The human visual cortex.
The discovery and analysis of cortical visual areas is a major accomplishment of visual neuroscience. In the past decade the use of noninvasive functional imaging, particularly functional magnetic resonance imaging (fMRI), has dramatically increased our detailed knowledge of the functional organization of the human visual cortex and its relation to visual perception. The fMRI method offers a major advantage over other techniques applied in neuroscience by providing a large-scale neuroanatomical perspective that stems from its ability to image the entire brain essentially at once. This bird's eye view has the potential to reveal large-scale principles within the very complex plethora of visual areas. Thus, it could arrange the entire constellation of human visual areas in a unified functional organizational framework. Here we review recent findings and methods employed to uncover the functional properties of the human visual cortex focusing on two themes: functional specialization and hierarchical processing.


Lumbar Disk Arthroplasty for Degenerative Disk Disease: Literature Review.
Low back pain is the principal cause of long-term disability worldwide. We intend to address one of its main causes, degenerative disk disease, a spinal condition involving degradation of an intervertebral disk. Following unsuccessful conservative treatment, patients may be recommended for surgery. The two main surgical treatments for lumbar degenerative disk disease are lumbar fusion: traditional standard surgical treatment and lumbar disk arthroplasty, also known as lumbar total disk replacement. Lumbar fusion aims to relieve pain by fusing vertebrae together to eliminate movement at the joint, but it has been criticized for problems involving insignificant pain relief, a reduced range of motion, and an increased risk of adjacent segment degeneration. This leads to development of the lumbar total disk replacement technique, which aims to relieve pain replacing a degenerated intervertebral disk with a moveable prosthesis, thus mimicking the functional anatomy and biomechanics of a native intervertebral disk. Over the years a large range of prosthetic disks has been developed. The efficacy and current evidence for these prostheses are discussed in this review. The results of this study are intended to guide clinical practice and future lumbar total disk replacement device choice and design.


Prenatal nitrosatable prescription drug intake, drinking water nitrate, and the risk of stillbirth: a register- and population-based cohort of Danish pregnancies, 1997-2017.
Nitrosatable drugs commonly prescribed during pregnancy can react with nitrite to form N-nitroso compounds which have been associated with an increased risk of stillbirth. Whether maternal residential drinking water nitrate modifies this association is unknown. We investigated, if household drinking water nitrate was associated with stillbirth, and if it modified the association between nitrosatable prescription drug intake and the risk of stillbirth. We conducted an individual-level register- and population-based cohort study using 652,810 women with the first recorded singleton pregnancy in the Danish Medical Birth Registry between 1997 and 2017. Nitrosatable drug exposure was recorded by use of the Danish National Patient Registry defined as women with a first redeemed prescription of a nitrosatable drug the first 22 weeks of pregnancy. The reference group was women with no redeemed prescription of a nitrosatable drug in this period. The average individual drinking water nitrate concentration level (mg/L) was calculated in the same period. We categorized nitrosatable drugs as secondary amines, tertiary amines, and amides. Cox hazard regression was used to estimate crude and adjusted hazard ratios with 95% confidence intervals for stillbirth stratified into five categories of nitrate concentrations: ≤1 mg/L, > 1- ≤ 2 mg/L, > 2- ≤ 5 mg/L, > 5- ≤ 25 mg/L, and > 25 mg/L. Drinking water nitrate exposure in the population was not associated with the risk of stillbirth. Among 100,244 women who had a nitrosatable prescription drug redeemed ≤22 weeks of pregnancy of pregnancy, 418 (0.42%) had a stillbirth compared to 1993 stillbirths (0.36%) among 552,566 referent women. Women with any nitrosatable prescription drug intake and > 1- ≤ 2 mg/L nitrate concentration had an increased risk of stillbirth [adjusted hazard ratio 1.55 (95% confidence interval, 1.15-2.09)] compared with referent women. In the stratified analyses, the highest risk of stillbirth was found among women with secondary amine intake and > 25 mg/L nitrate concentrations [adjusted hazard ratio 3.11 (95% CI, 1.08-8.94)]. The association between nitrosatable prescription drug intake and the risk of stillbirth may depend on the level of nitrate in household drinking water. Evaluations of the effect of nitrosatable drug intake on perinatal outcomes might consider nitrate exposure from drinking water.


High blood pressure-the silent killer.
Hypertension is an issue of international and national importance. The aetiology of hypertension is conjectural. However, its treatment must be regarded as one of the strongest weapons against coronary artery disease, cerebrovascular episodes and renal failure. Thus therapeutic compliance has become a major problem. Because only a small proportion of the population is receiving treatment a modular system, perhaps a tertiary health system, should be developed. The primary prevention of cardiovascular disease must be the ultimate goal and is clearly our most cost-effective strategy.


Fingolimod for relapsing-remitting multiple sclerosis.
Fingolimod was approved in 2010 for the treatment of patients with the relapsing-remitting (RR) form of multiple sclerosis (MS). It was designed to reduce the frequency of exacerbations and to delay disability worsening. Issues on its safety and efficacy, mainly as compared to other disease modifying drugs (DMDs), have been raised. To assess the safety and benefit of fingolimod versus placebo, or other disease-modifying drugs (DMDs), in reducing disease activity in people with relapsing-remitting multiple sclerosis (RRMS). We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System (CNS) Group's Specialised Trials Register and US Food and Drug Administration reports (15 February 2016). Randomised controlled trials (RCTs) assessing the beneficial and harmful effects of fingolimod versus placebo or other approved DMDs in people with RRMS. We used standard methodological procedures as expected by Cochrane. Six RCTs met our selection criteria. The overall population included 5152 participants; 1621 controls and 3531 treated with fingolimod at different doses; 2061 with 0.5 mg, 1376 with 1.25 mg, and 94 with 5.0 mg daily. Among the controls, 923 participants were treated with placebo and 698 with others DMDs. The treatment duration was six months in three, 12 months in one, and 24 months in two trials. One study was at high risk of bias for blinding, three studies were at high risk of bias for incomplete outcome reporting, and four studies were at high risk of bias for other reasons (co-authors were affiliated with the pharmaceutical company). We retrieved 10 ongoing trials; four of them have been completed.Comparing fingolimod administered at the approved dose of 0.5 mg to placebo, we found that the drug at 24 months increased the probability of being relapse-free (risk ratio (RR) 1.44, 95% confidence interval (CI) (1.28 to 1.63); moderate quality of evidence), but it might lead to little or no difference in preventing disability progression (RR 1.07, 95% CI 1.02 to 1.11; primary clinical endpoints; low quality evidence). Benefit was observed for other measures of inflammatory disease activity including clinical (annualised relapse rate): rate ratio 0.50, 95% CI 0.40 to 0.62; moderate quality evidence; and magnetic resonance imaging (MRI) activity (gadolinium-enhancing lesions): RR of being free from (MRI) gadolinium-enhancing lesions: 1.36, 95% CI 1.27 to 1.45; low quality evidence.The mean change of MRI T2-weighted lesion load favoured fingolimod at 12 and 24 months.No significant increased risk of discontinuation due to adverse events was observed for fingolimod 0.5 mg compared to placebo at six and 24 months. The risk of fingolimod discontinuation was significantly higher compared to placebo for the dose 1.25 mg at 24 months (RR 1.93, 95% CI 1.48 to 2.52).No significant increased risk of discontinuation due to serious adverse events was observed for fingolimod 0.5 mg compared to placebo at six and 24 months. A significant increased risk of discontinuation due to serious adverse events was found for fingolimod 5.0 mg (RR 2.77, 95% CI 1.04 to 7.38) compared to placebo at six months.Comparing fingolimod 0.5 mg to intramuscular interferon beta-1a, we found moderate quality evidence that the drug at one year slightly increased the number of participants free from relapse (RR 1.18, 95% CI 1.09 to 1.27) or from gadolinium-enhancing lesions (RR 1.12, 95% CI 1.05 to 1.19), and decreased the relapse rate (rate ratio 0.48, 95% CI 0.34 to 0.70). We did not detect any advantage for preventing disability progression (RR 1.02, 95% CI 0.99 to 1.06; low quality evidence). We did not detect any significant difference for MRI T2-weighted lesion load change.We found a greater likelihood of participants discontinuing fingolimod, as compared to other DMDs, due to adverse events in the short-term (six months) (RR 3.21, 95% CI 1.16 to 8.86), but there was no significant difference versus interferon beta-1a at 12 months (RR 1.51, 95% CI 0.81 to 2.80; moderate quality evidence). A higher incidence of adverse events was suggestive of the lower tolerability rate of fingolimod compared to interferon-beta 1a.Quality of life was improved in participants after switching from a different DMD to fingolimod at six months, but this effect was not found compared to placebo at 24 months.All studies were sponsored by Novartis Pharma. Treatment with fingolimod compared to placebo in RRMS patients is effective in reducing inflammatory disease activity, but it may lead to little or no difference in preventing disability worsening. The risk of withdrawals due to adverse events requires careful monitoring of patients over time. The evidence on the risk/benefit profile of fingolimod compared with intramuscular interferon beta-1a was uncertain, based on a low number of head-to-head RCTs with short follow-up duration. The ongoing trial results will possibly satisfy these issues.


Explanation of observational data engenders a causal belief about smoking and cancer.
Most researchers do not deliberately claim causal results in an observational study. But do we lead our readers to draw a causal conclusion unintentionally by explaining why significant correlations and relationships may exist? Here we perform a randomized controlled experiment in a massive open online course run in 2013 that teaches data analysis concepts to test the hypothesis that explaining an analysis will lead readers to interpret an inferential analysis as causal. We test this hypothesis with a single example of an observational study on the relationship between smoking and cancer. We show that adding an explanation to the description of an inferential analysis leads to a 15.2% increase in readers interpreting the analysis as causal (95% confidence interval for difference in two proportions: 12.8%-17.5%). We then replicate this finding in a second large scale massive open online course. Nearly every scientific study, regardless of the study design, includes an explanation for observed effects. Our results suggest that these explanations may be misleading to the audience of these data analyses and that qualification of explanations could be a useful avenue of exploration in future research to counteract the problem. Our results invite many opportunities for further research to broaden the scope of these findings beyond the single smoking-cancer example examined here.


