substance (TBARS)), microstructure (scanning electron microscopy) and microbiological (Brochothrix thermospacta, Clostridium perfringens, Lactic acid bacteria, Listeria monocytogenes, Salmonella spp, and yeasts and moulds) quality after vacuum packing, cooking, then refrigerated storage at 4 °C for 0, 2, 4, 8 or 10 weeks. Physicochemical parameters were improved by GP treatment (P < 0.05) while there was no effect of storage time on WBSF, TPA or microstructure. The microbial quality of sous vide cooked meat in refrigerated storage appeared to be four weeks and oxidation shelf life of the cooked meat was found to be two weeks under refrigerated storage.


The 3' portion of the gene for a Plasmodium yoelii merozoite surface antigen encodes the epitope recognized by a protective monoclonal antibody.
The 230-kDa merozoite antigen of the murine malarial parasite Plasmodium yoelii provides a potential model system for the development of a protective erythrocytic stage vaccine. To characterize this antigen at the molecular level, isolated P. yoelii 17XL DNA was used to construct a genomic library in the expression vector lambda gt11. A monoclonal antibody, mAb 302, which passively protected mice against P. yoelii challenge infection, was used to identify a lambda gt11 recombinant clone encoding a portion of the 230-kDa antigen of this parasite. Using this clone as a probe, we identified an mRNA of 7.6 kilobases by RNA blot analysis. Nucleic acid sequence analysis of the clone showed that the epitope recognized by the protective mAb 302 is encoded by the 3' portion of the gene for the 230-kDa antigen. The deduced amino acid sequence revealed that this antigen also contains the tandemly repeated tetrapeptide Gly-Ala-Val-Pro, a series of 10 cysteine residues located within the terminal 110 amino acids, and a potential membrane anchor of 18 hydrophobic residues. Comparison of this C-terminal sequence with the carboxyl segment of the 195-kDa merozoite antigen of Plasmodium falciparum revealed nucleic acid and amino acid sequence similarities ranging from 40% to 70%. The localization of a B-cell epitope recognized by the protective mAb 302 to this carboxyl region of the P. yoelii antigen, combined with the limited strain variability in this region of the homologous 195-kDa antigen of P. falciparum, has implications for the development of an effective erythrocytic stage malarial vaccine.


[Treatment of tumor hypercalcemia with clodronate. Effect on parathormone and calcitriol].
Clodronate (dichlormethylene diphosphonate) was administered to 21 patients with hypercalcemia due to malignant tumor. The drug was initially given intravenously, then orally. In 20 patients the serum calcium level had been reduced to the normal range within one week of the start of treatment (from 3.3 +/- 0.5 mmol/l to 2.4 +/- 0.3 mmol/l). With oral administration there was a renewed rise in calcium levels in some patients, which had to be treated with higher oral doses or intravenous administration. Parallel with the reduction in calcium levels there was an improvement in the originally impaired renal function. The serum level of intact parathormone(1-84) and 1.25-dihydroxy-vitamin-D3 (calcitriol) rose significantly from usually lowered initial levels. There was a non-linear inverse correlation between parathormone and calcium. No side effects were noted, even after long-term administration.


HOX gene analysis of endothelial cell differentiation in human bone marrow-derived mesenchymal stem cells.
Human bone marrow-derived mesenchymal stem cells (hMSCs) have been shown to possess multilineage differentiation potential. HOX genes function in transcriptional regulators, and are involved in stem cell differentiation. The aim of the present study was to demonstrate HOX genes that are related to angiogenesis. To identify the expression patterns of 37 HOX genes in the endothelial cell differentiation of hMSCs, we analyzed HOX genes through profiling with multiplex RT-PCR. The results showed that the expression patterns of four HOX genes, HOXA7, HOXB3, HOXA3, and HOXB13, significantly changed during angiogenesis. The expression levels of HOXA7 and HOXB3 were dramatically increased, whereas those of HOXA3 and HOXB13 were decreased during endothelial cell differentiation. When further analysis of the expressions of these HOX genes was performed with real-time PCR and an immunoblot assay, the expression patterns were also found to be well-matched with the results of multiplex RT-PCR. Here, we report that HOXA7, HOXB3, HOXA3, and HOXB13 might be involved in the angiogenesis of hMSCs.


