Predicting taxonomic and functional structure of microbial communities in acid mine drainage.
Predicting the dynamics of community composition and functional attributes responding to environmental changes is an essential goal in community ecology but remains a major challenge, particularly in microbial ecology. Here, by targeting a model system with low species richness, we explore the spatial distribution of taxonomic and functional structure of 40 acid mine drainage (AMD) microbial communities across Southeast China profiled by 16S ribosomal RNA pyrosequencing and a comprehensive microarray (GeoChip). Similar environmentally dependent patterns of dominant microbial lineages and key functional genes were observed regardless of the large-scale geographical isolation. Functional and phylogenetic β-diversities were significantly correlated, whereas functional metabolic potentials were strongly influenced by environmental conditions and community taxonomic structure. Using advanced modeling approaches based on artificial neural networks, we successfully predicted the taxonomic and functional dynamics with significantly higher prediction accuracies of metabolic potentials (average Bray-Curtis similarity 87.8) as compared with relative microbial abundances (similarity 66.8), implying that natural AMD microbial assemblages may be better predicted at the functional genes level rather than at taxonomic level. Furthermore, relative metabolic potentials of genes involved in many key ecological functions (for example, nitrogen and phosphate utilization, metals resistance and stress response) were extrapolated to increase under more acidic and metal-rich conditions, indicating a critical strategy of stress adaptation in these extraordinary communities. Collectively, our findings indicate that natural selection rather than geographic distance has a more crucial role in shaping the taxonomic and functional patterns of AMD microbial community that readily predicted by modeling methods and suggest that the model-based approach is essential to better understand natural acidophilic microbial communities.


Structural characterization of a broccoli polysaccharide and evaluation of anti-cancer cell proliferation effects.
Broccoli is a widely consumed vegetable with abundant amount of nutrients, which bring numerous beneficial effects on human health. The structural information of water-soluble polysaccharides in broccoli was eludicated for the first time in this work. A purified polysaccharide fraction (BPCa) was obtained by column chromatography. It comprised of arabinose (Ara), galactose (Gal), rhamnose (Rha) with a molar ratio of 5.3:0.8:1.0. Nuclear magnetic resonnance spectra data revealed that α-L-1,5-Araf and α-L-1,3,5-Araf are present in the backbone, while α-L-Araf terminal was attended in side chain. α-L-1,2-Rhap was found to be linked to α-L-1,5-Araf in heteronuclear multiple bond correlation spectra. The presences of β-D-1,4-Galp and α-D-1,4-GalpA were also detected. Furthermore, BPCa showed significant anti-cancer cell proliferation activities against HepG2, Siha and MDA-MB-231 carcinoma cell lines. The results indicated that BPCa had a good potential to be applied as functional food additives.


Segmental obstructing acute jejunitis in a child.
Acute localized enteritis is a disease of the terminal ileum in adults and children. We have observed acute enteritis confined to the jejunum in a 3 1/2 year-old girl presenting with partial upper intestinal obstruction. Surgical biopsy of the involved region of jejunum revealed acute inflammatory changes in the mucosa and severe edema of the submucosa. Resection of the edematous segment was followed by prompt and apparently permanent recovery.


[Clinical pharmacokinetics of anti-infective drugs in extracorporeal membrane oxygenation].
Extracorporeal membrane oxygenation (ECMO) is becoming more and more clinically important. The extracorporeal circuit for membrane oxygenation consists of a pump, a membrane oxygenator and large volume tubing. The ECMO device forms an additional compartment, which can absorb drugs with high lipophilia and protein binding. Thus, ECMO affects the volume of distribution and the clearance. As a consequence, the pharmacokinetic-pharmacodynamic (pk-pd) target parameters cannot be achieved. The selection of an appropriate substance and the mode of application, combined with therapeutic drug monitoring (TDM), can significantly improve the therapeutic outcome of critically ill patients.


Assessment of fed-batch, semicontinuous, and continuous epothilone D production processes.
Epothilone D is a member of a class of potent antineoplastic natural products produced by myxobacteria. Previously, we have described a fed-batch epothilone D production process in which an adsorber resin is incorporated into the bioreactor setup to capture and stabilize the product in situ, preventing its degradation within the bioreactor. The capture of epothilone D by these relatively large resin beads enables the development of continuous and semicontinuous culturing systems incorporating bead retention mechanisms to completely retain the product within the bioreactor, increasing the epothilone D product titer by almost 3-fold in both cases over a baseline fed-batch system. These product retention strategies, described here for production of the epothilones, are generally applicable to any system using adsorber resins as a method to capture product during a microbial cultivation.


Assessment of diagnostic accuracy and effectiveness of trans-abdominal real-time ultrasound imaging for pregnancy diagnosis in breeding sows under intensive management.
Early and accurate determination of pregnancy is critical to optimum reproductive performance in pigs and enables farmers to early rebreed or cull non-pregnant animals. Most of the conventional diagnostic methods are unsuitable for systematic application under practical conditions. The advent of real-time ultrasonography has made it possible to establish relatively more reliable pregnancy diagnosis. The present study was carried out to evaluate the diagnostic accuracy and effectiveness of trans-abdominal real-time ultrasound (RTU) imaging vis-à-vis pregnancy status in sows reared under intensive management. Trans-abdominal ultrasonographic examinations were performed using a mechanical sector array transducer and portable ultrasound system in crossbred sows from 20 days post-insemination for up to next 40 days. Animals were followed up for subsequent reproductive performance with farrowing data used as the definitive test for deriving predictive values. Accuracy for diagnosis was determined by diagnostic accuracy measures like sensitivity, specificity, predictive values, and likelihood ratios. Before 30 days of breeding, RTU imaging had 84.21% sensitivity and 75% specificity. Relatively higher false diagnosis rates were obtained in animals checked at or before 55 days after AI than in animals checked after 55 days (21.73% versus 9.09%). Negative pregnancy rate was low with 29.16% (7/24) false positives. Overall sensitivity and specificity, using farrowing history as the gold standard, were 94.74% and 70.83% respectively. The sensitivity of testing tended to be slightly lower in sows with litter size of less than 8 total born piglets, compared to sows with 8 or more piglets. Overall positive likelihood ratio was 3.25 while negative likelihood ratio was 0.07. The results indicate that pregnancy in swine herds can be reliably detected earlier in gestation by 30 days post-insemination using trans-abdominal RTU imaging. This non-invasive technique with portable imaging system can be used as an integral part of reproductive monitoring and sound management practices for profitable swine production systems.


In vitro effects of reactive O2 species on the beta-receptor-adenylyl cyclase system.
The irreversible loss of activity of the sarcolemma-localized beta-receptor-adenylyl cyclase system (beta-RAS) in myocardial ischemia is a well documented phenomenon. Alterations in the sarcolemma (SL) induced by reactive O2 species could be responsible for this loss. Therefore the influence of oxidation of SH-groups and lipid peroxidation induced by Fe2+/Vit. C on the beta-RAS activity was studied. During incubation of SL with Fe2+/Vit. C a transient enhancement followed by a continuous loss of the beta-RAS activity (isoprenaline-, NaF-, Gpp(NH)p-, forskolin-stimulated and basal activity) was observed. In contrast there occurred a continuous loss of SH-groups and lipid peroxidation, beginning immediately after the start of incubation. Loss of SH-groups and lipid peroxidation as well as changes in the beta-RAS did not take place in the presence of the antioxidant t-Butyl-4-hydroxyanisole (BHA) or the Fe(2+)-chelator EGTA. In view of the known ischemia-induced formation of reactive O2 species our results show that these powerful oxidants could contribute to the modulation of the beta-RAS during myocardial ischemia.


The use of lubrication in flexible fibreoptic nasendoscopy: a randomized controlled trial.
To determine how lubrication of the endoscope prior to flexible fibreoptic nasendoscopy affects levels of patient discomfort and pain during endoscopy. To assess the extent to which lubrication affects the ease of nasendoscopy and the quality of the image obtained. Single blind, randomized controlled trial. Outpatient clinic of the Department of Otolaryngology at a secondary level referral centre. A total of 150 participants selected sequentially from patients requiring a nasendoscopy where the endoscope would be passed far enough to view the larynx. Patients requiring topical anaesthetic were excluded. All participants who were entered in the study completed the study. Endoscopy was performed by all grades of medical staff. Levels of discomfort and pain experienced by the participants were assessed by a visual analogue scale (VAS). Difficulty of passing the scope was indicated by the endoscopist using a VAS, as was the quality of image obtained. There was no significant difference between mean scores for pain or discomfort of the lubricated and unlubricated groups (P = 0.46 and P = 0.82 respectively). Scores for difficulty of passing the scope were significantly lower in the lubricant group (P = 0.003) but loss of image was significantly greater (P = 0.008). Lubrication of the endoscope prior to nasendoscopy does not reduce levels of discomfort or pain for the patient, but increases ease in insertion for the operator. However, this may be at the expense of reduced image quality.