Short communication: urea transporter protein UT-B in the bovine parotid gland.
Ruminant nutrition relies upon the symbiotic relationship that exists with microbial populations in the rumen. Urea transported across the ruminal epithelia and secreted by the salivary glands is a key source of nitrogen for microbial growth in the rumen. As ruminal urea transport can be mediated by specific UT-B urea transporters, this study investigated whether UT-B urea transporters were also present in the bovine salivary gland. Western blotting experiments detected only small amounts of UT-B protein in whole-cell lysate from the bovine parotid gland. In contrast, strong 32 to 34 and 40 kDa UT-B proteins were detected in parotid plasma membrane-enriched protein, showing the importance of using enriched samples. These signals were also detected in rumen and correspond to bovine UT-B1 and UT-B2 urea transporters, respectively. Further immunolocalization studies identified that these proteins were located in the ductal system of the parotid gland. This study, therefore, confirmed the presence of UT-B urea transporter protein in the bovine parotid salivary gland.


A Systematic Review of the Techniques Used to Value Temporary Health States.
A broad literature on health state utility values exists, but compared with chronic health states (HSs), issues surrounding the valuation of temporary health states (THSs) have been poorly explored. To assess the methods used by previous studies to value HSs that are considered temporary so as to determine the strengths and limitations associated with various approaches and to inform future study designs. A systematic review was undertaken to explore the methods used, assess how the valuation was conducted for diseases that might lead to HSs deemed as temporary, and identify the challenges encountered in the valuation of THSs. Of the 36 relevant studies, 22 were explicit that the HS being valued was temporary. Most of the studies used more than one technique (often incorporating both conventional and adapted approaches). In using adapted techniques, the primary challenge was identifying an appropriate intermediate "anchor" HS and the possibility of negative utilities. There is no agreement on the most methodologically robust approach to THS valuation. Valuation is complex and important issues relating to the validity, practicality, and reliability of the techniques used were not adequately covered by most of the studies identified.


Does cannabis use increase anxiety disorders? A literature review.
Cannabis is widely used worldwide and cannabis use disorders are highly comorbid with anxiety disorders. In this review, we consider the recent literature on the effects of cannabis on the incidence, course, and treatment outcomes of anxiety disorders. Although cannabis use is mostly found to be associated with increased incidence of anxiety disorders, these findings are generally not sustained in adjusted analyses controlling for multiple confounders. There are some equivocal data suggesting higher risk for anxiety disorders among heavy cannabis users. The scarce data available indicates no clear effect of cannabis use on the course and treatment outcomes of anxiety disorders. Further research is needed focusing on trajectories of cannabis-induced acute anxiety, effects of cannabis use on treatment outcomes in anxiety disorders, and common genetic factors. Future epidemiological studies should utilize more precise measures of cannabis use and address several confounding factors which may affect the association between cannabis use and anxiety disorders.


Identifying the Active Ingredients of a Computerized Speech and Language Therapy Intervention for Poststroke Aphasia: Multiple Methods Investigation Alongside a Randomized Controlled Trial.
Aphasia is a communication disorder affecting more than one-third of stroke survivors. Computerized Speech and Language Therapy (CSLT) is a complex intervention requiring computer software, speech and language therapists, volunteers, or therapy assistants, as well as self-managed practice from the person with aphasia. CSLT was found to improve word finding, a common symptom of aphasia, in a multicenter randomized controlled trial (Clinical and Cost Effectiveness of Computer Treatment for Aphasia Post Stroke [Big CACTUS]). This study provides a detailed description of the CSLT intervention delivered in the Big CACTUS trial and identified the active ingredients of the intervention directly associated with improved word finding for people with aphasia. We conducted a multiple methods study within the context of a randomized controlled trial. In study 1, qualitative interviews explored key informants' understanding of the CSLT intervention, how the components interacted, and how they could be measured. Qualitative data were transcribed verbatim and analyzed thematically. Qualitative findings informed the process measures collected as part of a process evaluation of the CSLT intervention delivered in the Big CACTUS trial. In study 2, quantitative analyses explored the relationship between intervention process measures (length of computer therapy access; therapists' knowledge of CSLT; degree of rationale for CSLT tailoring; and time spent using the software to practice cued confrontation naming, noncued naming, and using words in functional sentences) and change in word-finding ability over a 6-month intervention period. Qualitative interviews were conducted with 7 CSLT approach experts. Thematic analysis identified four overarching components of the CSLT approach: (1) the StepByStep software (version 5; Steps Consulting Ltd), (2) therapy setup: tailoring and personalizing, (3) regular independent practice, and (4) support and monitoring. Quantitative analyses included process and outcome data from 83 participants randomized to the intervention arm of the Big CACTUS trial. The process measures found to be directly associated with improved word-finding ability were therapists providing a thorough rationale for tailoring the computerized therapy exercises and the amount of time the person with aphasia spent using the computer software to practice using words in functional sentences. The qualitative exploration of the CSLT approach provided a detailed description of the components, theories, and mechanisms underpinning the intervention and facilitated the identification of process measures to be collected in the Big CACTUS trial. Quantitative analysis furthered our understanding of which components of the intervention are associated with clinical improvement. To optimize the benefits of using the CSLT approach for word finding, therapists are advised to pay particular attention to the active ingredients of the intervention: tailoring the therapy exercises based on the individual's specific language difficulties and encouraging people with aphasia to practice the exercises focused on saying words in functional sentences. ISRCTN Registry ISRCTN68798818; https://www.isrctn.com/ISRCTN68798818.


Roles of Cognitive Status and Intelligibility in Everyday Communication in People with Parkinson's Disease: A Systematic Review.
Communication is fundamental to human interaction and the development and maintenance of human relationships and is frequently affected in Parkinson's disease (PD). However, research and clinical practice have both tended to focus on impairment rather than participation aspects of communicative deficit in PD. In contrast, people with PD have reported that it is these participation aspects of communication that are of greatest concern to them rather than physical speech impairment. To systematically review the existing body of evidence regarding the association between cognitive status and/or intelligibility and everyday communication in PD. Five online databases were systematically searched in May 2015 (Medline Ovid, EMBASE, AMED, PsycINFO and CINAHL) and supplementary searches were also conducted. Two reviewers independently evaluated retrieved records for inclusion and then performed data extraction and quality assessment using standardised forms. Articles were eligible for inclusion if they were English-language original peer-reviewed research articles, book chapters or doctoral theses investigating the associations between at least one of cognitive status and level of intelligibility impairment and an everyday communication outcome in human participants with PD. 4816 unique records were identified through database searches with 16 additional records identified through supplementary searches. 41 articles were suitable for full-text screening and 15 articles (12 studies) met the eligibility criteria. 10 studies assessed the role of cognitive status and 9 found that participants with greater cognitive impairment had greater everyday communication difficulties. 4 studies assessed the role of intelligibility and all found that participants with greater intelligibility impairment had greater everyday communication difficulties, although effects were often weak and not consistent. Both cognitive status and intelligibility may be associated with everyday communicative outcomes in PD. The contribution of intelligibility to everyday communication appears to be of small magnitude, suggesting that other factors beyond predominantly motor-driven impairment-level changes in intelligibility may play an important role in everyday communication difficulties in PD.


Spectrum of Wind Power Fluctuations.
Wind power fluctuations for an individual turbine and plant have been widely reported to follow the Kolmogorov spectrum of atmospheric turbulence; both vary with a fluctuation time scale τ as τ^{2/3}. Yet, this scaling has not been explained through turbulence theory. Using turbines as probes of turbulence, we show the τ^{2/3} scaling results from a large scale influence of atmospheric turbulence. Owing to this long-range influence spanning 100s of kilometers, when power from geographically distributed wind plants is summed into aggregate power at the grid, fluctuations average (geographic smoothing) and their scaling steepens from τ^{2/3}→τ^{4/3}, beyond which further smoothing is not possible. Our analysis demonstrates grids have already reached this τ^{4/3} spectral limit to geographic smoothing.


Comparative Study on Knowledge and Awareness of Common Ocular Diseases Among Rural and Urban Community in Siraha District of Nepal: The Lahan Study.
Awareness and knowledge about the common ocular conditions can help people to seek early eye care services. The understanding and acceptance of the importance of routine eye examinations can help in timely detection and treatment of the eye diseases and thus help to reduce the burden of avoidable ocular blindness from the general population. This study aims to assess and analyze the information related to knowledge and awareness of common ocular diseases and eye health among the rural and urban communities of the Siraha district, Nepal. A descriptive cross-sectional study was conducted between April and June 2018 in Lahan Municipality ward number 6 (urban) and Sakhuwa Nankarkatti Rural Municipality ward number 4 (rural) in Siraha district. The sample size of 975 was calculated from study population of 3247. A systematic random sampling technique was used to interview adults above 18 years of age, using a pre-tested structured questionnaire. The collected data was analyzed. Out of total 975 participants, 514 (52.7%) were from rural community in Sakhuwa Rural Municipality and 461 (47.3%) were from urban community in Lahan Municipality. The mean age was 38.38 ± 15 years. Female participants were more (63.2%) compared to male (36.8%). Overall, 58.3% were literate and 41.7% were illiterate. Rural community had more uneducated participants (48%) compared to urban community (34%). In rural community, 69% were aware about cataract, 83% had knowledge about its treatment; while in urban community 81% were aware about cataract and 86% had knowledge about its treatment. The awareness of glaucoma among the participants was poor, more so in rural cohort (15%) than the urban cohort (25%). The knowledge of glaucoma was 14% in rural and 62% in urban cohort. Awareness that diabetes can affect the eye was found to be significantly lower (p = 0.01) in rural population (25%) compared to that in urban population (41%) in this study. The knowledge about diabetic retinopathy was lower in rural community (38%) compared to urban community (49%). Awareness about Night Blindness was lesser in rural (62%) compared to urban (70%) community (p = 0.17). Awareness about refractive errors were 37% in rural compared to 60% in urban community. The major sources of information were society and eye hospital in both community. The knowledge and awareness level regarding common ocular diseases was high among the community people of urban community (Lahan) in comparison to rural community (Sakhuwa Nankarkatti). Awareness and knowledge level mainly regarding glaucoma and diabetic retinopathy was very poor in both urban and rural community. There is need to conduct comprehensive awareness programs on common ocular diseases like cataract, glaucoma, diabetic retinopathy, night blindness, congenital eye disease, ocular trauma, eye donations and others in both rural and urban areas to raise the awareness level and improve attitudes and right practices reducing the burden of avoidable blindness.