Intranuclear Positions of HIV-1 Proviruses Are Dynamic and Do Not Correlate with Transcriptional Activity.
The relationship between spatiotemporal distribution of HIV-1 proviruses and their transcriptional activity is not well understood. To elucidate the intranuclear positions of transcriptionally active HIV-1 proviruses, we utilized an RNA fluorescence in situ hybridization assay and RNA stem loops that bind to fluorescently labeled bacterial protein (Bgl-mCherry) to specifically detect HIV-1 transcription sites. Initially, transcriptionally active wild-type proviruses were located closer to the nuclear envelope (NE) than expected by random chance in HeLa (∼1.4 μm) and CEM-SS T cells (∼0.9 μm). Disrupting interactions between HIV-1 capsid and host cleavage and polyadenylation specificity factor (CPSF6) resulted in localization of proviruses to lamina-associated domains (LADs) adjacent to the NE in HeLa cells (∼0.9 - 1.0 μm); however, in CEM-SS T cells, there was little or no shift toward the NE (∼0.9 μm), indicating cell-type differences in the locations of transcriptionally active proviruses. The distance from the NE was not correlated with transcriptional activity, and transcriptionally active proviruses were randomly distributed throughout the HeLa cell after several cell divisions, indicating that the intranuclear locations of the chromosomal sites of integration are dynamic. After nuclear import HIV-1 cores colocalized with nuclear speckles, nuclear domains enriched in pre-mRNA splicing factors, but transcriptionally active proviruses detected 20 h after infection were mostly located outside but near nuclear speckles, suggesting a dynamic relationship between the speckles and integration sites. Overall, these studies establish that the nuclear distribution of HIV-1 proviruses is dynamic and the distance between HIV-1 proviruses and the NE does not correlate with transcriptional activity. IMPORTANCE HIV-1 integrates its genomic DNA into the chromosomes of the infected cell, but how it selects the site of integration and the impact of their location in the 3-dimensional nuclear space is not well understood. Here, we examined the nuclear locations of proviruses 1 and 5 days after infection and found that integration sites are first located near the nuclear envelope but become randomly distributed throughout the nucleus after a few cell divisions, indicating that the locations of the chromosomal sites of integration that harbor transcriptionally active proviruses are dynamic. We also found that the distance from the nuclear envelope to the integration site is cell-type dependent and does not correlate with proviral transcription activity. Finally, we observed that HIV-1 cores were localized to nuclear speckles shortly after nuclear import, but transcriptionally active proviruses were located adjacent to nuclear speckles. Overall, these studies provide insights into HIV-1 integration site selection and their effect on transcription activities.


Evolution of patterning.
Developing tissues are patterned in space and time; this enables them to differentiate their cell types and form complex structures to support different body plans. Although space and time are two independent entities, there are many examples of spatial patterns that originate from temporal ones. The most prominent example is the expression of the genes hunchback, Krüppel, pdm, and castor, which are expressed temporally in the neural stem cells of the Drosophila ventral nerve cord and spatially along the anteroposterior axis of the blastoderm stage embryo. In this Viewpoint, we investigate the relationship between space and time in specific examples of spatial and temporal patterns with the aim of gaining insight into the evolutionary history of patterning.


c-myc null cells misregulate cad and gadd45 but not other proposed c-Myc targets.
We report here that the expression of virtually all proposed c-Myc target genes is unchanged in cells containing a homozygous null deletion of c-myc. Two noteworthy exceptions are the gene cad, which has reduced log phase expression and serum induction in c-myc null cells, and the growth arrest gene gadd45, which is derepressed by c-myc knockout. Thus, cad and gadd45 are the only proposed targets of c-Myc that may contribute to the dramatic slow growth phenotype of c-myc null cells. Our results demonstrate that a loss-of-function approach is critical for the evaluation of potential c-Myc target genes.


Dealing with the impact of the COVID-19 outbreak: Are some athletes' coping profiles more adaptive than others?
The public health policies and sanitary measures taken by governments in various countries to stem the spread of the COVID-19 pandemic (e.g. lockdown, social distancing) have major implications for athletes. The radical changes are challenging and risk causing significant career disruption to athletes, with subsequent negative psychological effects. Thus, the ways athletes cope with such adversity is of critical importance. The present study aimed to identify athletes' coping profiles using a person-centred approach, based on their reported use of multiple coping strategies in response to the impact of the COVID-19 outbreak, and to compare levels of anxiety, stress appraisals, interpersonal coping strategies, and availability and appreciation of the major sources of support across profiles. A total of 526 French athletes competing at national to elite levels answered an online questionnaire during the lockdown. Latent profile analysis results yielded four distinct coping profiles (i.e. self-reliant, engaged, avoidant, active and social). The MANOVA showed that athletes belonging to the four profiles differed on anxiety, stress appraisals, social support, and interpersonal coping. In particular, avoidant copers reported high levels of anxiety, threat, and uncontrollability, and appeared less able to regulate responses to the impact of the COVID-19 outbreak. Using a person-centred approach, the findings could inform the development of more adequate care, support, and intervention for athletes, especially avoidant copers, who were characterized by the least effective coping skills and resources. Accordingly, stress reappraisal and stress mindset interventions could be promising approaches to effectively manage pandemic-related impact during and after the COVID-19 crisis.HighlightsThe COVID-19 outbreak has major implications for athletes and is causing significant disruption to their careers. Using a person-centred approach, four coping profiles emerge showing athletes' preferred use of several coping strategies in response.The four coping profiles (i.e. self-reliant, engaged, avoidant, active and social) differentiate distinct groups of athletes in relation to anxiety, stress appraisals, social support, and interpersonal coping.Avoidant copers were characterized by the least effective coping skills and social context of coping. Management of the COVID-19 situation may be more problematic for them than other in mitigating its negative psychological effects.Using a person-centred approach, the findings could inform the development of more adequate care, support, and intervention for athletes, especially avoidant copers, who were characterized by the least effective coping skills and resources.


