Postoperative radiotherapy for stage IB carcinoma of the uterine cervix.
Sixty patients, treated with postoperative radiation therapy following radical hysterectomy and pelvic lymphadenectomy for stage lb carcinoma of the uterine cervix between Jan. 1980 and Dec. 1984 at Department of Radiation Oncology, Yonsei University College of Medicine, were retrospectively analysed. The minimum follow-up period was 5 years. The indications for postoperative radiotherapy were positive pelvic lymph node (34 pts), a large tumor size more than 3 cm in longest diameter (18 pts), positive surgical margin (10 pts), deep stromal invasion (10 pts), and lymphatic permeation (9 pts). The overall 5-year survival rate was 81.8%. The univariate analysis of prognostic factors disclosed tumor size (less than 3cm, greater than or equal to 3cm) and the status of the surgical margin (positive, negative) as significant factors (tumor size; 88.1% vs 6.3%, surgical margin; 85.5% vs 60%, p less than 0.05). Age (less than or equal to 40, greater than 40 yrs) was marginally significant (90.2% vs 73.1%, p less than 0.1). Multivariate analysis clarified two independent prognostic factors; tumor size (p = 0.010) and surgical margin (p = 0.004). Analysis of the tumor factors with the radiation dose disclosed a better survival rate for patients with a positive surgical margin who were given over 50 Gy than for those who were given below 50 Gy in patients (4/4, 100% vs 2/6, 33.4%; p = 0.06). Significant complications requiring surgical correction were not observed. In conclusion, it is believed that the status of the surgical margin and tumor size both have important prognostic significance, and that a radiation dose over 50 Gy is advisable for patients with a positive surgical margin.


Handheld vital microscopy for the identification of microcirculatory alterations in cervical intraepithelial neoplasia and cervical cancer.
Ninety percent of cervical cancer (CC) diagnoses and deaths occur in low and middle-income countries (LMICs). Especially in these countries, where human and material resources are limited, there is a need for real-time screening methods that enable immediate treatment decisions (i.e., 'see and treat'). To evaluate whether handheld vital microscopy (HVM) enables real-time detection of microvascular alterations associated with cervical intraepithelial neoplasia (CIN) and CC. A cross-sectional study was conducted in an oncologic hospital and outpatient clinic, and included ten healthy controls, ten women with CIN, and ten women with CC. The microvasculature was assessed in four quadrants of the uterine cervix using HVM. The primary outcome was the presence of abnormal angioarchitecture (AA). Secondary outcomes included capillary loop density (CD), total vessel density (TVD), functional capillary density (FCD), and the proportion of perfused vessels (PPV). 198 image sequences of the cervical microvasculature were recorded. Compared to healthy controls, significantly more abnormal image sequences were observed in women with high-grade CIN (11 % vs. 44 %, P < 0.001) and women with CC (11 % vs. 69 %, P < 0.001). TVD, FCD, and PPV were lower in women with CIN and CC. HVM enables easy, real-time, non-invasive assessment of cervical lesions through the detection of microvascular alterations. Thereby, HVM potentially provides an opportunity for point-of-care screening, which may enable immediate treatment decisions (see and treat) and reduce the number of unnecessary surgical interventions.


Visual phenomena, disturbances, and hallucinations.
The visual system and its processing of sensory information can be affected in a variety of ways that may be either normal or associated with numerous disorders and diseases. Visual images produced by the intrinsic components of the eyes are often normal and are known as entoptic phenomena. In contrast, the visual system may be disrupted by various disorders and pathologic processes, which can result in metamorphopsia, transient loss of vision, and positive scotomas. Such disruptions can be secondary to retinal and optic nerve disease, migraines associated with visual auras, and cerebrovascular and neurologic diseases; they can also be side effects of certain drugs. In addition, the visual system may process incoming sensory information in such a way that what is seen is perceived incorrectly, i.e. illusion; or the visual system may produce images of things not really there, i.e. hallucination. Various types of visual phenomena, disturbances, and hallucinations are discussed. The numerous visual presentations need to be differentiated so that appropriate treatment, management, and patient education can be rendered.


[Evaluation of central and peripheral components of muscular fatigue in neuropathic and myopathic patients].
In a group of patients chronically denervated and other with primary muscle involvement a search was made for mechanisms involved in the muscular fatigue. It was found that there was no major differences between patients chronically denervated and controls, while in those others with primary muscle disorders a loss of functional motor units during effort and a transient impairment of neuromuscular transmission play a role together with the central events normally occurring in fatigue.


[Induction of anti-meningitis immunity using the synthetic peptides. I. The immunoreactive synthetic fragments of porin A from Neisseria meningitidis].
Fourteen peptides corresponding to sequences of all the exposed and some of the transmembrane protein regions of porin A from the outer membrane of Neisseria meningitidis strain B:15:P1.7,16 were synthesize. Mice of various lines were immunized with the free peptides not conjugated with any protein carrier. It was shown that the majority of the peptides possess immunogenic properties. Two peptides were identified binding to antibodies present in the serum of mice after meningitis. Protective properties of a number of the synthesized peptides were studied, and three peptide sequences inducing mice protection from an experimental infection with N. meningitidis were identified.


Three genes are required for trans-activation of Ty transcription in yeast.
Mutations in the SPT3 gene were isolated as one class of suppressors of Ty and solo delta insertion mutations in Saccharomyces cerevisiae. Previous work has shown that null mutations in SPT3 abolish the normal Ty delta-delta transcript; instead, a transcript that initiates 800 bases farther downstream is made, suggesting that SPT3 is required for transcription initiation in delta sequences. We have selected for new spt mutations and have screened for those with the unique suppression pattern of spt3 mutations with respect to two insertion mutations. Our selection and screen has identified two additional genes, SPT7 and SPT8, that are also required for transcription initiation in delta sequences. We show that mutations in SPT7 or SPT8 result in the same alteration of Ty transcription as do mutations in SPT3. In addition, mutations in all three genes cause a sporulation defect. By assay of a Ty-lacZ fusion we have shown that spt3, spt7 and spt8 mutations reduce transcription from a delta sequence by 10-25-fold. Finally, we show that SPT3 mRNA levels are unaffected in either spt7 or spt8 mutants, suggesting that these two genes do not regulate transcription of SPT3.


Does job stress affect injury due to labor accident in Japanese male and female blue-collar workers?
To clarify whether job stressors affecting injury due to labor accidents differ between Japanese male and female blue-collar workers, the Job Content Questionnaire (JCQ), assessing dimensions of job stressors based on the demand-control-support model, was applied to 139 blue-collar workers in a manufacturing factory. Of them, 24 male and 15 female workers suffered from injuries at work. In the female workers with the experience of work injury, the job demand score and job strain index (i.e., the ratio of job demand to job control) of the JCQ were significantly higher and the score of coworker support was significantly lower, than those in the female workers without the experience. High job demand (or, high job strain and low coworker support) was significantly related to work injury in all the female workers. Between the male workers with and without work injury, however, there was no significant difference in any job stressors. This pilot study suggests that high job strain (specifically, high job demand), as well as low coworker support, are important factors affecting work injury in Japanese female blue-collar workers. Further research with a large number of male blue-collar workers will be required to seek other factors that may be associated with work injury.


Structure of apolipoprotein A-I in spherical high density lipoproteins of different sizes.
Spherical high density lipoproteins (HDL) predominate in human plasma. However, little information exists on the structure of the most common HDL protein, apolipoprotein (apo) A-I, in spheres vs. better studied discoidal forms. We produced spherical HDL by incubating reconstituted discoidal HDL with physiological plasma-remodeling enzymes and compared apoA-I structure in discs and spheres of comparable diameter (79-80 and 93-96 A). Using cross-linking chemistry and mass spectrometry, we determined that the general structural organization of apoA-I was overall similar between discs and spheres, regardless of diameter. This was the case despite the fact that the 93 A spheres contained three molecules of apoA-I per particle compared with only two in the discs. Thus, apoA-I adopts a consistent general structural framework in HDL particles-irrespective of shape, size and the number of apoA-Is present. Furthermore, a similar cross-linking pattern was demonstrated in HDL particles isolated from human serum. We propose the first experiment-based molecular model of apoA-I in spherical HDL particles. This model provides a new foundation for understanding how apoA-I structure modulates HDL function and metabolism.


Neuroimaging in infections and demyelinating disease.
Computerized tomography and magnetic resonance imaging continue to illuminate the changes that occur in the central nervous system in infections and demyelinating disease. Imaging in the acquired immune deficiency syndrome helps to better understand neurological complications. Magnetic resonance imaging also helps to be specific about the diagnosis of cryptococcal meningitis and toxoplasmosis. Major contributions have been made to the understanding of the diagnosis and the living pathology of multiple sclerosis. Experimental studies have identified the mechanism of blood-brain barrier disruption in inflammatory disease.


[Combined action of juvenile hormone and ecdysterone on Drosophila cell lines in vitro].
The action of juvenile hormone used alone or combined with ecdysterone was studied on in vitro diploid cell lines or clones of Drosophila. The solubility of juvenile hormone in the culture medium was estimated to be 10(-8) M. At this concentration, which can be considered as physiological, juvenile hormone slows down the process of ecdysone-induced morphological modifications of the cells. This action is reversible. Concentrations of about 10(-4) M inhibit all reactions to ecdysterone and bring about the death of the cells. This effect is probably non-specific.


The Intersectionality of Racial and Gender Discrimination among Teens Exposed to Dating Violence.
Driven by intersectionality, a central tenet of Critical Race Theory, this study examines the combined associations of racial and gender discrimination, which are interlocking, macro-level social forces, and teen dating violence (TDV). Self-report surveys were administered via Audio Computer Assisted Self Interview (ACASI) equipment. Logistic regression models were used to estimate associations between racial and gender discrimination and TDV. Study participants were recruited during August 2003 to June 2004 from high school health classes and an after-school program located in South Bronx neighborhoods of New York City. Non-probability sample of 142 Black and Latino teens aged 13-19 years who reported experiences dating someone of a different sex. Experienced discrimination based on race and gender adapted from the Experiences of Discrimination (EOD) instrument, dating violence items from the Youth Dating Violence Survey. Of the participants, 40.1% reported experiencing both racial and gender discrimination, and nearly all (93%) experienced dating violence. Participants reporting both racial and gender discrimination were 2.5 times more likely to report experiencing the highest frequency of dating violence, adjusted for age and sex (95% CI: 1.0-6.7). A dose-response of EOD observed in unadjusted models (P for trend =.024) was no longer statistically significant after adjustment for age and sex (P for trend =.073). Strategies to prevent TDV in this population should not ignore the compounding negative effects of racial and gender discrimination.