Video-Based Education in Lung Cancer Screening.
Lung cancer (LC) is the leading cause of cancer mortality in the USA; the American Cancer Society (ACS) estimates upwards of 220,000 new cases will be diagnosed this year. Recently, the Center for Medicare/Medicaid Services (CMS) agreed to cover LC screening with low-dose computed tomography (CT) for patients; however, CMS requires prior documentation of a shared decision-making (SDM) visit between the patient and the referring clinician to inform them about risks of screening. LC screening programs have begun to use YouTube for patient recruitment, education, and marketing of screening. The objective of this study is to shed light on the role of YouTube in lung cancer screening in terms of guidelines, screening options, target population, steps after screening, and risks and benefits of screening. We searched YouTube.com ™ to identify videos dealing with lung screening using the keywords: lung cancer screening. Videos without sound, uploaded before 2009, longer than 20 min, duplicate videos, and videos in a language other than English were excluded. This method yielded 123 videos that fit criteria. Videos were coded for inclusion of LC screening process, risks and benefits of screening, screening guidelines, risk factors for LC, and treatment options after LC diagnosis. One hundred twenty-three videos had a cumulative 261,261 views across all videos. A total of 38.7% of the videos included no mention of United States Preventive Services Task Force (USPSTF) or CMS guidelines for LC screening. Only 30% included any mention of the risks associated with screening: 14% mentioned false positives, 12% radiation, and 4% anxiety associated with screening. Ninety-two percent of all videos sampled were intended for patients, and the majority of videos were created by medical institutions (66%) and news channels (17%). Lung cancer screening videos on YouTube's platform have garnered a substantial amount of views. While all videos sampled highlighted the benefits of LC screening, the majority fail to discuss the risks associated with the screening process. Most videos were produced for marketing purposes rather than educational and therefore should not be used as a substitute for SDM visits.


Effect of pimozide on the cytology of the eel pituitary. II. MSH-secreting cells.
Pimozide, a specific blocker of dopaminergic receptors, was injected for 4 or 9 days in freshwater (FW) eels or eels acclimated to sea water (SW) for 10 or 30 days. The daily dose was 100 or 200 microgram/100 g. Melanophore index values increase in FW and in 1 month-SW injected eels. All the treated fish react by a total or subtotal degranulation of the lead-hematoxylin positive cells in the pars intermedia. These cells were previously identified as alpha-MSH-secreting cells. The MSH cell nuclear area is significantly increased, nucleoli are larger and the endoplasmic reticulum more developed. The intensity of the response is similar in FW and SW eels, but it does not increase with the higher dose. The rapid release of pituitary alpha-MSH is also visualized by immunofluorescence and immunoenzymologic techniques. No effect on the second cell type of the pars intermedia (PAS-positive cell) is detected. The amount of neurosecretory material is often reduced in the neurohypophysis. These results suggest that the hypothalamic inhibitory control of MSH release and synthesis is mediated through dopaminergic fibers in the eel, but other factors cannot be ignored in this regulation.


High-intensity interval training in the therapy and aftercare of cancer patients: a systematic review with meta-analysis.
This review and meta-analysis aimed to evaluate the effects of high-intensity interval training (HIIT) compared to usual care (UC) or moderate-intensity training (MIE) on physical fitness and health-related outcomes in cancer patients across all stages of therapy and aftercare. Databases were systematically searched in accordance with the PRISMA guidelines until October 4th, 2018. Eligibility criteria included adult patients of various cancer types, performing HIIT vs. UC or MIE. Outcomes of interest included physical fitness (cardiorespiratory fitness [VO2peak] and functional capacity) and health-related outcomes (body composition, quality of life, cancer-related fatigue, and blood-borne biomarkers). Mean differences (MD) were calculated and pooled to generate effect sizes for VO2peak. The search identified 1453 studies, out of which 12 articles were included. The average duration of interventions was 6.7 ± 3.0 weeks, with 2.8 ± 0.5 sessions per week. The meta-analysis for VO2peak showed superiority of HIIT compared to UC (MD 3.73; 95% CI 2.07, 5.39; p < 0.001) but not MIE (MD 1.36; 95% CI - 1.62, 4.35; p = 0.370). Similarly, no superior effects of HIIT compared to MIE were found for quality of life or changes in lean mass, while evidence was provided for a larger reduction in fat mass. This systematic review showed that short-term HIIT induces similar positive effects on physical fitness and health-related outcomes as MIE but seems to be superior compared to UC. Thus, HIIT might be a time-efficient intervention for cancer patients across all stages of therapy and aftercare. High-intensity interval training (HIIT) is superior compared to usucal care in improving physical fitness and health-related outcomes in cancer patients across all stages of therapy and aftercare. Currently, there is no evidence for the benefits of HIIT compared to aerobic training of moderate intensity (MIE) for changes in cardiorespiratory fitness, lean mass and patient-reported outcomes. Reductions in fat mass may be more pronounced in HIIT compared to MIE when training is performed in aftercare.


Parent recruitment and retention in a universal prevention program for child behavior and emotional problems: barriers to research and program participation.
Despite the potential of parent training as a prevention and behavioral family intervention strategy, there are a number of important issues related to implementation (e.g., recruitment and retention of families). This paper presents recruitment and retention data from families enrolling in a randomized controlled universal prevention trial for child behavior problems conducted in Germany. The recruitment rate averaged 31% (general project participation), with families of lower socioeconomic status (SES) participating at a lower rate. Project-declining families most often reported intrusion of privacy as their primary concern. In contrast, once parents were enrolled in the project, participation among those randomized to the parent training group averaged 77% (program/intervention participation); non-participation was mostly due to logistical issues. Parents accepting the offer of parent training were more likely to report child behavior problems than did declining parents. Although parents from more disadvantaged areas had a lower overall level of participation in the project once recruited, parents with children having higher levels of behavior problems indeed were more likely to participate in the intervention. Different recruitment methods may be required to engage high-risk families from socioeconomically disadvantaged areas to further improve community-level impact on child mental health.


Psychological Trauma and the Trauma Surgeon.
Research has demonstrated that first responders may develop psychological trauma/ posttraumatic stress disorder (PTSD) in the performance of their duties. Often overlooked in these studies of police, firefighters, and paramedics is an additional group of providers in this health care delivery system: the trauma surgeons, who receive the victims transported by the first responders. Although limited in scope, the research literature does identify the presence of PTSD in trauma surgeons. These studies have repeatedly cited the need for further information about psychological trauma for trauma surgeons. This paper addresses that need with a brief overview of psychological trauma, where surgeons may encounter victims, and how to cope with its aftermath.


Effect of ramp slope on intensity thresholds based on correlation properties of heart rate variability during cycling.
An index of heart rate variability (HRV), detrended fluctuation analysis (DFA a1) has gathered interest as a surrogate marker of exercise intensity boundaries. The aim of this report was to examine heart rate variability threshold (HRVT) behavior across different ramp incremental (RI) slopes. Seventeen participants completed a series of three RI (15, 30, and 45 W · min-1 slopes) with monitoring of gas exchange parameters, heart rate (HR) and HRV. HRVT1 was defined as the V̇O2 or HR at which DFA a1 reached 0.75 and the HRVT2 at which these values reached 0.5. HRVTs were compared by Pearson's r, Bland-Altman analysis, ICC3,1 , ANOVA, and paired t-testing. An excellent degree of reliability was seen across all three ramps, with an ICC3,1 of 0.93 and 0.88 for the HRVT1 V̇O2 and HR, respectively, and 0.90 and 0.92 for the HRVT2 V̇O2 and HR, respectively. Correlations between HRVT1/2 of the individual ramps were high with r values 0.84-0.95 for both HR and V̇O2 . Bland-Altman differences ranged between -1.4 and 1.2 mL · kg-1 · min-1 and -2 and +2 bpm. Paired t-testing showed no mean differences between any HRVT1/2 ramp comparisons. Cycling ramp slope does not appear to affect either HRVT1 or HRVT2 in terms of HR or V̇O2 .


Brave Spaces in Discourse About Pregnant Persons', Women's, and Children's Health.
Discourse around implicit bias, intersectionality, and inequity in health care requires having conversations that may be uncomfortable. Within this space of discomfort, new understandings can occur. Reflecting on our own biases and assumptions is a moral obligation and a necessity to generate change. Health care settings may be a fitting forum to create and use brave spaces to have these conversations.


Different patterns of extracellular matrix protein expression in the convexity and the concavity of the dilated aorta with bicuspid aortic valve: preliminary results.
This study aimed to assess extracellular matrix protein expression patterns at the convexity (right anterolateral wall) and the concavity of the dilated ascending aorta in patients with bicuspid aortic valve disease. Aortic wall specimens were retrieved from the convexity and the concavity in 27 bicuspid aortic valve patients (12 with stenosis and 15 with regurgitation) and 6 heart donors (controls). Morphometry, immunohistochemistry, Western blot, and polymerase chain reaction were performed, focusing on matrix proteins involved in vascular remodeling. Type I and III collagens were significantly decreased in bicuspid-associated dilated aortas versus controls (P < .001), particularly at the convexity (P < .05 vs concavity). Expression of messenger RNA for collagens was lower than normal only in the regurgitant subgroup. At immunohistochemistry, proteins whose overproduction has been demonstrated in response to abnormal wall stress, such as tenascin and fibronectin, were more expressed in the convexity than in the concavity, especially in the stenosis subgroup. Tenascin, which is produced by smooth muscle cells in the synthetic phenotype, was nearly undetectable in controls. Fewer smooth muscle cells (stenosis, P = .017; regurgitation, P = .008) and more severe elastic fiber fragmentation (P = .029 and P < .001) were observed in the convexity versus the concavity. In bicuspid-associated aortic dilations, an asymmetric pattern of matrix protein expression was found that was consistent with the asymmetry in wall-stress distribution reported previously. Differences exist between patients with stenosis and those with regurgitation in terms of protein expression and content in the aortic wall. Further studies could clarify the relations between these findings and the pathogenesis of aortic dilatation in bicuspid aortic valve patients.


