Aberrant DNA methylation of MGMT and hMLH1 genes in prediction of gastric cancer.
We aimed to explore the association between aberrant DNA methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) and human mutL homolog 1 (hMLH1) genes with gastric cancer. A total of 283 gastric cancer patients who were confirmed by pathological diagnosis were included in our study. Aberrant DNA methylation of MGMT and hMLH1 were detected. The proportions of DNA hypermethylation in MGMT and hMLH1 in cancer tissues were significantly higher than those in remote normal-appearing tissues. The DNA hypermethylation of MGMT was correlated with the tumor-necrosis-metastasis stage in gastric cancer tissues. Results showed that individuals with gastric cancer in the N1 and M1 stages had a significantly higher risk of DNA hypermethylation of MGMT in cancer tissues [odds ratio (OR) = 1.97, 95% confidence interval (CI) = 1.15-3.37 for the N1 stage; OR (95%CI) = 5.39 (2.08-14.98) for the M1 stage]. In conclusion, we found that aberrant hypermethylation of MGMT could be a predictive biomarker for detecting gastric cancer.


XK469, a selective topoisomerase IIbeta poison.
XK469 (NSC 697887) is a synthetic quinoxaline phenoxypropionic acid derivative that possesses unusual solid tumor selectivity and activity against multidrug-resistant cancer cells. We report here that XK469 and its S(-) and R(+)-isomers induce reversible protein-DNA crosslinks in mammalian cells. Under protein denaturing conditions, the protein-DNA crosslinks are rendered irreversible and stable to DNA banding by CsCl gradient ultracentrifugation. Several lines of evidence indicate that the primary target of XK469 is topoisomerase IIbeta. Preferential targeting of topoisomerase IIbeta may explain the solid tumor selectivity of XK469 and its analogs because solid tumors, unlike leukemias, often have large populations of cells in the G(1)/G(0) phases of the cell cycle in which topoisomerase IIbeta is high whereas topoisomerase IIalpha, the primary target of many leukemia selective drugs, is low.


Design of oblate cylindrical perfect lens using coordinate transformation.
A circular cylindrical and an oblate cylindrical perfect lens are designed by using coordinate transformation theory. Theoretical analyses are performed to give an insight into the variant angular magnification in the oblate cylindrical perfect lens. We further take advantage of the oblate cylindrical coordinate system to make the object surface flat for future practical imaging and lithography applications. We also for the first time make systematical simulations of various kinds of perfect lens, including numerical confirmation of Mankei Tsang's statement about the magnification of the planar perfect lens and the imaging and magnifying performance beyond the diffraction limit of our designed perfect lens. All the calculated results agree well with our mathematical derivations, thus verifying the coordinate transformation method in designing perfect lenses.


Prostate-specific membrane antigen (PSMA) fusion imaging in prostate cancer: PET-CT vs PET-MRI.
To investigate whether PET-CT or PET-MRI is more appropriate for imaging prostate cancer, in terms of primary tumor detection, local staging and recurrence, as well as lymph nodes and distant metastases. A systematic literature search was conducted on Embase, PubMed/MEDLINE, and the Cochrane Library database. Studies evaluating the diagnostic performance of PET-CT vs PET-MRI in prostate cancer patients were emphasized. We reviewed 57 original research articles during the period 2016-2021: 14 articles regarding the radiotracer PSMA; 18 articles regarding the primary tumor detection, local tumor staging, managing local recurrence; 17 articles for managing lymph node metastases; and eight articles for managing bone and other distant metastases. PSMA PET could be complementary to mpMRI for primary prostate cancer localization and is particularly valuable for PI-RADS three lesions. PET-MRI is better than PET-CT in local tumor staging due to its specific benefit in predicting extracapsular extension in MRI-occult prostate cancer patients. PET-MRI is likely superior as compared with PET-CT in detecting local recurrence, and has slightly higher detection rates than PET-CT in lymph node recurrence. PET-CT and PET-MRI seem to have equivalent performance in detecting distant bony or visceral metastases. In conclusion, PET-MRI is suitable for local and regional disease, either primary staging or restaging, whereas PET-CT is valuable for managing distant bony or visceral metastasis. We reviewed the emerging applications of PET-MRI and PET-CT in clinical aspects. Readers will gain an objective overview on the strength and shortfalls of PET-MRI or PET-CT in the management of prostate cancer.


Effects of the label "schizophrenia" on causal attributions of violence.
We investigated the relation between the label of "schizophrenia" and causal attributions of violence. Undergraduates read 1 of 10 scenarios in which two variables were manipulated: a psychiatric label and environmental stress. The scenario described an employee who acted violently toward his boss. Subjects made causal attributions for the employee's behavior by completing an adapted version of the Causal Dimension Scale II. Subjects also completed a questionnaire designed to explore several issues concerning the effects of the schizophrenia label on perceptions of behavior. Contrary to the primary hypothesis, the schizophrenia label did not lead subjects to make significantly more personality causal attributions for violent behavior. With increasing environmental stress, subjects did make significantly fewer personality attributions. A follow-up study using practicing clinicians as subjects yielded similar findings. The results of these studies are discussed in light of perceived stereotypes of persons with schizophrenia and conceptual issues in attribution research.


Portal motor velocity and internal force resisting viral DNA packaging in bacteriophage phi29.
During the assembly of many viruses, a powerful molecular motor compacts the genome into a preassembled capsid. Here, we present measurements of viral DNA packaging in bacteriophage phi29 using an improved optical tweezers method that allows DNA translocation to be measured from initiation to completion. This method allowed us to study the previously uncharacterized early stages of packaging and facilitated more accurate measurement of the length of DNA packaged. We measured the motor velocity versus load at near-zero filling and developed a ramped DNA stretching technique that allowed us to measure the velocity versus capsid filling at near-zero load. These measurements reveal that the motor can generate significantly higher velocities and forces than detected previously. Toward the end of packaging, the internal force resisting DNA confinement rises steeply, consistent with the trend predicted by many theoretical models. However, the force rises to a higher magnitude, particularly during the early stages of packaging, than predicted by models that assume coaxial inverse spooling of the DNA. This finding suggests that the DNA is not arranged in that conformation during the early stages of packaging and indicates that internal force is available to drive complete genome ejection in vitro. The maximum force exceeds 100 pN, which is about one-half that predicted to rupture the capsid shell.


Maternal smoking during pregnancy and childhood overweight and fat distribution: the KOALA Birth Cohort Study.
What is already known about this subject There is an association between maternal smoking during pregnancy and higher body mass index (BMI) and overweight in childhood. What this study adds The association between maternal smoking during pregnancy and childhood overweight develops with age, starting with a lower birth weight, followed by weight catch-up in the first year after birth, finally leading to overweight at school age. Children of mothers who had smoked during pregnancy had a higher risk of exceeding the 85th percentile of BMI, waist circumference and total skinfold thickness at school age. Maternal smoking during pregnancy is associated with childhood overweight, but the association with fat distribution is not clear. To explore the longitudinal association between smoking during pregnancy and childhood overweight and fat distribution. In the KOALA Birth Cohort Study, repeated questionnaires were administered to 2698 mother-child pairs, including questions on smoking at 14 and 34 weeks of pregnancy. Main outcomes were birth weight, weight gain in the first year, body mass index (BMI) z-scores and overweight (BMI ≥85th percentile) at 1, 2, 4-5 and 6-7 years (n = 1730) and waist circumference and four skinfold thicknesses measured at home visits at age 6-7 years in a subgroup (n = 418). We used multivariable linear and logistic regression, with generalized estimating equations (GEE) for repeated measurements. Maternal smoking was associated with lower birth weight, higher weight gain in the first year and increasing overweight after infancy (change with age P = 0.02 in the GEE). Maternal smoking vs. non-smoking during pregnancy was associated with a higher risk of the child exceeding the 85th percentile of BMI (adjusted odds ratio [aOR] 3.72; 95% CI 1.33-10.4), waist circumference (aOR 2.65; 95% CI 1.06-6.59) and sum of skinfold thicknesses (aOR 4.45; 95% CI 1.63-12.2) at the age of 6-7 years. Maternal smoking during pregnancy is associated with lower birth weight, weight catch-up and development of overweight into childhood.


Long-Chain Polyphosphate Is a Potential Agent for Inducing Mucosal Healing of the Colon in Ulcerative Colitis.
The goal of ulcerative colitis (UC) treatment has recently been shown to be "mucosal healing," as no drug directly induces mucosal healing. Probiotics possess sufficient safety, but their efficacy in the treatment of UC remains controversial because of the influence of intestinal conditions. It is believed that the identification of bioactive molecules produced by probiotics and their application will help to solve this issue. We therefore identified a probiotic-derived long-chain polyphosphate as a molecule enhancing the intestinal barrier function. This study demonstrated that long-chain polyphosphate exhibited antiinflammatory effects in a human macrophage and interleukin-10 knockout transfusion mouse model. The first-in-human trial showed that 7 of the 10 enrolled patients acquired clinical remission, 4 of whom achieved endoscopic remission despite a history of treatment with anti-tumor necrosis factor (TNF)-α agents. No adverse reactions were observed. Long-chain polyphosphate might be useful for the treatment of refractory UC, even in patients with failure or intolerance to anti-TNF-α therapy.


Ribulose bisphosphate carboxylase/oxygenase in toluene-permeabilized Rhodospirillum rubrum.
Toluene-permeabilized Rhodospirillum rubrum cells were used to study activation of and catalysis by the dual-function enzyme ribulose bisphosphate carboxylase/oxygenase. Incubation with CO2 provided as HCO3-, followed by rapid removal of CO2 at 2 degrees C and subsequent incubation at 30 degrees C before assay, enabled a determination of decay rates of the carboxylase and the oxygenase. Half-times at 30 degrees C with 20 mM-Mg2+ were 10.8 and 3.7 min respectively. Additionally, the concentrations of CO2 required for half-maximal activation were 56 and 72 microM for the oxygenase and the carboxylase respectively. After activation and CO2 removal, inactivation of ribulose bisphosphate oxygenase in the presence of 1 mM- or 20mM-Mn2+ was slower than that with the same concentrations of Co2+ or Mg2+. Only the addition of Mg2+ supported ribulose bisphosphate carboxylase activity, as Mn2+, Co2+ and Ni2+ had no effect. A pH increase after activation in the range 6.8-8.0 decreased the stability of the carboxylase but in the range 7.2-8.0 increased the stability of the oxygenase. With regard to catalysis. Km values for ribulose 1,5-bisphosphate4- were 1.5 and 67 microM for the oxygenase and the carboxylase respectively, and 125 microM for O2. Over a broad range of CO2 concentrations in the activation mixture, the pH optima were 7.8 and 8-9.2 for the carboxylase and the oxygenase respectively. The ratio of specific activities was constant (9:1 for the carboxylase/oxygenase) of ribulose bisphosphate carboxylase/oxygenase in toluene-treated Rsp. rubrum. Below concentrations of 10 microM-CO2 in the activation mixture, this ratio increased.