Estimating a constant WTP for a QALY-a mission impossible?
Economic evaluations are an important input to decision-making and priority-setting in the health care sector. Measuring preferences for health improvements, as the demand-side value (willingness to pay) of gaining a quality-adjusted life year (QALY), is one relevant component in the interpretation of the results from health economic evaluations. Our article addresses whether willingness to pay for a QALY (WTP-Q) is sensitive to the size of the health differences and the probability for improvement. We use data from a contingent valuation survey based on 1400 respondents conducted in the spring of 2014. The results show that the expectation of sensitivity to scope, or higher WTP to the larger expected quality of life improvement, is not supported. We find WTP-Q values that conform reasonably well to previous studies in Sweden.


Theabrownin suppresses in vitro osteoclastogenesis and prevents bone loss in ovariectomized rats.
Drinking tea exhibits beneficial effects on bone health and may protect against osteoporosis, particularly in postmenopausal women. Theabrownin (TB) is the main component responsible for the biological activities of Pu-erh tea, but whether it possesses anti-osteoporotic potential remains unknown. Here we investigated the in vitro and in vivo anti-osteoporotic effects of TB in the RAW 264.7 cell line and ovariectomized (OVX) rats, respectively. Our in vitro studies showed that TB significantly suppressed RANKL-induced osteoclastogenesis and the expression of related marker proteins, including NFATc1, TRAP, c-Fos, and cathepsin K. In vivo studies showed that TB treatment effectively ameliorated blood biochemical parameters, organ weights and organ coefficients in OVX rats. In addition, TB treatment significantly improved femoral bone mineral density (BMD) and biomechanical properties. What's more, TB treatment strikingly ameliorated bone microarchitecture in OVX rats because of increased cortical bone thickness and trabecular bone area in the femur. Our study therefore demonstrated that TB can inhibit RANKL-induced osteoclastogenesis in vitro and prevent bone loss in ovariectomized rats. Consequently, TB has a promising potential in postmenopausal osteoporosis treatment.


Heavy water and (15) N labelling with NanoSIMS analysis reveals growth rate-dependent metabolic heterogeneity in chemostats.
To measure single-cell microbial activity and substrate utilization patterns in environmental systems, we employ a new technique using stable isotope labelling of microbial populations with heavy water (a passive tracer) and (15) N ammonium in combination with multi-isotope imaging mass spectrometry. We demonstrate simultaneous NanoSIMS analysis of hydrogen, carbon and nitrogen at high spatial and mass resolution, and report calibration data linking single-cell isotopic compositions to the corresponding bulk isotopic equivalents for Pseudomonas aeruginosa and Staphylococcus aureus. Our results show that heavy water is capable of quantifying in situ single-cell microbial activities ranging from generational time scales of minutes to years, with only light isotopic incorporation (∼0.1 atom % (2) H). Applying this approach to study the rates of fatty acid biosynthesis by single cells of S. aureus growing at different rates in chemostat culture (∼6 h, 1 day and 2 week generation times), we observe the greatest anabolic activity diversity in the slowest growing populations. By using heavy water to constrain cellular growth activity, we can further infer the relative contributions of ammonium versus amino acid assimilation to the cellular nitrogen pool. The approach described here can be applied to disentangle individual cell activities even in nutritionally complex environments.


Applications of the InChI in cheminformatics with the CDK and Bioclipse.
The InChI algorithms are written in C++ and not available as Java library. Integration into software written in Java therefore requires a bridge between C and Java libraries, provided by the Java Native Interface (JNI) technology. We here describe how the InChI library is used in the Bioclipse workbench and the Chemistry Development Kit (CDK) cheminformatics library. To make this possible, a JNI bridge to the InChI library was developed, JNI-InChI, allowing Java software to access the InChI algorithms. By using this bridge, the CDK project packages the InChI binaries in a module and offers easy access from Java using the CDK API. The Bioclipse project packages and offers InChI as a dynamic OSGi bundle that can easily be used by any OSGi-compliant software, in addition to the regular Java Archive and Maven bundles. Bioclipse itself uses the InChI as a key component and calculates it on the fly when visualizing and editing chemical structures. We demonstrate the utility of InChI with various applications in CDK and Bioclipse, such as decision support for chemical liability assessment, tautomer generation, and for knowledge aggregation using a linked data approach. These results show that the InChI library can be used in a variety of Java library dependency solutions, making the functionality easily accessible by Java software, such as in the CDK. The applications show various ways the InChI has been used in Bioclipse, to enrich its functionality.