Bacterial resistance to antibiotics: enzymatic degradation and modification.
Antibiotic resistance can occur via three general mechanisms: prevention of interaction of the drug with target, efflux of the antibiotic from the cell, and direct destruction or modification of the compound. This review discusses the latter mechanisms focusing on the chemical strategy of antibiotic inactivation; these include hydrolysis, group transfer, and redox mechanisms. While hydrolysis is especially important clinically, particularly as applied to beta-lactam antibiotics, the group transfer approaches are the most diverse and include the modification by acyltransfer, phosphorylation, glycosylation, nucleotidylation, ribosylation, and thiol transfer. A unique feature of enzymes that physically modify antibiotics is that these mechanisms alone actively reduce the concentration of drugs in the local environment; therefore, they present a unique challenge to researchers and clinicians considering new approaches to anti-infective therapy. This review will present the current status of knowledge of these aspects of antibiotic resistance and discuss how a thorough understanding of resistance enzyme molecular mechanism, three-dimensional structure, and evolution can be leveraged in combating resistance.


Why is safety in intrapartum electronic fetal monitoring so hard? A qualitative study combining human factors/ergonomics and social science analysis.
Problems in intrapartum electronic fetal monitoring with cardiotocography (CTG) remain a major area of preventable harm. Poor understanding of the range of influences on safety may have hindered improvement. Taking an interdisciplinary perspective, we sought to characterise the everyday practice of CTG monitoring and the work systems within which it takes place, with the goal of identifying potential sources of risk. Human factors/ergonomics (HF/E) experts and social scientists conducted 325 hours of observations and 23 interviews in three maternity units in the UK, focusing on how CTG tasks were undertaken, the influences on this work and the cultural and organisational features of work settings. HF/E analysis was based on the Systems Engineering Initiative for Patient Safety 2.0 model. Social science analysis was based on the constant comparative method. CTG monitoring can be understood as a complex sociotechnical activity, with tasks, people, tools and technology, and organisational and external factors all combining to affect safety. Fetal heart rate patterns need to be recorded and interpreted correctly. Systems are also required for seeking the opinions of others, determining whether the situation warrants concern, escalating concerns and mobilising response. These processes may be inadequately designed or function suboptimally, and may be further complicated by staffing issues, equipment and ergonomics issues, and competing and frequently changing clinical guidelines. Practice may also be affected by variable standards and workflows, variations in clinical competence, teamwork and situation awareness, and the ability to communicate concerns freely. CTG monitoring is an inherently collective and sociotechnical practice. Improving it will require accounting for complex system interdependencies, rather than focusing solely on discrete factors such as individual technical proficiency in interpreting traces.


Working under the 2021 Heat Dome: A Content Analysis of Occupational Impacts Mentioned in the Canadian Media.
Extreme heat events directly impact worker health and cause additional cascading and transitional workplace impacts. However, current investigations on these impacts often rely on specific datasets (e.g., compensation claims, hospitalizations). Thus, to continue to work towards preventing and mitigating the occupational risks posed by extreme heat events, this study aimed to explore the occupational impacts of the 2021 Heat Dome in Canada using a qualitative content analysis method on a news-based dataset. A systematized review of news articles published before, during, and after the 2021 Heat Dome was conducted on academic (n = 8) and news (n = 5) databases, along with targeted grey literature. Two researchers qualitatively coded the articles in NVivo for occupational impacts or references mentioned within the articles. Overall, 52 different occupations were identified as being impacted by the 2021 Heat Dome. Impacts were diverse and ranged from work cancellations or delays to work modifications and reports of heat-related illnesses. The 2021 Heat Dome impacted the health and safety of many occupational groups and provided new insights into the expanding impacts that extreme heat events can have on the Canadian workforce. With climate projections showing a growing trend of more hot days and intense heat waves in Canada, addressing these concerns should be a critical priority.


Human cytomegalovirus inhibition by cardiac glycosides: evidence for involvement of the HERG gene.
Infection with human cytomegalovirus (HCMV) continues to be a major threat for pregnant women and the immunocompromised population. Although several anti-HCMV therapies are available, the development of new anti-HCMV agents is highly desired. There is growing interest in identifying compounds that might inhibit HCMV by modulating the cellular milieu. Interest in cardiac glycosides (CG), used in patients with congestive heart failure, has increased because of their established anticancer and their suggested antiviral activities. We report that the several CG--digoxin, digitoxin, and ouabain--are potent inhibitors of HCMV at nM concentrations. HCMV inhibition occurred prior to DNA replication, but following binding to its cellular receptors. The levels of immediate early, early, and late viral proteins and cellular NF-κB were significantly reduced in CG-treated cells. The activity of CG in infected cells correlated with the expression of the potassium channel gene, hERG. CMV infection upregulated hERG, whereas CG significantly downregulated its expression. Infection with mouse CMV upregulated mouse ERG (mERG), but treatment with CG did not inhibit virus replication or mERG transcription. These findings suggest that CG may inhibit HCMV by modulating human cellular targets associated with hERG and that these compounds should be studied for their antiviral activities.


Partial deletion of the beta-globin gene: a common beta-thalassaemia allele in Asian Indians.
We have examined 11 families of Asian Indian origin, who are segregating beta-thalassaemia alleles, for coupled restriction enzyme site markers. A beta-thalassaemia deletion allele, which removes over 600 base pairs, is a common cause of thalassaemia in this population. This deletion can be conveniently detected in AvaII restriction enzyme digests. Consequently AvaII digests are particularly informative in this population because both the deletion and a coupled restriction site polymorphism may be simultaneously observed.


Efficiency Records in Mesoscopic Dye-Sensitized Solar Cells.
The aim of the present review article is to show the progress achieved in the efficiency of dye-sensitized solar cells (DSSCs) by evolution in the structure and composition of the dye. After an initial brief description of DSSCs and the operating mechanism the major part of the present article is organized according to the type of dye, trying to show the logic in the variation of the dye structure in order to achieve strong binding on the surface of the layer of nanoparticulate TiO2 , efficient interfacial electron injection between the excited dye and the semiconductor, and minimization of the unwanted dark current processes. Besides metal complexes, including polypyridyls and nitrogenated macro rings, organic dyes and inorganic light harvesters such as quantum dots and perovskites have also been included in the review. The last section summarizes the current state of the art and provides an overview on future developments in the field.


[A review of the principle mythical gods in ancient greek medicine].
Like their prehistoric ancestors, the people of early civilizations lived related to the supernatural. Facing life-threatening situations, such as illness and death, people of ancient civilizations resorted to divination, prophecy, or the oracle. Regarding the curative activities of the ancient Greek civilization, there was a period in which these processes were exclusively linked to a supernatural perspective of the origin of disease. This stage of development of Greek healing practices corresponds to what might be called pre-Hippocratic Greek medicine. In ancient Greek civilization, myths exerted a strong influence on the concepts of disease and the healing processes. Although the first divine figure of Greek mythology related to medicine was Paeon, healing cults related to Apollo and Asclepius had a higher importance in tradition and Greek mythology. The Apollonian divine healing consisted in the ability to eliminate chaos and keep away evil, while in the Asclepian perspective, the role of healer was linked to specific procedures. Personal and medical skills allowed Asclepius to surpass his father and achieve his final consecration as a god of medicine.


Evaluation of carcinoembryonic antigen levels in gastric juice, stomach mucosa and plasma in high-risk and gastric cancer patients.
The aim of this study is to compare the levels of carcinoembryonic antigen (CEA) in the gastric juice, stomach mucosa and plasma of gastrectomy patients at risk of developing cancer with those in normal controls and gastric cancer subjects. Blood samples, gastric juices and biopsy material were taken from 52 patients (8 normal, 10 gastric carcinomas, 24 gastroresected according to Billroth II and 10 according to Billroth I). No significant correlation was found between age, sex or smoking habits and CEA levels in plasma, gastric juice or stomach mucosa. A significant correlation between CEA levels in gastric secretion and those in tissue emerged from out data (n = 52; r = 0.67; p less than 0.01). A minor correlation was found between tissue and plasma CEA values (r = 0.34; p less than 0.05). The mean levels of CEA in plasma did not show significant differences between controls and neoplastic risk subjects. The average level of CEA in gastric secretions and in tissue were significantly lower in normal controls than in neoplastic and gastroresected patients; in this latter group, we have observed a correlation between the severity of the histological lesions and the levels of CEA in the biopsy specimens; no correlation was found with the type of operation (Billroth I or Billroth II). The level of CEA in gastric juices and in biopsy material, therefore, appears to be more useful than in plasma in recognizing cancer risk subjects.


Magnetization transfer imaging of suicidal patients with major depressive disorder.
Magnetization transfer imaging (MTI) provides a quantitative measure of the macromolecular structural integrity of brain tissue, as represented by magnetization transfer ratio (MTR). In this study, we utilized MTI to identify biophysical alterations in MDD patients with a history of suicide attempts relative to MDD patients without such history. The participants were 36 medication-free MDD patients, with (N = 17) and without (N = 19) a history of a suicide attempt, and 28 healthy controls matched for age and gender. Whole brain voxel-based analysis was used to compare MTR across three groups and to analyze correlations with symptom severity and illness duration. We identified decreased MTR in left inferior parietal lobule and right superior parietal lobule in suicide attempters relative to both non-attempters and controls. Non-attempters also showed significantly reduced MTR in left inferior parietal lobule relative to controls, as well as an MTR reduction in left cerebellum. These abnormalities were not correlated with symptom severity or illness duration. Depressed patients with a history of suicide attempt showed bilateral abnormalities in parietal cortex compared to nonsuicidal depressed patients and healthy controls. Parietal lobe abnormalities might cause attentional dysfunction and impaired decision making to increase risk for suicidal behavior in MDD.