Topical analgesia treats pain and decreases propofol use during lumbar punctures in a randomized pediatric leukemia trial.
Lumbar punctures are frequently performed in pediatric leukemia for central nervous system leukemic prophylaxis. The contribution of local anesthetic with deep sedation is unknown. The objective was to evaluate EMLA (eutectic mixture of local anesthetics) cream as a pain reliever in conjunction with propofol in the setting of routine lumbar punctures. We included patients with acute lymphoblastic leukemia aged 3-21 years requiring at least two routine lumbar punctures. Patients were randomly assigned to receive EMLA or placebo cream and the alternate treatment with the second procedure. Patients, personnel and outcome assessors were blinded to allocation. The primary outcome included three indirect measures of pain: total median propofol doses, patient movement and heart rate changes at the time of skin puncture in both treatment groups. Twenty-six patients were enrolled and 25 were analyzed. With EMLA cream, 4 mg/kg (median) of propofol was required (95% CI 3.5-4.4). With placebo, 4.9 mg/kg of propofol was needed (95% CI 4.3-5.6; P = 0.008). When EMLA cream was applied, 8% of patients moved, whereas 84% moved with placebo cream (P < 0.0001). There was a lower average heart rate by seven beats in the EMLA treatment compared to placebo (95% CI -2.3-4.3; 4.1-12.4; P = 0.009). There were no adverse events in either treatment group. This study demonstrated that the combination of EMLA cream with propofol is beneficial. Topical analgesics are at the discretion of the oncologist, allowing us to advocate for patients by providing safe and efficacious pain management for lumbar punctures.


Microsatellite Loci Reveal High Genetic Diversity, Mutation, and Migration Rates as Invasion Drivers of Callery Pear (Pyrus calleryana) in the Southeastern United States.
Pyrus calleryana Decne. (Callery pear) is a deciduous tree native to China, Japan, Korea, and Taiwan. It is a popular ornamental tree in the United States (US) with early spring blooms and vibrant fall color. There are at least 26 cultivars of P. calleryana available in the US of which "Bradford" is the most well-known. Open-pollinated P. calleryana escapees are becoming one of the most common invasive tree species in the eastern United States. Developing better management practices for invasive P. calleryana requires detailed knowledge about reproductive biology and genetic diversity of the species, however, little is currently known about genetic variability within those open-pollinated populations. We investigated genetic diversity and population structure of non-cultivated, escaped P. calleryana populations within a ∼177 km radius in the southeastern United States. Because P. calleryana exhibits a range of morphological variation with great evolutionary potential, we hypothesized that a high genetic diversity would be manifested among escaped P. calleryana. Using 15 previously developed microsatellite loci, we genotyped 180 open-pollinated P. calleryana individuals that were collected across six naturally occurring sites in Tennessee, Georgia, and South Carolina, United States. Our results demonstrated the presence of a population structure with high genetic diversity, high gene flow, and high genetic differentiation between individuals across collection sites. Our results revealed that P. calleryana populations had differentiated shortly after the introduction to the US, most likely from specimens imported from Asia, consistent with historical records and our prior findings. The high invasive potential of the species is perhaps best underscored by transformation of P. calleryana specimens introduced from Asia into escape populations at continental scale across the United States. Our data also provided novel insight into potential issues that could be problematic for the future as P. calleryana may pose a potential threat to the economy, ecology, and native biodiversity in invaded areas.


The Emerging Role of CD24 in Cancer Theranostics-A Novel Target for Fluorescence Image-Guided Surgery in Ovarian Cancer and Beyond.
Complete cytoreductive surgery is the cornerstone of the treatment of epithelial ovarian cancer (EOC). The application of fluorescence image-guided surgery (FIGS) allows for the increased intraoperative visualization and delineation of malignant lesions by using fluorescently labeled targeting biomarkers, thereby improving intraoperative guidance. CD24, a small glycophosphatidylinositol-anchored cell surface receptor, is overexpressed in approximately 70% of solid cancers, and has been proposed as a prognostic and therapeutic tumor-specific biomarker for EOC. Recently, preclinical studies have demonstrated the benefit of CD24-targeted contrast agents for non-invasive fluorescence imaging, as well as improved tumor resection by employing CD24-targeted FIGS in orthotopic patient-derived xenograft models of EOC. The successful detection of miniscule metastases denotes CD24 as a promising biomarker for the application of fluorescence-guided surgery in EOC patients. The aim of this review is to present the clinical and preclinically evaluated biomarkers for ovarian cancer FIGS, highlight the strengths of CD24, and propose a future bimodal approach combining CD24-targeted fluorescence imaging with radionuclide detection and targeted therapy.


Pulmonary lipiodol embolism during transcatheter arterial chemoembolization for hepatoblastoma under general anaesthesia.
We present a case of pulmonary embolism that occurred during the injection of lipiodol during transcatheter arterial chemoembolization under general anaesthesia. A 7-year-old child suffering from a large hepatoblastoma was admitted for arterial chemoembolization and carcinostatic administration. Pulmonary embolism due to lipiodol during arterial chemoembolization was evident by a sudden fall in oxyhaemoglobin saturation from 100 to 90%. This was associated with a spread of lipiodol into both lungs, particularly the middle lung zones and detected by chest fluoroscopy. Arterial blood gases returned to normal values 1 day later but pulmonary infiltration persisted for 7 days before final clearance. Pulmonary embolism caused by lipiodol during arterial chemoembolization is infrequent, but such a complication could prove fatal. Understanding the risk of pulmonary embolism in patients receiving lipiodol, during and after arterial chemoembolization, and late onset pulmonary injury is important and a close follow-up for several days after arterial chemoembolization is advisable.


Angle-insensitive flow measurement using Doppler bandwidth.
The ability to measure the velocity of blood flow independent of the orientation of the blood vessel could aid in evaluation of many disease processes, such as coronary lesions. Conventional ultrasonic Doppler techniques require knowledge of the beam-to-flow angle, and the Doppler effect vanishes when this angle is 90 degrees . By employing a spherically symmetrical range cell and the Doppler bandwidth instead of the Doppler shift, preliminary results show that flow measurement of ideal uniform flow that has a blunt velocity profile can be made without knowledge of tile orientation of the vessel, even when the angle of orientation is around 90 degrees . But when the technique is applied to a real how that has a parabolic velocity profile, the Doppler bandwidth decreases as the beam-to-flow angle increases. Although the Doppler bandwidth is sensitive to the transducer angle in this situation, the error in determining flow velocity might be acceptable if the transducer angle can be estimated to be within a small range. For this method to be regarded as practical for clinical use, however, a consistent relationship between bandwidth and flow velocity must be demonstrated over some set of clinically relevant conditions. The experimental techniques and results for how measurements of both the ideal uniform flow and the real flow are presented in this paper.


Ethnic Differences in Mental Health Status and Service Utilization: A Population-Based Study in Ontario, Canada.
The purpose of this study was to compare the prevalence of self-reported mental health factors, mental health service use, and unmet needs across the 4 largest ethnic groups in Ontario, Canada: white, South Asian, Chinese, and black groups. The study population was derived from the Canadian Community Health Survey, using a cross-sectional sample of 254,951 white, South Asian, Chinese, and black residents living in Ontario, Canada, between 2001 and 2014. Age- and sex-standardized prevalence estimates for mental health factors, mental health service use, and unmet needs were calculated for each of the 4 ethnic groups overall and by sociodemographic characteristics. We found that self-reported physician-diagnosed mood and anxiety disorders and mental health service use were generally lower among South Asian, Chinese, and black respondents compared to white respondents. Chinese individuals reported the weakest sense of belonging to their local community and the poorest self-rated mental health and were nearly as likely to report suicidal thoughts in the past year as white respondents. Among those self-reporting fair or poor mental health, less than half sought help from a mental health professional, ranging from only 19.8% in the Chinese group to 50.8% in the white group. The prevalence of mental health factors and mental health service use varied widely across ethnic groups. Efforts are needed to better understand and address cultural and system-level barriers surrounding high unmet needs and to identify ethnically tailored and culturally appropriate clinical supports and practices to ensure equitable and timely mental health care.


Synthesis of Rutin Derivatives to Enhance Lipid Solubility and Development of Topical Formulation with a Validated Analytical Method.
Rutin is available on the market as a topical formulation for the treatment of several conditions, such as internal bleeding, hemorrhoids, and varicose veins. However, these gels have low solubility and limited bioavailability due to their decreased lipid solubility. In this study, we aimed to synthesize potentially novel lipophilic rutin prodrugs. The suggested library of these rutin prodrugs includes changing the solubility profile to facilitate rutin transport across biological barriers, thereby improving drug delivery through topical application. Six rutin derivatives were synthesized based on the ester prodrug strategy. The synthesized compounds were formulated as topical ointments, and their permeability via Franz diffusion was measured. An ultraviolet (UV) analytical method was developed in our laboratories to quantify rutin derivatives both as raw materials and in final dosage forms. The analytical method was then validated. The results of Franz diffusion analyses showed that transdermal permeability increased by 10-fold for decaacetylated rutin compared to the other esterified rutins. A simple analytical method for the analysis of the formulated rutin ester was developed and validated. Moreover, the formulated ointment of decaacetylated rutin in our research laboratory was found to be stable under stability accelerated conditions. Synthesis of potentially more lipophilic compounds would yield novel rutin prodrugs suitable for topical formulation. This project provides a synthetic approach for many similar natural products. The research idea and strategy followed in this research project could be adapted by pharmaceutical and herbal establishments.


A modified Gamblegram for the visual representation of acid-base disorders according to the Stewart-Figge approach.
The Gamblegram consists of two bars, each of which represents the sum of the charges of individual positively and negatively charged ions and is commonly used for visualizing changes in acid-base and electrolyte charges. However, according to the Stewart-Figge theory, the metabolic independent acid-base variables include the strong ion difference ([SID]) and the total concentrations of weak acids (albumin and inorganic phosphate), which are not shown in the conventional Gamblegram. Thus, the Gamblegram in its current form is unsuitable for visualizing acid-base perturbations using the Stewart-Figge approach. To overcome this problem the following modifications are proposed: 1) The positive bar is represented exclusively by strong ion difference ([SID]) 2) The negative bar is comprised of [HCO3̄], unmeasured ion charge ([X]) and albumin and inorganic phosphate charges which are considered proportional to their total concentrations assuming a standard pH of 7.4 (0.28⋅[Albumin] (g/l) and 1.8⋅[Phosphate] (mmol/l), respectively). The proposed method treats [HCO3̄] as a global index of the metabolic acid-base status, whose concentration is expressed as a function of the Stewart-Figge independent acid-base variables ([SID], [Albumin], [Phosphate] and [X]).