Heart rate variability as a marker of myocardial perfusion.
RR variability (HRV), an independent predictor of death following myocardial infarction, may also be related to other features of coronary artery disease. We evaluated its ability to differentiate among sedentary patients with chest pain >/=45 years of age demonstrating either normal or abnormal myocardial perfusion with rest and exercise thallium-210 tomographic imaging. The major HRV difference between 48 men and 50 women with normal perfusion was a significantly higher high frequency power in women. No significant differences in mean HRV values were found between the 57 men with abnormal perfusion scans and the 48 men with normal perfusion. In both men and women with normal perfusion scans, duration of exercise was significantly related to age. In men with abnormal scans, impaired myocardial perfusion alters the relationship between exercise duration and age, and a group of individuals with diminished HRV and low levels of physical fitness, regardless of age, can be identified. Despite these latter selective findings, we conclude that HRV is not a sensitive indicator to differentiate patients with normal and abnormal myocardial perfusion.


Recovery and economy; salary and allowances: a 10-year follow-up of income for persons diagnosed with first-time psychosis.
Persons with severe mental health problems (SMHP) point out financial strain as one of their main problems. De-institutionalisation in welfare countries has aimed at normalisation of their living conditions. The aim of the study was to follow the changes in income and source of income during a 10-year period for persons with a first-time psychosis diagnosis (FTPD). Data were gathered from different registers. Data from persons with FTPD were compared to data on the general population. Two groups with different recovery paths were also compared: one group without contact with the mental health services during the last five consecutive years of the 10-year follow-up, and the other with contact with both 24/7 and community-based services during the same period. SMHP led to poverty, even if the financial effects of SMHP were attenuated by welfare interventions. Even a recovery path associated with work did not resolve the inequalities generated by SMHP. Attention should be paid to the risks of confusing the effects of poverty with symptoms of SMHP and thus pathologizing poverty and its impact on human beings. Adequate interventions should consider to improve the financial situation of persons with SMHP.


[Knowledge management in medicine: in search of lost information].
This paper offers a brief review of the application of knowledge management in the field of the health sciences. This new current, which emerged in the business sphere, is seeking to win itself a space in disciplines characterised by their intensive use of information and which had traditionally assumed many of the proposals presented as novelties by these currents. The challenges and problems that knowledge management poses in the health sciences are discussed and, focusing on explicit knowledge management, solutions that are currently being developed are described.


How orange carotenoid protein controls the excited state dynamics of canthaxanthin.
Orange Carotenoid Protein (OCP) is a ketocarotenoid-binding protein essential for photoprotection in cyanobacteria. The main steps of the photoactivated conversion which converts OCP from its resting state to the active one have been extensively investigated. However, the initial photochemical event in the ketocarotenoid which triggers the large structural changes finally leading to the active state is still not understood. Here we employ QM/MM surface hopping nonadiabatic dynamics to investigate the excited-state decay of canthaxanthin in OCP, both in the ultrafast S2 to S1 internal conversion and the slower decay leading back to the ground state. For the former step we show the involvement of an additional excited state, which in the literature has been often named the SX state, and we characterize its nature. For the latter step, we reveal an excited state decay characterized by multiple timescales, which are related to the ground-state conformational heterogeneity of the ketocarotenoid. We assigned the slowly decaying population to the so-called S* state. Finally, we identify a minor decay pathway involving double-bond photoisomerization, which could be the initial trigger to photoactivation of OCP.


The Neutralization of the Eosinophil Peroxidase Antibody Accelerates Eosinophilic Mucin Decomposition.
Eosinophilic airway inflammation, complicated by bronchial asthma and eosinophilic chronic rhinosinusitis (ECRS), is difficult to treat. The disease may become refractory when eosinophilic mucin associated with eosinophil peroxidase (EPX) and autoantibodies fills in the paranasal sinus and small airway. This study investigated the functional role of an anti-EPX antibody in eosinophilic mucin of ECRS in eosinophilic airway inflammation. Eosinophilic mucin was obtained from patients with ECRS. The effects of the anti-EPX antibody on dsDNA release from eosinophils and eosinophilic mucin decomposition were evaluated. Immunofluorescence or enzyme-linked immunosorbent assays were performed to detect the anti-EPX antibody and its supernatant and serum levels in eosinophilic mucin, respectively. The serum levels of the anti-EPX antibody were positively correlated with sinus computed tomography score and fractionated exhaled nitrogen oxide. Patients with refractory ECRS had higher serum levels of the anti-EPX antibody than those without. However, dupilumab treatment decreased the serum levels of the anti-EPX antibody. Immunoglobulins (Igs) in the immunoprecipitate of mucin supernatants enhanced dsDNA release from eosinophils, whereas the neutralization of Igs against EPX stopped dsDNA release. Furthermore, EPX antibody neutralization accelerated mucin decomposition and restored corticosteroid sensitivity. Taken together, the anti-EPX antibody may be involved in the formulation of eosinophilic mucin and be used as a clinical marker and therapeutic target for intractable eosinophilic airway inflammation.


Bilateral anterior corona radiata microstructure organisation relates to impaired social cognition in schizophrenia.
The Corona Radiata (CR) is a large white matter tract in the brain comprising of the anterior CR (aCR), superior CR (sCR), and posterior CR (pCR), which have associations with cognition, self-regulation, and, in schizophrenia, positive symptom severity. This study tested the hypothesis that the microstructural organisation of the aCR, as measured by Fractional Anisotropy (FA) using Diffusion Tensor Imaging (DTI), would relate to poorer social cognitive outcomes and higher positive symptom severity for people with schizophrenia, when compared to healthy participants. We further hypothesised that increased positive symptoms would relate to poorer social cognitive outcomes. Data were derived from n = 178 healthy participants (41 % females; 36.11 ± 12.36 years) and 58 people with schizophrenia (30 % females; 42.4 ± 11.1 years). The Positive and Negative Symptom Severity Scale measured clinical symptom severity. Social Cognition was measured using the Reading the Mind in the Eyes Test (RMET) Total Score, as well as the Positive, Neutral, and Negative stimuli valence. The ENIGMA-DTI protocol tract-based spatial statistics (TBSS) was used. There was a significant difference in FA for the CR, in individuals with schizophrenia compared to healthy participants. On stratification, both the aCR and pCR were significantly different between groups, with patients showing reduced white matter tract microstructural organisation. Significant negative correlations were observed between positive symptomatology and reduced microstructural organisation of the aCR. Performance for RMET negative valence items was significantly correlated bilaterally with the aCR, but not the sCR or pCR, and no relationship to positive symptoms was observed. These data highlight specific and significant microstructural white-matter differences for people with schizophrenia, which relates to positive clinical symptomology and poorer performance on social cognition stimuli. While reduced FA is associated with higher positive symptomatology in schizophrenia, this study shows the specific associated with anterior frontal white matter tracts and reduced social cognitive performance. The aCR may have a specific role to play in frontal-disconnection syndromes, psychosis, and social cognitive profile within schizophrenia, though further research requires more sensitive, specific, and detailed consideration of social cognition outcomes.


Early assessment of cardiac troponin I predicts the postoperative cardiac status and clinical course after congenital heart disease surgery.
Cardiac troponin I (cTnI) is a regulatory protein with a high sensitivity and specificity for cardiac injury. Preoperative and postoperative elevations of cTnI are usually considered predictors of the mortality and morbidity. However, little is known about the relationship between the cTnI and postoperative course after the congenital heart disease (CHD) operation. Sixty-five consecutive patients who underwent cardiac surgery for CHD at our institution between March 2016 and January 2017 were included. The cTnI was measured after the operation. Also, the association between the cTnI and duration of the catecholamine use, ICU stay, aortic cross clamp time, and other clinical parameters were assessed. The cTnI level on postoperative day 1 was positively correlated with the duration of the catecholamine use (p < 0.001) and ICU stay (p < 0.001). Also, a higher cTnI level was associated with a lower urine volume and higher lactate level 24 h after the ICU admission. In the multivariable regression analysis, the cTnI was a significant independent predictor of the catecholamine use (p = 0.002) and ICU stay (p = 0.003). The cTnI level on postoperative day 1 was a predictor of the duration of the catecholamine use and ICU stay.


Overview on the incidence and the characteristics of HIV-related opportunistic infections and neoplasms of the heart: impact of highly active antiretroviral therapy.
The manifestation of cardiac involvement in the course of HIV infection has been significantly changed since the introduction of highly active antiretroviral therapy. While in the pre-highly active antiretroviral therapy era the predominant cardiac pathology was represented by localization of opportunistic infection, now new forms of heart involvement are described. Among infectious agents, viruses and bacteria caused the majority of infections. The 'classic' opportunistic agents, such as Toxoplasma, non-tuberculous mycobacteria, cytomegalovirus and Cryptococcus, have virtually disappeared. Endocarditis is still the most frequent infectious disease of the heart in HIV-infected patients, occurring mainly in drug users, and with the improvement in prognosis, the need for cardiac surgery is increasing. Tuberculosis, the incidence of which is still high in poor resources settings where antiretroviral drugs are not available, is a frequent cause of pericarditis, frequently evolving into cardiac tamponade. Recent studies suggest the direct role of HIV as the cause of myocarditis and heart vessel pathology. This finding points out the need of improving our knowledge about the pathogenesis, diagnosis and treatment of this kind of complication.