A survey on Swiss women's preferred menstrual/withdrawal bleeding pattern over different phases of reproductive life and with use of hormonal contraception.
Today, options for bleeding-free lifestyle are actively promoted by the media, the pharmaceutical industry and health specialists. With regard to contraceptive counselling it is important to find out what women really want. In the present study we collected information on women's attitudes towards monthly bleeding and preferences, if they could have the option to modify their individual bleeding pattern. Furthermore we evaluated the preferences with use of combined hormonal contraceptives (CHCs). Switzerland has never been surveyed before with regard to these issues. Questionnaires were distributed in our family planning clinic and two outdoor offices to clients aged 15 to 19 years, 25 to 34 years, and 45 to 49 years. Of 530 questionnaires, 292 were eligible for analysis. Around 50 of the participants would appreciate having fewer menstrual period-related symptoms. Some 37% preferred experiencing a monthly bleeding; 32% opted for every 2 to 6 months; and 29%, for no bleeding at all. This heterogeneous distribution did not differ between clients with and without menstrual symptoms. With regard to CHC use, predictable bleeding was rated as very positive and breakthrough bleeding as negative. Contraceptive counsellors should be aware that women's wishes differ widely. Predictability of bleeding seems to be more important to them than postponing it.


Influence of Organizational Structure and Administrative Processes on the Performance of State-Level Malaria Programs in Nigeria.
Abstract-Studies have found links between organizational structure and performance of public organizations. Considering the wide variation in uptake of malaria interventions and outcomes across Nigeria, this exploratory study examined how differences in administrative location (a dimension of organizational structure), the effectiveness of administrative processes (earmarking and financial control, and communication), leadership (use of data in decision making, state ownership, political will, and resourcefulness), and external influences (donor influence) might explain variations in performance of state malaria programs in Nigeria. We hypothesized that states with malaria program administrative structures closer to state governors will have greater access to resources, greater political support, and greater administrative flexibility and will therefore perform better. To assess these relationships, we conducted semistructured interviews across three states with different program administrative locations: Akwa-Ibom, Cross River, and Niger. Sixty-five participants were identified through a snowballing approach. Data were analyzed using a thematic framework. State program performance was assessed across three malaria service delivery domains (prevention, diagnosis, and treatment) using indicators from Nigeria Demographic and Health Surveys conducted in 2008 and 2013. Cross River State was best performing based on 2013 prevention data (usage of insecticide-treated bednets), and Niger State ranked highest in diagnosis and treatment and showed the greatest improvement between 2008 and 2013. We found that organizational structure (administrative location) did not appear to be determinative of performance but rather that the effectiveness of administrative processes (earmarking and financial control), strong leadership (assertion of state ownership and resourcefulness of leaders in overcoming bottlenecks), and donor influences differed across the three assessed states and may explain the observed varying outcomes.


Duloxetine for the treatment of major depressive disorder: safety and tolerability associated with dose escalation.
Duloxetine has demonstrated efficacy for the treatment of major depressive disorder (MDD) at a dose of 60 mg/day (given once daily). Whereas the target dose for the majority of patients is 60 mg/day, higher duloxetine doses (up to 120 mg/day) have been studied using a twice-daily dosing schedule. To further investigate the pharmacological profile of duloxetine within a once-daily dosing regimen at doses above 60 mg, we examined the safety and tolerability of duloxetine during a dose escalation from 60 mg/day to 120 mg/day. This single-arm, non-placebo-controlled study incorporated a 7-week dose escalation phase, in which patients and investigators were blinded as to timing of dose increases, followed by an open-label extension phase of up to 2 years duration. Patients (age >or=18 years) meeting DSM-IV criteria for MDD (n=128) received placebo for 1 week, followed by duloxetine (60 mg/day) titrated after 1 week to 90 mg/day, and after a further week to 120 mg/day. The dose of 120 mg/day was then maintained for 4 weeks. The extension phase comprised an initial 6-week dose stabilization period, during which duloxetine was tapered to the lowest effective dose, followed by continuation therapy at the stabilized dose. We assessed safety using spontaneously reported treatment-emergent adverse events (TEAEs), changes in vital signs, electrocardiograms (ECGs), laboratory analytes, and visual analogue scales (VAS) for gastrointestinal (GI) disturbance. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and VAS assessments of pain severity and interference. The rate of discontinuation due to adverse events during the acute phase of the study was 15.6%. The most frequently reported TEAEs were nausea, headache, dry mouth, dizziness, and decreased appetite. The majority of TEAEs were associated with initial duloxetine dosing; further escalations in dose produced few additional adverse events. VAS measures of GI disturbance worsened significantly compared with baseline values after 1 week of duloxetine treatment. Subsequent assessments of GI disturbance, following dose escalation to 90 mg/day and 120 mg/day, showed either no significant difference or a significant improvement from baseline. Significant improvements (P<.001) were observed in all assessed depression efficacy measures, and in five of six VAS pain outcomes, during acute phase treatment. During 2 years of extension phase therapy, the rate of discontinuation due to adverse events was 11.9%, and the only TEAEs reported by >10% of patients were upper respiratory tract infection (13.1%), headache (10.7%), and insomnia (10.7%). Mean changes from baseline to the end of the extension phase in supine systolic and diastolic blood pressure were 3.8 and 0.5 mm Hg, respectively, and there were no reports of sustained hypertension. Mean increase in heart rate was 5.9 bpm, while patients exhibited a mean weight increase of 3.1 kg over 2 years of treatment. Results from this study suggest that rapid dose escalation of duloxetine (60 mg/day --> 90 mg/day --> 120 mg/day) is safe and tolerable. Despite weekly escalation, the majority of adverse events were mild and transient and occurred in the first week of duloxetine dosing (at 60 mg once daily). Long-term treatment at a stabilized duloxetine dose was associated with a relatively low incidence of TEAEs and treatment discontinuation due to adverse events. Time course profiles of body weight and heart rate showed modest increases during 2 years of treatment [ClinicalTrials.gov number, NC T000 42575].


TBK1 regulates YAP/TAZ and fibrogenic fibroblast activation.
Idiopathic pulmonary fibrosis (IPF) results in scarring of the lungs by excessive extracellular matrix (ECM) production. Resident fibroblasts are the major cell type involved in ECM deposition. The biochemical pathways that facilitate pathological fibroblast activation leading to aberrant ECM deposition are not fully understood. Tank binding protein kinase-1 (TBK1) is a kinase that regulates multiple signaling pathways and was recently identified as a candidate regulator of fibroblast activation in a large-scale small-interfering RNA (siRNA) screen. To determine the effect of TBK1 on fibroblast activation, TBK1 was inhibited pharmacologically (MRT-68601) and genetically (siRNA) in normal and IPF human lung fibroblasts. Reducing the activity or expression of TBK1 led to reduction in α-smooth muscle actin stress fiber levels by 40-60% and deposition of ECM components collagen I and fibronectin by 50% in TGF-β-stimulated normal and IPF fibroblasts. YAP and TAZ are homologous mechanoregulatory profibrotic transcription cofactors known to regulate fibroblast activation. TBK1 knockdown or inhibition decreased the total and nuclear protein levels of YAP/TAZ. Additionally, low cell-cell contact and increased ECM substrate stiffness augmented the phosphorylation and activation of TBK1, consistent with cues that regulate YAP/TAZ. The action of TBK1 toward YAP/TAZ activation was independent of LATS1/2 and canonical downstream TBK1 signaling mediator IRF3 but dependent on proteasomal machinery of the cell. This study identifies TBK1 as a fibrogenic activator of human pulmonary fibroblasts, suggesting TBK1 may be a novel therapeutic target in pulmonary fibrosis.


Mosaic hepatitis B virus core particles allow insertion of extended foreign protein segments.
Because of its particular immunological properties, the core protein of hepatitis B virus (HBcAg) has become one of the favoured 'virus-like particles' for use as a carrier of foreign epitopes. A new strategy to construct core particles presenting extended foreign protein segments was established based on the introduction of a linker containing a translational stop codon between sequences encoding a C-terminally truncated HBcAg (HBcAg delta) and a foreign protein sequence. Expression in an Escherichia coli suppressor strain allowed the simultaneous synthesis of both HBcAg delta and a read-through fusion protein containing a part of the hantavirus nucleocapsid protein. After purification, the presence of core-like mosaic particles with HBc and hantavirus antigenicity was demonstrated by electron microscopy and immunological tests. This strategy of partial stop codon suppression should improve the use of HBcAg as a carrier of foreign epitopes by allowing insertion of long foreign sequences into particle-forming proteins. The resulting mosaic particles should be of general interest for further vaccine developments.


Gentics of urogenital abnormalities in ACI inbread rats.
The frequency of urogenital abnormalities in adult ACI rats was 18.8%. These abnormalities consisted of a spectrum of defects ranging from focal aplasia of the ureter to the complete absence of the ureter, kidney, and tubular genital tract on the affected side. When ACI rats with normal urogenital tracts tracts were crossed with F344 rats the frequency of the defects decreased to a constant level in the F1, F2, and F3 generations. There was no clearly significant decrease in the frequency of the defects in the backcross offspring of (ACI times F344)F1 times ACI matings, but there was a significant and dramatic decrease in the backcross to F344 rats. Attempts to select against these defects by brother-sister matings among normal ACI rats were not successful: 5 generations of inbreeding did not alter the frequency of the urogenital abnormalities. The frequency of the abnormalities was the same in the offspring of affected parents as in the offspring of normal parents, indicating homozygosity of the factors responsible for the defects. The results suggest that the transmission of these defects is polygenic.