Amphiphilic Graft Copolymer Nanospheres: From Colloidal Self-Assembly to CO2 Capture Membranes.
Colloidal nanosphere self-assembly effectively generates ordered nanostructures, prompting tremendous interest in many applications such as photonic crystals and templates for inverse opal fabrication. Here we report the self-assembly of low-cost, graft copolymer nanospheres for CO2 capture membranes. Specifically, poly(dimethylsiloxane)-graft-poly(4-vinylpyridine) (PDMS-g-P4VP) is synthesized via one-pot, free radical dispersion polymerization to give discrete monodisperse nanospheres. These nanospheres comprise a surface-anchored highly permeable PDMS layer and internal CO2-philic P4VP spherical core. Their diameter is controllable below the submicrometer range by varying grafting ratios. The colloidal dispersion forms a long-range, close-packed hexagonal array on a substrate by inclined deposition and convective assembly. The array shows dispersion medium-dependent packing characteristics. A thermodynamic correlation is determined using different solvents to obtain stable PDMS-g-P4VP dispersions and interpreted in terms of Flory-Huggins interaction parameter. As a proof-of-concept, the implementation of these nanospheres into membranes simultaneously enhances the CO2 permeability and CO2/N2 selectivity of PDMS-based transport matrixes. Upon physical aging of the solution, the CO2/N2 selectivity is improved up to 26, one of the highest values for highly permeable PDMS-based polymeric membranes.


[Clinical reasoning and decision making in practice. A 39-year-old woman with somnolence, hypertension and haemolysis].
A 39-year-old woman was admitted with somnolence, severe hypertension and thrombotic microangiopathy. Both malignant hypertension and thrombotic thrombocytopenic purpura (TTP) were considered. Immediate therapy was instituted to treat both diseases because of severe clinical deterioration. Eventually, TTP was considered less likely due to the presence of grade IV hypertensive retinopathy (papilloedema and soft exudates) and a normal Von Willebrand factor-cleaving protease level. Differentiating TTP from malignant hypertension can be difficult as both diseases have similar clinical, laboratory and radiological features. In both diseases, hypertension, thrombotic microangiopathy and encephalopathy with white-matter lesions in the posterior regions of the brain may be apparent. Funduscopic abnormalities consistent with grade III and IV hypertensive retinopathy are rare in TTP, as are normal levels ofVon Willebrand factor-cleaving protease. Therefore, the diagnosis TTP was considered less likely and plasmapheresis was stopped. Hereafter, the laboratory values pointing towards haemolysis remained normal with adequate blood pressure control supporting the rejection of TTP as the cause of the symptoms.


Interventional Treatment of Bronchiectasis Macrosomia Based on Multirow CT Tomography Monitoring.
We present in this paper an in-depth study and analysis of bronchiectasis haemoptysis by multirow CT tomography and a multifaceted treatment and analysis of the interventions monitored by the scan. Although coronary CT is of great clinical value in the diagnosis and monitoring of coronary artery disease, the potential radiation damage caused by coronary CT should not be underestimated because CT imaging is based on X-rays and the actual effective dose is 5-30 mSv, which is reported in the literature to be high when using conventional imaging modalities for coronary CT. Although there is no direct evidence of a definite causal relationship between X-ray exposure during CT examinations and tumorigenesis, theoretically, even small doses of radiation exposure may pose some potential health risk. Therefore, in clinical practice, coronary CT examinations should be performed in strict compliance with the radiation protection rule "as low as reasonably achievable" (ALARA) recognized by the radiation industry. For longitudinal openings in the range of 0° to 59° and transverse openings in the range of 0° to 44°, the CB2 catheter is significantly more stable than the MIK catheter, and for longitudinal openings in the range of 60° to 119° and transverse openings in the range of 0° to 44°, the CB2 catheter is more stable than the MIK catheter. For longitudinal openings from 0° to 120° and lateral openings from 45° to 90°, there was no significant difference in cannulation stability between the CB2 and MIK catheters. There was a potential tendency for MIK cannulation stability to be higher than CB2 for longitudinal openings in the range of 120° to 180° and lateral openings in the range of 45° to 90°, but there was no significant difference.


Uric acid and plasma lipids in cerebrovascular disease. I. Prevalence of hyperuricaemia.
Serum uric acid levels measured by the phosphotungstic sodium cyanide method have been estimated in 60 patients suffering from a cerebrovascular incident. Patients with diseases known to predispose to hyperuricaemia were excluded. Twenty-five per cent. of patients with acute strokes had hyperuricaemia, and this did not appear to be a transitory phenomenon. These findings suggest that hyperuricaemia may be one of the factors in the pathogenesis of atheroma.


Characterization of knee dysfunction and related risk factors during pregnancy.
Knee pain can be a common complaint during pregnancy; however, the severity of symptoms and their associated risk factors have not been described. The aim of this study was to characterize knee-related dysfunction and describe risk factors in a general obstetric population. Patients in obstetric clinics completed the International Knee Documentation Committee (IKDC) questionnaire to assess their knee function, as well as the Pregnancy Physical Activity Questionnaire (PPAQ), a validated tool to assess physical activity. Age, weeks gestation, height, weight, and history of knee problems prior to pregnancy were analyzed to identify independent associations with IKDC score and determine predictors of knee dysfunction. 310 patients were included in this study, of which 68, 111 and 131 were in their first, second and trimesters, respectively. Mean age of the total study group was 30.3 ± 5.5 years. Knee function decreased with each trimester, from a mean IKDC score of 88.9 ± 13.0 in the first trimester, 84.5 ± 16.8 in the second, and 82.0 ± 20.0 in the third, with corresponding decreases in activity levels of 258.5 ± 141.7, 254.0 ± 141.5, and 246.1 ± 156.6 MET-h/wk. Of the total study group, 26.1% had IKDC scores <75, including 13.2%, 25.2%, and 33.6% in the first, second and third trimesters. Risk factors for knee dysfunction included high activity levels of PPAQ ≥ 500 MET-h/wk (OR 2.8), history of knee problems (OR 2.7), age <25 years (OR 2.6), and BMI ≥ 30 kg/m2 (OR 1.9). In our cohort, 26.1% of pregnant women reported severe knee dysfunction, and this was associated with high levels of activity, younger age, greater BMI, and history of knee problems. These findings may have implications for women who wish to maintain training and fitness during pregnancy. Future studies are recommended to assess the need for intervention, as well as to identify optimal methods to prevent and address symptoms in this population. IV, Case Series.


The modified unified interaction model: incorporation of dose-dependent localised recombination.
The unified interaction model (UNIM) was developed to simulate thermoluminescence (TL) linear/supralinear dose-response and the dependence of the supralinearity on ionisation density, i.e. particle type and energy. Before the development of the UNIM, this behaviour had eluded all types of TL modelling including conduction band/valence band (CB/VB) kinetic models. The dependence of the supralinearity on photon energy was explained in the UNIM as due to the increasing role of geminate (localised recombination) with decreasing photon/electron energy. Recently, the Ben Gurion University group has incorporated the concept of trapping centre/luminescent centre (TC/LC) spatially correlated complexes and localised/delocalised recombination into the CB/VB kinetic modelling of the LiF:Mg,Ti system. Track structure considerations are used to describe the relative population of the TC/LC complexes by an electron-hole or by an electron-only as a function of both photon/electron energy and dose. The latter dependence was not included in the original UNIM formulation, a significant over-simplification that is herein corrected. The modified version, the M-UNIM, is then applied to the simulation of the linear/supralinear dose-response characteristics of composite peak 5 in the TL glow curve of LiF:Mg,Ti at two representative average photon/electron energies of 500 and 8 keV.


Effect of a Collaborative Care Model on Depressive Symptoms and Glycated Hemoglobin, Blood Pressure, and Serum Cholesterol Among Patients With Depression and Diabetes in India: The INDEPENDENT Randomized Clinical Trial.
Mental health comorbidities are increasing worldwide and worsen outcomes for people with diabetes, especially when care is fragmented. To assess whether collaborative care vs usual care lowers depressive symptoms and improves cardiometabolic indices among adults with diabetes and depression. Parallel, open-label, pragmatic randomized clinical trial conducted at 4 socioeconomically diverse clinics in India that recruited patients with type 2 diabetes; a Patient Health Questionnaire-9 score of at least 10 (range, 0-27); and hemoglobin A1c (HbA1c) of at least 8%, systolic blood pressure (SBP) of at least 140 mm Hg, or low-density lipoprotein (LDL) cholesterol of at least 130 mg/dL. The first patient was enrolled on March 9, 2015, and the last was enrolled on May 31, 2016; the final follow-up visit was July 14, 2018. Patients randomized to the intervention group (n = 196) received 12 months of self-management support from nonphysician care coordinators, decision support electronic health records facilitating physician treatment adjustments, and specialist case reviews; they were followed up for an additional 12 months without intervention. Patients in the control group (n = 208) received usual care over 24 months. The primary outcome was the between-group difference in the percentage of patients at 24 months who had at least a 50% reduction in Symptom Checklist Depression Scale (SCL-20) scores (range, 0-4; higher scores indicate worse symptoms) and a reduction of at least 0.5 percentage points in HbA1c, 5 mm Hg in SBP, or 10 mg/dL in LDL cholesterol. Prespecified secondary outcomes were percentage of patients at 12 and 24 months who met treatment targets (HbA1c <7.0%, SBP <130 mm Hg, LDL cholesterol <100 mg/dL [<70 mg/dL if prior cardiovascular disease]) or had improvements in individual outcomes (≥50% reduction in SCL-20 score, ≥0.5-percentage point reduction in HbA1c, ≥5-mm Hg reduction in SBP, ≥10-mg/dL reduction in LDL cholesterol); percentage of patients who met all HbA1c, SBP, and LDL cholesterol targets; and mean reductions in SCL-20 score, Patient Health Questionnaire-9 score, HbA1c, SBP, and LDL cholesterol. Among 404 patients randomized (mean [SD] age, 53 [8.6] years; 165 [40.8%] men), 378 (93.5%) completed the trial. A significantly greater percentage of patients in the intervention group vs the usual care group met the primary outcome (71.6% vs 57.4%; risk difference, 16.9% [95% CI, 8.5%-25.2%]). Of 16 prespecified secondary outcomes, there were no statistically significant between-group differences in improvements in 10 outcomes at 12 months and in 13 outcomes at 24 months. Serious adverse events in the intervention and usual care groups included cardiovascular events or hospitalizations (4 [2.0%] vs 7 [3.4%]), stroke (0 vs 3 [1.4%]), death (2 [1.0%] vs 7 [3.4%]), and severe hypoglycemia (8 [4.1%] vs 0). Among patients with diabetes and depression in India, a 12-month collaborative care intervention, compared with usual care, resulted in statistically significant improvements in a composite measure of depressive symptoms and cardiometabolic indices at 24 months. Further research is needed to understand the generalizability of the findings to other low- and middle-income health care settings. ClinicalTrials.gov Identifier: NCT02022111.