Development of fast singing muscles in a katydid.
In males of the katydid Neoconocephalus robustus, mesothoracic wings are used in flight (wing stroke frequence = 20 Hz) and stridulation (200 Hz), while the metathoracic wings are used in flight alone. Most mesothoracic wing muscles produce much briefer isometric twitches than metathoracic counterparts. The mesothoracic first tergocoxal muscle (TCX1) has a twitch duration (onset to 50% relaxation, 35 degrees C) of 6-8 ms and the metathoracic TXC1 a twitch duration of 12-15 ms. The TCX1 muscles from animals one and two instars from adulthood produce twitches similar in duration to those of the adult metathoracic TCX1. The twitch duration of the mesothoracic TCX1 acquires its adult brevity gradually over the first 5 days of adult life. Both TCX1 muscles increase greatly in size and mitochondrial content around the time of the terminal molt. During this period the mesothoracic TCX1 develops narrower myofibrils and a smaller ratio of fibril volume to sarcoplasmic reticulum volume than is characteristic of the metathoracic TCX1. Changes in the ultrastructure of the mesothoracic TCX1 precede changes in contraction kinetics around the time of the terminal molt so that there is not a strict correlation between muscle structure and performance during the period of rapid growth.


Socioeconomic measures and CKD in the United States and The Netherlands.
According to the cost of health care utilization systems, there may be regional differences in the relative strength of association of income and education-based socioeconomic status measures with CKD. This study investigated the relative strength of the association of income and education with CKD in a United States and a Dutch population. This cross-sectional study examined individuals who participated in the 1999-2002 National Health and Nutritional Examination Survey (NHANES) and in Prevention of Renal and Vascular End-stage Disease (PREVEND 1997-1998), general population-based cohorts in the United States and The Netherlands, respectively. The main outcome was CKD, defined as estimated GFR <60 ml/min per 1.73 m(2) (using creatinine) or albuminuria ≥ 30 mg/24 hours or albumin-to-creatinine ratio ≥ 30 mg/g. In NHANES (n=6428), income was strongly associated with CKD (adjusted odds ratio, 2.34 [95% confidence interval (CI), 1.68 to 3.27]; P for trend<0.001) but education was not (adjusted odds ratio, 1.62 [95% CI, 0.87 to 2.25]; P for trend=0.05]. In contrast, in PREVEND (n=7983), low income was weakly associated with CKD whereas low education had a strong association. The fit of the logistic regression model estimating association of income and education with CKD was significantly improved only after income was added in NHANES (P<0.001) and education was added in PREVEND (P=0.01). Sensitivity analyses that used other CKD-defining variables and restricted analyses to participants <65 years of age resulted in similar findings. In the United States, where access to health care is traditionally income dependent, income appeared more strongly associated with CKD than in The Netherlands, where education showed a stronger association.


[Personality traits (type A) in patients with intermittent claudication. 1. Results of the Bortner test].
It has never been considered whether type A (coronary prone) behavior can also be found in patients with peripheral atherosclerotic disease (intermittent claudication). This question has been studied by means of the 14-item (Bortner) questionnaire. The questionnaire was filled out by 10 patients (self-assessment) with coronary artery disease and intermittend claudication, 13 with intermittent claudication alone and 10 with comparably severe, but not arteriovascular disease and independently by their wives (relative's assessment). In the self-assessment the test discriminated significantly between the three groups (Kruskal-Wallis p less than 0.05). The correlation coefficient (Spearman) between expression of type A behavior and extent of atherosclerosis was 0.3720 (p less than 0.02). In the relative's assessment the groups were also differentiated significantly (Kruskal-Wallis p less than 0.05). The correlation coefficient (Spearman) was 0.4080 (p less than 0.009). The results indicate that patients with intermittent claudication demonstrate a predilection for type A behavior, which is more pronounced in those with additional coronary artery disease. The multiple stepwise regression indicated that type A behavior is related to atherosclerosis independently of other factors.


Host defence mechanisms against Japanese encephalitis virus infection in mice.
The role of antibody and cell-mediated immunity in the resistance to Japanese encephalitis virus (JEV) infection was studied in adult mice. Passively transferred antibodies obtained up to 2 weeks after primary infection protected the recipient mice against a challenge infection with JEV. Antibody obtained at 4 or 5 weeks failed to protect despite the presence of high titres of neutralizing antibody. Protection was abrogated by pretreatment of the early serum with 2-mercaptoethanol to remove IgM. Similarly, adoptive transfer of immune spleen cells obtained up to 2 weeks after immunization provided protection. The protective effect was abolished by pretreatment of the immune spleen cells with anti-Thy 1.2 antiserum and complement. These findings suggest a role of T lymphocytes and IgM antibody in recovery from JEV infection.


Magnetic resonance imaging of Asians with multiple sclerosis was similar to that of the West.
Magnetic resonance imaging (MRI) of the brain is the most important paraclinical diagnostic test in multiple sclerosis (MS). The appearance of MRI in Asians with MS is not well defined. We retrospectively surveyed the first brain and spinal cord MRI in patients diagnosed to have MS, according to Poser's criteria in seven regions throughout Asia to define the MRI changes among Asians with MS. There were 101 patients with first brain, and 86 with first spinal cord MRI, 66 of whom had both. The brain MRI showed a mean of 17 lesions per patient in T2 weighted images, mostly asymptomatic. Almost all the lesions were in the white matter, particularly in the juxtacortical, deep and periventricular white matter. A third of the lesions were greater than 5 mm, 14% enhanced with gadolinium. There were more supratentorial than infratentorial lesions at a ratio of 7.5: 1. Ninety five percent of the spinal cord lesions were in cervical and thoracic regions, 34% enhanced with gadolinium. The lesions extended over a mean of 3.6 +/- 3.3 vertebral bodies in length. Fifty (50%) of the brain and 54 (63%) of the spinal MRI patients had the optic-spinal form of MS. The MRI of the optic-spinal and classical groups of patients were similar in appearance and distribution, except that the optic-spinal MS patients have fewer brain but longer and more severe spinal cord lesions. In conclusion, the brain and spinal cord MRI of Asian patients with MS was similar to that of the West, although, in this study, Asian MS patients had larger spinal cord lesions.


Bahamas National Implementation Project: Proposal for Sustainability of an Evidence-based HIV Prevention Intervention in a School Setting.
Sustained implementation of school-based prevention programs is low. Effective strategies are needed to enhance both high-level implementation fidelity and sustainability of prevention programs. This proposed study aims to determine if the provision of either biweekly monitoring and feedback and site-based assistance and mentorship or both to at-risk and moderate-performing teachers with monitoring through an enhanced decision-making platform by the Ministry of Education (MOE) and Ministry of Health (MOH) based on the real-time implementation data will increase national implementation fidelity and result in sustained implementation over time. This study will target government schools including 200 grade 6 teachers in 80 primary schools and 100 junior/middle high school teachers (and their classes) on 12 Bahamian islands. Teacher and school coordinator training will be conducted by the MOE in year 1, followed by an optimization trial among teachers in the capital island. Informed by these results, an implementation intervention will be conducted to train using different levels of educational intensity all at-risk and moderate-performing teachers. Subsequently selected training and implementation strategies will be evaluated for the national implementation of Focus on Youth in the Caribbean and Caribbean Informed Parents and Children Together in years 2 to 5. It is hypothesized that a more intensive training and supervision program for at-risk and moderate-performing teachers will enhance their implementation fidelity to the average level of the high-performing group (85%), an HIV prevention program delivered at the national level can be implemented with fidelity in grade 6 and sustained over time (monitored annually), and student outcomes will continue to be highly correlated with implementation fidelity and be sustained over time (assessed annually through grade 9). The proposed study is funded by the National Institute of Child Health and Human Development from August 1, 2018, through May 31, 2023. The study will explore several theory-driven implementation strategies to increase sustained teacher implementation fidelity and thereby increase the general public health impact of evidence-based interventions. The proposed project has potential to make significant contributions to advancing school-based HIV prevention research and implementation science and serve as a global model for the Fast Track strategy. PRR1-10.2196/14816.


[Rapid identification of enteroviruses by countercurrent immunoelectrophoresis].
The results of identification of 115 enterovirus strains by means of counter immunoelectrophoresis and the neutralization tests in cell culture are presented. Even at a high rate of agreement of the two methods, counter immuno-electrophoresis was shown to be more rapid, economic, less labour-consuming but requiring concentrated viral antigens.


Activated protein C modulates inflammation, apoptosis and tissue factor procoagulant activity by regulating endoplasmic reticulum calcium depletion in blood monocytes.
The endoplasmic reticulum (ER) is responsible for the synthesis and folding of secretory, transmembrane and ER-resident proteins. Conditions that impair protein folding or overwhelm its protein folding capacity disrupt ER homeostasis, thereby causing ER stress. ER stress-induced apoptosis and inflammation are involved in the pathogenesis of inflammatory diseases. Activated protein C (APC) inhibits inflammation and apoptosis in monocytes, and this may partly explain the protective effects of APC treatment in severe sepsis. However, the precise molecular pathways by which APC modulates these effects remain unknown. To investigate whether APC modulates the ER stress response in human monocytes. We treated monocytes with ER stress-inducing agents in the presence or absence of APC to determine the effect on this response. Protein and mRNA levels were determined by immunoblotting and real-time PCR, respectively. Enzyme assays and flow cytometry were used to determine the role of APC in this model. In thapsigargin (Tg)-treated cells, APC dampened unfolded protein response activation, as indicated by reduced levels of the 78-kDa glucose-regulated protein (GRP78), in an endothelial protein C receptor-independent and protease-activated receptor-1-independent manner. Consistent with this, APC decreased phosphorylated eukaryotic translational initiation factor 2α and C/EBP homologous protein levels induced by Tg. APC inhibited Tg-induced ER Ca(2+) flux and reactive oxygen species generation. Functionally, APC diminished Tg-induced caspase-3 activity and degradation of the nuclear factor kappaB inhibitor IκBα. Furthermore, APC dampened the induction of tissue factor procoagulant activity facilitated by Tg. These studies suggest that APC modulates the adverse effects of ER Ca(2+) depletion in human monocytes.


[Climatotherapy in chronic inflammations of the uvea].
Treatment of uveitis depends on the inhibition of the inflammatory reaction by corticosteroids or immunosuppressive agents. "Climatotherapy" remains a controversial subject and is generally not accepted. To test its efficacy a pilot study was undertaken. Children with chronic iridocyclitis or intermediate uveitis were sent to Israel for 3 weeks. During the follow-up period of 26 months there was an initial regression of the inflammatory reaction in most cases, followed by varied courses depending on the severity of the disease. Although no definite conclusions can be drawn owing to the small number of patients (5) there might been a beneficial effect. It seems very difficult to prove the efficacy of such "treatment", since not only the climate but also many other environmental factors were changed.