[Fibrin-fragment D-protector equilibrium system. Quantitative determination of protector activity].
Equilibrium distribution of fibrin between clot fibres and liquid phase was studied as affected by the protector fraction of fibrinogen tryptic hydrolyzate in the presence of fragment D. It was found that in such a system the protector counteracting the solubilizing fibrin-effect of fragment D evokes an increase in the content of the fibrin solid phase. The effect is suggested to be used as a quantitative index of the protector activity. The presence of equilibrium between the protector--fragment D complex and products of its dissociation is shown. This equilibrium is a part of a more complex fibrin--fragment D-protector equilibrium system.


Randomized, placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B.
Tenofovir disoproxil fumarate (DF) is highly effective for the suppression of hepatitis B virus (HBV) in chronically infected adults. This study evaluated the safety and efficacy of tenofovir DF in adolescents with chronic hepatitis B (CHB). In this double-blind, placebo-controlled trial, adolescents 12 to <18 years of age with CHB were randomized to tenofovir DF 300 mg (n = 52) or placebo (n = 54) once daily for 72 weeks. The primary endpoint was virologic response (HBV DNA <400 copies/mL) at week 72. One hundred six patients were enrolled; 101 patients completed 72 weeks of treatment. At baseline, 91% of patients were hepatitis B e antigen-positive and 85% had prior exposure to HBV therapy. A virologic response was observed in 89% (46/52) of patients who received tenofovir DF and 0% (0/54) of patients who received placebo (P < 0.001). Treatment response was not affected by prior HBV treatment. Furthermore, no resistance to tenofovir DF developed through week 72. Among patients with an alanine aminotransferase (ALT) level greater than the upper limit of normal at baseline, normalization of ALT occurred in 74% of patients receiving tenofovir DF and 31% of patients receiving placebo (P < 0.001). The rate of grade 3/4 adverse events was higher among patients treated with placebo (24%) than patients treated with tenofovir DF (10%). No patients met the safety endpoint of a 6% decrease in spine bone mineral density at week 72. Tenofovir DF therapy in HBV-infected adolescents was well tolerated and highly effective at suppressing HBV DNA and normalizing ALT values in both treatment-naïve adolescents and those with prior exposure to HBV therapy.


Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis.
In the adult mammalian brain, neural stem cells (NSCs) located in highly restricted niches sustain the generation of new neurons that integrate into existing circuits. A reduction in adult neurogenesis is linked to ageing and neurodegeneration, whereas dysregulation of proliferation and survival of NSCs have been hypothesized to be at the origin of glioma. Thus, unravelling the molecular underpinnings of the regulated activation that NSCs must undergo to proliferate and generate new progeny is of considerable relevance. Current research has identified cues promoting or restraining NSCs activation. Yet, whether NSCs depend on external signals to survive or if intrinsic factors establish a threshold for sustaining their viability remains elusive, even if this knowledge could involve potential for devising novel therapeutic strategies. Kidins220 (Kinase D-interacting substrate of 220 kDa) is an essential effector of crucial pathways for neuronal survival and differentiation. It is dramatically altered in cancer and in neurological and neurodegenerative disorders, emerging as a regulatory molecule with important functions in human disease. Herein, we discover severe neurogenic deficits and hippocampal-based spatial memory defects accompanied by increased neuroblast death and high loss of newly formed neurons in Kidins220 deficient mice. Mechanistically, we demonstrate that Kidins220-dependent activation of AKT in response to EGF restraints GSK3 activity preventing NSCs apoptosis. We also show that NSCs with Kidins220 can survive with lower concentrations of EGF than the ones lacking this molecule. Hence, Kidins220 levels set a molecular threshold for survival in response to mitogens, allowing adult NSCs growth and expansion. Our study identifies Kidins220 as a key player for sensing the availability of growth factors to sustain adult neurogenesis, uncovering a molecular link that may help paving the way towards neurorepair.


Management of renal cell carcinoma with solitary metastasis.
Distant metastasis are common in Renal cell carcinoma (RCC) nearly one forth of the patients have metastasis at presentation while another 50% develop metastasis during the follow-up. A small percentage of these are solitary metastasis. We describe survival after surgical excision or radiotherapy of solitary metastatic lesion from renal cell carcinoma. Between 1988-2001, 43 patients with solitary metastasis to different sites from renal cell carcinoma underwent either surgical excision or radiotherapy were analyzed. The solitary nature of the lesions was confirmed by investigations. All patients have had radical nephrectomy for the primary lesion. Survival analysis was carried out by Kaplan Meier Method. All solitary metastatic lesions were treated with intent of cure either by excision or radiotherapy. Of these, 13 patients had solitary metastasis at the time of presentation in whom 3-year overall median survival was 26 months. The survival of those who developed solitary metastases during follow-up after nephrectomy for primary was 45 months. The patients with long interval between diagnosis and development of metastasis, early stage and low grade of the primary tumor had better prognosis. Complete resection of either synchronous or metachronous solitary metastases from renal cell carcinoma is justified and can contribute to a long-term survival in this select group of patients.


Socioeconomic disparities and dementia in China.
This study aimed to investigate the associations between individual-level SES, area-level SES, and their interaction with dementia in China. This study used data from the Second China National Sample Survey on Disability and restricted our finalized analysis to 688,507 participants aged 50 years or older. Dementia was ascertained according to the International Statistical Classification of Diseases, Tenth Revision. Multilevel logistic regression models were fitted to examine the associations between individual-level SES, area-level SES, and their interaction with dementia. Participants with higher individual SES were less likely to develop dementia; the risk of dementia decreased by 18% for each standard deviation increase in individual SES (OR=0.82, 95% CI=0.77, 0.88). Advantaged areas were associated with an increased risk of dementia in Chinese adults by 1.52 (95% CI=1.43, 1.62). Analysis of the combination between individual-level SES and area-level SES revealed that as the level of area SES increased, the risk of dementia in lower SES people was significantly higher than in higher SES people (OR=1.09, 95% CI=1.04,1.14). This study found that people with lower SES living in high-SES areas had a higher risk of dementia than people with lower SES living in low-SES areas. Significant socioeconomic differences in the risk of dementia exist in China, and more attention should be given to low-SES populations living in high-SES areas.


News media coverage of extreme risk protection order policies surrounding the Parkland shooting: a mixed-methods analysis.
Following the 2018 mass shooting at Marjory Stoneman Douglas High School in Parkland, Florida, there was a dramatic increase in media coverage of extreme risk protection orders (ERPOs) and in state policy proposals for ERPO laws. This study documents the frequency of news coverage of ERPOs throughout 2018 and examines the narratives used by media outlets to describe this risk-based firearm policy. Using a mixed-method descriptive design, we examine the frequency of national news media coverage of ERPO legislation in 2018, before and after the Parkland shooting, and analyze the content of news articles related to a sample of states that considered ERPO legislation after the shooting. We find a sharp increase in the frequency of articles related to ERPOs following the Parkland shooting and smaller increases in coverage surrounding ERPO policy proposals and other public mass shootings that year. Nearly three-quarters of articles in our content analysis mentioned the Parkland shooting. The news media often mentioned or quoted politicians compared to other stakeholders, infrequently specified uses for ERPOs (e.g., prevention of mass violence, suicide, or other violence), and rarely included evidence on effectiveness of such policies. More than one-quarter of articles mentioned a mass shooting perpetrator by name, and one-third of articles used the term "gun control." This study describes the emerging public discourse, as informed by media messaging and framing, on ERPOs as states continue to debate and implement these risk-based firearm violence prevention policies.


Control methods for Aedes aegypti: Have we lost the battle?
The past twenty years have been a period of remarkable innovation in Aedes vector control, and several methods with varying success rates have been used. Here we discussed the main intervention categories of vector control applied nowadays and their main weaknesses. It is urgent to have more efficient design and management of control programs, and the requirement for studies to evaluate and compare methods must be prioritised. The world must better articulate actions and cooperate with other sectors beyond health; it is necessary to work together with managers and entomologists in action plans and adapt them to the condition of each region.


Sequence based HLA-DRB1, -DQB1 and -DPB1 allele and haplotype frequencies in The Gambia.
Class II HLA loci DRB1, DQB1 and DPB1 were typed for a total of 939 Gambian participants by locus-specific amplicon sequencing. Participants were from multiple regions of The Gambia and drawn from two studies: a family study aiming to identify associations between host genotype and trachomatous scarring (N = 796) and a cohort study aiming to identify correlates of immunity to trachoma (N = 143). All loci deviated from Hardy-Weinberg equilibrium, likely due to the family-based nature of the study: 608 participants had at least one other family member included in the study population. The most common alleles for HLA-DRB1, DQB1 and DPB1 respectively were DRB1*13:04 (18.8 %), DQB1*03:19 (27.9 %) and DPB1*01:01 (25.4 %). Participants belonged to a variety of ethnicities, including the Mandinka, Fula, Wolof and Jola ethnic groups.