Comparison of cecal intubation and adenoma detection between hospitals can provide incentives to improve quality of colonoscopy.
Cecal intubation rate (CIR) and adenoma detection rate (ADR) have been found to be inversely associated with the occurrence of post-colonoscopy colorectal cancer. Depicting differences in CIR and ADR between hospitals could provide incentives for quality improvement. The aim of this study was to compare quality parameters of routine colonoscopies between seven hospitals in The Netherlands in order to determine the extent to which possible differences were attributable to procedural and institutional factors. Consecutive patients undergoing colonoscopy were prospectively included between November 2012 and January 2013 at two academic and five nonacademic hospitals. Patients with inflammatory bowel disease or hereditary colorectal cancer syndromes were excluded. Main outcome measures were CIR and ADR. A total of 3129 patients were included (mean age 59 ± 15 years; 45.5 % male). The majority of patients (86.2 %) had a Boston Bowel Preparation Scale (BBPS) score ≥ 6. Overall CIR was 94.8 %, ranging from 89.4 % to 99.2 % between hospitals. After adjustment for case mix (age, sex, American Society of Anesthesiologists score, and indication for colonoscopy), factors associated with CIR were hospital and a BBPS score ≥ 6. Overall ADR was 31.8 % and varied between hospitals, ranging from 24.8 % to 46.8 %. Independent predictors for ADR were hospital, BBPS score ≥ 6, and cecal intubation. By combining CIR and ADR for each hospital, a colonoscopy quality indicator (CQI) was developed, which can be used by hospitals to stimulate quality improvement. Differences in the quality of colonoscopy between hospitals can be demonstrated using CIR and ADR. As both indicators are affected by institution and bowel preparation, a comparison between hospitals based on the newly developed CQI could assist in further improving the quality of colonoscopy.


Treatment of radiation-induced dermatitis with light-emitting diode (LED) photomodulation.
Light-emitting diode (LED) photomodulation increases dermal collagen and reduces inflammation. This study evaluated the use of LED photomodulation in the prevention of radiation-induced dermatitis in breast cancer. Patients (n=19) were treated with LED photomodulation (Gentlewaves, Light BioScience, LLC, Virginia Beach, VA) after each of a series of intensity-modulated radiation treatments (IMRT). Skin reactions were monitored weekly with National Cancer Institute (NCI) criteria. Age-matched controls (n=28) received IMRT without LED photomodulation. In LED-treated patients, 18 (94.7%) had grade 0 or 1 reaction and 1 (5.3%) had grade 2 reaction. Among controls, 4 (14.3%) had a grade 1 reaction, 24 (85.7%) had a grade 2 or 3 reaction. One LED-treated patient (5.3%) and 19 controls (67.9%) had to interrupt treatment. LED photomodulation treatments immediately after IMRT reduces the incidence of NCI grades 1, 2, and 3 skin reactions in patients with breast cancer treated by radiation therapy (RT) postlumpectomy.


A Derived Positional Mapping of Inhibitory Subtypes in the Somatosensory Cortex.
Obtaining a catalog of cell types is a fundamental building block for understanding the brain. The ideal classification of cell-types is based on the profile of molecules expressed by a cell, in particular, the profile of genes expressed. One strategy is, therefore, to obtain as many single-cell transcriptomes as possible and isolate clusters of neurons with similar gene expression profiles. In this study, we explored an alternative strategy. We explored whether cell-types can be algorithmically derived by combining protein tissue stains with transcript expression profiles. We developed an algorithm that aims to distribute cell-types in the different layers of somatosensory cortex of the developing rat constrained by the tissue- and cellular level data. We found that the spatial distribution of major inhibitory cell types can be approximated using the available data. The result is a depth-wise atlas of inhibitory cell-types of the rat somatosensory cortex. In principle, any data that constrains what can occur in a particular part of the brain can also strongly constrain the derivation of cell-types. This draft inhibitory cell-type mapping is therefore dynamic and can iteratively converge towards the ground truth as further data is integrated.


Analysis of a novel offset cone-beam computed mammotomography system geometry for accomodating various breast sizes.
We evaluate a newly developed dedicated cone-beam transmission computed mammotomography (CmT) system configuration using an optimized quasi-monochromatic cone beam technique for attenuation correction of SPECT in a planned dual-modality emission and transmission system for pendant, uncompressed breasts. In this study, we perform initial CmT acquisitions using various sized breast phantoms to evaluate an offset cone-beam geometry. This offset geometry provides conjugate projections through a full 360 degree gantry rotation, and thus yields a greatly increased effective field of view, allowing a much wider range of breast sizes to be imaged without truncation in reconstructed images. Using a tungsten X-ray tube and digital flat-panel X-ray detector in a compact geometry, we obtained initial CmT scans without shift and with the offset geometry, using geometrical frequency/resolution phantoms and two different sizes of breast phantoms. Acquired data were reconstructed using an ordered subsets transmission iterative algorithm. Projection images indicate that the larger, 20 cm wide, breast requires use of a half-cone-beam offset scan to eliminate truncation artifacts. Reconstructed image results illustrate elimination of truncation artifacts, and that the novel quasi-monochromatic beam yields reduced beam hardening. The offset geometry CmT system can indeed potentially be used for structural imaging and accurate attenuation correction for the functional dedicated breast SPECT system.


Preventive Effects of Apple Polyphenol Extract on High-Fat-Diet-Induced Hepatic Steatosis Are Related to the Regulation of Hepatic Lipid Metabolism, Autophagy, and Gut Microbiota in Aged Mice.
Our previous study confirmed that the ameliorated effects of an intervention with an apple polyphenol extract (APE) on hepatic steatosis induced by a high-fat diet (HFD) are dependent on SIRT1. Since SIRT1 expression decreases with age, it remains unclear whether APE intervention is effective against hepatic steatosis in aged mice. Thus, 12-month-old C57BL/6 male mice were fed with an HFD to establish an aging model of hepatic steatosis and treated with 500 mg/(kg·bw·d) APE for 12 weeks. Young mice (two months old) and baseline mice were used as controls to examine the effects of natural aging on hepatic steatosis. Compared with baseline mice, no obvious difference in hepatic histopathological assessment was observed for both young and aged mice on normal diets. Meanwhile, HFD induced much higher nonalcoholic fatty liver disease (NAFLD) activity scores in aged mice than in young mice. APE intervention ameliorated lipid and glucose metabolic disorders and liver injury in HFD-fed aged mice, improved hepatic steatosis, and reduced NAFLD activity scores. The upregulated expressions of SIRT1, HSL, ATG5, Ulk1, and Becn1 and downregulated expressions of HMGCR and FOXO1 suggested improved lipid metabolism and activated autophagy. APE intervention decreased the ratio of Firmicutes/Bacteroidetes and elevated the Akkermansia probiotics abundance. In summary, HFD showed a more significant effect on hepatic steatosis compared to the natural aging process in aged mice, and APE might be a promising dietary ingredient for alleviating hepatic steatosis.


Chest trauma.
Trauma is a major cause of morbidity and mortality worldwide. Despite the advent of specialised trauma centres the outcome of patients who sustain major trauma remains disappointing. Plain radiography and more advanced imaging techniques such as ultrasound, computerised tomography (CT) and angiography, have a major role to play in the early decision making and subsequent management of patients who sustain polytrauma. This article discusses the choice of emergency imaging techniques available in chest trauma for clinicians and radiologists; their evaluation and some of the common pitfalls that may lead to errors of interpretation.


Inhibition of miR-141-3p attenuates apoptosis of neural stem cells via targeting PBX1 to regulate PROK2 transcription in MCAO mice.
MicroRNA-141-3p (miR-141-3p) has been found to be altered in the brain following a stroke. Herein, we investigate the impact of miR-141-3p on the apoptosis of neural stem cells (NSCs) in mice with middle cerebral artery occlusion (MCAO) and the potential mechanisms involved. Eight-week-old mice were injected intracerebroventricularly with miR-141-3p, antagomir-141-3p, or agomir negative control 2 h before MCAO, and animal behavior tests and infraction volume measurements were performed 24 h later. MCAO-mediated brain injury and NSCs apoptosis were observed by H&E, TTC, and TUNEL staining. The expression of cleaved caspase-3 and Ki67 was detected by western blotting. The luciferase reporter assay proved that miR-141-3p in combination with its target gene PBX homeobox 1 (PBX1). Exogenous miR-141-3p (agomir-141-3p) treatment increased infraction volume and brain edema and damaged neurological functions compared to control mice. Agomir-141-3p increased miR-141-3p expression in brain tissue of mice with MCAO and suppressed PBX1 expression. The effects of the agomir-141-3p-induced apoptosis in NSCs treated with oxygen-glucose deprivation (OGD)/reoxygenation (R) were abolished by PBX1 overexpression. The results from UCSC and JASPAR database showed that prokineticin 2 (PROK2) was a transcription factor of PBX1. The expression of PROK2 was transcriptionally regulated by PBX1 using RT-PCR and western blot assays. The effects of the apoptosis-promoting caused by PBX1 inhibition in NSCs treated with OGD/R were reversed by PROK2 inhibition. In conclusion, the miR-141-3p/PBX1/PROK2 axis might be a novel therapeutic target for the apoptosis of NSCs in MCAO.