Methicillin-resistant Staphylococcus aureus.
Since the 1960s, methicillin-resistant Staphylococcus aureus (MRSA) has emerged, disseminated globally and become a leading cause of bacterial infections in both health-care and community settings. However, there is marked geographical variation in MRSA burden owing to several factors, including differences in local infection control practices and pathogen-specific characteristics of the circulating clones. Different MRSA clones have resulted from the independent acquisition of staphylococcal cassette chromosome mec (SCCmec), which contains genes encoding proteins that render the bacterium resistant to most β-lactam antibiotics (such as methicillin), by several S. aureus clones. The success of MRSA is a consequence of the extensive arsenal of virulence factors produced by S. aureus combined with β-lactam resistance and, for most clones, resistance to other antibiotic classes. Clinical manifestations of MRSA range from asymptomatic colonization of the nasal mucosa to mild skin and soft tissue infections to fulminant invasive disease with high mortality. Although treatment options for MRSA are limited, several new antimicrobials are under development. An understanding of colonization dynamics, routes of transmission, risk factors for progression to infection and conditions that promote the emergence of resistance will enable optimization of strategies to effectively control MRSA. Vaccine candidates are also under development and could become an effective prevention measure.


Ontogeny and Consistent Individual Differences Mediate Trophic Interactions.
Ecologists use species traits to predict responses to environmental change and, ultimately, to understand the composition of biological communities. However, this ignores known and substantial intraspecific variation that can have important consequences for species interactions and community composition. This within-species variation results from two distinct sources: ontogeny and consistent individual differences. Ontogeny and consistent differences interact to produce phenotypes, but the community-level consequences of this interaction have not been studied. Using larval dragonfly communities, I investigate patterns of intraguild predation by manipulating (1) consistent individual differences in activity rate and (2) the ontogeny of the focal and interacting species. I show that activity rate is a consistent individual trait but that the effect of activity rate on intraguild predation depends on the functional role of an organism in the community (predator or prey). An organism's functional role itself varies across ontogeny of both the focal and interacting individuals. I suggest that ontogeny and consistent individual differences interact to produce intraspecific variation, with consequences for species interactions, communities, and eco-evolutionary dynamics.


HIV prevalence and characteristics of sex work among female sex workers in Hargeisa, Somaliland, Somalia.
To measure prevalence of HIV and syphilis and describe characteristics of sex work among female sex workers (FSWs) in Hargeisa, Somaliland, Somalia. A cross-sectional survey recruited 237 FSWs using respondent-driven sampling (RDS). A face-to-face, structured interview using handheld-assisted personal interviewing (HAPI) on personal digital assistants (PDAs) was completed and blood collected for serological testing. FSWs 15-19 years old accounted for 6.9% of the population; 20-24 year-old constituted an additional 18.0%. The majority (86.6%) never attended school. International (59.0%) and interzonal (10.7%) migration was common. Most (95.7%) reported no other source of income; 13.8% had five or more clients in the last 7 days. A minority (38.4%) had heard of STIs, even fewer (6.9%) held no misconceptions about HIV. Only 24% of FSW reported using a condom at last transactional sex, and 4% reported ever been tested for HIV. HIV prevalence was 5.2% and syphilis prevalence was 3.1%. Sex work in Hargeisa, Somaliland, Somalia, is characterized by high numbers of sexual acts and extremely low knowledge of HIV. This study illustrates the need for targeted HIV prevention interventions focusing on HIV testing, risk-reduction awareness raising, and review of condom availability and distribution mechanisms among FSWs and males engaging with FSWs.


Implementing culture change in health care: theory and practice.
To review some of the key debates relating to the nature of organizational culture and culture change care organizations and systems. A literature review was conducted that covered both theoretical contributions and published studies of the processes and outcomes of culture change programmes across a range of health and non-health care settings. There is little consensus among scholars over the precise meaning of organizational culture. Competing claims exist concerning whether organizational cultures are capable of being shaped by external manipulation to beneficial effect. A range of culture change models has been developed. A number of underlying factors that commonly attenuate culture change programmes can be identified. Key factors that appear to impede culture change across a range of sectors include: inadequate or inappropriate leadership; constraints imposed by external stakeholders and professional allegiances; perceived lack of ownership; and subcultural diversity within health care organizations and systems. Managing organizational culture is increasingly viewed as an essential part of health system reform. To transform the culture of a whole health system such as the UK National Health Service would be a complex, multi-level, and uncertain process, comprising a range of interlocking strategies and supporting tactics unfolding over a period of years.


Biodegradable arginine-based poly(ester-amide)s as non-viral gene delivery reagents.
A novel family of synthetic biodegradable poly(ester-amide)s (Arg-PEAs) was evaluated for their biosafety and capability to transfect rat vascular smooth muscle cells, a major cell type participating in vascular diseases. Arg-PEAs showed high binding capacity toward plasmid DNA, and the binding activity was inversely correlated to the number of methylene groups in the diol segment of Arg-PEAs. All Arg-PEAs transfected smooth muscle cells with an efficiency that was comparable to the commercial transfection reagent Superfect. However, unlike Superfect, Arg-PEAs, over a wide range of dosages, had minimal adverse effects on cell morphology, viability or apoptosis. Using rhodamine-labeled plasmid DNA, we demonstrated that Arg-PEAs were able to deliver DNA into nearly 100% of cells under optimal polymer-to-DNA weight ratios, and that such a high level of delivery was achieved through an active endocytosis mechanism. A large portion of DNA delivered, however, was trapped in acidic endocytotic compartments, and subsequently was not expressed. These results suggest that with further modification to enhance their endosome escape, Arg-PEAs can be attractive candidates for non-viral gene carriers owning to their high cellular uptake nature and reliable cellular biocompatibility.


Botulinum neurotoxins and botulism: a novel therapeutic approach.
Specific treatment is not available for human botulism. Current remedial mainstay is the passive administration of polyclonal antibody to botulinum neurotoxin (BoNT) derived from heterologous species (immunized animal or mouse hybridoma) together with supportive and symptomatic management. The antibody works extracellularly, probably by blocking the binding of receptor binding (R) domain to the neuronal receptors; thus inhibiting cellular entry of the holo-BoNT. The antibody cannot neutralize the intracellular toxin. Moreover, a conventional antibody with relatively large molecular size (150 kDa) is not accessible to the enzymatic groove and, thus, cannot directly inhibit the BoNT zinc metalloprotease activity. Recently, a 15-20 kDa single domain antibody (V(H)H) that binds specifically to light chain of BoNT serotype A was produced from a humanized-camel VH/V(H)H phage display library. The V(H)H has high sequence homology (>80%) to the human VH and could block the enzymatic activity of the BoNT. Molecular docking revealed not only the interface binding between the V(H)H and the toxin but also an insertion of the V(H)H CDR3 into the toxin enzymatic pocket. It is envisaged that, by molecular linking the V(H)H to a cell penetrating peptide (CPP), the CPP-V(H)H fusion protein would be able to traverse the hydrophobic cell membrane into the cytoplasm and inhibit the intracellular BoNT. This presents a novel and safe immunotherapeutic strategy for botulism by using a cell penetrating, humanized-single domain antibody that inhibits the BoNT by means of a direct blockade of the groove of the menace enzyme.


Outcome of acute myocardial infarction according to the specialty of the admitting physician.
In order to limit costs, health care organizations in the United States are shifting medical care from specialists to primary care physicians. Although primary care physicians provide less resource-intensive care, there is little information concerning the effects of this strategy on outcomes. We examined mortality according to the specialty of the admitting physician among 8241 Medicare patients who were hospitalized for acute myocardial infarction in four states during a seven-month period in 1992. Proportional-hazards regression models were used to examine survival up to one year after the myocardial infarction. To determine the generalizability of our findings, we also examined insurance claims and survival data for all 220,535 patients for whom there were Medicare claims for hospital care for acute myocardial infarction in 1992. After adjustment for characteristics of the patients and hospitals, patients who were admitted to the hospital by a cardiologist were 12 percent less likely to die within one year than those admitted by a primary care physician (P<0.001). Cardiologists also had the highest rate of use of cardiac procedures and medications, including medications (such as thrombolytic agents and beta-blockers) that are associated with improved survival. Health care strategies that shift the care of elderly patients with myocardial infarction from cardiologists to primary care physicians lower rates of use of resources (and potentially lower costs), but they may also cause decreased survival. Additional information is needed to elucidate how primary care physicians and specialists should interact in the care of severely ill patients.


Adherence and drop-out in randomized controlled trials of exercise interventions in people with multiple sclerosis: A systematic review and meta-analyses.
The short-term benefits of exercise in people with multiple sclerosis (MS) are well established. To sustain benefits exercise needs to continue long-term. Despite important clinical implications, no systematic reviews have synthesized evidence on adherence and drop-out in MS exercise interventions. 1) To summarize reported adherence and drop-out data from randomized controlled trials (RCTs) of exercise interventions, and 2) identify moderators related to adherence and drop-out. Nine databases were electronically searched in October 2018. Included studies were RCTs of exercise interventions in adults with MS published from January 1993 to October 2018. Abstracts and full texts were independently screened and selected for inclusion by two reviewers. Methodological quality was assessed using the TESTEX rating scale. Ninety three articles reporting 81 studies were included. Forty one studies (51%) reported both adherence and drop-out data during the intervention period with three (4%) also reporting follow-up data. Of the 41 studies, < 25% pre-defined adherence or described how adherence was measured. Meta-analyses of 59 interventions (41 studies) showed a pooled adherence estimate of 0.87 (95% CI 0.83 to 0.90) and 0.73 (CI 0.68-0.78) when including drop-outs. Mean age, proportion of females and intervention duration were inversely associated with adherence. Little consensus existed on definition of adherence or determination of drop-out in MS exercise studies, with reporting generally of poor quality, if done at all. Hence it is largely unknown what can moderate adherence and whether exercise continued following an exercise intervention. Researchers should ensure clear transparent measurement and reporting of adherence and drop-out data in future trials.


Coronary CTA: indications, patient selection, and clinical implications.
Recent technical advancements of modern multislice computed tomography scanners including improved temporal and spatial resolution allow for the evaluation of cardiac patients. These modern techniques have been applied to bypass imaging, assessment of pulmonary veins following ablative therapy, congenital and acquired anatomic abnormalities, and also the evaluation of coronary artery disease. Cardiac computed tomography angiography is a valuable tool for patients with equivocal stress test results or inconclusive echocardiography in patients with intermediate likelihood of coronary artery disease. Future applications of this study include coronary plaque imaging, triage of patients with chest pain in the emergency room, and evaluation of myocardial viability.