Congenital hypoplasia of the thumb with absence of the extrinsic extensors, abductor pollicis longus, and thenar muscles.
An unusual congenital anomaly of the thumb has been seen in 10 hands of eight patients. It consists of skeletal hypoplasia, instability of the metacarpophalangeal joint, absence of the extrinsic extensors and abductor, and adduction contracture of the first web space. Surgical reconstruction consisted of transfer of the extensor indicis proprius, the palmaris longus, and the abductor digiti minimi, as well as ankylosis of the metacarpophalangeal joint and release of the web space contracture. Useful grasp and pinch were provided for all patients. The patients were followed from 2 to 5 years.


Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences.
Histone lysine methylation influences processes such as gene expression and DNA repair. Thirty Jumonji C (JmjC) domain-containing proteins have been identified and phylogenetically clustered into seven subfamilies. Most JmjC domain-containing proteins have been shown to possess histone demethylase activity toward specific histone methylation marks. One of these subfamilies, the KDM5 family, is characterized by five conserved domains and includes four members. Interestingly, de novo loss-of-function and missense variants in KDM5B were identified in patients with intellectual disability (ID) and autism spectrum disorder (ASD) but also in unaffected individuals. Here, we report two novel de novo splice variants in the KDM5B gene in three patients with ID and ASD. The c.808 + 1G > A variant was identified in a boy with mild ID and autism traits and is associated with a significant reduced KDM5B mRNA expression without alteration of its H3K4me3 pattern. In contrast, the c.576 + 2T > C variant was found in twins with global delay in developmental milestones, poor language and ASD. This variant causes the production of an abnormal transcript which may produce an altered protein with the loss of the ARID1B domain with an increase in global gene H3K4me3. Our data reinforces the recent observation that the KDM5B haploinsufficiency is not a mechanism involved in intellectual disability and that KDM5B disorder associated with LOF variants is a recessive disorder. However, some variants may also cause gain of function, and need to be interpreted with caution, and functional studies should be performed to identify the molecular consequences of these different rare variants.


BCRP protein levels do not differ regionally in adult human livers, but decline in the elderly.
The aim of this study was to characterize the ontogeny and variability of the BCRP (ABCG2) transporter in healthy human liver. Levels of BCRP mRNA and protein were determined with q-RT-PCR and western blot in a cohort of 87 human livers aged from 7 days to 87 years. A study of the regional expression of BCRP within adult livers was also performed in a nested cohort of 14 individuals with multiple samples per person collected from pre-selected sites. Levels of BCRP mRNA were not significantly different at any age, but protein levels for BCRP were lower in the elderly compared with adults (p < 0.001) and children (p < 0.05). The intra-liver levels of BCRP protein ranged approximately 6.5-fold and inter-liver BCRP protein varied 8.5-fold in the cohort. No differences in BCRP mRNA or protein were observed with sex or ethnicity, although higher levels of BCRP mRNA were observed in livers from overweight individuals (Body Mass Index ≥ 25-29.9) as compared to underweight or ideal weight individuals. There were no differences in the levels of BCRP mRNA or protein in different regions of the large lobe (n = 3 regions), small lobe (n = 3 regions), directly adjacent to the portal vein or directly adjacent to the common bile duct. This indicates that BCRP researchers can source tissue from all parts of the adult liver without artificial bias in their results. Lower BCRP protein expression in the elderly may be associated with compromised xeno- and endobiotic transport.


Peroxisomal dysfunction is associated with up-regulation of apoptotic cell death via miR-223 induction in knee osteoarthritis patients with type 2 diabetes mellitus.
Recent increasing evidences showing the interconnection between mitochondria and peroxisome in performing metabolic functions imply that peroxisome dysfunction could lead to a wide variety of human diseases including cancer and osteoarthritis (OA) as mitochondria dysfunction. Even though there is a higher incidence and development of OA in diabetes mellitus (DM) patients, there is not much evidential mechanism study in this inter-regulation between OA and OA with DM in a new view of peroxisome. In this study, we analyzed the alteration of peroxisomal gene expression that could responsible for pathological difference between OA chondrocytes and OA/DM chondrocytes. To discriminate responsible genes in the OA/DM pathogenesis, the expressions of three hundred sixty-two genes reported to differentially relate to peroxisome were analyzed with OA chondrocytes in OA cartilage and OA/DM chondrocytes in the cartilage of OA with DM patient. Among them, PEX-16, a component of peroxisome, was significantly down-regulated in OA/DM chondrocytes and this down-regulation of PEX-16 increased the miR-223 induction. Knockdown studies using PEX-16 null cell line and PEX-16 specific siRNA showed the significant increase in apoptotic cell death. Moreover, over-expression of miR-223 stimulates apoptotic cell death in human articular chondrocytes and induced severe cartilage destruction in db/db mice. In conclusion, our study showed the differential peroxisomal gene expression profiles for OA/DM chondrocytes from OA chondrocytes and suggests the possibility that peroxisomal dysfunction in OA/DM could be responsible for early incidence and development of OA in DM patients.


Burns trauma: management and nursing care Chrissie Bosworth Bailliere Tindall 220pp £19.95 1-873853-32-7 1873853327.
The management and nursing care of burn trauma is a specialised area that requires a wealth of knowledge and clinical skills from the members of a large multidisciplinary team.


Assessment of mental wellbeing of undergraduate pharmacy students from 14 countries: The role of gender, lifestyle, health-related, and academic-related factors.
Pharmacy students will assume future roles as frontline healthcare providers. Therefore, evaluating their current state of mental wellbeing and its associated factors is essential for better planning students' support initiatives. This study aimed to assess mental wellbeing and its associated factors among undergraduate pharmacy students from 14 countries during the pandemic. A cross-sectional study was conducted among undergraduate pharmacy students in 14 countries in Asia and the Middle East. The validated Warwick-Edinburgh Mental Wellbeing Scale (the 14-item WEMWBS) was adopted to assess mental wellbeing. Data collection was performed online between February and April 2022. Descriptive and inferential statistics were used as appropriate. A total of 2,665 responses were received, mainly from females (68.7%) with a higher presence of private universities (59.1%). About 34.9% had low mental wellbeing levels, while 57 and 8.1% had medium, and high levels, respectively. Binary logistic regression showed that males (AOR: 1.34; CI 95%: 1.11-1.61; p < 0.01) and students with no chronic illnesses (AOR: 2.01; CI 95%: 1.45-2.80; p < 0.001) were more likely to have higher mental wellbeing. Also, participants who did not engage in any exercise (AOR: 0.71; CI 95%: 0.52-0.98; p = 0.04) and those in public universities (AOR: 0.82; CI 95%: 0.69-0.97; p = 0.02) were less likely to have higher mental wellbeing. Additionally, students who had interest/passion for pharmacy (AOR: 1.69; CI 95%: 1.07-2.68; p = 0.02), and those who known pharmacists inspired (AOR: 1.81; CI 95%: 1.06-3.12; p = 0.03), were more likely to have higher mental wellbeing compared with those who had no specific reason for their choice to study pharmacy. The participants with excellent (AOR: 1.87; CI 95%: 1.29-2.70; p = 0.001) or very good self-reported academic performance (AOR: 1.57; CI 95%: 1.12-2.22; p = 0.01) were more likely to have higher mental wellbeing compared to those with fair academic performance. More than a third of the participants had low mental wellbeing. Various demographic, lifestyle, medical and academic factors appeared to affect students' mental wellbeing. Careful consideration of these factors and their integration into the pharmacy schools' plans for student support services and academic advising would be essential to improve students' mental wellbeing.


Field evaluation of Abbott Real Time HIV-1 Qualitative test for early infant diagnosis using dried blood spots samples in comparison to Roche COBAS Ampliprep/COBAS TaqMan HIV-1 Qual test in Kenya.
Timely diagnosis and treatment of infants infected with HIV are critical for reducing infant mortality. High-throughput automated diagnostic tests like Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 Qual Test (Roche CAPCTM Qual) and the Abbott Real Time HIV-1 Qualitative (Abbott Qualitative) can be used to rapidly expand early infant diagnosis testing services. In this study, the performance characteristics of the Abbott Qualitative were evaluated using two hundred dried blood spots (DBS) samples (100 HIV-1 positive and 100 HIV-1 negative) collected from infants attending the antenatal facilities in Kisumu, Kenya. The Abbott Qualitative results were compared to the diagnostic testing completed using the Roche CAPCTM Qual in Kenya. The sensitivity and specificity of the Abbott Qualitative were 99.0% (95% CI: 95.0-100.0) and 100.0% (95% CI: 96.0-100.0), respectively, and the overall reproducibility was 98.0% (95% CI: 86.0-100.0). The limits of detection for the Abbott Qualitative and Roche CAPCTM Qual were 56.5 and 6.9copies/mL at 95% CIs (p=0.005), respectively. The study findings demonstrate that the Abbott Qualitative test is a practical option for timely diagnosis of HIV in infants.