Exploring physics students' engagement with online instructional videos in an introductory mechanics course.
The advent of new educational technologies has stimulated interest in using online videos to deliver content in university courses. We examined student engagement with 78 online videos that we created and were incorporated into a one-semester flipped introductory mechanics course at the Georgia Institute of Technology. We found that students were more engaged with videos that supported laboratory activities than with videos that presented lecture content. In particular, the percentage of students accessing laboratory videos was consistently greater than 80% throughout the semester. On the other hand, the percentage of students accessing lecture videos dropped to less than 40% by the end of the term. Moreover, the fraction of students accessing the entirety of a video decreases when videos become longer in length, and this trend is more prominent for the lecture videos than the laboratory videos. The results suggest that students may access videos based on perceived value: students appear to consider the laboratory videos as essential for successfully completing the laboratories while they appear to consider the lecture videos as something more akin to supplemental material. In this study, we also found that there was little correlation between student engagement with the videos and their incoming background. There was also little correlation found between student engagement with the videos and their performance in the course. An examination of the in-video content suggests that students engaged more with concrete information that is explicitly required for assignment completion (e.g., actions required to complete laboratory work, or formulas or mathematical expressions needed to solve particular problems) and less with content that is considered more conceptual in nature. It was also found that students' in-video accesses usually increased toward the embedded interaction points. However, students did not necessarily access the follow-up discussion of these interaction points. The results of the study suggest ways in which instructors may revise courses to better support student learning. For example, external intervention that helps students see the value of accessing videos may be required in order for this resource to be put to more effective use. In addition, students may benefit more from a clicker question that reiterates important concepts within the question itself, rather than a clicker question that leaves some important concepts to be addressed only in the discussion afterwards.


Variable effects of retinoids on two pigmenting human melanoma cell lines.
Two melanoma cell lines, each derived from a different patient with metastatic disease, were very similar in their appearance, their growth characteristics, and their tendency to differentiate and to pigment in culture as they become confluent. These lines, UCT-Mel 1 and UCT-Mel 2, were used to study the effects of retinoic acid and other derivatives of vitamin A. When added to UCT-Mel 1 cells, retinoids had only a modest effect on plasminogen activator release and were without measurable effect on morphology, growth, or tyrosinase synthesis. In contrast, when added to UCT-Mel 2 cells, retinoids appeared to induce a more differentiated state evident as an inhibition of cell proliferation and the assumption of a dendritic morphology. Paradoxically, however, retinoids caused a striking inhibition of the density-dependent intracellular accumulation of tyrosinase and melanin that was taken to represent spontaneous in vitro differentiation. Culture of UCT-Mel 2 cells in the presence of retinoic acid resulted in initial inhibition followed by marked stimulation of cellular plasminogen activator release. The data suggest that the manner in which retinoids exert their effects on cells in vitro does not depend on the histological origin of the tumor cells being studied but on the innate responsiveness of that particular cell line to the retinoid or compound in question.


An exploration of paternal-fetal attachment behavior.
A 63-item questionnaire utilizing the modified Maternal-Fetal Attachment Scale (PFA) (Cranley, 1981), the Marital Relationship Scale (Wapner, 1976), and the Physical History Scale (Wapner, 1976) was tested on 100 expectant fathers who had wives in their third trimester of pregnancy. Scores on the PFA were positively correlated with the strength of the marital relationship as perceived by the expectant father during pregnancy. A positive but weak association was shown between paternal-fetal attachment and the incidence of physical symptoms resembling pregnancy in the expectant father. Further testing of the PFA and related variables is indicated.


R403Q and L908V mutant beta-cardiac myosin from patients with familial hypertrophic cardiomyopathy exhibit enhanced mechanical performance at the single molecule level.
Familial hypertrophic cardiomyopathy (FHC) is a disease of the sarcomere. In the beta-myosin heavy chain gene, which codes for the mechanical enzyme myosin, greater than 40 point mutations have been found that are causal for this disease. We have studied the effect of two mutations, the R403Q and L908V, on myosin molecular mechanics. In the in vitro motility assay, the mutant myosins produced a 30% greater velocity of actin filament movement (v(actin)). At the single molecule level, v(actin) approximately d/t(on), where d is the myosin unitary step displacement and t(on) is the step duration. Laser trap studies were performed at 10 microM MgATP to estimate d and t(on) for the normal and mutant myosin molecules. The increase in v(actin) can be explained by a significant decrease in the average t(on)'s in both the R403Q and L908V mutants (approximately 30 ms) compared to controls (approximately 40 ms), while d was not different for all myosins tested (approximately 7 nm). Thus the mutations affect the kinetics of the cross-bridge cycle without any effect on myosin's inherent motion and force generating capacity. Based on these studies, the primary signal for the hypertrophic response appears to be an apparent gain in function of the individual mutant myosin molecules.


Reverse genetics recovery of Lujo virus and role of virus RNA secondary structures in efficient virus growth.
Arenaviruses are rodent-borne viruses with a bisegmented RNA genome. A genetically unique arenavirus, Lujo virus, was recently discovered as the causal agent of a nosocomial outbreak of acute febrile illness with hemorrhagic manifestations in Zambia and South Africa. The outbreak had a case fatality rate of 80%. A reverse genetics system to rescue infectious Lujo virus from cDNA was established to investigate the biological properties of this virus. Sequencing the genomic termini showed unique nucleotides at the 3' terminus of the S segment promoter element. While developing this system, we discovered that reconstructing infectious Lujo virus using the previously reported L segment intergenic region (IGR), comprising the arenaviral transcription termination signal, yielded an attenuated Lujo virus. Resequencing revealed that the correct L segment IGR was 36 nucleotides longer, and incorporating it into the reconstructed Lujo virus restored the growth rate to that of the authentic clinical virus isolate. These additional nucleotides were predicted to more than double the free energy of the IGR main stem-loop structure. In addition, incorporating the newly determined L-IGR into a replicon reporter system enhanced the expression of a luciferase reporter L segment. Overall, these results imply that an extremely stable secondary structure within the L-IGR is critical for Lujo virus propagation and viral protein production. The technology for producing recombinant Lujo virus now provides a method to precisely investigate the molecular determinants of virulence of this newly identified pathogen.


Assessing children's cognitive flexibility with the Shape Trail Test.
In this paper we report an initial validation of the Shape Trail Test-Child Version (STT-CV) with a non-clinical sample of children aged 6 to 9 years. The STT-CV has been developed as an age-appropriate and culturally fair direct downward extension of the Trail Making Test (TMT) for the assessment of cognitive flexibility. Children completed the STT-CV and four established measures of executive functions that assessed working memory, inhibitory control and task switching. Results showed the expected age-based differences in completion times for both parts of the STT-CV (Trail A and Trail B). Children's performance on the STT-CV correlated significantly with all four measures of executive functions. After controlling for the effects of chronological age, completion times for Trail B remained correlated with most other measures of executive functions. These findings provide emerging evidence for the utility of the STT-CV, and highlight the need for designing and using appropriate variants of the TMT in the behavioural assessment of cognitive flexibility in developmentally and culturally diverse populations.


T lymphocytes and cytokine production in ascitic fluid of ovarian malignancies.
The activation status of T lymphocytes and the presence of various cytokines in ascitic fluid were examined to test peritoneal immunity in women with ovarian malignancies. Peripheral blood and peritoneal fluid were collected from 12 patients with primary ovarian cancer with ascites and 27 normal control subjects during laparoscopic examination. Lymphocyte subpopulations and the expression of activation markers on T lymphocytes were analyzed by dual-color flow cytometry. The concentrations of various cytokines and soluble interleukin (IL)-2 receptor-alpha were measured. CD8 T lymphocytes were the main component of peritoneal lymphocytes. CD69 and HLA-DR, but not CD25, were highly expressed on peritoneal T lymphocytes compared to those in peripheral blood. In ascitic fluid of ovarian malignancies, CD4 T lymphocyte concentrations were further decreased, resulting in a decreased CD4/CD8 ratio. Decreased expression of CD69 and CD25 was also noted on T lymphocytes from ascites compared with T lymphocytes in normal peritoneal fluid. IL-1b, tumor necrosis factor-alpha, IL-6, and soluble IL-2 receptor-alpha concentrations were increased significantly in the ascitic fluid of women with ovarian cancer. The decrease in activation markers on T lymphocytes is suggestive of an immunosuppressive state, despite the presence of abundant stimulatory cytokines. The immunosuppression may be multifactorial, attributed, in part, to the increased concentrations of soluble IL-2 receptor-alpha and other inhibitors.


A child's garden of curses: a gender, historical, and age-related evaluation of the taboo lexicon.
Child swearing is a largely unexplored topic among language researchers, although assumptions about what children know about taboo language form the basis for language standards in many settings. The purpose of the studies presented here is to provide descriptive data about the emergence of adultlike swearing in children; specifically, we aim to document what words children of different ages know and use. Study 1 presents observational data from adults and children (ages 1-12). Study 2 compares perceptions of the inappropriateness of taboo words between adults and older (ages 9-12) and younger (ages 6-8) children. Collectively these data indicate that by the time children enter school they have the rudiments of adult swearing, although children and adults differ in their assessments of the inappropriateness of mild taboo words. Comparisons of these data with estimates obtained in the 1980s allow us to comment on whether swearing habits are changing over the years. Child swearing data can be applied to contemporary social problems and academic issues.


Relationship of physical fitness test results and hockey playing potential in elite-level ice hockey players.
The primary purpose of this study was to determine the fitness variables with the highest capability for predicting hockey playing potential at the elite level as determined by entry draft selection order. We also examined the differences associated with the predictive abilities of the test components among playing positions. The secondary purpose of this study was to update the physiological profile of contemporary hockey players including positional differences. Fitness test results conducted by our laboratory at the National Hockey League Entry Draft combine were compared with draft selection order on a total of 853 players. Regression models revealed peak anaerobic power output to be important for higher draft round selection in all positions; however, the degree of importance of this measurement varied with playing position. The body index, which is a composite score of height, lean mass, and muscular development, was similarly important in all models, with differing influence by position. Removal of the goalies' data increased predictive capacity, suggesting that talent identification using physical fitness testing of this sort may be more appropriate for skating players. Standing long jump was identified as a significant predictor variable for forwards and defense and could be a useful surrogate for assessing overall hockey potential. Significant differences exist between the physiological profiles of current players based on playing position. There are also positional differences in the relative importance of anthropometric and fitness measures of off-ice hockey tests in relation to draft order. Physical fitness measures and anthropometric data are valuable in helping predict hockey playing potential. Emphasis on anthropometry should be used when comparing elite-level forwards, whereas peak anaerobic power and fatigue rate are more useful for differentiating between defense.