Training for success: Do simulated aerial landings replicate successful aerial landings performed in the ocean?
Physical preparation of competitive surfers includes substantial dry-land training. It is currently unknown, however, how closely these exercises replicate surfing maneuvers performed in the ocean. This study compared the technique features displayed by surfers when landing simulated aerial maneuvers on land to critical features previously established as necessary for surfers to successfully land aerials in the ocean during competition. Fourteen competitive surfers (age 20.6 ± 5.7 years, height 178.1 ± 9.50 cm, mass 70.6 ± 10.8 kg) were recruited to perform two variations of a simulated aerial task, a Frontside Air (FA) and Frontside Air Reverse (FAR). Joint ranges of motion (ROM), center of pressure, and apparent gaze data were collected during the landing event. Paired t tests or Wilcoxon signed-rank tests were used to identify any significant differences in the outcome variables between the two aerial tasks. Participants displayed 100% and 60% of the critical features associated with successfully landing a FA and FAR, respectively. In both the simulated FA and FAR, participants landed in 1.0-3.7° of dorsiflexion, moving through significantly less ankle joint ROM in the lead limb during the FAR (P < .01). Participants also displayed significantly less knee and hip ROM (P = .002-.048) while landing the FAR compared to the FA. The simulated FA and FAR tasks are appropriate training tools for surfers to replicate most of the critical features that a surfer should display to successfully land aerial maneuvers in the ocean. These tasks therefore enable surfers to practice these complex movements in a controlled environment.


Atypical lipomatous tumor/"well-differentiated liposarcoma" of the skin clinically presenting as a skin tag: clinicopathologic, immunohistochemical, and molecular analysis of 2 cases.
Liposarcomas are extremely rare in the skin. When they involve the skin, it is usually by upward spread from a subcutaneous or deeper seated liposarcoma. Very rarely, liposarcoma metastasize to the skin or arise as a primary dermal lesion. We describe 2 cases of atypical lipomatous tumor "well-differentiated liposarcoma" located in dermis. Both presented clinically as a skin tag. The neoplasms arose in a 56-year-old female and a 69-year-old male patient. Both lesions were treated by excision and reexcision. In addition to classical morphology of atypical lipomatous tumor with evidence of lipoblasts and atypical adipocytes, immunohistochemistry with nuclear murine double-minute type 2 protein and cyclin-dependent kinase-4 expression as well as fluorescence in situ hybridization analysis showing an amplification of murine double-minute type 2 protein and cyclin-dependent kinase-4 were helpful to establish the diagnosis. None of the cases recurred after surgical treatment. These 2 cases show the importance of not to misdiagnose lesions which clinically may appear to be benign.


Epidemiology of COVID-19 Outbreak on Cruise Ship Quarantined at Yokohama, Japan, February 2020.
To improve understanding of coronavirus disease (COVID-19), we assessed the epidemiology of an outbreak on a cruise ship, February 5-24, 2020. The study population included persons on board on February 3 (2,666 passengers, 1,045 crew). Passengers had a mean age of 66.1 years and were 55% female; crew had a mean age of 36.6 years and were 81% male. Of passengers, 544 (20.4%) were infected, 314 (57.7%) asymptomatic. Attack rates were highest in 4-person cabins (30.0%; n = 18). Of crew, 143 (13.7%) were infected, 64 (44.8%) asymptomatic. Passenger cases peaked February 7, and 35 had onset before quarantine. Crew cases peaked on February 11 and 13. The median serial interval between cases in the same cabin was 2 days. This study shows that severe acute respiratory syndrome coronavirus 2 is infectious in closed settings, that subclinical infection is common, and that close contact is key for transmission.


TNM cancer staging: can it help develop a novel staging system for type 2 diabetes?
Type 2 diabetes (DM2) constitutes 90%-95% of the diabetes cases and is increasing at an alarming rate in the world. The Centers for Disease Control and Prevention (CDC) estimates that more than 29 million people in the United States have diabetes, which often causes mortality from macrovascular complications and morbidity from microvascular complications. Despite these troubling facts, there is currently no widely accepted staging system for DM2 like there is for cancer. TNM oncologic staging has taken a complex condition like cancer and conveyed likelihood of survival in simple alpha-numeric terms that both patients and providers can understand. Oncology is now entering the era of precision medicine where cancer treatment is increasingly being tailored to each patient's cancer. In contrast, DM2 lacks a staging system and remains a largely invisible disease even though it kills more Americans and costs more to treat than cancer. Is a comparable staging system for DM2 possible? We propose the Diabetes Staging System for DM2 that utilizes macrovascular events, microvascular complications, estimated glomerular filtration rate (GFR), and hemoglobin A1C to stage DM2.


Targeting Hsp90 with small molecule inhibitors induces the over-expression of the anti-apoptotic molecule, survivin, in human A549, HONE-1 and HT-29 cancer cells.
Survivin is a dual functioning protein. It inhibits the apoptosis of cancer cells by inhibiting caspases, and also promotes cancer cell growth by stabilizing microtubules during mitosis. Since the molecular chaperone Hsp90 binds and stabilizes survivin, it is widely believed that down-regulation of survivin is one of the important therapeutic functions of Hsp90 inhibitors such as the phase III clinically trialed compound 17-AAG. However, Hsp90 interferes with a number of molecules that up-regulate the intracellular level of survivin, raising the question that clinical use of Hsp90 inhibitors may indirectly induce survivin expression and subsequently enhance cancer anti-drug responses. The purpose of this study is to determine whether targeting Hsp90 can alter survivin expression differently in different cancer cell lines and to explore possible mechanisms that cause the alteration in survivin expression. Here, we demonstrated that Hsp90 inhibitors, geldanamycin and 17-AAG, induced the over-expression of survivin in three different human cancer cell lines as shown by Western blotting. Increased survivin mRNA transcripts were observed in 17-AAG and geldanamycin-treated HT-29 and HONE-1 cancer cells. Interestingly, real-time PCR and translation inhibition studies revealed that survivin was over-expressed partially through the up-regulation of protein translation instead of gene transcription in A549 cancer cells. In addition, 17-AAG-treated A549, HONE-1 and HT-29 cells showed reduced proteasomal activity while inhibition of 26S proteasome activity further increased the amount of survivin protein in cells. At the functional level, down-regulation of survivin by siRNA further increased the drug sensitivity to 17-AAG in the tested cancer cell lines. We showed for the first time that down-regulation of survivin is not a definite therapeutic function of Hsp90 inhibitors. Instead, targeting Hsp90 with small molecule inhibitors will induce the over-expression of survivin in certain cancer cell lines and subsequently enhances the ability of cell survival in drug-treated situations. The current study suggests that dual inhibition of Hsp90 and survivin may be warranted.


Effects of intravenous lipopolysaccharide administration on feed intake, ruminal forage degradability, and liquid parameters and physiological responses in beef cattle.
This experiment compared DMI, ruminal forage degradability, and liquid parameters as well as physiological responses in beef cattle receiving a lipopolysaccharide (LPS) challenge or not. Eight ruminally cannulated Angus × Hereford steers (485 ± 16 kg BW) were housed in individual pens on d -7, ranked by BW, and allocated to 1 of 2 treatments administered on d 0: 1) an intravenous (i.v.) bolus dose (0.5 μg/kg of BW, diluted in 5 mL of 0.9% sterile saline) of bacterial LPS ( 0111:B4) or 2) a 5-mL i.v. injection of 0.9% sterile saline (CON). Steers had free-choice access to mixed alfalfa-grass hay, water, and a commercial vitamin + mineral mix during the experiment (d -7 to 6). Hay DMI was evaluated daily from d -5 to 6. Immediately prior to treatment administration (h 0), polyester bags containing 4 g of ground dietary hay (DM basis) were immersed into the rumen of each steer and incubated for 0, 4, 8, 12, 24, 36, and 48 h for DM and NDF degradability evaluation. Steers were also intraruminally pulse-dosed with 5 g of Co-EDTA immediately prior to treatment administration, and rumen fluid samples were collected at 0, 2, 4, 6, 8, 12, 16, and 24 h for ruminal liquid volume and dilution rate calculations. Blood was collected every 2 h from -2 to 8 h, every 4 h from 8 to 16 h, every 12 h from 24 to 72 h, and every 24 h from 96 to 144 h relative to treatment administration. Values obtained before treatment administration were used as a covariate within each respective analysis. Steers receiving LPS had less ( ≤ 0.03) DMI on d 0 and 1 compared with CON steers. Steers receiving LPS had reduced ( ≤ 0.05) rumen liquid volume and dilution rate as well as ruminal disappearance rate and effective degradability of DM and NDF compared with CON steers. Steers receiving LPS had greater ( ≤ 0.05) plasma tumor necrosis factor α at 2 h, greater plasma haptoglobin from 24 to 72 h, greater plasma cortisol from 12 to 16 h, greater serum NEFA from 6 to 48 h, greater plasma insulin and glucose at 2 h, reduced plasma glucose from 4 to 12 h, greater plasma cholecystokinin at 16 h, and greater plasma leptin concentrations at 8, 12, 16, 36, 48, and 60 h after treatment administration compared with CON steers. Hence, LPS administration transiently reduced DMI in steers via physiological reactions that modulate gastrointestinal motility and satiety centers in the central nervous system, in addition to potential host-microbiome endocrine interactions that impaired ruminal hay DM and NDF degradability.


[Epidemiological study on diet, smoking and alcohol drinking in the relationship to prostatic weight].
There have been no epidemiological studies on the relationship between the prostatic weight and blood examination data. This study was carried out to evaluate this relationship. Blood examination (beta-carotene, GOT, GPT, total cholesterol, etc.) and measurement of the prostatic weight were performed in 432 subjects aged 50 years or more of a town in Japan, and the possible relationship between blood analysis data and the prostatic weight was evaluated. The prostates were examined by transrectal ultrasonography (TRUS) and classified into the normal prostate and benign prostatic hypertrophy (BPH). The prostatic weight was measured by Watanabe's method based on TRUS images. In addition, the possible association between the prostatic weight and smoking, drinking, height, body weight, or age was evaluated. Analysis by the logistic procedure and the general linear models procedure showed a significant positive correlation between the normal prostatic weight and beta-carotene, height, as well as body weight and a significant negative correlation between the normal prostatic weight and smoking. Comparison between subjects with the normal prostate and those with BPH suggested that serum beta-carotene is a significant positive risk for BPH, and HDL-cholesterol, drinking, and smoking are negative risks by logistic procedure analysis. It was thought that serum beta-carotene and smoking are associated with the development of BPH.