[The importance of Holter ECG monitoring in the diagnosis of latent arrhythmias in patients with acute respiratory viral infections].
Altogether 37 patients suffering from influenza and acute respiratory viral infections were examined. In 25 patients, acute infections ran their course in association with coronary heart disease. According to the ECG readings, 15% of the patients had rhythm and conduction disorders. Meanwhile Holter ECG monitoring revealed the above disorders in 70% of the patients afflicted with influenza and acute respiratory viral infections.


Effect of faecal calprotectin assay variability on the management of inflammatory bowel disease and potential role of faecal S100A12.
To prospectively evaluate whether between-assay variability of different faecal calprotectin (f-Cp) assays influences diagnostic accuracy for inflammatory bowel disease (IBD) in a cohort of patients with confirmed IBD and irritable bowel syndrome (IBS). To also evaluate the diagnostic accuracy of faecal S100A12 (f-S100A12) against f-Cp in the same patient cohort and assess whether f-S100A12 offers additional diagnostic value. F-Cp using four commercially available f-Cp assays, f-S100A12 and blood biomarkers were measured in patients, recruited from the local IBD clinic, who had established IBS or active ulcerative colitis (UC) and Crohn's disease (CD). Diagnostic sensitivities and specificities for each assay and biomarker were calculated and compared. Median f-Cp levels in all assays were significantly higher in UC (347-884 µg/g; n=28) and CD (377-838 µg/g; n=15) compared with IBS (6-27 µg/g; n=17). Sensitivities and specificities at 50 µg/g were 94%-100% and 82%-100%, respectively. Median f-S100A12 levels were significantly higher in UC (81.0 µg/g; IQR 38.3-159.8) and CD (47.2 µg/g; IQR 5.3-108.9) compared with IBS (0.7 µg/g; IQR 0.5-0.8). At 2.8 µg/g, f-S100A12 had a sensitivity of 97% and specificity of 94%. The blood biomarkers demonstrated sensitivities and specificities of 44%-63% and 80%-92%, respectively. The diagnostic sensitivity of the calprotectin assays was similar despite inter-kit variability in absolute values. There is a need for f-Cp assay standardisation, but in its absence assay-specific cut-off values may optimise their diagnostic performance. F-S100A12 demonstrated comparable sensitivity and specificity to f-Cp and although a research tool at present, may have a future role to play in the diagnosis and management of these patients.


High Tumor Burden Predicts Poor Response to Enzalutamide in Metastatic Castration-Resistant Prostate Cancer Patients.
To assess the predictive value of tumor burden on the biochemical response, and radiological response in Taiwanese metastatic castration-resistant prostate cancer (mCRPC) patients receiving enzalutamide. The mCRPC patients treated with enzalutamide were recruited from three hospitals. High tumor burden (HTB) was classified as metastases at either appendicular bone or visceral organ. Good prostate-specific antigen (PSA) response was defined as PSA reduction of 80%. In this cohort, there were 104 (54.2%) HTB patients and 88 (45.8%) with low tumor burden (LTB). Compared to LTB patients, fewer HTB patients had good PSA response (odds ratio: 0.43, range: 0.22-0.87, p = 0.019) and fewer radiological response (complete and partial remission) (odds ratio: 0.78, range: 0.36-1.68, p = 0.52) to enzalutamide. The disease control rate which also contained stable disease, was still lower in HTB (76.0%) than LTB group (92.9%, OR: 0.24, range: 0.07-0.77, p = 0.016) in the multivariable model. In addition, HTB patients had significantly shorter progression-free survival duration than did LTB patients (median: 8.3 vs. 21.6 months, log-rank test p = 0.003) in the univariable analysis. The tumor burden before the use of enzalutamide was associated with treatment outcomes. HTB reduced PSA response rate, radiological response rate and progression-free survival duration.


Study on self-assembled monolayers of functionalized azobenzene thiols on gold: XPS, electrochemical properties, and surface-enhanced Raman spectroscopy.
Self-assembled monolayers (SAMs) of 4-acetamino-4'-(4-mercaptobutoxy)azobenzene (CH3)CONH-ph-N=N-ph-O(CH2)(4)SH, abbr. aaAzoC4SH) and 4-mercaptobutoxy azobenzene (ph-N=N-ph-O(CH2)(4)SH, abbr. AzoC4SH) on a gold surface have been studied by X-ray photoelectron spectroscopy (XPS), FT Raman spectroscopy, and electrochemistry. A surface-enhanced Raman scattering (SERS)-active system with a "sandwiched" structure of Ag/R-Azo-C4S-/Au was conveniently obtained by the method of Tollen's test. The relationship between the SERS effect and the structural nature of the system indicates that the enhancement correlates to both the silver islands above and the gold substrate underneath. The redox behaviors of the self-assembly on gold electrodes showed that the SAMs of the two compounds exhibit well-behaved voltammetric responses in a Britton-Robinson buffer corresponding to the irreversible two-electron, two-proton reduction-oxidation of azobenzene. The apparent electron-transfer rate kinetics is very sluggish, and the rate constant k(app) of aaAzoC4SH/Au (1.34 x 10(-6) s(-1)) is lower than that of AzoC4SH/Au (1.63 x 10(-4) s(-1)), which may be attributed to the different spatial restriction of close-packing structures on the conformational change accompanied by electron and proton transfer in the SAMs.