Effects of Peutz-Jeghers syndrome (PJS) causing missense mutations L67P, L182P, G242V and R297S on the structural dynamics of LKB1 (Liver kinase B1) protein.
The liver kinase B1 (LKB1) is encoded by LKB1 gene. Several pathogenic mutations of LKB1 causing Peutz-Jeghers syndrome and also cancers in breast, gastric, pancreas, and colon have been reported. The present study is focused to analyze the effects on the structural dynamics of LKB1 caused by the 4 pathogenic missense mutations (L67P, L182P, G242V, and R297S), which are reported to reduce the catalytic activity. In this study, the structural changes of LKB1 in apo- and in heterotrimeric complex (LKB1-STRADα-MO25α) form with wild and mutated LKB1 are investigated using all atomistic molecular dynamic simulation. The present study reveals that these four mutations initiate local structural distortions and the solvent accessibility of the surrounding regions of ATP-binding pocket such as glycine-rich loop, αB and αC loop, activation and catalytic loops. The mutations of L67P, L182P, and G242 V induce distortions of the secondary structure of β1-β3 sheets, π - π interaction (observed between Phe204 of LKB1 and Phe243 of MO25α), and increase the helical properties (both helical twist and length) of the adjacent αH-helix, respectively. The active kinase features like the conformation of catalytic and activation loops, salt bridge and, finally, the formation of stable R- and C-hydrophobic spines are also found to be perturbed by these mutations. Hence, the observed mutation-induced structural distortions fail to coordinate the essential binding nature of LKB1 with STRADα and MO25α, which eventually affects the native function of LKB1. These observations are in line with the experimentally reported reduced kinase activity of LKB1.


Production of Human IFNγ Protein in Nicotiana benthamiana Plant through an Enhanced Expression System Based on Bamboo mosaic Virus.
Plant-based systems are safe alternatives to the current platforms for the production of biologically active therapeutic proteins. However, plant-based expression systems face certain major challenges, including the relatively low productivity and the generation of target proteins in biologically active forms. The use of plant virus-based expression systems has been shown to enhance yields, but further improvement is still required to lower the production cost. In this study, various strategies were employed to increase the yields of an important therapeutic protein, human interferon gamma (IFNγ), in Nicotiana benthamiana through modifications of expression vectors based on potexviruses. Among these, the vector based on a coat protein (CP)-deficient Bamboo mosaic virus (BaMV), pKB△CHis, was shown to exhibit the highest expression level for the unmodified IFNγ. Truncation of the N-terminal signal peptide of IFN (designated mIFNγ) resulted in a nearly seven-fold increase in yield. Co-expression of a silencing suppressor protein by replacing the coding sequence of BaMV movement protein with that of P19 led to a 40% increase in mIFNγ accumulation. The fusion of endoplasmic reticulum (ER) retention signal with mIFNγ significantly enhanced the accumulation ratio of biologically active dimeric mIFNγ to 87% relative to the non-active monomeric form. The construct pKB19mIFNγER, employing the combination of all the above enhancement strategies, gave the highest level of protein accumulation, up to 119 ± 0.8 μg/g fresh weight, accounting for 2.5% of total soluble protein (TSP) content. These findings advocate the application of the modified BaMV-based vector as a platform for high-level expression of therapeutic protein in N. benthamiana.


Dopaminergic Therapy for Motor Symptoms in Early Parkinson Disease Practice Guideline Summary: A Report of the AAN Guideline Subcommittee.
To review the current evidence on the options available for initiating dopaminergic treatment of motor symptoms in early-stage Parkinson disease and provide recommendations to clinicians. A multidisciplinary panel developed practice recommendations, integrating findings from a systematic review and following an Institute of Medicine-compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence. Initial treatment with levodopa provides superior motor benefit compared to treatment with dopamine agonists, whereas levodopa is more likely than dopamine agonists to cause dyskinesia. The comparison of different formulations of dopamine agonists yielded little evidence that any one formulation or method of administration is superior. Long-acting forms of levodopa and levodopa with entacapone do not appear to differ in efficacy from immediate-release levodopa for motor symptoms in early disease. There is a higher risk of impulse control disorders associated with the use of dopamine agonists than levodopa. Recommendations on initial therapy for motor symptoms are provided to assist the clinician and patient in choosing between treatment options and to guide counseling, prescribing, and monitoring of efficacy and safety.


Chlorobenzoate-degrading bacteria in similar pristine soils exhibit different community structures and population dynamics in response to anthropogenic 2-, 3-, and 4-chlorobenzoate levels.
A study was conducted to determine the diversity of 2-, 3-, and 4-chlorobenzoate (CB) degraders in two pristine soils with similar physical and chemical characteristics. Surface soils were collected from forested sites and amended with 500 microg of 2-, 3-, or 4-CB g(-1) soil. The CB levels and degrader numbers were monitored throughout the study. Degraders were isolated, grouped by DNA fingerprints, identified via 16S rDNA sequences, and screened for plasmids. The CB genes in selected degraders were isolated and/or sequenced. In the Madera soil, 2-CB and 4-CB degraded within 11 and 42 d, respectively, but 3-CB did not degrade. In contrast, 3-CB and 4-CB degraded in the Oversite soil within 14 and 28 d, respectively, while 2-CB did not degrade. Approximately 10(7) CFU g(-1) of degraders were detected in the Madera soil with 2-CB, and the Oversite soil with 3- and 4-CB. No degraders were detected in the Madera soil with 4-CB even though the 4-CB degraded. Nearly all of the 2-CB degraders isolated from the Madera soil were identified as a Burkholderia sp. containing chromosomally encoded degradative genes. In contrast, several different 3- and 4-CB degraders were isolated from the Oversite soil, and their populations changed as CB degradation progressed. Most of these 3-CB degraders were identified as Burkholderia spp. while the majority of 4-CB degraders were identified as Bradyrhizobium spp. Several of the 3-CB degraders contained the degradative genes on large plasmids, and there was variation between the plasmids in different isolates. When a fresh sample of Madera soil was amended with 50, 100, or 200 microg 3-CB g(-1), 3-CB degradation occurred, suggesting that 500 microg 3-CB g(-1) was toxic to the degraders. Also, different 3-CB degraders were isolated from the Madera soil at each of the three lower levels of 3-CB. No 2-CB degradation was detected in the Oversite soil even at lower 2-CB levels. These results indicate that the development of 2-, 3-, and 4-CB degrader populations is site-specific and that 2-, 3-, and 4-CB are degraded by different bacterial populations in pristine soils. These results also imply that the microbial ecology of two soils that develop under similar biotic and abiotic environments can be quite different.


Production of high docosahexaenoic acid by Schizochytrium sp. using low-cost raw materials from food industry.
The low-cost substrates from food industry, including maize starch hydrolysate and soybean meal hydrolysate, were used to produce docosahexaenoic acid (DHA) by Schizochytrium limacinum OUC88. Glucose derived from maize starch hydrolysate was used as the carbon source and soybean meal hydrolysate as the nitrogen sources. In 10L bioreactor fermentation, by using the soybean meal hydrolysate as the main nitrogen source, the biomass of Schizochytrium limacinum OUC88 reached 85.27 g L(-1), and the yields of DHA was 20.7g L(-1). As a comparison, when yeast extract was used as the main nitrogen source, the yields of biomass and DHA were 68.93 g L(-1) and 13.3 g L(-1), respectively. From the results of this study, these hydrolysates can provide all the nutrients required for high-density cultivation of S. limacinum OUC88 and DHA production, that will improve the economical and competitive efficiency of commercial DHA production.


Mental health service delivery in long-term care homes.
The prevalence of mental disorders in long-term care (LTC) homes is high, but quality and availability of mental health services to assess and help in management of cases have been criticized. Literature concerning mental health problems in LTC homes was reviewed, especially regarding models of mental health service delivery and factors that affect development, persistence and reduction of symptoms and distress. The advantages of consultation-liaison arrangements and of telepsychiatry were noted. Discussions led to development of recommendations aimed at improving mental health expertise and provision of assessment and intervention services in LTC homes in diverse countries. Prompt recognition of mental health problems among residents is required, with availability of a team working within the facility to deal with these problems. Commonly such multidisciplinary teams are formed by facility staff linking with visiting mental health professionals or services. Quality of care is also affected by the organization, attitudes and education within LTC facilities. Provision of optimal mental health care in LTC settings is dependent on adequate funding, availability of expertise and education, positive and caring attitudes, recognition of needs, and supportive teamwork. The latter should include cooperative links between well-resourced and under-resourced regions.


Rapid Tuberculosis Diagnosis Using Reporter Enzyme Fluorescence.
Tuberculosis is the most frequent cause of death in humans from a single infectious agent. Due to low numbers of bacteria present in sputum during early infection, diagnosis does not usually occur until >3 to 4 months after symptoms develop. We created a new more sensitive diagnostic that can be carried out in 10 min with no processing or technical expertise. This assay utilizes the Mycobacterium tuberculosis-specific biomarker BlaC in reporter enzyme fluorescence (REF) that has been optimized for clinical samples, designated REFtb, along with a more specific fluorogenic substrate, CDG-3. We report the first evaluation of clinical specimens with REFtb assays in comparison to the gold standards for tuberculosis diagnosis, culture and smear microscopy. REFtb assays allowed diagnosis of 160 patients from 16 different countries with a sensitivity of 89% for smear-positive, culture-positive samples and 88% for smear-negative, culture-positive samples with a specificity of 82%. The negative predictive value of REFtb for tuberculosis infection is 93%, and the positive predictive value is 79%. Overall, these data point toward the need for larger accuracy studies by third parties using a commercially available REFtb kit to determine whether incorporation of REFtb into the clinical toolbox for suspected tuberculosis patients would improve case identification. If results similar to our own can be obtained by all diagnostic laboratories, REFtb would allow proper treatment of more than 85% of patients that would be missed during their initial visit to a clinic using current diagnostic strategies, reducing the potential for further spread of disease.