Melatonin as an Antioxidant and Immunomodulator in Atopic Dermatitis-A New Look on an Old Story: A Review.
Atopic dermatitis (AD) is common inflammatory dermatosis, typically with chronic and recurrent course, which significantly reduces the quality of life. Sleep disturbances are considered to be remarkably burdensome ailments in patients with AD, and are routinely included during assessment of disease severity. Therefore, endogenous substances engaged in the control of circadian rhythms might be important in pathogenesis of AD and, possibly, be used as biomarkers of disease severity or even in development of novel therapies. Melatonin (MT), the indoleamine produced by pineal gland (but also by multiple other tissues, including skin), plays a pivotal role in maintaining the sleep/wake homeostasis. Additionally, it possesses strong antioxidant and anti-inflammatory properties, which might directly link chronic skin inflammation and sleep abnormalities characteristic of AD. The objective of this work is to systematically present and summarize the results of studies (both experimental and clinical) that investigated the role of MT in the AD, with a focus on the antioxidant and immunomodulatory effects of MT.


Severe hypoglycemia rates and associated costs among type 2 diabetics starting basal insulin therapy in the United States.
To derive current real-world data on the rates and costs of severe hypoglycemia (SH) for people with type 2 diabetes mellitus (T2D) who have initiated basal insulin therapy and to examine differences in SH rates and costs stratified by history of prior SH events. We used a nation-wide electronic health records database that included encounter and laboratory data, as well as clinical notes, to estimate the rates and costs of SH events among adults with T2D who initiated basal insulin between 2008 and 2011. Unadjusted and regression-adjusted rates and quarterly costs were calculated for all patients as well as stratified by history of a SH event before starting basal insulin and history of a SH event during the basal insulin titration period. We identified 7235 incident cases of basal insulin use among patients with T2D who did not use insulin during the previous 12 months. Regression-adjusted incidence and total event rates were 10.36 and 11.21 per 100 patient-years, respectively. A history of SH events during the pre-index baseline and post-index titration periods were statistically significantly associated with both the incidence and total event rates (p < 0.01). Regression-adjusted total healthcare and diabetes-related costs were statistically significantly (p < 0.01) higher in those quarters when a SH event occurred than in those quarters without any SH events ($3591 vs. $487 and $3311 vs. $406, respectively). A history of previous SH or SH events during the titration period were not statistically significantly associated with costs. These results suggest that the real-world burden of SH is high among people with T2D who start using basal insulin and that history of previous SH events, both before starting insulin and during the insulin titration period, influences future SH. These results can also provide insights into interventions that can prevent or delay SH. These results should, however, be interpreted in light of the key limitations of our study: not all SH events may have been captured or coded in the database, data on filled prescriptions were not available, and the post-titration follow-up period could have been divided into time units other than quarters (3 month blocks) resulting in potentially different conclusions. Further real-world studies on the frequency and costs of SH, using methods to identify as many SH events as possible, can allow healthcare providers to make more informed decisions on the risks and benefits of basal insulin therapy in T2D patients.


Perceived Illness and Treatment Adherence to Hypertension Among Patients Attending a Tertiary Hospital in Kathmandu, Nepal.
Hypertension (HTN) is a silent killer, accountable for life-threatening complications. An individual's illness perception may affect adherence to treatment which is crucial to prevent complications of HTN. The objective of this study was to identify illness perception and treatment adherence among patients with HTN in a tertiary hospital in Kathmandu, Nepal. Descriptive correlational study was conducted in the out-patient department of Manmohan Cardiothoracic Vascular and Transplant Center, Kathmandu Nepal. Non-probability purposive sampling was used. A face-to-face interview was conducted from September to December 2018, using a structured questionnaire that included socio-demographic variables, illness perception questionnaire (revised) and Hill bone compliance to high blood pressure therapy scale. Data analysis was done by using descriptive and inferential statistics (chi-square test, Spearman rank correlation). Among 204 participants, 51% were male, 77% were literate, mean ± S.D. age was 60±12. About 72% experienced headache and 88% said that headache is related to HTN. Behavioural factors and psychological factors were regarded as the leading cause of HTN. Almost 63% participants believed HTN as highly threatening illness. Higher scores in timeline (acute/chronic), personal control, and treatment control revealed that patients believed HTN as a chronic disease with a higher rate of personal and treatment control. Regarding treatment adherence, the mean score was 16.58 (SD = 2.08), and only 14.7% had perfect adherence. Participants were more adherent to medication and appointment keeping rather than reduce salt intake. Duration of HTN diagnosis (p=0.027) and duration under HTN medication (p= 0.021) were found to be significantly associated with treatment adherence. There was a significant positive correlation between illness perception and treatment adherence (ρ = 0.282, p<0.01). Illness perception and treatment adherence are correlated. Hence, it is beneficial to improve illness perception to achieve perfect treatment adherence. Reinforcement is essential to maintain adherence to both medications and behaviour therapy.


[Supernumerary clavicle: a case report].
We report a case of left sided supernumerary clavicle in a male child, 3 years old with impossibility to the flexion and extension of the neck and lateralization since birth, in the 3D CAT SCAN we could appreciate the presence of bone tissue with italic S shape that was articulated with the jaw and the left sternun clavicle region. Previous evaluation from the rehabilitation service the patient underwent the removal of the lesion. The pathology study confirmed that this piece was osseous tissue with distal joints surfaces and central bone marrow.


The Role of Immune Dysfunction in Parkinson's Disease Development.
Recent research has unveiled intriguing insights suggesting that the body's immune system may be implicated in Parkinson's disease (PD) development. Studies have observed disparities in pro-inflammatory and anti-inflammatory markers between PD patients and healthy individuals. This finding underscores the potential influence of immune system dysfunction in the genesis of this condition. A dysfunctional immune system can serve as a primary catalyst for systemic inflammation in the body, which may contribute to the emergence of various brain disorders. The identification of several genes associated with PD, as well as their connection to neuroinflammation, raises the likelihood of disease susceptibility. Moreover, advancing age and mitochondrial dysfunction can weaken the immune system, potentially implicating them in the onset of the disease, particularly among older individuals. Compromised integrity of the blood-brain barrier could facilitate the immune system's access to brain tissue. This exposure may lead to encounters with native antigens or infections, potentially triggering an autoimmune response. Furthermore, there is mounting evidence supporting the notion that gut dysbiosis might represent an initial trigger for brain inflammation, ultimately promoting neurodegeneration. In this comprehensive review, we will delve into the numerous hypotheses surrounding the role of both innate and adaptive immunity in PD.


Gallium-Based Liquid Metal Amalgams: Transitional-State Metallic Mixtures (TransM2ixes) with Enhanced and Tunable Electrical, Thermal, and Mechanical Properties.
Metals are excellent choices for electrical- and thermal-current conducting. However, either the stiffness of solid metals or the fluidity of liquid metals could be troublesome when flexibility and formability are both desired. To address this problem, a reliable two-stage route to improve the functionalities of gallium-based liquid metals is proposed. A series of stable semiliquid/semisolid gallium-based liquid metal amalgams with well-controlled particle packing ratios, which we call TransM2ixes, are prepared and characterized. Through effectively packing the liquid metal with copper particles (which are found to turn into intermetallic compound, CuGa2, after dispersing), remarkable enhancements in electrical conductivity (6 × 106 S m-1, ∼80% increase) and thermal conductivity (50 W m-1 K-1, ∼100% increase) are obtained, making the TransM2ixes stand out from current conductive soft materials. The TransM2ixes also exhibit appealing semiliquid/semisolid mechanical behaviors such as excellent adhesion, tunable formability, and self-healing ability. As a class of highly conductive yet editable metallic mixtures, the TransM2ixes demonstrate potential applications in fields like printed and/or flexible electronics and thermal interface materials, as well as other circumstances where the flexibility and conductivity of interfaces and connections are crucial.


"Suiting Up" to Enhance Empathy Toward Aging: A Randomized Controlled Study.
Background: Healthcare professionals who have a positive attitude and who are more empathetic toward older adults are in a better position to deliver quality healthcare. This study examines the impact of using an aging simulation suit on undergraduate pharmacy students' empathy levels. Methods: One hundred and twenty first-year students enrolled in the Bachelor of Pharmacy course were randomized to either a medication review polypharmacy workshop (control) or an immersive aging simulation suit and medication review polypharmacy workshop (intervention). Intervention participants donned the aging suit and performed a series of tasks, including walking up a flight of stairs and filling up a form to simulate the physical limitations experienced by an older adult. The workshop was delivered at week 10 of semester. Both groups also completed a medication review polypharmacy workshop at week 12 of semester. The primary outcome was a measurement of change on the Jefferson Empathy Scale-Healthcare Professional Questionnaire among both groups at week 12 of semester. Secondary outcomes include the longitudinal impact of intervention after 3 months of the workshop and perceptions on learning. Results: The use of a simulation suit did not increase participants' self-rated empathy compared to control. However, the suit enhanced the ability of participants to understand the physical limitations and visual issues associated with aging. Participants also felt that it enhanced their health advocacy, as it taught them the importance of listening, patience and respect for older adults. Conclusion: The use of an immersive aging suit can be a useful adjunctive tool to help enhance students' understanding of the physical limitations and visual limitations of aging. Further research is needed to understand how these limitations affect other healthcare students. Trial Registration: ClinicalTrials.gov identifier: NCT04133727.


Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.
Two novel antibodies (abs) directed to γ-aminobutyric acid B receptor (GABA(B)R) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in patients with limbic encephalitis (LE) were first described by the Philadelphia/Barcelona groups and confirmed by the Mayo group. We present a novel series for further clinical and paraclinical refinement. Serum and cerebrospinal fluid samples from a diagnostic laboratory were selected if found to be positive for GABA(B)R or AMPAR abs within a broad antineuronal ab panel. Data were retrospectively compiled. In 10 patients, we detected abs to GABA(B)R. Median age was 70 years. Five of them were diagnosed with small cell lung cancer (SCLC). Intrathecal GABA(B)R ab synthesis was found in all six patients with sufficient data available (median ab-index: 76.8). On MRI, we found bilateral mediotemporal and in two cases cortical abnormalities. EEG revealed encephalopathy, partly with epileptiform discharges. Five patients received immunotherapy, two patients tumour treatment and three both therapies. Three patients died, in five patients cognitive functions declined, one patient improved slightly and one patient fully recovered. AMPAR abs were detected in three patients with mnestic disturbances. Median age was 60.7 years. The only female patient was diagnosed with ovarian cancer. None of the patients had intrathecal ab synthesis. MRI findings showed bilateral mediotemporal abnormalities. EEG was normal in all patients. Two of the three immunologically treated patients improved, one patient stabilised on a low level. GABA(B)R and AMPAR abs are well associated with LE. GABA(B)R abs lead to severe clinical, neuroradiological and EEG abnormalities with poorer outcome.


Chronic ankle pain and fibrosis successfully treated with a new noninvasive augmented soft tissue mobilization technique (ASTM): a case report.
This clinical case report demonstrates the clinical effectiveness of a new form of soft tissue mobilization in the treatment of excessive connective tissue fibrosis (scar tissue) around an athlete's injured ankle. The scar tissue was causing the athlete to have pain with activity, pain on palpation of the ankle, decreased range of motion, and loss of function. Surgery and several months of conventional physical therapy failed to alleviate the athlete's symptoms. As a final resort, augmented soft tissue mobilization (ASTM) was administered. ASTM is an alternative nonsurgical treatment modality that is being researched at Performance Dynamics (Muncip, IN). ASTM is a process that uses ergonomically designed instruments that assist therapists in the rapid localization and effective treatment of areas exhibiting excessive soft tissue fibrosis. This is followed by a stretching and strengthening program. Upon the completion of 6 wk of ASTM therapy, the athlete had no pain and had regained full range of motion and function. This case report is an example of how a noninvasive augmented form of soft tissue mobilization (ASTM) demonstrated impressive clinical results in treating a condition caused by connective tissue fibrosis.


Staphylococcal enterotoxin sensitization in a community-based population: a potential role in adult-onset asthma.
Recent studies suggest that Staphylococcus aureus enterotoxin sensitization is a risk factor for asthma. However, there is a paucity of epidemiologic evidence on adult-onset asthma in community-based populations. We sought to evaluate the epidemiology and the clinical significance of staphylococcal enterotoxin sensitization in community-based adult populations. The present analyses were performed using the baseline data set of Korean adult population surveys, consisting of 1080 adults (mean age = 60.2 years) recruited from an urban and a rural community. Questionnaires, methacholine challenge tests, and allergen skin tests were performed for defining clinical phenotypes. Sera were analysed for total IgE and enterotoxin-specific IgE using ImmunoCAP. Staphylococcal enterotoxin sensitization (≥ 0.35 kU/L) had a prevalence of 27.0%. Risk factors were identified as male sex, current smoking, advanced age (≥ 61 years), and inhalant allergen sensitization. Current asthma was mostly adult onset (≥ 18 years old) and showed independent associations with high enterotoxin-specific IgE levels in multivariate logistic regression tests. In multivariate linear regressions, staphylococcal enterotoxin-specific IgE level was identified as the major determinant factor for total IgE level. Staphylococcal enterotoxin sensitization was independently associated with adult-onset asthma in adult community populations. Strong correlations between the enterotoxin-specific IgE and total IgE levels support the clinical significance. The present findings warrant further studies for the precise roles of staphylococcal enterotoxin sensitization in the asthma pathogenesis.


Occupational exposure to gaseous and particulate contaminants originating from additive manufacturing of liquid, powdered, and filament plastic materials and related post-processes.
The aim of this study was to measure the concentrations of gaseous and particulate contaminants originated from additive manufacturing operations and post-processes in an occupational setting when plastics were used as feedstock materials. Secondary aims were to evaluate the concentration levels based on proposed exposure limits and target values and to propose means to reduce exposure to contaminants released in additive manufacturing processes. Volatile organic compounds were sampled with Tenax TA adsorption tubes and analyzed with a thermo desorption gas chromatography-mass spectrometry instrument. Carbonyl compounds were sampled with DNPH-Silica cartridges and analyzed with a high-performance liquid chromatography device. Particles were measured with P-Trak instrument and indoor air quality was sampled with IAQ-Calc instrument. Dust mass concentrations were measured simultaneously with a DustTrak DRX instrument and IOM-samplers. Particle concentrations were highest (2070-81 890 #/cm3 mean) during manufacturing with methods where plastics were thermally processed. Total volatile organic compounds concentrations, in contrast, were low (113-317 µg/m3 mean) during manufacturing with such methods, and vat photopolymerization. However, total volatile organic compounds concentrations of material jetting and multi jet fusion methods were higher (1,114-2,496 µg/m3 mean), perhaps because of material and binder spraying, where part of the spray can become aerosolized. Chemical treatment of manufactured objects was found to be a severe volatile organic compounds source as well. Formaldehyde was detected in low concentrations (3-40 µg/m3) in all methods except for material jetting method, in addition to several other carbonyl compounds. Notable dust concentrations (1.4-9.1 mg/m3) were detected only during post-processing of powder bed fusion and multi jet fusion manufactured objects. Indoor air quality parameters were not found to be notably impacted by manufacturing operations. Only low concentrations (below 2 ppm) of CO were detected during several manufacturing processes. All studied additive manufacturing operations emitted potentially harmful contaminants into their environments, which should be considered in occupational additive manufacturing and workplace design. According to the measured contaminant levels it is possible that adverse additive manufacturing related health effects may occur among exposed workers.


Doxycycline as an inhibitor of the epithelial-to-mesenchymal transition and vasculogenic mimicry in hepatocellular carcinoma.
This study was conducted to examine the effects of doxycycline on the survival time and proliferation of hepatocellular carcinoma (HCC) in vivo and on the biologic functions of HCC in vitro. This study was also designed to evaluate the effects of doxycycline on epithelial-to-mesenchymal transition (EMT)- and vasculogenic mimicry (VM)-related protein expression and on matrix metalloproteinase (MMP) and DNA methyltransferase (DNMT) activity in vitro. Human MHCC97H cells were injected into BALB/c mice, which were divided into treatment and control groups. Doxycycline treatment prolonged the mouse survival time and partly suppressed the growth of engrafted HCC tumor cells, with an inhibition rate of 43.39%. Higher amounts of VM and endothelium-dependent vessels were found in the control group than the treatment group. IHC indicated that epithelial (E)-cadherin expression was increased in the doxycycline-treated mice compared with the control group. In in vitro experiments, doxycycline promoted HCC cell adhesion but inhibited HCC cell viability, proliferation, migration, and invasion. Western blot analysis, semiquantitative RT-PCR, qRT-PCR, and immunofluorescence demonstrated that doxycycline inhibited the degradation of the epithelial marker E-cadherin and downregulated the expression levels of EMT promoters, the mesenchymal marker vimentin, and the VM-associated marker vascular endothelial (VE)-cadherin. Furthermore, the activities of MMPs and DNMTs were examined in different groups via gelatin zymography and a DNMT activity assay kit. A methylation-specific PCR was performed to assess the promoter methylation of CDH1 (the gene encoding E-cadherin). Doxycycline prolonged the mouse survival time by inhibiting EMT progression and VM formation.


The effect of hepatic blood flow on taurocholate extraction by the isolated perfused rat liver.
The effect of the rate of portal blood flow on the fractional extraction of the bile salt sodium taurocholate was studied in the isolated perfused rat liver. Thirty-two livers were perfused with a 60 microM solution of taurocholate at flow rates varying from 0.65 to 3.55 ml/min/gm of liver. Extraction was determined from the difference in the concentration of taurocholate in the portal and hepatic vein perfusates. At the low flow rates, the extraction of taurocholate was nearly complete. However, as the rate of perfusion of the portal vein was increased, the extraction of taurocholate decreased exponentially. It is concluded that the single-pass extraction of taurocholate by the liver is related to the rate of sinusoidal flow.


A new method for optimum dose distribution determination taking tumour mobility into account.
A method for determining the optimum dose distribution in the planning target volume is proposed when target volumes are deliberately enlarged to account for tumour mobility in external beam radiotherapy. The optimum dose distribution is a dose distribution that will result in an acceptable level of tumour control probability (TCP) in most of the arising cases of tumour dislocation. An assumption is made that the possible shifts of the tumour are subject to a Gaussian distribution with mean zero and known variance. The idea of a reduced (mean in ensemble) tumour cell density is introduced. On this basis, the target volume and dose distribution in it are determined. The tumour control probability as a function of the shift of the tumour has been calculated. The Monte Carlo method has been used to simulate TCP distributions corresponding to tumour mobility characterized by different variances. The obtained TCP distributions are independent of the variance of the mobility because the dose distribution in the planning target volume is prescribed so that the mobility variance is taken into account. For simplicity a one-dimensional model is used but three-dimensional generalization can be done.


Threonine requirement of commercial laying hens fed a corn-soybean meal diet.
Two experiments were conducted with Hy-Line W36 hens to evaluate their Thr requirement in a corn-soybean meal diet. Eight experimental diets were used in Experiment 1 with graded levels of Thr: 0.53,0.50, 0.48, 0.45, 0.42, 0.40, 0.37, and 0.35%. Seven experimental diets were used in Experiment 2 with graded levels of Thr: 0.58, 0.53, 0.50, 0.48, 0.45, 0.42, and 0.40%. Supplemental amino acids (AA) were added to all diets to ensure that Thr was the first-limiting AA. Egg production (EP), egg mass (EM), and daily Thr intake were significantly increased with increasing dietary Thr levels. Broken-line regression indicated a daily Thr requirement of 439.0 and 462.1 mg per hen per d in Experiment 1 and of 393.9 and 447.1 mg per hen per d in Experiment 2 for EP and EM, respectively. The Thr requirements to produce 1 g of EM were 8.76 and 9.44 mg in Experiments 1 and 2, respectively.