Using relevance mapping methodology to design an adolescent mental health intervention in India.
Adolescents in low and middle-income countries experience pronounced mental health needs in contexts where infrastructure and resources are scarce. While evidence-based treatment are readily available, they may not fit the unique needs of certain contexts. This manuscript illustrates the systematic process of applying 'relevance mapping' methodology to leverage the youth mental health evidence base to identify candidate practices for inclusion in the development of a contextually appropriate psychological treatment protocol for common adolescent mental health problems in India. The practice identification was informed by two datasets obtained from adolescent samples in India. The first was an epidemiological dataset from a large community sample in Goa (N = 2,048); the second incorporated 'youth top problems' reported by service-seeking students presenting to school counsellors in Goa and Delhi (N = 78). Problems identified in each dataset were categorized using structured codes. Problem codes and youth demographics were then indexed against a database of hundreds of evidence-based psychological treatments and their associated clinical trials. This methodology revealed the most common practice elements (discrete therapeutic strategies) and their most efficient combinations with evidence of effectiveness matching the demographics and diagnostic category (anxiety, disruptive behaviors and depression) prevalent in the planned treatment population. For anxiety, the most common practice elements for this age group were exposure, cognitive coping, and psychoeducation. For disruptive behaviors, the most common practices were problem-solving, goal-setting, and rapport-building. For depression, cognitive coping, behavioral activation, and psychoeducation were the most common practice elements. These practice elements provided the treatment development team with a preliminary list of candidate content for the development of an intensive psychological treatment within a stepped care service model to address common adolescent mental health problems in schools in India.


Homozygous deletion of six olfactory receptor genes in a subset of individuals with Beta-thalassemia.
Progress in the functional studies of human olfactory receptors has been largely hampered by the lack of a reliable experimental model system. Although transgenic approaches in mice could characterize the function of individual olfactory receptors, the presence of over 300 functional genes in the human genome becomes a daunting task. Thus, the characterization of individuals with a genetic susceptibility to altered olfaction coupled with the absence of particular olfactory receptor genes will allow phenotype/genotype correlations and vindicate the function of specific olfactory receptors with their cognate ligands. We characterized a 118 kb β-globin deletion and found that its 3' end breakpoint extends to the neighboring olfactory receptor region downstream of the β-globin gene cluster. This deletion encompasses six contiguous olfactory receptor genes (OR51V1, OR52Z1, OR51A1P, OR52A1, OR52A5, and OR52A4) all of which are expressed in the brain. Topology analysis of the encoded proteins from these olfactory receptor genes revealed that OR52Z1, OR52A1, OR52A5, and OR52A4 are predicted to be functional receptors as they display integral characteristics of G-proteins coupled receptors. Individuals homozygous for the 118 kb β-globin deletion are afflicted with β-thalassemia due to a homozygous deletion of the β-globin gene and have no alleles for the above mentioned olfactory receptors genes. This is the first example of a homozygous deletion of olfactory receptor genes in human. Although altered olfaction remains to be ascertained in these individuals, such a study can be carried out in β-thalassemia patients from Malaysia, Indonesia and the Philippines where this mutation is common. Furthermore, OR52A1 contains a γ-globin enhancer, which was previously shown to confer continuous expression of the fetal γ-globin genes. Thus, the hypothesis that β-thalassemia individuals, who are homozygous for the 118 kb deletion, may also have an exacerbation of their anemia due to the deletion of two copies of the γ-globin enhancer element is worthy of consideration.


Adverse effects of heavy prenatal maternal smoking on attentional control in children with ADHD.
Exposure to heavy maternal cigarette smoking in pregnancy and severe maternal psychosocial stress during pregnancy appear to be important risk factors for the development of ADHD. This study aimed to determine whether these perinatal risk factors were associated with neuropsychological deficits commonly seen in ADHD. We examined the effect of these two risk factors on measures of attentional control, motor inhibition, visual-motor integration, and fine motor coordination in a group of 81 children with ADHD, aged from 8 to 18 years. The neuropsychological battery included the Connors' Continuous Performance Test (CPT), the Stroop Color-Word Interference Test, the Beery Visual-Motor Integration Test, and the Purdue Pegboard Test. Heavy maternal smoking during pregnancy was associated with slower reaction times (p < .002), and reaction time variability (p < .007) on the CPT. This study suggests a persistent negative effect of heavy prenatal maternal smoking on attentional control in children with ADHD. Future studies should examine the neurobiological basis and determine the degree to which inherited genetic susceptibility factors contribute to this finding.