Molecular and clinical characterization of human respiratory syncytial virus in South Korea between 2009 and 2014.
Respiratory syncytial virus (RSV) can cause serious respiratory infections, second only to influenza virus. In order to know RSV's genetic changes we examined 4028 respiratory specimens from local hospital outpatients in Gyeonggi Province, South Korea over six consecutive years by real-time one-step RT-PCR; 183 patients were positive for RSV infection. To investigate the specific distribution of RSV genotypes, we performed partial sequencing of the glycoprotein gene. Of the 131 RSV-A specimens sequenced, 61 (43·3%) belonged to the ON1 genotype, 66 (46·8%) were NA1 genotype, 3 (2·1%) were GA5 genotype, and 1 (0·7%) belonged to the GA1 genotype. Of the 31 RSV-B specimens sequenced, 29 were BA9 genotype (87·9%) and 2 were BA10 genotype (6·1%). The most common clinical symptoms were fever, cough, nasal discharge, and phlegm; multiple logistic regression analysis showed that RSV-positive infection on pediatric patients was strongly associated with cough (OR = 2·8, 95% CI 1·6-5·1) and wheezing (OR = 2·8, 95% CI 1·7-4·4). The ON1 genotype was significantly associated with phlegm (OR = 11·8, 95% CI 3·8-46·7), while the NA1 genotype was associated with the pediatric patients' gender (males, OR = 2·4, 95% CI 1·1-5·4) and presence of chills (OR = 5·1, 95% CI 1·1-27·2). RSV subgroup B was showed association with nasal obstruction (OR = 4·6, 95% CI 1·2-20·0). The majority of respiratory virus coinfections with RSV were human rhinovirus (47·2%). This study contributes to our understanding of the molecular epidemiological characteristics of RSV, which promotes the potential for improving RSV vaccines.


Choledochocele--a rare cause of necrotising pancreatitis in childhood.
Recurring complaints of unknown origin in the upper abdomen during childhood are not frequent. Choledochoceles, or type III choledochal cysts, are rare congenital abnormalities of unclear aetiology. They are rarely considered in the differential diagnosis of upper abdominal symptoms in childhood. Only 130 cases of choledochoceles have been reported in world literature to date. Only 20% of these patients were children or adolescents. The symptoms do not specifically suggest a choledochocele, and are usually attributed to other disorders of the upper intestinal tract, frequently resulting in a delayed diagnosis. We present the case of a 10-year old girl in whom a congenital choledochocele was diagnosed by gastro-intestinal studies and endoscopic retrograde cholangiopancreatography (ERCP) following a 2-years history of recurrent pancreatitis. Various types of choledochoceles are presented in the literature, classified according to morphology and histology. Most authors consider them to be a form of choledochal cyst. Their embryonic development is related to that of congenital duodenal diverticula. Although congenital intraluminal duodenal dilatations are of known oncogenic significance, only two cases of adenocarcinoma arising from a choledochocele have been described to date. Established treatment of large choledochoceles in childhood is transduodenal marsupialization.


A reverse dot-blot method for rapid detection of non-deletion alpha thalassaemia.
A reverse dot blot method based on membrane-bound allele-specific oligonucleotides as hybridization targets for amplified alpha-gene fragments has been developed for the rapid detection of four non-deletion alpha thalassaemia defects found in the Chinese. Since these non-deletion defects account for 22 8% of haemoglobin H disease, a sensitive, specific and rapid screening method should be of value.


Effects of Temperature and Wetness Duration on Infection by Coniella diplodiella, the Fungus Causing White Rot of Grape Berries.
Grapevine white rot, caused by Coniella diplodiella, can severely damage berries during ripening. The effects of temperature and wetness duration on the infection severity of C. diplodiella were investigated by artificially inoculating grape berries through via infection pathways (uninjured and injured berries, and through pedicels). The effect of temperature on incubation was also studied, as was that of inoculum dose. Injured berries were affected sooner than uninjured berries, even though 100% of the berries inoculated with C. diplodiella conidia became rotted whether injured or not; infection through pedicels was less severe. On injured berries, the disease increased as the inoculum dose increased. Irrespective of the infection pathway, 1 h of wetness was sufficient to cause infection at any temperature tested (10-35 °C); with the optimal temperature being 23.8 °C. The length of incubation was shorter for injured berries than for uninjured ones, and was shorter at 25-35 °C than at lower temperatures; the shortest incubation period was 14 h for injured berries at 30 °C. Mathematical equations were developed that fit the data, with R2 = 0.93 for infection through any infection pathway, and R2 = 0.98 for incubation on injured berries, which could be used to predict infection period and, therefore, to schedule fungicide applications.


Mycobacterium ulcerans-Bordetella trematum chronic tropical cutaneous ulcer: A four-case series, Côte d'Ivoire.
Chronic tropical cutaneous ulcers remain a neglected medical condition in West Africa, particularly Buruli ulcer, which is caused by mycolactone cytotoxin-secreting Mycobacterium ulcerans (M. ulcerans). Medical management of this highly debilitating and necrotising skin infection may be modified by colonisation and co-infection of the ulcer by opportunistic and pathogenic microorganisms, which considerably delays and increases the cost of treatment. We diagnosed chronic tropical cutaneous ulcers in nine patients in Côte d'Ivoire using M. ulcerans-specific PCRs and culturomics. This revealed M. ulcerans in 7/9 ulcer swabs and 5/9 control swabs as well as an additional 122 bacterial species, 32 of which were specific to ulcers, 61 specifics to the controls, and 29 which were shared, adding 40 bacterial species to those previously reported. Whole genome sequencing of four Bordetella trematum (B. trematum) isolates in four Buruli ulcer swabs and no controls indicated cytolethal distending toxins, as confirmed by cytotoxic assay. In four cases of Buruli ulcer in Côte d'Ivoire, B. trematum was a co-pathogen which was resistant to rifampicin and clarithromycin, unmatching M. ulcerans antibiotic susceptibility profile and counteracting the current treatment of Buruli ulcer in West Africa and Australia. Thus, we report here chronic mixed M. ulcerans-B. trematum chronic tropical ulcer as a specific form of Buruli ulcer in West Africa.


An Aggressive Form of Langerhan Cell Histiocytosis in an Adult: Therapeutic Challenges.
Langerhans cell histiocytosis (LCH) is rare in adults. Regular follow-up is mandatory due to reoccurrence. A 35-year-old male with an incidental left iliac bone lesion was diagnosed with LCH. He later became symptomatic with hip pain and spread of the disease. Despite excision of the symptomatic iliac lesion, he had progression while on cytarabine and nivolumab, evidenced by increased bone pain and involvement of other bones on imaging. He underwent excision of the jaw lesion followed by vinblastine; he was pain free and had stable disease on PET imaging after 3 months. LCH is an uncommon neoplasia. Treatment is reserved for symptomatic patients while asymptomatic patients are observed. Follow-up is imperative due to the risk of reoccurrence. Despite surgical treatment together with one of the front-line agents for refractory disease, in this case cytarabine, he still had progression of the disease. Furthermore, the trial of nivolumab was of no benefit. This case highlights good response to vinblastine which is previously reported to have good success. No trials are published, and the optimal strategy has yet to be defined. LCH with multiple bony involvement can be aggressive and therapeutically challenging.


Risk factors for loco-regional recurrence after radical cystectomy of muscle-invasive bladder cancer: A systematic-review and framework for adjuvant radiotherapy.
Radical cystectomy (RC) associated with pelvic lymph node dissection (PLND) is the most common local therapy in the management of non-metastatic muscle invasive bladder cancer (MIBC). Loco-regional recurrence (LRR), however, remains a common and important therapeutic challenge associated with poor oncologic outcomes. We aimed to systematically review evidence regarding factors associated with LRR and to propose a framework for adjuvant radiotherapy (RT) in patients with MIBC. We performed this systematic review in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. We searched the PubMed database for articles related to MIBC and associated treatments, published between January 1980 and June 2015. Articles identified by searching references from candidate articles were also included. We retrieved 1383 publications from PubMed and 34 from other sources. After an initial screening, a review of titles and abstracts, and a final comprehensive full text analysis of papers assessed for eligibility, a final consensus on 32 studies was obtained. LRR is associated with specific patient-, tumor-, center- or treatment-related variables. LRR varies widely, occurring in as many as 43% of the cases and is strongly related to survival outcomes. While perioperative treatment does not impact on LRR, pathological factors such as pT, pN, positive margins status, extent of PLND, number of lymph nodes removed and/or invaded are correlated with LRR. Patients with pT3-T4a and/or positive lymph-nodes and/or limited pelvic lymph-node dissection and/or positive surgical margins have been distributed in LRR risk groups with accuracy. LRR patterns are well-known and for selected patients, adjuvant treatments could target this event. Intrinsic tumor subtype may guide future criteria to define a personalized treatment strategy. Prospective trials evaluating safety and efficacy of adjuvant RT are ongoing in several countries.


DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 4-aminobiphenyl are infrequently detected in human mammary tissue by liquid chromatography/tandem mass spectrometry.
Some epidemiological investigations have revealed that frequent consumption of well-done cooked meats and tobacco smoking are risk factors for breast cancer in women. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic aromatic amine that is formed in well-done cooked meat, and 4-aminobiphenyl (4-ABP) is an aromatic amine that arises in tobacco smoke and occurs as a contaminant in the atmosphere. Both compounds are rodent mammary carcinogens, and putative DNA adducts of PhIP and 4-ABP have been frequently detected, by immunohistochemistry (IHC) or (32)P-post-labeling methods, in mammary tissue of USA women. Because of these findings, PhIP and 4-ABP have been implicated as causal agents of human breast cancer. However, the biomarker data are controversial: both IHC and (32)P-post-labeling are non-selective screening methods and fail to provide confirmatory spectral data. Consequently, the identities of the lesions are equivocal. We employed a specific and sensitive liquid chromatography/mass spectrometry (MS) method, to screen tumor-adjacent normal mammary tissue for DNA adducts of PhIP and 4-ABP. Only 1 of 70 biopsy samples obtained from Minneapolis, Minnesota breast cancer patients contained a PhIP-DNA adduct. The level was three adducts per 10(9) nucleotides, a level that is 100-fold lower than the mean level of PhIP adducts reported by IHC or (32)P-post-labeling methods. The occurrence of 4-ABP-DNA adducts was nil in those same breast tissues. Our findings, derived from a specific mass spectrometry method, signify that PhIP and 4-ABP are not major DNA-damaging agents in mammary tissue of USA women and raise questions about the roles of these chemicals in breast cancer.