FIGO good practice recommendations on modifiable causes of iatrogenic preterm birth.
Iatrogenic preterm birth is a planned delivery that occurs before 37 weeks of gestation due to maternal and/or fetal causes. However, in some cases, such deliveries also occur with no apparent medical indication. The increasing numbers of iatrogenic preterm deliveries worldwide have led researchers to identify modifiable causes that allow the formulation of preventive strategies that could impact the overall preterm birth rate. The present document contains the FIGO (International Federation of Gynecology and Obstetrics) Working Group for Preterm Birth recommendations, aiming to reduce the rates of iatrogenic preterm birth based on four of the most common clinical scenarios and issues related to iatrogenic preterm delivery. The working group supports efforts to identify the contribution of iatrogenic preterm delivery to the overall preterm birth rate and encourages health authorities to establish preventive measures accordingly. We encourage care providers to maintain single embryo transfer policies to prevent multiple pregnancies as a substantial contributor of iatrogenic preterm birth. The working group also recommends that efforts to reduce unnecessary cesarean sections must be warranted, and mechanisms to ensure the appropriate time of delivery and strengthening of education and communication processes must be pursued.


Decreased usage and increased effectiveness of percutaneous coronary intervention in complex older patients with acute coronary syndromes.
Application of percutaneous coronary intervention (PCI) in patients with acute coronary syndromes (ACS) is suboptimal in older frail individuals. This study was conducted to verify if background risk is a risk factor for underuse and diminished effectiveness of PCI in older patients. An observational cohort study was conducted using data from the Acute Myocardial Infarction in Florence 2 registry, including all ACS hospitalised in 1 year in the area of Florence, Italy. Patients aged 75+ years were selected, whose background risk was stratified with the Silver Code (SC), a validated tool predicting mortality based upon administrative data. Multivariable OR for PCI application and HR for 1-year mortality by PCI usage were calculated. In 698 patients (358 women, mean age 83 years), of whom 176 had ST-segment elevation myocardial infarction (STEMI), for each point increase in SC score the odds for application of PCI decreased by 11%, whereas the hazard of 1-year mortality increased by 10%, adjusting for positive and negative predictors. PCI reduced 1-year mortality progressively more with increasing SC, with HR (95% CI) of 0.8 (0.19 to 1.21), 0.41 (0.18 to 0.45), 0.41 (0.23 to 0.74) and 0.26 (0.14 to 0.48) for SC of 0-3, 4-6, 7-10 and 11+. Application of PCI in older ACS patients decreased with increasing background risk. This therapeutic attitude could not be justified by decreasing effectiveness of PCI in more compromised patients: conversely, application of PCI was associated with a long-term survival advantage that increased progressively with background risk, as expressed by SC.


Aqueous humor dynamics in the owl monkey with comparison to cynomolgus.
The owl monkey is used in experimental ocular studies, but little data are available regarding its aqueous humor dynamics. We determined aqueous humor flow rate (AHF), anterior chamber elimination coefficient (Ke), and corneal endothelial transfer coefficient (Ka) fluorophotometrically; total outflow facility (C) by 2-level constant pressure perfusion; and the facility response to intravenous and intracameral pilocarpine in pentobarbital anesthetized owl monkeys. Baseline values (mean +/- S.E.M., n eyes) were: AHF = 1.52 +/- 0.14 microliter X min-1, n = 24; Ke = 6.54 +/- 0.65 min-1 X 10(-3), n = 24; Ka = 3.84 +/- 0.40 min-1 X 10(-3), n = 24; C = 0.35 +/- 0.03 microliter X min-1 X mm Hg-1, n = 26. Intracameral pilocarpine caused a dose-dependent facility increase, with the maximum response (a tripling of resting facility) occurring between 20 and 100 micrograms; intravenous pilocarpine, 2 mg/kg, also doubled to tripled facility. With certain qualifications, these findings are comparable to those in other primate species and confirm the usefulness of the owl monkey in carefully chosen experimental studies of aqueous dynamics.


Olfactory nerve fibers.
Cross sections of olfactory nerves present a unique appearance. They indicate the presence of large numbers of very small nerve fibers, with a modal diameter of about 0.2 micro and a narrow range for their size variation. From one side of the nasal septum of a pig the yield of fibers was estimated at 6,000,000; the number arising from the turbinates would be considerably larger. The fibers are attached to the membranes of the Schwann sheaths in large bundles through mesaxons longer and more branched than those that have been seen in other nerves. Continuity of the axons between the nerves and the bipolar cells was traced in an examination of the olfactory mucous membrane; and the indication of a one-to-one relationship between cells and axons was reinforced by a comparative count. After the axons leave the bipolar cells they become incased in the central projections of the sustentacular cells. Where the latter come into contact with the basal cells the axons emerge to push back the plasma membranes of the basal cells in the first step in acquiring their nerve sheaths. Later steps are described. When the axons are delivered by the basal cells to the collecting Schwann tubes, they are already aggregated into small bundles with sheaths fundamentally the same as those they will possess until they are delivered to the glia in the olfactory bulb. Some of the aspects of the cytology of the bipolar cells and adjoining sustentacular cells are described. A survey of the physiological properties of olfactory nerve fibers was made in some experiments on the olfactory nerve of the pike. Almost all of the action potential is encompassed within a single elevation, manifesting at its front a conduction velocity of 0.2 m./sec. For a comparison, the last elevation in the C action potential in the sciatic nerve of the frog is cited as an example of conduction at the same velocity. Though expressed through long time constants, the properties of the pike olfactory fibers conform to the generalized schema for properties of vertebrate nerve fibers. This conformity signalizes that they differ from the exceptional properties of the unmedullated fibers of dorsal root origin. An afferent function for unmedullated nerve fibers does not imply that the fibers concerned are alike in their physiological properties.


Molecular genetic studies on 167 pediatric ALL patients from different areas of Pakistan confirm a low frequency of the favorable prognosis fusion oncogene TEL-AML1 (t 12; 21) in underdeveloped countries of the region.
TEL-AML1 fusion oncogene (t 12; 21) is the most common chromosomal abnormality in childhood acute lymphoblastic leukemia (ALL). This translocation is associated with a good prognosis and rarely shows chemotherapeutic resistance to 3-drug based remission induction phase of treatment as well as overall treatment. Thus, the higher the frequency of this fusion oncogene, the easier to manage childhood ALL in a given region with less intensive chemotherapy. Although global frequency of TEL-AML1 has been reported to be 20-30%, a very low frequency has been found in some geographical regions, including one study from Lahore, Punjab, Pakistan and others from India. The objective of present study was to investigate if this low frequency of TEL- AML1 in pediatric ALL is only in Lahore region or similar situation exists at other representative oncology centers of Pakistan. A total of 167 pediatric ALL patients were recruited from major pediatric oncology centers situated in Lahore, Faisalabad, Peshawar and Islamabad. Patients were tested for TEL-AML1 using nested reverse transcription polymerase chain reaction (RT-PCR). Only 17 out of 167 (10.2%) patients were found to be TEL-AML1 positive. TEL-AML1+ALL patients had favorable prognosis, most of them (82.4%, 14/17) showing early remission and good overall survival. Thus, our findings indicate an overall low frequency of TEL-AML1 in Pakistan pediatric ALL patients, in accordance with lower representation of this prognostically important genetic abnormality in other less developed countries, specifically in south Asia, thus associating it with poor living standards in these ethnic groups. It also indicates ethnic and geographical differences in the distribution of this prognostically important genetic abnormality among childhood ALL patients, which may have a significant bearing on ALL management strategies in different parts of the world.


Spatiotemporal expression of HDAC2 during the postnatal development of the rat hippocampus.
Histone acetylation, which is a chromatin modification of histone tails, can dynamically regulate the expression of various genes in normal development. HDAC2 is a negative regulatory factor of acetylation and closely related to learning and memory. NSE is a nerve marker and vital for maintaining physiological functions in nervous system. Currently, few studies associated with the expression pattern of HDAC2 in postnatal rat hippocampus have been reported. This study aimed to explore the temporal and spatial expression pattern of HDAC2, helping to reveal the expression characteristics of HDAC2 during postnatal neuronal maturation. With NSE as a biomarker of neuronal maturation at postnatal days 1, 3, 7 and weeks 2, 4, and 8 (P1D, P3D, P7D, P2W, P4W, P8W), the expression patterns of HDAC2 in rat hippocampus were examined using real-time PCR and western blotting. Additionally, the subcellular distribution of HDAC2 was analysed by immunofluorescence. We found that HDAC2 was highly expressed in the neonatal period and decreased gradually. HDAC2 expression was widely distributed in neurons of hippocampal CA1, CA3 and DG regions and gradually shifted from the nucleus to the cytoplasm during postnatal development. Altogether, the expression of HDAC2 decreased gradually with different subcellular localizations throughout development. The observed results indicate that the expression levels of HDAC2 become lower and with different subcellular localizations in neurons during hippocampal neuronal maturation, suggesting the specific expression characteristics of HDAC2 might play an important role during postnatal learning-memory function and development.


[The effects of ticlopidine administration at low doses on the incidence of restenosis following percutaneous transluminal coronary angioplasty].
The incidence of restenosis remains the same as initially reported (30%) and no therapeutic approach has reduced its appearance. Platelets-induced smooth muscle cell proliferation probably play a preponderant role in the pathogenesis of restenosis. The aim of this study was to evaluate the effects of ticlopidine (250 mg/day) on restenosis rate after single lesion coronary angioplasty. One hundred seventy nine consecutive patients were prospectively included in this study and were assigned to ticlopidine (group T, n = 91) or to a control group (n = 88) in an alternative fashion. Age (60 +/- 10 vs 58 +/- 9 years), gender (87% vs 87% male), treatment, coronary risk factors, lesion morphology, stenosis severity pre- and postangioplasty, type of vessel, collateral circulation, and left ventricular ejection fraction, were similar in the T and control groups, respectively. Unstable angina was more frequently found in group T patients (81% vs 65%, p less than 0.01). A late angiographic follow-up (7 +/- 2 months after angioplasty) revealed restenosis (greater than 50% luminal narrowing) in 26 patients (28%) in group T and in 21 patients (24%) in the control group (NS). At that time, 88% and 98% of patients without restenosis vs 35% and 48% of patients with restenosis were asymptomatic in the T and control groups, respectively. An exercise test prior to the late control angiogram was abnormal (angina and/or ST segment depression) in 77% and 73% of patients with restenosis in T and control groups, respectively. Thus, in our experience, ticlopidine at a dosage of 250 mg/day was unable to reduce restenosis rate after single lesion coronary angioplasty.