Chronic invasive rhinosinusitis by Conidiobolus coronatus, an emerging microorganism.
Fungi from the Conidiobolus genus have been implicated in the development of chronic invasive fungal rhinosinusitis, mainly in tropical countries. The mycosis associated to these fungi may cause irreversible facial deformities and is potentially fatal. The authors present the first case of a chronic invasive fungal rhinosinusitis due to Conidiobolus coronatus diagnosed in a 66-year-old Caucasian male patient, living in Portugal without any travels abroad and complaining of progressive refractory nasal obstruction, facial pain and anosmia. Upon the culture of samples collected during sinus endoscopic surgery, colonies that presented a macroscopic aspect remembering wax were detected. The microscopic evaluation allowed the observation of simple conidiophores forming spherical conidia, and of conidiophores that presented hair-like appendages. Together, these characteristics allowed the identification of the fungi as a Conidiobolus, which was confirmed upon the DNA sequencing. The authors emphasised the role of this fungi as an emergent microorganism as well as the difficulties associated to the diagnosis and treatment.


How Is Health Literacy Related to Pap Testing Among US Women?
While Pap testing has significantly reduced the burden of cervical cancer, not all women follow prevention recommendations of cervical cancer screening every 3 years. Health literacy regarding Pap testing may influence the adoption of this behavior. The objective of this study was to assess the health literacy-related factors associated with Pap testing among a nationally representative sample of women in the USA. The Health Information National Trends Survey Cycles 4.4 and 5.1 were restricted to women 21-65 years of age (N = 2992). Questions were selected using the Integrated Model of Health Literacy domains: access (i.e., seeking cancer information), understand (i.e., HPV awareness, HPV knowledge), appraise (i.e., prevention not possible, chance of getting cancer), and apply (i.e., received a Pap in last 3 years [outcome]). Survey-weighted, logistic regression models estimated how the health literacy domains were associated with Pap testing, using SAS 9.4. In the sample, 81.1% of women received a Pap test within the last 3 years. The analysis revealed women who knew HPV is an STD (aOR = 1.64, 95% CI 1.20-2.26) were more likely to have received a Pap test in the last 3 years, while controlling for sociodemographic factors. These findings indicate that knowledge about HPV may be associated with Pap testing behavior among US women. Continued research is needed to examine the impact of health literacy on Pap testing given the changes in screening guidelines, with the ultimate goal of decreasing cervical cancer.


The characterization and localization of the glutamate receptor subunit GluR1 in the rat brain.
The cloning of cDNAs that encode functional glutamate receptors makes it possible to produce antibodies that can be used as high-affinity probes for the localization and characterization of these receptors in the mammalian brain. We have made antibodies to different regions of the first cloned member of this family, GluR1, using bacterially overproduced antigen. On Western blots, these antisera detect glycoprotein(s) of 105 kDa present in crude membranes of the hippocampus and cerebellum. The 105-kDa band is associated with postsynaptic densities, and it is observed in cultured cells upon transfection with the GluR1 cDNA. Although glutamate receptors are thought to be the most prevalent excitatory ligand-gated ion channel in the mammalian brain, immunohistochemistry reveals that the receptors recognized by these antisera are localized predominantly in neurons of the cerebellum and some structures of the limbic system, including the hippocampus, the central nucleus of the amygdala, and portions of the septum. This pattern of expression is, in general, consistent with the distribution of GluR1 mRNA as determined by in situ hybridization histochemistry. Our results suggest that glutamate excitatory circuits recognized by these antisera are predominantly found in regions of the limbic system that are reciprocally interconnected.


Is Dietary Vitamin A Associated with Myopia from Adolescence to Young Adulthood?
Potential links may exist between vitamin A intake and myopia via various pathways. In this study, we examined the association between dietary vitamin A intake during adolescence and myopia in early adulthood. We performed a prospective analysis utilizing data collected from participants of the Raine Study Gen2. Dietary vitamin A intake, determined via food frequency questionnaires completed at ages 14, 17, and 20 years, was compared with ophthalmic measurements collected at year 20. Low vitamin A levels were defined as <600 µg/day. Regression models were used to adjust for ocular sun exposure level, educational level, and parental myopia as potential confounders. A total of 642 subjects were analyzed. Although those with adequate vitamin A intakes were less likely to be myopic (P = 0.03), this association became insignificant when adjusted for potential confounding factors in logistic regression modeling (odds ratio, 0.59; 95% confidence interval, 0.98-2.52; P = 0.06). There were no significant associations between total vitamin A intakes during adolescence and year 20 refractive errors after adjustment for confounders. Replication of this finding and further investigations are essential to rule out the suggestion that sufficient vitamin A intake during adolescence is associated with lower risk of myopia in early adulthood. Our findings are not definitive that ingesting foods high in vitamin A during childhood and adolescence does not have a role for preventing myopia in early adulthood.