Laser-driven semiconductor switch for generating nanosecond pulses from a megawatt gyrotron.
A laser-driven semiconductor switch (LDSS) employing silicon (Si) and gallium arsenide (GaAs) wafers has been used to produce nanosecond-scale pulses from a 3 μs, 110 GHz gyrotron at the megawatt power level. Photoconductivity was induced in the wafers using a 532 nm laser, which produced 6 ns, 230 mJ pulses. Irradiation of a single Si wafer by the laser produced 110 GHz RF pulses with a 9 ns width and >70% reflectance. Under the same conditions, a single GaAs wafer yielded 24 ns 110 GHz RF pulses with >78% reflectance. For both semiconductor materials, a higher value of reflectance was observed with increasing 110 GHz beam intensity. Using two active wafers, pulses of variable length down to 3 ns duration were created. The switch was tested at incident 110 GHz RF power levels up to 600 kW. A 1-D model is presented that agrees well with the experimentally observed temporal pulse shapes obtained with a single Si wafer. The LDSS has many potential uses in high power millimeter-wave research, including testing of high-gradient accelerator structures.


Long-term clinical outcomes of Ahmed valve implantation in patients with refractory glaucoma.
To evaluate the long-term efficacy of intraocular pressure (IOP) reduction and complications of Ahmed Glaucoma Valve (AGV) implantation in patients with refractory glaucoma. Retrospective study. The study involved 302 refractory glaucoma patients who underwent AGV implantation and had a minimum follow-up of 6 months between March 1995 and December 2013. An operation was defined as successful when (1) the postoperative IOP remained between 5 and 21 mmHg and was reduced 30% compared to the baseline IOP with or without medication, (2) there was no loss of light perception or vision-threatening severe complications, and (3) no additional filtering or aqueous drainage surgery was required. Clinical records were reviewed. IOP, anti-glaucoma medications, and complications. The mean follow-up period was 62.25 months (range, 6 to 190 months). The cumulative probability of success was 89% at 6 months, 81% at 1 year, 66% at 3 years, 44% at 10 years, and 26% at 15 years. IOP was reduced from a mean of 32.2 ± 10.5 mmHg to 18.6 ± 9.1 mmHg at 1 month, 15.2 ± 7.0 mmHg at 6 months, and 14.2 ± 3.5 mmHg at 15 years. Surgical failures were significantly increased when preoperative IOP was high, and when severe complications occurred after AGV implantation (P < 0.05). AGV implantation was successful for IOP control in patients with refractive glaucoma in the long term. However, the success rate of surgery decreased over time. Preoperative high IOP and severe complications related to the operation were significant risk factors for failure.


Salivary anti-spectrin autoantibodies in Sjögren's syndrome.
The purpose of this study was done to compare the anti-spectrin autoantibody levels in the parotid saliva of Sjögren's syndrome patients and in the parotid saliva of healthy control subjects. The salivary anti-spectrin autoantibody levels of 20 Sjögren's patients and of 20 healthy controls were compared by means of the slot blot immunoassay and the alkaline phosphatase method. Various anti-spectrin autoantibody levels were detected in the saliva of both patients and controls. The color intensity of the blots was scored on a scale of 1 to 3. The scores were deemed to indicate the anti-spectrin autoantibody levels in saliva (1 = low, 2 = moderate, and 3 = high). The Mann-Whitney U test did not reveal a significant difference in the anti-spectrin autoantibody levels of patients and the anti-spectrin autoantibody levels of controls (P > or = .31). These results do not support a pathologic role for anti-spectrin autoantibody in Sjögren's syndrome. The overall result of this study substantiates that anti-spectrin autoantibodies occur naturally in saliva. Their role in immune surveillance or pathology is not clear at present.


Herpes simplex virus-induced suppression of macrophage-mediated tumoricidal activity in murine macrophages.
Herpes simplex virus (HSV) infections can enhance the progression of neoplastic diseases. Since macrophages can be activated to become tumorilytic and may figure prominently in host defense against cancer, the ability of HSV to modify macrophage-mediated tumoricidal functions was evaluated. Murine peritoneal macrophages treated with HSV could not be activated to a tumoricidal state by mouse recombinant gamma-interferon (IFN-gamma). Addition of HSV 4 h after treatment with IFN-gamma, at a time when the macrophages are fully committed to developing the cytotoxic phenotype, blocked macrophage-mediated lysis of syngeneic melanoma target cells. This inhibition of activation and cytotoxicity was not due simply to uptake of virus particles, because treatment with heat-inactivated HSV at 4-h posttreatment with IFN-gamma had no effect. In addition, HSV did not undergo a productive infection within macrophages, suggesting that the observed inhibitory activity might be due to a virus-induced product. In this regard, treatment of macrophages with recombinant alpha-interferon suppressed the activation of these cells by IFN-gamma, suggesting that virus-induced alpha-interferon may be mediating all or part of the suppressive activity. These studies suggest that enhancement of tumor progression following HSV infection may be related to the virus-induced suppression of macrophage-mediated tumoricidal activity.


STD and HIV screening in general practice: a survey related to termination of pregnancy in south Thames.
It has been recommended that screening for sexually transmitted disease (STDs) be carried out at the time of termination of pregnancy to allow prevention of post-abortion infection. Screening offers the opportunity to treat an infected woman and prevent serious complications following the termination procedure. Our findings indicate that general practitioners (GPs) in South Thames did not routinely carry out screening and few realized it took place at referral centres.


Molecular mechanisms of cancer metastasis via the lymphatic versus the blood vessels.
Cancer metastasis is the process by which primary cancer cells invade through the lymphatic or blood vessels to distant sites. The molecular mechanisms by which cancer cells spread either through the lymphatic versus blood vessels or both are not well established. Two major developments have helped us to understand the process more clearly. First, the development of the sentinel lymph node (SLN) concept which is well established in melanoma and breast cancer. The SLN is the first lymph node in the draining nodal basin to receive cancer cells. Patients with a negative SLN biopsy show a significantly lower incidence of distant metastasis, suggesting that the SLN may be the major gateway for cancer metastasis in these cancer types. Second, the discovery and characterization of several biomarkers including VEGF-C, LYVE-1, Podoplanin and Prox-1 have opened new vistas in the understanding of the induction of lymphangiogenesis by cancer cells. Cancer cells must complete multiple steps to invade the lymphatic system, some of which may be enabled by the evolution of new traits during cancer progression. Thus, cancer cells may spread initially through the main gateway of the SLN, from which evolving cancer clones can invade the blood vessels to distant sites. Cancer cells may also enter the blood vessels directly, bypassing the SLN to establish distant metastases. Future studies need to pinpoint the molecules that are used by cancer cells at different stages of metastasis via different routes so that specific therapies can be targeted against these molecules, with the goal of stopping or preventing cancer metastasis.


EUCALYPT: efficient tree reconciliation enumerator.
Phylogenetic tree reconciliation is the approach of choice for investigating the coevolution of sets of organisms such as hosts and parasites. It consists in a mapping between the parasite tree and the host tree using event-based maximum parsimony. Given a cost model for the events, many optimal reconciliations are however possible. Any further biological interpretation of them must therefore take this into account, making the capacity to enumerate all optimal solutions a crucial point. Only two algorithms currently exist that attempt such enumeration; in one case not all possible solutions are produced while in the other not all cost vectors are currently handled. The objective of this paper is two-fold. The first is to fill this gap, and the second is to test whether the number of solutions generally observed can be an issue in terms of interpretation. We present a polynomial-delay algorithm for enumerating all optimal reconciliations. We show that in general many solutions exist. We give an example where, for two pairs of host-parasite trees having each less than 41 leaves, the number of solutions is 5120, even when only time-feasible ones are kept. To facilitate their interpretation, those solutions are also classified in terms of how many of each event they contain. The number of different classes of solutions may thus be notably smaller than the number of solutions, yet they may remain high enough, in particular for the cases where losses have cost 0. In fact, depending on the cost vector, both numbers of solutions and of classes thereof may increase considerably. To further deal with this problem, we introduce and analyse a restricted version where host switches are allowed to happen only between species that are within some fixed distance along the host tree. This restriction allows us to reduce the number of time-feasible solutions while preserving the same optimal cost, as well as to find time-feasible solutions with a cost close to the optimal in the cases where no time-feasible solution is found. We present Eucalypt, a polynomial-delay algorithm for enumerating all optimal reconciliations which is freely available at http://eucalypt.gforge.inria.fr/.


A quantum biochemistry investigation of willardiine partial agonism in AMPA receptors.
We employ quantum biochemistry methods based on the Density Functional Theory (DFT) approach to unveil the detailed binding energy features of willardiines co-crystallized with the AMPA receptor. Our computational results demonstrate that the total binding energies of fluorine-willardiine (FW), hydrogen-willardiine (HW), bromine-willardiine (BrW) and iodine-willardiine (IW) to the iGluR2 ligand-pocket correlate with the agonist binding energies, whose experimental sequential data match our computational counterpart, excluding the HW case. We find that the main contributions to the total willardiine-iGluR2 binding energy are due to the amino acid residues in decreasing order Glu705 > Arg485 > Ser654 > Tyr450 > T655. Furthermore, Met708, which is positioned close to the 5-substituent, attracts HW and FW, but repels BrW and IW. Our results contribute significantly to an improved understanding of the willardiine-iGluR2 binding mechanisms.


Dysregulated JAK2 expression by TrkC promotes metastasis potential, and EMT program of metastatic breast cancer.
Metastatic breast cancers are aggressive tumors associated with high levels of epithelial-mesenchymal transition (EMT) markers, activation of IL6/JAK2/STAT3 and PI3K/AKT pathways for cell growth, mobility, invasion, metastasis, and CSC status. We identified a new molecular and functional network present in metastasis that regulates and coordinates with TrkC. Inhibition of SOCS3-mediated JAK2 degradation by TrkC increases total JAK2/STAT3 expression, and then leads to upregulation of Twist-1 through activation of JAK2/STAT3 cascade. Also, TrkC increases secretion and expression of IL-6, suggesting that this autocrine loop generated by TrkC maintains the mesenchymal state by continued activation of the JAK2/STAT3 cascade and upregulation of Twist expression. Moreover, TrkC interacts with the c-Src/Jak2 complex, which increases Twist-1 and Twist-2 levels via regulation of JAK2/STAT3 activation and JAK2/STAT3 expression. Furthermore, TrkC enhances metastatic potential of breast cancer via induction of EMT by upregulating Twist-1 and Twist-2. Additionally, TrkC significantly enhances the ability of breast cancer cells to form pulmonary metastases and primary tumor formation. Unexpectedly, we found that TrkC expression and clinical breast tumor pathological phenotypes show significant correlation. These findings suggest that TrkC plays a central role in tumorigenicity, metastasis, and self-renewal traits of metastatic breast cancer.