An Objective and Easy-to-Use Glaucoma Functional Severity Staging System Based on Artificial Intelligence.
The objective of this study was to develop an objective and easy-to-use glaucoma staging system based on visual fields (VFs). A total of 13,231 VFs from 8077 subjects were used to develop models and 8024 VFs from 4445 subjects were used to validate models. We developed an unsupervised machine learning model to identify clusters with similar VF values. We annotated the clusters based on their respective mean deviation (MD). We computed optimal MD thresholds that discriminate clusters with the highest accuracy based on Bayes minimum error principle. We evaluated the accuracy of the staging system and validated findings based on an independent validation dataset. The unsupervised k -means algorithm discovered 4 clusters with 6784, 4034, 1541, and 872 VFs and average MDs of 0.0 dB (±1.4: SD), -4.8 dB (±1.9), -12.2 dB (±2.9), and -23.0 dB (±3.8), respectively. The supervised Bayes minimum error classifier identified optimal MD thresholds of -2.2, -8.0, and -17.3 dB for discriminating normal eyes and eyes at the early, moderate, and advanced stages of glaucoma. The accuracy of the glaucoma staging system was 94%, based on identified MD thresholds with respect to the initial k -means clusters. We discovered that 4 severity levels based on MD thresholds of -2.2, -8.0, and -17.3 dB, provides the optimal number of severity stages based on unsupervised and supervised machine learning. This glaucoma staging system is unbiased, objective, easy-to-use, and consistent, which makes it highly suitable for use in glaucoma research and for day-to-day clinical practice.


A systematic review of anti-cancer roles and mechanisms of kaempferol as a natural compound.
It has been shown in multiple experimental and biological investigations that kaempferol, an edible flavonoid generated from plants, may be used as an anti-cancer drug and has been shown to have anti-cancer properties. Many signaling pathways are altered in cancer cells, resulting in cell growth inhibition and death in various tumor types. Cancer is a multifaceted illness coordinated by multiple external and internal mechanisms. Natural extracts with the fewest side effects have piqued the attention of researchers in recent years, attempting to create cancer medicines based on them. An extensive array of natural product-derived anti-cancer agents have been examined to find a successful method. Numerous fruits and vegetables have high levels of naturally occurring flavonoid kaempferol, and its pharmacological and biological effects have been studied extensively. Certain forms of cancer are sensitive to kaempferol-mediated anti-cancer activity, although complete research is needed. We have endeavored to concentrate our review on controlling carcinogenic pathways by kaempferol in different malignancies. Aside from its extraordinary ability to modify cell processes, we have also discussed how kaempferol has the potential to be an effective therapy for numerous tumors.


Metabolism of esterified cholesterol in the plasma very low density lipoproteins of the rabbit.
The in vivo metabolism of esterified cholesterol and triglyceride in plasma very low density lipoproteins (VLDL) has been studied in postabsorptive rabbits injected with endogenously 3H-labelled preparations of VLDL. The rates at which the injected esterified [3H]cholesterol and [3H]triglyceride were removed from the recipient VLDL fraction were remarkably similar. But, whereas most of the [3H]triglyceride was rapidly lost from the plasma compartment, more than 60% of the esterified [3H]cholesterol removed from VLDL was recovered in the plasma low density lipoprotein (LDL) and high density lipoprotein (HDL) fractions, an observation in direct contrast to previous findings in rats and guinea pigs in which hepatic uptake accounted for the major proportion of esterified cholesterol removed from VLDL. The appearance of VLDL-esterified [3H]cholesterol in rabbit LDL was quite compatible with the well-documented catabolic conversion of VLDL to LDL. The appearance in HDL, on the other hand, could not be so explained and was further investigated in studies performed in vitro. It was found that, concurrent with a net mass transfer of esterified cholesterol from HDL to VLDL, there was a much more rapid transfer of esterified [3H]cholesterol in the reverse direction, implying the existence of a process of molecular exchange of esterified cholesterol between the two fractions, analogous to that recently described between VLDL and LDL.


Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS.
Mutations in the genes encoding pyrin and mevalonate kinase (MVK) cause distinct interleukin-1β (IL-1β)-mediated autoinflammatory diseases: familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS). Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. The binding of 14-3-3 and PKN proteins to FMF-associated mutant pyrin was substantially decreased, and the constitutive IL-1β release from peripheral blood mononuclear cells of patients with FMF or HIDS was attenuated by activation of PKN1 and PKN2. Defects in prenylation, seen in HIDS, led to RhoA inactivation and consequent pyrin inflammasome activation. These data suggest a previously unsuspected fundamental molecular connection between two seemingly distinct autoinflammatory disorders.


Sudden cardiac death in athletes: a guide for emergency physicians.
A conditioned athlete is usually regarded as a member of the healthiest segment of society, and exercise itself is looked upon as a means to improve health. Although extremely uncommon, sudden cardiac death (SCD) in young athletes is a devastating medical event to all involved (patient, family, community, team, and caregivers). Most etiologies of SCD in athletes result in the same final common denominator (cardiac arrest) on presentation to an emergency physician. There are, however, certain historic, physical examination, and electrocardiographic features of many of these disease processes that emergency physicians should have a working knowledge of to try to identify them before they result in SCD. This review examines the clinical presentation, diagnostic techniques, and management options applicable to emergency practitioners.


Tight genetic linkage of prezygotic barrier loci creates a multifunctional speciation island in Petunia.
Most flowering plants depend on animal vectors for pollination and seed dispersal. Differential pollinator preferences lead to premating isolation and thus reduced gene flow between interbreeding plant populations. Sets of floral traits, adapted to attract specific pollinator guilds, are called pollination syndromes. Shifts in pollination syndromes have occurred surprisingly frequently, considering that they must involve coordinated changes in multiple genes affecting multiple floral traits. Although the identification of individual genes specifying single pollination syndrome traits is in progress in many species, little is known about the genetic architecture of coadapted pollination syndrome traits and how they are embedded within the genome. Here we describe the tight genetic linkage of loci specifying five major pollination syndrome traits in the genus Petunia: visible color, UV absorption, floral scent production, pistil length, and stamen length. Comparison with other Solanaceae indicates that, in P. exserta and P. axillaris, loci specifying these floral traits have specifically become clustered into a multifunctional "speciation island". Such an arrangement promotes linkage disequilibrium and avoids the dissolution of pollination syndromes by recombination. We suggest that tight genetic linkage provides a mechanism for rapid switches between distinct pollination syndromes in response to changes in pollinator availabilities.


Data of transcriptional effects of the merbarone-mediated inhibition of TOP2.
Type II DNA topoisomerases relax topological stress by transiently gating DNA passage in a controlled cut-and-reseal mechanism that affects both DNA strands. Therefore, they are essential to overcome topological problems associated with DNA metabolism. Their aberrant activity results in the generation of DNA double-strand breaks, which can seriously compromise cell survival and genome integrity. Here, we profile the transcriptome of human-telomerase-immortalized retinal pigment epithelial 1 (RPE-1) cells when treated with merbarone, a drug that catalytically inhibits type II DNA topoisomerases. We performed RNA-Seq after 4 and 8 h of merbarone treatment and compared transcriptional profiles versus untreated samples. We report raw sequencing data together with lists of gene counts and differentially expressed genes.


Construction of Vicinal Quaternary Stereogenic Centers by Enantioselective Direct Mannich-Type Reaction Using a Chiral Bis(guanidino)iminophosphorane Catalyst.
A novel asymmetric direct Mannich-type reaction of α-iminophenylacetate esters with thionolactones, bearing a substituent at the α-position, as a less acidic pronucleophile was developed. Using bis(guanidino)iminophosphorane as the chiral organosuperbase catalyst, the reaction afforded densely functionalized amino-acid derivatives having vicinal quaternary stereogenic centers, one of which is an all-carbon quaternary stereogenic center, in good yield with high diastereo- and enantioselectivities.


Myocardial injury, neurohormonal activation and inflammation after internal atrial defibrillation.
The effects of patient-activated atrial defibrillation on subclinical myocardial injury are unknown. Using biochemical markers, this study assessed the effect of a single internal atrial shock delivered by the implantable atrial defibrillator on myocardial damage, neurohormonal activation and inflammation. Twelve patients were implanted with a dual chamber defibrillator for the sole indication of drug refractory symptomatic persistent atrial fibrillation (AF). All had maximum defibrillation energy programmed to maximise the first shock success rate. Creatine kinase isoenzyme, troponin T, cortisol, catecholamines, C-reactive protein and brain natriuretic peptide were measured (i) during sinus rhythm, (ii) 8 h after onset of spontaneously occurring AF (before cardioversion) and (iii) 8 h following successful patient activated cardioversion. There was no change in creatine kinase, troponin T, cortisol or C-reactive protein during AF or following internal cardioversion. Brain natriuretic peptide levels rose from a median value of 56 pg/ml during sinus rhythm (inter-quartile range 14-92 pg/ml) to 133 pg/ml during AF (30-262 pg/ml), p=0.002. There was a decrease 8 h after cardioversion to baseline (52 and 40-189 pg/ml), p=0.01. There were increases in serum adrenaline and noradrenaline levels during AF from 0.43 (0.12-0.61) to 0.58 pg/ml (0.39-0.80 pg/ml), p=0.002 and from 2.06 (1.61-2.59) to 2.83 nmol/l (2.43-3.46 nmol/l), p=0.02, respectively. These figures reverted to baseline levels 8 h post-cardioversion. Internal atrial defibrillation does not result in myocardial injury. The onset of AF results in sympathetic activation and increased brain natriuretic peptide levels, which resolve following restoration of sinus rhythm.