Quantitative urinary proteomics using stable isotope labelling by peptide dimethylation in patients with prostate cancer.
Prostate cancer (PCa) is the most commonly diagnosed malignancy in men. The current prevalent diagnosis method, prostate-specific antigen (PSA) screening test, has low sensitivity, specificity and is poor at predicting the grade of disease. Thus, new biomarkers are urgently needed to improve the PCa diagnosis and staging for the management of patients. The aim of this study is to investigate the first voided urinary sample after massage for biomarker discovery for PCa. In this work, untargeted metabolomic profiling of the first voided urinary sample after massage from 28 confirmed prostate cancer patients, 20 benign enlarged prostate patients and 6 healthy volunteers was performed using liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-MS/MS). Single and multiple peptide protein and cross-linking molecules were identified using PEAKS software. Analytical and diagnostic performance was tested using the Student's t test, Benjamini Hochberg correction and the receiver operating characteristic (ROC) curves. Using differential display analysis to compare peptides and cross-linking molecules of urinary samples between patients with benign, enlarged prostate and malignant cancer, we identified multiple peptides derived from osteopontin (SPP1) and prothrombin (F2) that are lower in PCa patients than in benign and enlarged prostate. The diagnosis accuracies of SPP1 and F2 peptides are 0.65-0.77 and 0.68-0.72, respectively. In addition to this, there are significant differences between PCa and benign/enlarged prostate patients in pyridinoline (PYD) and deoxypyridinoline (DPD) (p value = 0.001). Differences also, as shown in the excretion of these molecules for different stages of PCa (p value = 0.04) as the level of DPD and DPD/PYD ratio, were high in patients with locally advanced tumours. The study underscores the importance of proteomics analysis, and our results demonstrate that a urinary-based in depth proteomic approach allows the potential identification of dysregulated pathways and diagnostic biomarkers.


Initial evidence on differences among Enterovirus 71, Coxsackievirus A16 and Coxsackievirus B4 in binding to cell surface heparan sulphate.
Cell surface heparan sulphate (HS) mediates infection for many viruses from diverse families. We demonstrated significant antiviral potencies for a number of HS mimetics against a cloned strain of Enterovirus 71 (EV71) in a previous study. Thus, the involvement of HS in mediating viral infection of isolates of human enteroviruses was investigated in Vero and human neural cells in the present work. In both cell lines, heparin and pentosan polysulphate significantly inhibited both infection and attachment of low passage clinical isolates of EV71 and Coxsackievirus A16 (CVA16) but showed no affect on Coxsackievirus B4 (CVB4) (p < 0.05). In addition, enzymatic removal of cell surface HS by heparinase I prevented binding of the clinical EV71 by nearly 50 % but failed to significantly inhibit CVA16 or CVB4 binding in Vero cells. Overall, the findings of this study provides evidence that whilst highly sulphated domains of HS serve as an essential attachment co-receptor for EV71, HS might be used as an alternative attachment receptor by the other member of Human Enterovirus group A, CVA16. In addition, HS may not mediate early infection in CVB4.


A framework for evaluating the appropriateness of clinical decision support alerts and responses.
Alerting systems, a type of clinical decision support, are increasingly prevalent in healthcare, yet few studies have concurrently measured the appropriateness of alerts with provider responses to alerts. Recent reports of suboptimal alert system design and implementation highlight the need for better evaluation to inform future designs. The authors present a comprehensive framework for evaluating the clinical appropriateness of synchronous, interruptive medication safety alerts. Through literature review and iterative testing, metrics were developed that describe successes, justifiable overrides, provider non-adherence, and unintended adverse consequences of clinical decision support alerts. The framework was validated by applying it to a medication alerting system for patients with acute kidney injury (AKI). Through expert review, the framework assesses each alert episode for appropriateness of the alert display and the necessity and urgency of a clinical response. Primary outcomes of the framework include the false positive alert rate, alert override rate, provider non-adherence rate, and rate of provider response appropriateness. Application of the framework to evaluate an existing AKI medication alerting system provided a more complete understanding of the process outcomes measured in the AKI medication alerting system. The authors confirmed that previous alerts and provider responses were most often appropriate. The new evaluation model offers a potentially effective method for assessing the clinical appropriateness of synchronous interruptive medication alerts prior to evaluating patient outcomes in a comparative trial. More work can determine the generalizability of the framework for use in other settings and other alert types.