Immune-modulating efficacy of a polyphenol-rich beverage on symptoms associated with the common cold: a double-blind, randomised, placebo-controlled, multi-centric clinical study.
In the present study, the immune-modulating efficacy of a polyphenol-rich beverage on symptoms associated with the common cold was evaluated. For this purpose, ninety-eight patients reporting common cold symptoms that began no longer than 24 h before the study intervention were randomly assigned to consume either the test beverage or placebo twice per d for 10 d. The severity of the disease was expressed as the total score of the five cold symptoms 'general feeling of sickness', 'headache and/or joint aches', 'sore throat and/or difficulty swallowing', 'hoarseness and/or cough' and 'stuffy nose/sniffle'. Consequently, the decrease from 10.2 (sd 3.1) points at the beginning to 2.1 (sd 2.7) points by the end of the study in the verum group demonstrated a clear improvement, whereas in the placebo group only a reduction from 10.5 (sd 3.0) to 6.3 (sd 3.8) points could be observed. The mean difference between the groups (primary efficacy criterion) of 3.9 points was highly significant (P < 0.01). At the end of the study there were highly significantly (P < 0.01) more patients in the verum group complaint free than in the placebo group (secondary efficacy criterion). In addition to these self-reported values, several local findings of the physical examination were also significantly improved in the verum group.


Coriolis effects on rotating Hele-Shaw flows: a conformal-mapping approach.
The zero surface tension fluid-fluid interface dynamics in a radial Hele-Shaw cell driven by both injection and rotation is studied by a conformal-mapping approach. The situation in which one of the fluids is inviscid and has negligible density is analyzed. When Coriolis force effects are ignored, exact solutions of the zero surface tension rotating Hele-Shaw problem with injection reveal suppression of cusp singularities for sufficiently high rotation rates. We study how the Coriolis force affects the time-dependent solutions of the problem, and the development of finite time singularities. By employing Richardson's harmonic moments approach we obtain conformal maps which describe the time evolution of the fluid boundary. Our results demonstrate that the inertial Coriolis contribution plays an important role in determining the time for cusp formation. Moreover, it introduces a phase drift that makes the evolving patterns rotate. The Coriolis force acts against centrifugal effects, promoting (inhibiting) cusp breakdown if the more viscous and dense fluid lies outside (inside) the interface. Despite the presence of Coriolis effects, the occurrence of finger bending events has not been detected in the exact solutions.


Quality of life measurement in gastrointestinal and liver disorders.
Modern medicine has had a considerable impact on mortality rates for serious illness. Many chronic diseases which have previously been associated with an increased mortality now have survival rates approaching those of the background population. However, chronic diseases such as cancer, chronic pain syndromes, and chronic inflammatory conditions impose a considerable burden on families, the health care system, and society. Health related quality of life (HRQOL) is a concept that has developed from the need to estimate the impact of such chronic diseases. HRQOL measurement is a conceptual framework which attempts to predict daily function and well being based on subjective attitudes and experiences of physical, social, and emotional health. It has been evaluated predominantly from the patient's viewpoint as proxy respondents appear to underestimate the full effect of chronic illness on functional status. Measuring HRQOL in clinical research is most frequently undertaken using multi-item questionnaires to estimate daily function. Factors which affect HRQOL can be broadly classed as disease related and disease independent. The use of different assessment techniques permits comparisons between and within disorders. Generic and disease specific instruments used together enhance the ability to direct treatment for individuals and patient populations. Psychometrically sound questionnaires must be used. However, the type of instrument and research methods adopted depend on the question of interest. We have attempted to catalogue and critically assess the disease specific instruments used in the assessment of chronic gastrointestinal disease.


Interpersonal Influences on Body Representations in the Infant Brain.
Within cognitive neuroscience, there is burgeoning interest in how the body is represented in the adult brain. However, there are large gaps in the understanding of neural body representations from a developmental perspective. Of particular interest are the interconnections between somatosensation and vision, specifically infants' abilities to register correspondences between their own bodies and the bodies of others. Such registration may play an important role in social learning and in engendering feelings of connectedness with others. In the current study, we further explored the interpersonal aspects of neural body representations by examining whether responses to tactile stimulation in 7-month-old infants are influenced by viewing another's body. During EEG recording, infants (N= 60) observed a live presentation of an experimenter's hand or foot being touched. During the presentation of touch to the adult's hand or foot, the infant received a brief tactile touch to their right hand or right foot. This resulted in four conditions: (i) receive hand stimulation/observe hand stimulation, (ii) receive hand stimulation/observe foot stimulation, (iii) receive foot stimulation/observe hand stimulation, and (iv) receive foot stimulation/observe foot stimulation. Analyses compared responses overlying hand and foot regions when the observed limb matched the stimulated limb (congruent) and did not match (incongruent). In line with prior work, tactile stimulation elicited a somatotopic pattern of results in the somatosensory evoked potential (SEP) and the sensorimotor mu rhythm (6-9 Hz). Cross-modal influences were observed in the beta rhythm (11-13 Hz) response and in the late potential of the SEP response (400-600 ms). Beta desynchronization was greater for congruent compared to incongruent conditions. Additionally, tactile stimulation to the foot elicited larger mean amplitudes for congruent compared to incongruent conditions. The opposite was true for stimulation to the hand. This set of novel findings suggests the importance of considering cross-modal effects in the study of neural body representations in the infant brain. Continued work in this new area of infant neuroscience research can inform how interpersonal aspects of body representations may serve to undergird early social learning.


Survey of extrachromosomal circular DNA derived from plant satellite repeats.
Satellite repeats represent one of the most dynamic components of higher plant genomes, undergoing rapid evolutionary changes of their nucleotide sequences and abundance in a genome. However, the exact molecular mechanisms driving these changes and their eventual regulation are mostly unknown. It has been proposed that amplification and homogenization of satellite DNA could be facilitated by extrachromosomal circular DNA (eccDNA) molecules originated by recombination-based excision from satellite repeat arrays. While the models including eccDNA are attractive for their potential to explain rapid turnover of satellite DNA, the existence of satellite repeat-derived eccDNA has not yet been systematically studied in a wider range of plant genomes. We performed a survey of eccDNA corresponding to nine different families and three subfamilies of satellite repeats in ten species from various genera of higher plants (Arabidopsis, Oryza, Pisum, Secale, Triticum and Vicia). The repeats selected for this study differed in their monomer length, abundance, and chromosomal localization in individual species. Using two-dimensional agarose gel electrophoresis followed by Southern blotting, eccDNA molecules corresponding to all examined satellites were detected. EccDNA occurred in the form of nicked circles ranging from hundreds to over eight thousand nucleotides in size. Within this range the circular molecules occurred preferentially in discrete size intervals corresponding to multiples of monomer or higher-order repeat lengths. This work demonstrated that satellite repeat-derived eccDNA is common in plant genomes and thus it can be seriously considered as a potential intermediate in processes driving satellite repeat evolution. The observed size distribution of circular molecules suggests that they are most likely generated by molecular mechanisms based on homologous recombination requiring long stretches of sequence similarity.


Bone mineral density is not related to osteophyte formation in osteoarthritis of the hip.
Reports have suggested that bone mineral density (BMD) is higher in patients with osteoarthritis (OA) of the hip than in healthy controls. Various types of OA of the hip caused by osteophyte formation were observed on radiographs during progression to the advanced degenerative stage, and the preoperative type of OA was reported to influence the results of surgical treatment. However, the mechanism underlying the development of different types of OA is still unknown. We measured BMD of patients with hip OA and determined whether higher BMD was observed in patients with osteophyte formation than in those without osteophytes. We measured BMD of the lumbar spine, radius, and calcaneus using dual-energy x-ray absorptiometry in 88 women who were scheduled to undergo total hip arthroplasty for endstage OA. Hips were evaluated for osteophyte formation using Bombelli's classification; 31 were graded as atrophic type, 30 as normotrophic, and 27 as hypertrophic. BMD at different skeletal sites were compared among the 3 types of OA. No significant difference in BMD of the lumbar spine, ultradistal radius, mid-radius, or calcaneus was observed among the atrophic, normotrophic, and hypertrophic types of OA. Our data suggest that osteophyte formation is not related to general BMD. Factors other than general bone status, for example the morphology of the hip joint, need to be analyzed to determine the pathomechanism of osteophyte formation in the osteoarthritic hip.


Drug screening identifies aldose reductase as a novel target for treating cisplatin-induced hearing loss.
Cisplatin is a frequently used chemotherapeutic medicine for cancer treatment. Permanent hearing loss is one of the most serious side effects of cisplatin, but there are few FDA-approved medicines to prevent it. We applied high-through screening and target fishing and identified aldose reductase, a key enzyme of the polyol pathway, as a novel target for treating cisplatin ototoxicity. Cisplatin treatment significantly increased the expression level and enzyme activity of aldose reductase in the cochlear sensory epithelium. Genetic knockdown or pharmacological inhibition of aldose reductase showed a significant protective effect on cochlear hair cells. Cisplatin-induced overactivation of aldose reductase led to the decrease of NADPH/NADP+ and GSH/GSSG ratios, as well as the increase of oxidative stress, and contributed to hair cell death. Results of target prediction, molecular docking, and enzyme activity detection further identified that Tiliroside was an effective inhibitor of aldose reductase. Tiliroside was proven to inhibit the enzymatic activity of aldose reductase via competitively interfering with the substrate-binding region. Both Tiliroside and another clinically approved aldose reductase inhibitor, Epalrestat, inhibited cisplatin-induced oxidative stress and subsequent cell death and thus protected hearing function. These findings discovered the role of aldose reductase in the pathogenesis of cisplatin-induced deafness and identified aldose reductase as a new target for the prevention and treatment of hearing loss.