Atherosclerosis: the carbonic anhydrase, carbon dioxide, calcium concerted theory.
Atherosclerosis is a dynamic multifaceted disease which affects the aorta and its major branches, characterized by the presence of lesions called atheromatous plaques. The plaque is a focal thickening of the intima caused by proliferation of smooth muscle cells, and the deposition of cholesterol, other lipids, hydroxyapatite and fibrous connective tissue. It is proposed that the determinant step of the process which leads to the disease atherosclerosis is the calcium precipitation which traps cholesterol in the plaque precursor matrix which contains lipoproteins, calcium carbonate, hydroxyapapatite, triglycerides, albumin, calmodulin and other proteins. The bear, a species which does not contract the disease is used as an example in support of the hypothesis. The bear's ability to regulate calcium levels and the regulation of acid base balance via regulation of carbon dioxide levels permits the control of the determinant step of plaque formation, that is calcification of the plaque.


Computer-assisted rational design, synthesis, and bioassay of non-steroidal anti-inflammatory agents.
A focused dataset of previously synthesized and tested [1,2,4]-triazolo[1,5-a]pyridines and pyridine-3-carboxylates was studied by Molecular Field Topology Analysis (MFTA) to identify steric and electronic determinants of anti-inflammatory activity useful for the design and synthesis of new anti-inflammatory agents. Rational design based on the MFTA model identified eleven novel pyridine-3-carboxylates (2a-e and 3a-f) as promising. After synthesis and screening, three of (2a, 2c, 3a) revealed potent anti-inflammatory activity exceeding that of indomethacin, the reference inhibitor for artificially induced edema in rats.


Two transient outward currents in histamine neurones of the rat hypothalamus in vitro.
1. The transient outward current exhibited by the histamine neurones of the tuberomammillary nucleus was studied using the single-electrode voltage clamp technique in an in vitro rat hypothalamic slice preparation. 2. The transient outward current exhibited steady-state inactivation at the resting potential. Inactivation was removed by priming hyperpolarization with a V1/2 of -85 +/- 1.2 mV, while the V1/2 for activation was -60.3 +/- 2.1 mV. 3. The decay of the transient outward current was best fitted by two exponentials with time constants of 104 +/- 36 and 568 +/- 128 ms. These two components were provisionally termed IA,f and IA,s for the fast and slowly decaying currents, respectively. 4. Removal of inactivation was time dependent; inactivation was fully removed by hyperpolarizing pulses to -110 mV of 200 ms or greater duration. Removal of inactivation of IA,f was rapid, becoming complete with hyperpolarizing pre-pulses of 50 ms or greater, while removal of inactivation of IA,s was not complete until hyperpolarizing pre-pulses were 200 ms in duration. 5. The fast decaying current IA,f was selectively blocked by 1 mM-4-aminopyridine. Tetraethylammonium chloride (10 mM) had no effect on either IA,f or IA,s. 6. The inactivation curves for IA,s, determined both by using the values obtained from the amplitude of the computed slower exponential function as well as that of the current remaining in 1 mM 4-aminopyridine, were negative to those of IA,f. Similarly derived activation curves for IA,s were positive to those of IA,f. 7. Superfusion with a nominal 0 Ca2+ medium containing 10 mM-Mg2+ did not reduce the maximal transient outward current. 8. The reversal potential of IA,s with 2.5 mM-K+ in the medium was -95 +/- 3 mV; the reversal potential of IA,f was at least 15 mV negative to that of IA,s. 9. It is concluded that histaminergic tuberomammillary neurones possess at least two transient outward currents which can be distinguished on the basis of their rates of decay, 4-aminopyridine sensitivity, voltage dependence and reversal potentials.


Rapid heterogeneous assembly of multiple magma reservoirs prior to Yellowstone supereruptions.
Large-volume caldera-forming eruptions of silicic magmas are an important feature of continental volcanism. The timescales and mechanisms of assembly of the magma reservoirs that feed such eruptions as well as the durations and physical conditions of upper-crustal storage remain highly debated topics in volcanology. Here we explore a comprehensive data set of isotopic (O, Hf) and chemical proxies in precisely U-Pb dated zircon crystals from all caldera-forming eruptions of Yellowstone supervolcano. Analysed zircons record rapid assembly of multiple magma reservoirs by repeated injections of isotopically heterogeneous magma batches and short pre-eruption storage times of 10(3) to 10(4) years. Decoupled oxygen-hafnium isotope systematics suggest a complex source for these magmas involving variable amounts of differentiated mantle-derived melt, Archean crust and hydrothermally altered shallow-crustal rocks. These data demonstrate that complex magma reservoirs with multiple sub-chambers are a common feature of rift- and hotspot related supervolcanoes. The short duration of reservoir assembly documents rapid crustal remelting and two to three orders of magnitude higher magma production rates beneath Yellowstone compared to continental arc volcanoes. The short pre-eruption storage times further suggest that the detection of voluminous reservoirs of eruptible magma beneath active supervolcanoes may only be possible prior to an impending eruption.


Pericolactines A-C, a New Class of Diterpenoid Alkaloids with Unusual Tetracyclic Skeleton.
Fusicoccane diterpenoids usually possess a fused 5-8-5 tricyclic ring system, which are biogenetically generated from geranylgeranyl diphosphate (GGDP). In our report, three novel diterpenoid alkaloids with fusicoccane skeleton, pericolactines A-C (1-3), were isolated from Periconia sp.. Their structures with absolute configurations were determined by spectroscopic analyses and quantum chemical ECD calculation. Pericolactines A-C (1-3) are a new class of diterpenoid alkaloids with an unusual fused 5-5-8-5 tetracyclic ring system, which derive from a geranylgeranyl diphosphate (GGDP) and serine conjugated biosynthesis. They belong to the atypical diterpenoid alkaloids.


Intracardiac echocardiographic guidance during microwave catheter ablation.
The purpose of this study was to explore the potential of intracardiac echocardiography in monitoring lesion formation and assisting with the assessment of ablative lesions using microwave energy. Microwave energy is a promising modality for catheter ablation. Because microwave lesions may have considerable variability in dimension, the ability to assess them may be particularly useful. One hundred twenty-five microwave lesions were created in vitro in ovine left ventricles. Correct assessment of catheter-endocardial contact was possible in virtually all cases. Intracardiac imaging always identified correctly whether or not an ablation was performed. During ablation, gas formation was observed in all instances. Sensitivity, specificity, and predictive values for identification of ablation lesions were 88% to 92%. Although the correlations with pathology for lesion dimensions were relatively poor, intracardiac imaging had a predictive accuracy of 80% to 85% to discriminate small from large lesions. Intracardiac guidance for microwave ablation is useful for verifying tissue-electrode contact, monitoring lesion formation, and localizing lesions. It is also a useful tool for the assessment of lesion size. These attributes, combined with the ability to facilitate transseptal catheterization and to identify complications such as hemopericardium, make intracardiac echocardiography a potentially useful method for guiding microwave ablation of arrhythmic foci.


Neural abnormalities of reward processing in adolescents with bipolar disorders: An ERP study.
Adolescent onset is common in bipolar disorders (BDs) and is associated with a worse illness course in adulthood. A model of BDs suggests that a dysregulated behavioral approach system (BAS), a neural system that mobilizes reward-seeking behavior, is at the root of BDs. Normative adolescence is often accompanied by dynamic changes to neural structures underlying the BAS and related cognitive processes. It is possible that adolescent-onset BDs is associated with abnormal BAS neurodevelopment. Consistently, the present study is the first to compare specific BAS-relevant anticipatory and consummatory reward processes as indexed by event-related potentials (ERPs) in adolescents with BDs and typically developing peers. Using a sample of 43 adolescents with BDs and 56 without psychopathology, we analyzed N1 and P3 responses to anticipatory cues and feedback-related negativity (FRN) and P3 responses to feedback stimuli during a monetary incentive delay (MID) task. Hierarchical linear models examined relationships between ERP amplitudes and diagnostic group, MID condition, sex, and age. During anticipation phase, adolescent boys with BDs exhibited significantly larger N1 amplitudes in loss than even or gain trials. During feedback phase, compared to their healthy peers, adolescents with BDs had smaller FRN amplitudes across all conditions. Additional effects involving age, sex and trial type were observed. The findings indicate subtle, non-ubiquitous BAS-relevant neural abnormalities involving early attentional processes during reward anticipation and reward learning following feedback in adolescents with BDs. Adolescents with BDs did not show overall hypersensitive neural responses to monetary reward anticipation or feedback observed in adults with BDs.


Randomized comparison of self-fixating and sutured mesh in open inguinal hernia repair.
Chronic groin pain after mesh repair of inguinal hernia has been attributed to the presence of sutures. This randomized clinical trial compared inguinal hernia repair using a self-fixating composite mesh or a sutured lightweight mesh, with pain at 1 year as primary outcome. Patients completed a self-evaluation questionnaire at 2 weeks and were examined after 1 year. Some 198 patients received self-fixating mesh and 196 sutured mesh. There were no differences between the groups in mean pain scores measured on a visual analogue scale during 2 weeks of immediate convalescence or at 1 year. Chronic pain and discomfort was experienced by 36.3 per cent of patients in the self-fixating and 34.1 per cent in the sutured mesh group (P = 0.658), affecting the everyday life of 1.1 and 2.8 per cent respectively (P = 0.448). Open inguinal hernia repair with a composite self-fixating mesh resulted in similar pain in the early postoperative convalescence period and at 1 year as repair with a sutured lightweight mesh.