A placebo-controlled study of pyritinol ('Encephabol') in dementia.
A double-blind, placebo-controlled trial was carried out on 40 patients suffering from moderately advanced dementia. The patients were allocated randomly either pyritinol (800 mg daily) or identical placebo for 3 months. Assessments using a modified Crichton Geriatric Behavioural Rating Scale were made pre-treatment and monthly up to 3 months, and then at follow-up at 6 months. Patients on pyritinol showed significantly higher levels of improvement than did those on placebo. Laboratory tests conducted throughout remained within normal limits for both groups.


Elevated Plasma Interleukin-18 Identifies High-Risk Acute Respiratory Distress Syndrome Patients not Distinguished by Prior Latent Class Analyses Using Traditional Inflammatory Cytokines: A Retrospective Analysis of Two Randomized Clinical Trials.
Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct "high-risk" patients not captured by prior LCA classifications. Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar's test and then tested the correlation between IL-18 and LCA biomarkers using Pearson's exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup. Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients. Six hundred eighty-three patients in SAILS and 511 patients in HARP-2. None. We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17-0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8-6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2-3.8; p = 0.009). Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts.


Crystal structure and activity of human p23, a heat shock protein 90 co-chaperone.
p23 is a co-chaperone for the heat shock protein, hsp90. This protein binds hsp90 and participates in the folding of a number of cell regulatory proteins, but its activities are still unclear. We have solved a crystal structure of human p23 lacking 35 residues at the COOH terminus. The structure reveals a disulfide-linked dimer with each subunit containing eight beta-strands in a compact antiparallel beta-sandwich fold. In solution, however, p23 is primarily monomeric and the dimer appears to be a minor component. Conserved residues are clustered on one face of the monomer and define a putative surface region and binding pocket for interaction(s) with hsp90 or protein substrates. p23 contains a COOH-terminal tail that is apparently less structured and is unresolved in the crystal structure. This tail is not needed for the binding of p23 to hsp90 or to complexes with the progesterone receptor. However, the tail is necessary for optimum active chaperoning of the progesterone receptor, as well as the passive chaperoning activity of p23 in assays measuring inhibition of heat-induced protein aggregation.


Sickle cell anaemia: haemorheological aspects.
The maintenance of erythrocyte shape and membrane integrity is bound to the modification of deformability and/or permeability. Usually, this features are not investigated with normal laboratory tests. The membrane stiffness, the cell geometry, and the viscoelasticity components are influencing factors on survival and functionality of the erythrocytes. Only few studies have analyzed the viscoelastic characteristics of red blood cells, even less are the studies on patients affected by sickle cell disease (SCD), a pathology characterized by acute and chronic impairment of cell flexibility due to the formation of intracellular sickle haemoglobin (Hb S) polymers. A critical point of SCD is represented by the rheologic alterations of sickle cells determined by the transition from sol to gel of haemoglobin producing a dramatic change in cell viscosity and viscoelastic properties. We have investigated the behaviour of the blood in SCD, from an original rheological point of view, by evaluating the viscoelastic properties of sickle cells in oscillating harmonic sinusoidal mode. A comparison between patients with different severity of the disease, with transfusion dependence (TD) or without transfusion dependence (NTD), has been carried out. This study has confirmed the rheologic impairment of SC blood. The TD patients showed a minor heterogeneneity of rheologic behaviour in comparison with NTD patients, because of the normalizing effect of transfusion. The analysis of viscoelastic properties might be an additional useful tool for monitoring transfusional and pharmacological treatments.


Efficacy and Safety of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia: Retrospective Analysis of Real-Life Data
This study aimed to retrospectively evaluate the efficacy, safety, and survival outcome of single-agent ibrutinib therapy in chronic lymphocytic leukemia patients. A total of 136 patients (mean age ± standard deviation: 64.6±10.3 years, 66.9% males) who had received at least one dose of ibrutinib were included in this retrospective multicenter, noninterventional hospital-registry study conducted at 33 centers across Turkey. Data on patient demographics, baseline characteristics, laboratory findings, and leukemia-cell cytogenetics were retrieved. Treatment response, survival outcome including overall survival (OS) and progression-free survival (PFS), and safety data were analyzed. Overall, 36.7% of patients were categorized as Eastern Cooperative Oncology Group (ECOG) class 2-3, while 44.9% were in Rai stage 4. Fluorescence in situ hybridization revealed the presence of del(17p) in 39.8% of the patients. Patients received a median of 2.0 (range: 0-7) lines of pre-ibrutinib therapy. Median duration of therapy was 8.8 months (range: 0.4-58.0 months). The 1-year PFS and OS rates were 82.2% and 84.6%, respectively, while median PFS time was 30.0 (standard error, 95% confidence interval: 5.1, 20.0-40.0) months and median OS time was 37.9 (3.2, 31.5-44.2) months. Treatment response (complete or partial response), PFS time, and OS time were better with 0-2 lines versus 3-7 lines of prior therapy (p<0.001, p=0.001, and p<0.001, respectively), with ECOG class 0-1 versus class 2-3 (p=0.006, p=0.011, and p=0.001, respectively), and with Rai stage 0-2 versus 3-4 (p=0.002, p=0.001, and p=0.002, respectively). No significant difference was noted in treatment response rates or survival outcome with respect to the presence of comorbidity, bulky disease, or del(17p). While 176 adverse events (AEs) were reported in 74 (54.4%) patients, 46 of those 176 AEs were grade 3-4, including pneumonia (n=12), neutropenia (n=11), anemia (n=5), thrombocytopenia (n=5), and fever (n=5). This real-life analysis confirms the favorable efficacy and safety profile of long-term ibrutinib treatment while emphasizing the potential adverse impacts of poorer ECOG performance status, heavy treatment prior to ibrutinib, and advanced Rai stage on patient compliance, treatment response, and survival outcomes.


Homocysteine-thiolactone and S-nitroso-homocysteine mediate incorporation of homocysteine into protein in humans.
Indirect pathways, involving homocysteine (Hcy)-thiolactone and S-nitroso-Hcy, allow incorporation of Hcy into protein. Hcy-thiolactone, synthesized by methionyl-tRNA synthetase in all organisms investigated, including human, modifies proteins post-translationally by forming adducts in which Hcy is linked by amide bonds to epsilon-amino group of protein lysine residues. S-Nitroso-Hcy, synthesized in human vascular endothelial cells, is incorporated translationally into peptide bonds in protein at positions normally occupied by methionine. Hcy-N-hemoglobin and Hcy-N-albumin constitute a major pool of Hcy in human blood. Hcy-thiolactone is present in human plasma. Modification with Hcy-thiolactone leads to protein damage. Hcy-thiolactone is detoxified by Hcy-thiolactonase/paraoxonase present in a subset of high-density lipoprotein particles in humans.


Distance measurement based on pixel variation of CCD images.
This paper presents a distance measurement method based on pixel number variation of CCD images by referencing to two arbitrarily designated points in the image frames. By establishing a relationship between the displacement of the camera movement along the photographing direction and the difference in pixel count between reference points in the images, the distance from an object can be calculated via the proposed method. To integrate the measuring functions into digital cameras, a circuit design implementing the proposed measuring system in selecting reference points, measuring distance, and displaying measurement results on CCD panel of the digital camera is proposed in this paper. In comparison to pattern recognition or image analysis methods, the proposed measuring approach is simple and straightforward for practical implementation into digital cameras. To validate the performance of the proposed method, measurement results using the proposed method and ultrasonic rangefinders are also presented in this paper.


Comparison of serum levels of iron, zinc and copper in anaemic and non-anaemic pregnant women in China.
Zinc and copper deficiency is associated with anaemia or iron deficiency and affects fetus growth and pregnant women during pregnancy. To examine iron, zinc and copper status of Chinese pregnant women with and without anaemia in the third trimester, 1185 subjects were enrolled for measurements of Hb, ferritin, transferrin, soluble transferrin receptor (sTfR), and serum iron, zinc and copper. The results showed that there were lower levels of ferritin (14.1 microg/L) and transferrin (3.33 g/L) in subjects with Hb<or=100g/L as compared with subjects with Hb>or=101 g/L. sTfR levels in subjects with Hb<or=100g/L were significantly higher than those in subjects with Hb>or=120 g/L (38.5 nmol/L vs. 25.04 nmol/L, P<0.001). Serum iron was lower in subjects with Hb<or=100 g/L than those with Hb>or=120 g/L (871 microg/L vs. 990 microg/L, P<0.01). Lower levels of serum iron and zinc were also found in anaemic (Hb<110 g/L) as compared with non-anaemic women (Hb>or=110 g/L). Frequencies of marginal deficiencies in serum iron and zinc were 41.58% and 51.05% respectively higher in anaemic than in non-anaemic subjects. Distribution of serum zinc and iron showed a decreasing trend as Hb decreased. Few anaemic as well as non-anaemic subjects had copper deficiency although copper and Hb levels were found inversely correlated and the ratio of copper/iron was higher in anaemic than in non-anaemic group. In conclusion, a lower level of serum zinc in anaemic pregnant women might be related to anaemia and iron deficiency during pregnancy. Therefore, combined zinc and iron supplementation should be recommended to Chinese pregnant women, especially those with anaemia.