Quality and consistency of guidelines for the management of mild traumatic brain injury in the emergency department.
The objective was to provide an overview of the recommendations and quality of evidence-based clinical practice guidelines (CPGs) for the emergency management of mild traumatic brain injury (mTBI), with a view to informing best practice and improving the consistency of recommendations. Electronic searches of health databases (MEDLINE, EMBASE, The Cochrane Library, PsycINFO), CPG clearinghouse websites, CPG developer websites, and Internet search engines up to January 2010 were conducted. CPGs were included if 1) they were published in English and freely accessible, 2) their scope included the management of mTBI in the emergency department (ED), 3) the date of last search was within the past 10 years (2000 onward), 4) systematic methods were used to search for evidence, and 5) there was an explicit link between the recommendations and the supporting evidence. Four authors independently assessed the quality of the included CPGs using the Appraisal of Guidelines, Research and Evaluation (AGREE) Instrument. The authors extracted and categorized recommendations according to initial clinical assessment, imaging, management, observation, discharge planning, and patient information and follow-up. The search identified 18 potential CPGs, of which six met the inclusion criteria. The included CPGs varied in scope, target population, size, and guideline development processes. Four CPGs were assessed as "strongly recommended." The majority of CPGs did not provide information about the level of stakeholder involvement (mean AGREE standardized domain score = 57%, range = 25% to 81%), nor did they address the organizational/cost implications of applying the recommendations or provide criteria for monitoring and review of recommendations in practice (mean AGREE standardized domain score = 46.6%, range = 19% to 94%). Recommendations were mostly consistent in terms of the use of the Glasgow Coma Scale (GCS) score (adult and pediatric) to assess the level of consciousness, initial assessment criteria, the use of computed tomography (CT) scanning as imaging investigation of choice, and the provision of patient information. The CPGs defined mTBI in a variety of ways and described different rules to determine the need for CT scanning and therefore used different criteria to identify high-risk patients. Higher-quality CPGs for mTBI are consistent in their recommendations about assessment, imaging, and provision of patient information. There is not, however, an agreed definition of mTBI, and the quality of future CPGs could be improved with better reporting of stakeholder involvement, procedures for updating, and greater consideration of the applicability of the recommendations (cost implications, monitoring procedures). Nevertheless, guideline developers may benefit from adapting existing CPGs to their local context rather than investing in developing CPGs de novo.


EU-USA pathology panel for uniform diagnosis in randomised controlled trials for HRCT screening in lung cancer.
Randomised controlled trials for lung cancer screening using high-resolution computed tomography are now underway. In order to allow effective future comparison of the different trials, as well as strengthening conclusions based upon the analysis of larger data sets, uniformity and consistency of pathology diagnosis are essential. The aim of the present study was to determine the effectiveness of the learning process in this difficult area of diagnostic pathology. Eight pathologists received two CD-ROMs, each with digital images of 30 cases. After diagnosing the first series, selected background reading was provided. Kappa (kappa) scores were calculated for each pathologist and category, and were compared to the consensus score. The readings of the first series showed a moderate agreement kappa score: mean+/-sd for category numbers 8 (all eight categories) and 2 were 0.53+/-0.05 and 0.65+/-0.04, respectively. The kappa 2 score distinguished between categories denoting benign and malignant lesions. The second series resulted in a good agreement kappa score: 0.65+/-0.06 for category number 8 and 0.81+/-0.02 for category number 2. In conclusion, this study demonstrates that screen-detected cases pose particular problems for pathologists and that a trained pathology panel serving randomised controlled trials is likely to lead to more consistent and accurate tissue diagnosis.


Hexagonal diamonds in meteorites: implications.
A new polymorph of carbon, hexagonal diamond, has been discovered in the Canyon Diablo and Goalpara meteorites. This phase had been synthesized recently under specific high-pressure conditions in the laboratory. Our results: provide strong evidence that diamonds found in these meteorites were produced by intense shock pressures acting on crystalline graphite inclusions present within the meteorite before impact, rather than by disintegration of larger, statically grown diamonds, as some theories propose.


Inappropriate expression of human transforming growth factor (TGF)-alpha in the uterus of transgenic mouse causes downregulation of TGF-beta receptors and delays the blastocyst-attachment reaction.
In the mouse, the initiation of the attachment reaction between the blastocyst trophectoderm and luminal epithelium of the receptive uterus occurs in the evening (2200-2300 h) of day 4 of pregnancy (day 1 = vaginal plug) and is followed by proliferation and differentiation of stromal cells into decidual cells at the sites of blastocyst attachment. This investigation demonstrates that an inappropriate expression of the human transforming growth factor alpha (hTGF-alpha) transgene in the uterus under the direction of a mouse metallothionein-I promoter downregulates uterine expression of TGF-beta receptor subtypes and delays the initiation of implantation (attachment reaction) resulting in delayed parturition. This delay in the attachment reaction is accompanied by deferred uterine expression of amphiregulin. The results suggest that a coordinated 'cross-talk' between the signaling pathways executed by epidermal growth factor-like growth factors and TGF-beta 5 is important for the normal implantation process.