Renal stones in Wilson's disease.
Fifty-four patients with Wilson's disease were studied with regard to renal stones. Seven of the 45 patients (16 per cent) who underwent roentgenographic procedures of the urinary tract had unequivocal evidence of renal stones. In four of the seven patients with Wilson's disease who had renal stones, the stones were discovered at the time or before the diagnosis of Wilson's disease was made. Of the several possible factors that may predispose patients with Wilson's disease to renal stone formation, the renal tubular acidosis pattern of abnormality in acid-base excretion is probably the most significant. In general, patients with renal stones and unexplained neurologic, bony or hepatic abnormalities should be screened for Wilson's disease by slit-lamp examination, determination of serum copper and ceruloplasmin concentrations, and urinary excretion of copper, particularly if they have relatively alkaline urine.


CXCR4/CXCL12 expression and signalling in kidney cancer.
CXCL12 (SDF-1), a CXC-chemokine, and its specific receptor, CXCR4, have recently been shown to be involved in tumourgenesis, proliferation and angiogenesis. Therefore, we analysed CXCL12alpha/CXCR4 expression and function in four human kidney cancer cell lines (A-498, CAKI-1, CAKI-2, HA-7), 10 freshly harvested human tumour samples and corresponding normal kidney tissue. While none of the analysed tumour cell lines expressed CXCL12alpha, A-498 cells were found to express CXCR4. More importantly, real-time RT-PCR analysis of 10 tumour samples and respective adjacent normal kidney tissue disclosed a distinct and divergent downregulation of CXCL12alpha and upregulation of CXCR4 in primary tumour tissue. To prove that the CXCR4 protein is functionally active, rhCXCL12alpha was investigated for its ability to induce changes of intracellular calcium levels in A-498 cells. Moreover, we used cDNA expression arrays to evaluate the biological influence of CXCL12alpha. Comparing gene expression profiles in rhCXCL12alpha stimulated vs unstimulated A-498 kidney cancer cells revealed specific regulation of 31 out of 1176 genes tested on a selected human cancer array, with a prominent stimulation of genes involved in cell-cycle regulation and apoptosis. The genetic changes reported here should provide new insights into the developmental paths leading to tumour progression and may also aid the design of new approaches to therapeutic intervention.


Protocol for tumor dissociation and fluorescence-activated cell sorting of human head and neck cancers.
Tumors originating from the head and neck represent diverse histologies and are comprised of several cell types, including malignant cells, cancer-associated fibroblasts, endothelial cells, and immune cells. In this protocol, we describe a step-by-step approach for the dissociation of fresh human head and neck tumor specimens, followed by isolation of viable single cells using fluorescence-activated cell sorting. Our protocol facilitates the effective downstream use of techniques, including single-cell RNA sequencing and generation of three-dimensional patient-derived organoids. For complete details on the use and execution of this protocol, please refer to Puram et al. (2017)1 and Parikh et al. (2022).2.


[Empowering patients suffering from chronic pain].
Living with chronic, daily pain generates a variety of reactions for every individual. To provide the best possible support for sufferers, management strategies have diversified, becoming multimodal and encompassing pharmacological, non-pharmacological, psychological, physiotherapeutic and educational therapies. It is within this framework that therapeutic patient education, hypnoanalgesia and self-hypnosis have been deployed.


Humeral shaft fractures treated with a ready-made fracture brace.
Twenty patients, 17 to 87 years of age, were treated with a dynamic brace for fractures of the humerus. The brace acts by compressing the soft tissues surrounding the fractured bone while the dependent arm of the ambulatory patient helps to pull the displaced bone fragments into normal relationship. As soon as the initial swelling and pain subsides the brace can be applied, usually within the first week. The brace permits early exercise of all the joints; it gives good comfort to the patient. There were two nonunions. Eighteen fractures healed with good anatomical and functional outcome.


Factors influencing collagen-induced autoimmune ear disease.
In 1981, the authors described a type II collagen-induced autoimmune ear disease (CIAED) model. The purpose of this study was to gather further evidence that this is a sound animal model to use in evaluating inner ear diseases. The temporal bone lesions of CIAED in Lewis and Wistar rats were characterized by the presence of sensorineural hearing loss with mild atrophy of the organ of Corti and spiral ganglion degeneration, vestibular dysfunction with vacuolar degeneration of the crista ampullaris, otospongiosis-like lesions in the tympanic annules, cochlear vasculitis, and eustachian tube disease. Both cellular and humoral immune responses to type II collagen were demonstrated. The induction of ear lesions depends on many factors. In general, animals immunized with antigens in complete Freund's adjuvant showed relatively more severe lesions than animals immunized with antigens in incomplete Freund's adjuvant, but the duration of the immunization seems to be a more important factor in reproducing severe lesions. The strain and the source of the animals are also important factors in autoimmune inner ear diseases, as is the condition of the host animals. Subclinical or clinical mycoplasma infection in the rat markedly reduced the incidence and severity of lesions in type II collagen-induced arthritis. Many researchers did not consider sialoductal adenovirus, widely present among laboratory rats, a lesion-producing factor in rats. Although many factors influence the induction and severity of CIAED, these animal models provide an excellent new avenue of inner ear research.


A symptomatic child with ceftriaxone-associated biliary pseudolithiasis.
A 5-year-old boy who had pneumonia was treated in a neighboring hospital. Ceftriaxone was administrated 2 g/day divided into two equal intravenous doses. After 1 week of ceftriaxone therapy, the patient developed abdominal pain. In our hospital, an abdominal sonogram showed a hyperechoic band with postacoustic shadow within the collapsed gallbladder. He was diagnosed with ceftriaxone-associated biliary pseudolithiasis, and ceftriaxone therapy was ceased. On the 8th our hospital day, he again complained of right abdominal pain after supper. A sonogram revealed high-amplitude echoes within the gallbladder neck and common bile duct. Furthermore, bile duct dilatation was observed. He was managed conservatively, after which the symptoms were resolved. On the 11th day, a sonogram showed only sludge within the gallbladder, and on the 13th day, he was discharged from our hospital. It is important for sonographers to recognize the possible occurrence of biliary pseudolithiasis in ceftriaxone-treated patients, especially when a high dose is used in children.


A double-radionuclide autoradiographic method using N-isopropyl-iodoamphetamine for sequential measurements of local cerebral blood flow.
A double-radionuclide autoradiographic method has been assessed for sequential determinations of local CBF (LCBF). It is based on two successive intravascular injections of N-isopropyl-p-iodoamphetamine (IMP) labelled with different radionuclides, whose concentrations can later be differentiated in the same tissue section using double-radionuclide autoradiography. Previous studies suggested that the distribution of IMP, up to 30 min after its administration, still represents LCBFs. Our data indicate that, provided the tracer is injected directly into the left ventricle, there is little back diffusion from normal brain to blood under physiological conditions for at least 35 min following the tracer injection and an injection of unlabelled IMP, in a dose larger than that used for blood flow determination, does not displace any labelled IMP previously taken up by the brain, nor does it displace any labelled IMP previously accumulated in the lung that would lead to secondary brain uptake. On the basis of these results, we conclude that sequential autoradiographic determinations of LCBF using IMP labelled with different radionuclides is possible. This is a promising experimental method for the simultaneous investigation of changes in LCBF in several CNS structures.


Influence of pelvic volume on surgical outcome after low anterior resection for rectal cancer.
Low anterior resection (LAR) for rectal cancer is a potentially challenging operation due to limited space in the pelvis. CT pelvimetry allows to quantify pelvic space, so that its relationship with outcome after LAR may be assessed. Studies investigating this, however, yielded conflicting results. We hypothesized that a small pelvis is associated with a higher rate of incomplete mesorectal excision, anastomotic leakages, and increased rate of urinary dysfunction in patients operated for rectal cancer. In a single-center retrospective analysis, we studied 74 patients that underwent LAR for rectal cancer with primary anastomosis. Thin-layered multi-slice CT datasets were used for slice by slice depiction of the inner pelvic surface, and the inner pelvic volume was automatically compounded. The primary outcome was quality of total mesorectal excision (TME; Mercury grading); secondary outcomes were anastomotic leakage and urinary dysfunction with regard to pelvic dimensions. Univariate analyses and multiple logistic regression analyses were performed for the primary and the secondary outcomes. Shorter obstetric conjugate diameters were associated with a higher probability of a worse TME quality (110.8 ± 10.2 vs. 105.0 ± 8.6 mm; OR 0.85; 95% CI 0.73-0.99; p = 0.038). Short interspinous distance showed a trend towards an increased risk for deteriorated TME quality (OR 0.88; 95% CI 0.76-1.0; p = 0.06). Anastomotic leakage was associated with anemia (OR 2.77; 95% CI 1.0-7.7; p = 0.047). Association between pelvic diameters or pelvic volume and anastomotic leakage or urinary dysfunction was not observed. Perioperative blood transfusions were administered more often in patients with postoperative urinary dysfunction (OR 17.67; 95% CI 2.44-127.7; p = 0.004). Shorter obstetric conjugate diameter might be a risk factor for incompleteness of total mesorectal excision. Anastomotic leakage seems to be influenced more by clinical factors such as anemia rather than pelvic dimensions. Further studies have to prove the influence of pelvic diameter on local recurrence of rectal cancer after LAR.