Long-term results of a minimally invasive surgical pulmonary vein isolation and ganglionic plexi ablation for atrial fibrillation.
Ganglionated plexi (GP) ablation has been become an adjunct to pulmonary vein isolation (PVI). This study describes the long-term results of minimally invasive surgical PVI, ablation of GPs, and exclusion of the left atrial appendage for atrial fibrillation (AF). Long-term follow-up of 55 months was performed in 139 consecutive patients (age 58.3±20.8 years) with symptomatic, drug-refractory lone AF who underwent minimally invasive surgical PVI, GPs ablation, and exclusion of the left atrial appendage. Success was defined as freedom from AF, atrial flutter, or atrial tachycardia off antiarrhythmic drugs. AF was paroxysmal in 77.7%, persistent in 12.2% and long-standing persistent in 10.1%. Single-procedure success rate was 71.7%, 59.4% and 46.6% at 12, 24 and 60 months respectively. Single-procedure success rate was 72.9%, 62.6% and 51.8% for paroxysmal AF, 64.7%, 35.3%, and 28.2% for persistent AF, 71.4%, 64.3% and 28.6% for long-standing persistent AF at 12, 24 and 60 months respectively. Duration of AF>24 months (hazard ratio [HR]: 3.09, 95% confidence interval [CI]: 1.51 to 6.32; p = 0.002), left atrial diameter≥40 mm (HR: 4.03, 95% CI: 1.88 to 8.65; p<0.001), early recurrence of AF (HR: 4.66, 95% CI: 2.25 to 9.63; p<0.001) independently predicted long-term recurrence of AF. There was no procedure-related death. One patient converted to median sternotomy because of uncontrolled bleeding. Two patients underwent perioperative cerebrovascular events. At nearly 5-year of clinical follow-up, single-procedure success rate of minimally invasive surgical PVI with GP ablation was 51.8% for paroxysmal AF, 28.2% for persistent AF, 28.6% for long-standing persistent AF after initial procedure. Patients with AF duration≤24 months, left atrial diameter<40 mm and no early recurrence of AF, had favorable outcomes.


Generation of patient-derived pediatric pilocytic astrocytoma in-vitro models using SV40 large T: evaluation of a modeling workflow.
Although pediatric low-grade gliomas (pLGG) are the most common pediatric brain tumors, patient-derived cell lines reflecting pLGG biology in culture are scarce. This also applies to the most common pLGG subtype pilocytic astrocytoma (PA). Conventional cell culture approaches adapted from higher-grade tumors fail in PA due to oncogene-induced senescence (OIS) driving tumor cells into arrest. Here, we describe a PA modeling workflow using the Simian Virus large T antigen (SV40-TAg) to circumvent OIS. 18 pLGG tissue samples (17 (94%) histological and/or molecular diagnosis PA) were mechanically dissociated. Tumor cell positive-selection using A2B5 was perfomed in 8/18 (44%) cases. All primary cell suspensions were seeded in Neural Stem Cell Medium (NSM) and Astrocyte Basal Medium (ABM). Resulting short-term cultures were infected with SV40-TAg lentivirus. Detection of tumor specific alterations (BRAF-duplication and BRAF V600E-mutation) by digital droplet PCR (ddPCR) at defined time points allowed for determination of tumor cell fraction (TCF) and evaluation of the workflow. DNA-methylation profiling and gene-panel sequencing were used for molecular profiling of primary samples. Primary cell suspensions had a mean TCF of 55% (+/- 23% (SD)). No sample in NSM (0/18) and ten samples in ABM (10/18) were successfully transduced. Three of these ten (30%) converted into long-term pLGG cell lines (TCF 100%), while TCF declined to 0% (outgrowth of microenvironmental cells) in 7/10 (70%) cultures. Young patient age was associated with successful model establishment. A subset of primary PA cultures can be converted into long-term cell lines using SV40-TAg depending on sample intrinsic (patient age) and extrinsic workflow-related (e.g. type of medium, successful transduction) parameters. Careful monitoring of sample-intrinsic and extrinsic factors optimizes the process.


Organization of the cytoskeleton in resting, discoid platelets: preservation of actin filaments by a modified fixation that prevents osmium damage.
This study evaluates the structural organization of the cytoskeleton within unactivated, discoid platelets. Previously, such studies have been difficult to interpret because of the ease with which platelets are stimulated, the sensitivity of actin filaments to cell extraction buffers, and the general problem of preserving actin filaments with conventional fixatives, compounded by the density of the cytoplasm in the platelet. In this study we have employed a new fixative containing lysine, which protects actin filaments against damage during fixation and thin-section processing. We used thick (0.25-micron) sections and conventional thin sections of extracted cells (fixed and lysed simultaneously by the addition of 1% Triton X-100 to the initial fixative) as well as thin sections of whole cells to examine three preparations of human platelets: discoid platelets washed by sedimentation; discoid platelets isolated by gel filtration; and circulating platelets collected by dripping blood directly from a vein into fixative. In all of these preparations, long, interwoven actin filaments were observed within the platelet and were particularly concentrated beneath the plasma membrane. These filaments appeared to be linked at irregular intervals to the membrane and to each other via short, approximately 20- to 50-nm-long cross-links of variable width. Although most filaments were outside the circumferential band of microtubules and the cisternae of the open canalicular system, individual filaments dipped down into the cytoplasm and were found between the microtubules and in association with other membranes. The ease with which single actin filaments can be seen in the dense cytoplasm of the human platelet after lysine/aldehyde fixation suggests the great potential of this new fixative for other cells.


A Component-Based Vocabulary-Extensible Sign Language Gesture Recognition Framework.
Sign language recognition (SLR) can provide a helpful tool for the communication between the deaf and the external world. This paper proposed a component-based vocabulary extensible SLR framework using data from surface electromyographic (sEMG) sensors, accelerometers (ACC), and gyroscopes (GYRO). In this framework, a sign word was considered to be a combination of five common sign components, including hand shape, axis, orientation, rotation, and trajectory, and sign classification was implemented based on the recognition of five components. Especially, the proposed SLR framework consisted of two major parts. The first part was to obtain the component-based form of sign gestures and establish the code table of target sign gesture set using data from a reference subject. In the second part, which was designed for new users, component classifiers were trained using a training set suggested by the reference subject and the classification of unknown gestures was performed with a code matching method. Five subjects participated in this study and recognition experiments under different size of training sets were implemented on a target gesture set consisting of 110 frequently-used Chinese Sign Language (CSL) sign words. The experimental results demonstrated that the proposed framework can realize large-scale gesture set recognition with a small-scale training set. With the smallest training sets (containing about one-third gestures of the target gesture set) suggested by two reference subjects, (82.6 ± 13.2)% and (79.7 ± 13.4)% average recognition accuracy were obtained for 110 words respectively, and the average recognition accuracy climbed up to (88 ± 13.7)% and (86.3 ± 13.7)% when the training set included 50~60 gestures (about half of the target gesture set). The proposed framework can significantly reduce the user's training burden in large-scale gesture recognition, which will facilitate the implementation of a practical SLR system.


Linkage analysis and QTL mapping in a tetraploid russet mapping population of potato.
Genome-wide single nucleotide polymorphism (SNP) markers coupled with allele dosage information has emerged as a powerful tool for studying complex traits in cultivated autotetraploid potato (Solanum tuberosum L., 2n = 4× = 48). To date, this approach has been effectively applied to the identification of quantitative trait loci (QTLs) underlying highly heritable traits such as disease resistance, but largely unexplored for traits with complex patterns of inheritance. In this study, an F1 tetraploid russet mapping population (162 individuals) was evaluated for multiple quantitative traits over two years and two locations to identify QTLs associated with tuber sugar concentration, processing quality, vine maturity, and other high-value agronomic traits. We report the linkage maps for the 12 potato chromosomes and the QTL location with corresponding genetic models and candidate SNPs explaining the highest phenotypic variation for tuber quality and maturity related traits. Significant QTLs for tuber glucose concentration and tuber fry color were detected on chromosomes 4, 5, 6, 10, and 11. Collectively, these QTLs explained between 24 and 46% of the total phenotypic variation for tuber glucose and fry color, respectively. The QTL on chromosome 10 was associated with apoplastic invertases, with 'Premier Russet' contributing the favorable allele for fry processing quality. On chromosome 5, minor-effect QTLs for tuber glucose concentration and fry color co-localized with various major-effect QTLs, including vine maturity, growth habit, tuber shape, early blight (Altenaria tenuis), and Verticillium wilt (Verticillium spp.). Linkage analysis and QTL mapping in a russet mapping population (A05141) using SNP dosage information successfully identified favorable alleles and candidate SNPs for resistance to the accumulation of tuber reducing sugars. These novel markers have a high potential for the improvement of tuber processing quality. Moreover, the discovery of different genetic models for traits with overlapping QTLs at the maturity locus clearly suggests an independent genetic control.


Expression of a cleaved brain-specific extracellular matrix protein mediates glioma cell invasion In vivo.
Malignant gliomas (primary brain tumors) aggressively invade the surrounding normal brain. This invasive ability is not demonstrated by brain metastases of nonglial cancers. The brain-specific, brain-enriched hyaluronan binding (BEHAB)/brevican gene, which encodes an extracellular hyaluronan-binding protein, is consistently expressed by human glioma and is not expressed by tumors of nonglial origin (Jaworski et al., 1996). BEHAB/brevican can be cleaved into an N-terminal fragment that contains a hyaluronan-binding domain (HABD) and a C-terminal fragment (Yamada et al., 1995). Here, using antisera to peptides in the predicted N-terminal and C-terminal proteolytic fragments, we demonstrate that the BEHAB/brevican protein is cleaved in invasive human and rodent gliomas. A role for this protein in glioma cell invasion was tested by transfecting a noninvasive cell line with the BEHAB/brevican gene. The noninvasive 9L glioma cell was transfected with either full-length BEHAB/brevican or the HABD and tested for invasion in in vitro and in vivo invasion assays. Although both constructs increased invasion in vitro, only the HABD increased invasion by tumors growing in vivo. Experimental intracranial tumors from full-length transfectants showed no increase in invasion over control tumors, whereas tumors from HABD transfectants showed a marked potentiation of tumor invasion, producing new tumor foci at sites distant from the main tumor mass. This work demonstrates a role for a brain-specific extracellular matrix protein in glioma invasion, opening new therapeutic avenues for a uniformly fatal disease.