ME-Class2 reveals context dependent regulatory roles for 5-hydroxymethylcytosine.
Since the discovery of 5-hydroxymethylcytosine (5hmC) as a prominent DNA modification found in mammalian genomes, an emergent question has been what role this mark plays in gene regulation. 5hmC is hypothesized to function as an intermediate in the demethylation of 5-methylcytosine (5mC) and in the reactivation of silenced promoters and enhancers. Further, weak positive correlations are observed between gene body 5hmC and gene expression. We previously demonstrated that ME-Class is an effective tool to understand relationships between whole-genome bisulfite sequencing data and expression. In this work, we present ME-Class2, a machine-learning based tool to perform integrative 5mCG, 5hmCG and expression analysis. Using ME-Class2 we analyze whole-genome single-base resolution 5mCG and 5hmCG datasets from 20 primary tissue and cell samples to reveal relationships between 5hmCG and expression. Our analysis indicates that conversion of 5mCG to 5hmCG within 2 kb of the transcription start site associates with distinct functions depending on the summed level of 5mCG + 5hmCG. Unchanged levels of 5mCG + 5hmCG (conversion from 5mCG to stable 5hmCG) associate with repression. Meanwhile, decreases in 5mCG + 5hmCG (5hmCG-mediated demethylation) associate with gene activation. Our results demonstrate that ME-Class2 will prove invaluable to interpret genome-wide 5mC and 5hmC datasets and guide mechanistic studies into the function of 5hmCG.


E74-Like Factor 3 Is a Key Regulator of Epithelial Integrity and Immune Response Genes in Biliary Tract Cancer.
The transcription factor E74-like factor 3 (ELF3) is inactivated in a range of cancers, including biliary tract cancer (BTC). Here, we investigated the tumor-suppressive role of ELF3 in bile duct cells by identifying several previously unknown direct target genes of ELF3 that appear to be implicated in biliary duct carcinogenesis. ELF3 directly repressed ZEB2, a key regulator of epithelial-mesenchymal transition, and upregulated the expression of CGN, an integral element in lumen formation. Loss of ELF3 led to decreased cell-cell junctions and enhanced cell motility. ALOX5 and CXCL16 were also identified as additional direct targets of ELF3; their corresponding proteins 5-lipoxygenase and CXCL16 play a role in the immune response. Conditioned medium from cells overexpressing ELF3 significantly enhanced the migration of natural killer cells and CD8+ T cells toward the conditioned medium. Gene expression profiling for BTC expressing high levels of ELF3 revealed significant enrichment of the ELF3-related genes. In a BTC xenograft model, activation of ELF3 increased expression of ELF3-related genes, enhanced the tubular structure of the tumors, and led to a loss of vimentin. Overall, our results indicate that ELF3 is a key regulator of both epithelial integrity and immune responses in BTC. SIGNIFICANCE: Thease finding shows that ELF3 regulates epithelial integrity and host immune responses and functions as a tumor suppressor in biliary tract cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/2/489/F1.large.jpg.


Multidimensional analysis to elucidate the possible mechanism of bone metastasis in breast cancer.
Breast cancer (BC) patients tend to suffer from distant metastasis, especially bone metastasis. All the analysis based on open-accessed data was performed in R software, dependent on multiple algorithms and packages. The RNA levels of specific genes were detected using quantitative Real-time PCR as a method of detecting the RNA levels. To assess the ability of BC cells to proliferate, we utilized the CCK8 test, colony formation, and the 5-Ethynyl-20-deoxyuridine assay. BC cells were evaluated for invasion and migration by using Transwell assays and wound healing assays. In our study, we identified the molecules involved in BC bone metastasis based on the data from multiple BC cohorts. Then, we comprehensively investigated the effect pattern and underlying biological role of these molecules. We found that in the identified molecules, the EMP1, ACKR3, ITGA10, MMP13, COL11A1, and THY1 were significantly correlated with patient prognosis and mainly expressed in CAFs. Therefore, we explored the CAFs in the BC microenvironment. Results showed that CAFs could activate multiple carcinogenic pathways and most of these pathways play an important role in cancer metastasis. Meanwhile, we noticed the interaction between CAFs and malignant, endothelial, and M2 macrophage cells. Moreover, we found that CAFs could induce the remodeling of the BC microenvironment and promote the malignant behavior of BC cells. Then, we identified MMP13 for further analysis. It was found that MMP13 can enhance the malignant phenotype of BC cells. Meanwhile, biological enrichment and immune infiltration analysis were conducted to present the effect pattern of MMP13 in BC. Our result can improve the understanding of researchers on the underlying mechanisms of BC bone metastasis.


Equity of use of specialist palliative care by age: cross-sectional study of lung cancer patients.
The equitable provision of care is a core principle of the National Health Service. Previous research has suggested that older cancer patients may be less likely to use specialist palliative care, but such research has been limited by retrospective design and the failure to measure clinical need. The objective of this study was to examine the extent to which the use of specialist palliative care in lung cancer patients varies by age, after accounting for need. A cross-sectional survey of patients and their carers attending four hospital lung cancer clinics in London was conducted between June 2006 and April 2007. Two hundred and fifty-two patients and 137 carers participated in the study. Thirty-nine percent of participants received specialist palliative care. Metastatic disease, global quality of life and the clinic where treatment was provided were associated with use of specialist palliative care. Age, gender, deprivation, living alone, current or most recent line of treatment, number of co-morbidities and carer stress were not associated with receipt of such services. This suggests that, for patients within the specialist cancer care system, access to specialist palliative care is offered on the basis of need.


Inexpensive device for the aerobic and anaerobic sampling of microorganisms in lake and shallow ocean waters.
An inexpensive device suitable for sampling microorganisms in water and easily constructed from readily available laboratory equipment is described. The need to transfer subsamples to culturing flasks after collection is eliminated by partly filling the sampling vessels with growth medium prior to sampling. The device is readily adapted for sampling different volumes, is simple and quick to operate, and is suitable for use with prereduced media. Contamination from layers others than that being sampled is insignificant.


WinBEST-KIT: Biochemical Reaction Simulator for Analyzing Multi-Layered Metabolic Pathways.
We previously developed the biochemical reaction simulator WinBEST-KIT. In recent years, research interest has shifted from analysis of individual biochemical reactions to analysis of metabolic pathways as systems. These large-scale and complicated metabolic pathways can be considered as characteristic multi-layered structures, which, for convenience, are separated from whole biological systems according to their specific roles. These pathways include reactants having the same name but with unique stoichiometric coefficients arranged across many different places and connected between arbitrary layers. Accordingly, in this study, we have developed a new version of WinBEST-KIT that allows users (1) to utilize shortcut symbols that can be arranged with multiple reactants having the same name but with unique stoichiometric coefficients, thereby providing a layout that is similar to metabolic pathways depicted in biochemical textbooks; (2) to create layers that divide large-scale and complicated metabolic pathways according to their specific roles; (3) to connect the layers by using shortcut symbols; and (4) to analyze the interactions between these layers. These new and existing features allow users to create and analyze such multi-layered metabolic pathways efficiently. Furthermore, WinBEST-KIT supports SBML, making it possible for users to utilize these new and existing features to create and publish SBML models.


Looking upstream to prevent HIV transmission: can interventions with sex workers alter the course of HIV epidemics in Africa as they did in Asia?
High rates of partner change in 'upstream' sex work networks have long been recognized to drive 'downstream' transmission of sexually transmitted infections (STIs). We used a stochastic microsimulation model (STDSIM) to explore such transmission dynamics in a generalized African HIV epidemic. We refined the quantification of sex work in Kisumu, Kenya, from the 4-cities study. Interventions with sex workers were introduced in 2000 and epidemics projected to 2020. We estimated the contribution of sex work to transmission, and modelled standard condom and STI interventions for three groups of sex workers at feasible rates of use and coverage. Removing transmission from sex work altogether would have resulted in 66% lower HIV incidence (range 54-75%) and 56% lower prevalence (range 44-63%) after 20 years. More feasible interventions reduced HIV prevalence from one-fifth to one-half. High rates of condom use in sex work had the greatest effect, whereas STI treatment contributed to HIV declines at lower levels of condom use. Interventions reaching the 40% of sex workers with most clients reduced HIV transmission nearly as much as less targeted approaches attempting to reach all sex workers. Declines were independent of antiretroviral therapy rollout and robust to realistic changes in parameter values. 'Upstream' transmission in sex work remains important in advanced African HIV epidemics even in the context of antiretroviral therapy. As in concentrated Asian epidemics, feasible condom and STI interventions that reach the most active sex workers can markedly reduce the size of HIV epidemics. Interventions targeting 'transactional' sex with fewer clients have less impact.


Association of the Degree of Erythroid Expansion and Maturation Arrest with the Clinical Severity of β0-Thalassemia/Hemoglobin E Patients.
β-Thalassemia/hemoglobin E represents one-half of all the clinically severe β-thalassemias worldwide. Despite similar genetic backgrounds, patients show clinical heterogeneity ranging from nearly asymptomatic to transfusion-dependent thalassemia. The underlying disease modifying factors remain largely obscure. To elucidate the correlation between ineffective erythropoiesis and β0-thalassemia/hemoglobin E (HbE) disease severity, in vitro culture of erythroid cells derived from patients with different clinical symptoms was established. Cell proliferation, viability, and differentiation were investigated. To identify potential molecular mechanisms leading to the arrested erythroid maturation, the expression levels of erythropoiesis modifying factors were measured. The β0-thalassemia/HbE cells exhibited enhanced proliferation, limited differentiation, and impaired erythroid terminal maturation but did not show accelerated erythroblast differentiation and increased cell death. Erythroblasts derived from mild patients showed the highest proliferation rate with a faster cell division time, while erythroblasts derived from severe patients displayed extremely delayed erythroid maturation. Downregulation of growth differentiation factor 11 and FOXO3a was observed in mild β0-thalassemia/HbE erythroblasts, while upregulation of heat shock protein 70 and activin receptor 2A was revealed in severe erythroblasts. The degree of erythroid expansion and maturation arrest contributes to the severity of β0-thalassemia/HbE patients, accounting for the disease heterogeneity. The findings suggest a restoration of erythroid maturation as a promising targeted therapy for severe patients.


An expeditious enantioselective total synthesis of valilactone.
The title compound was synthesized through an expeditious route using Crimmins aldolization to establish the two key stereogenic centers and a hydroxyl group activation (HGA) protocol to construct the anti alpha,beta-disubstituted beta-lactone from the corresponding syn aldol.