Evaluation of 16S rRNA gene-based PCR assays for genus-level identification of Helicobacter species.
The inclusivity, exclusivity, and detection limit of six 16S rRNA gene-based Helicobacter genus-specific PCR assays were examined. Five out of six assays were 100% inclusive, but the tests varied considerably in their exclusivity (9.1 to 95.5%). The clinical detection limit varied between 10(3) and 1 viable bacterial cell per reaction mixture.


A standalone bioreactor system to deliver compressive load under perfusion flow to hBMSC-seeded 3D chitosan-graphene templates.
The availability of engineered biological tissues holds great potential for both clinical applications and basic research in a life science laboratory. A prototype standalone perfusion/compression bioreactor system was proposed to address the osteogenic commitment of stem cells seeded onboard of 3D chitosan-graphene (CHT/G) templates. Testing involved the coordinated administration of a 1 mL/min medium flow rate together with dynamic compression (1% strain at 1 Hz; applied twice daily for 30 min) for one week. When compared to traditional static culture conditions, the application of perfusion and compression stimuli to human bone marrow stem cells using the 3D CHT/G template scaffold induced a sizable effect. After using the dynamic culture protocol, there was evidence of a larger number of viable cells within the inner core of the scaffold and of enhanced extracellular matrix mineralization. These observations show that our novel device would be suitable for addressing and investigating the osteogenic phenotype commitment of stem cells, for both potential clinical applications and basic research.


Genetic epidemiology and Mendelian randomization for informing disease therapeutics: Conceptual and methodological challenges.
The past decade has been proclaimed as a hugely successful era of gene discovery through the high yields of many genome-wide association studies (GWAS). However, much of the perceived benefit of such discoveries lies in the promise that the identification of genes that influence disease would directly translate into the identification of potential therapeutic targets, but this has yet to be realized at a level reflecting expectation. One reason for this, we suggest, is that GWAS, to date, have generally not focused on phenotypes that directly relate to the progression of disease and thus speak to disease treatment.


Ochratoxin A and other mycotoxins in Polish cereals and foods.
In 1990-2000 selected Polish cereals, cereal products and some different commodities collected in several regions of Poland were analysed for ochratoxin A (OTA) and aflatoxins. The frequency and the level of contamination of Polish cereals and cereal products by ochratoxin A seem to be similar as in most European countries. Aflatoxins in cereals and their products does not seem to be a problem in Poland, however the attention should be pay to some imported products like peanuts.


Implementation study of SARS-CoV-2 antigen lateral flow tests in men's professional (Premiership) rugby union sports squads in England during the COVID-19 pandemic.
This study evaluated the validity and utility of antigen-detection rapid diagnostic tests (Ag-RDTs) for SARS-CoV-2 in elite sports. The data on utility, ease of use and application for Ag-RDTs as a new testing format were positive from players and staff. This evaluation was limited by the low prevalence of SARS-CoV-2 circulating within the three squads. This study highlights the need for continued service evaluations for SARS-CoV-2 Ag-RDTs in elite sport settings.


Selective antagonism of cJun for cancer therapy.
The activator protein-1 (AP-1) family of transcription factors modulate a diverse range of cellular signalling pathways into outputs which can be oncogenic or anti-oncogenic. The transcription of relevant genes is controlled by the cellular context, and in particular by the dimeric composition of AP-1. Here, we describe the evidence linking cJun in particular to a range of cancers. This includes correlative studies of protein levels in patient tumour samples and mechanistic understanding of the role of cJun in cancer cell models. This develops an understanding of cJun as a focal point of cancer-altered signalling which has the potential for therapeutic antagonism. Significant work has produced a range of small molecules and peptides which have been summarised here and categorised according to the binding surface they target within the cJun-DNA complex. We highlight the importance of selectively targeting a single AP-1 family member to antagonise known oncogenic function and avoid antagonism of anti-oncogenic function.


Correction of coarctation of the aorta in neonates and young infants. An individualized surgical approach.
Because of the controversy concerning the ideal surgical repair for symptomatic coarctation of the aorta presenting in neonates and infants, our entire series of 179 children under the age of 12 months undergoing repair between January 1, 1976 and December 31, 1984 was reviewed. Of this group, 109 were neonates, 43 infants aged 31-90 days and 27 infants aged 90 days-12 months. Twenty patients had a simple coarctation and 159 had complex coarctation with additional intracardiac anomalies such as ventricular septal defect (37 patients also had pulmonary artery banding). One hundred and twenty-four were repaired with a subclavian flap operation, 32 with resection and end-to-end anastomosis and 23 with complex repairs (e.g. patch and reversed flap). Type of repair was the surgeon's choice and was selected on the basis of the anatomy of the coarctation. Total perioperative mortality was 15% (N = 27) while late mortality was 12% (N = 21). Twenty-one risk factors for mortality were evaluated by logistic analysis and the method of Cox. There was no risk difference between end-to-end versus subclavian flap repairs and all but one death occurred in patients with complex coarctations. Risk for in hospital death was increased by only one variable: the need for repair in the neonatal period. Risk for death in the first year of life was increased by the presence of congestive heart failure at initial presentation while later death correlated with intracardiac surgery. Recoarctation occurred in 28 patients (18.4%), all but 4 of these occurred in patients undergoing neonatal repairs.(ABSTRACT TRUNCATED AT 250 WORDS)


Economic evaluation of tele-resuscitation intervention on emergency department pediatric visits in the Niagara Region, Canada a pilot study.
The use of telemedicine in critical care is emerging, however, there is a paucity of information surrounding the costs relative to health gains in the pediatric population. This study aimed to estimate the cost-effectiveness of a pediatric tele-resuscitation (Peds-TECH) intervention compared to the usual care in five community hospital emergency departments (EDs). Using a decision tree analysis approach with secondary retrospective data from a 3-year time period, this cost-effectiveness analysis was completed. A mixed methods quasi-experimental design was embedded in the economic evaluation of Peds-TECH intervention. Patients aged <18 years triaged as Canadian Triage and Acuity Scale 1 or 2 at EDs were eligible to receive the intervention. Qualitative interviews were conducted with parents/caregivers to explore the out-of-pocket (OOP) expenses. Patient-level health resource utilization was extracted from Niagara Health databases. The Peds-TECH budget calculated one-time technology and operational costs per patient. Base-case analyses determined the incremental cost per year of life lost (YLL) averted, and additional sensitivity analysis confirmed the robustness of the results. Odds ratio for mortality among cases was 0.498 (95% CI: 0.173, 1.43). The average cost of a patient receiving the Peds-TECH intervention was $2,032.73 compared to $317.45 in usual care. In total, 54 patients received the Peds-TECH intervention. Fewer children died in the intervention group resulting in 4.71 YLL. The probabilistic analysis revealed an incremental cost-effectiveness ratio of $64.61 per YLL averted. Peds-TECH appears to be a cost-effective intervention for resuscitating infants/children in hospital emergency departments.


Prevention of lymphatic filariasis with insecticide-treated bednets in Cambodia.
Potential risk factors for lymphatic filariasis (LF), including the failure to use insecticide-treated bednets (ITN), were studied in four north-eastern provinces of Cambodia, using 43 cases of LF and 248 apparently healthy controls who were matched with the cases in terms of age (+/-5 years), gender and village. The results of a univariate matched analysis indicated that lack of ITN [odds ratio (OR)=20.1; 95% confidence interval (CI)=2.2-182.4; P=0.008] and frequent overnight stays in forests or paddy fields outside the village (OR=3.6; CI=1.3-10.0; P=0.012) were the most important risk factors. In a multivariate matched analysis, frequent overnight stays outside the village combined with bednet use showed a clear dose-response relationship, with untreated nets offering significant protection during such stays but ITN offering significantly better protection. Even if villagers used ITN during such stays, they were significantly more likely to develop LF than villagers who did not travel (OR=5.0; CI=1.5-16.3; P=0.008), and if they used untreated or no nets while away they were even more likely than the non-travellers to develop the disease (OR=1413; CI=28.0-71,189; P<0.001). Taken together, these results provide further evidence for the importance of bednet use and their impregnation in the prevention of LF. At least in north-eastern Cambodia, the use of bednets and, preferably, ITN is particularly important during overnight stays outside the home village. In areas where LF is endemic, the sustained distribution of insecticide-treated bednets or hammock nets appears to be a very good idea.


Autoantigens in thyroid diseases.
The autoantigens involved in autoimmune thyroid disease have now been extensively characterised, and the autoantibodies they evoke provide important aids to diagnosis, leading to early treatment of thyroid autoimmunity. The next stage in the puzzle is to determine towards which epitopes on the autoantigens the immune response is directed. We have already come a long way in the identification of immunodominant epitopes and have been able to identify one T cell epitope which has pathogenic capabilities. Identification of other T cell and B cell epitopes will help us understand the cell-mediated and humoral responses in greater detail and in time lead to more specific therapeutic intervention. A greater understanding of the mechanisms underlying one particular autoimmune disease will give us insights into other diseases, due to the belief that there may well be common underlying defects that, due to a multitude of factors, manifest as different diseases. The susceptibility factors in autoimmune thyroidits and autoimmune disease in general are very complex. A greater understanding is required of HLA associations and how particular peptides are presented in vivo. Are susceptible MHC types the ones capable of presenting the pathogenic peptides? Our major T cell thyroiditogenic epitope contains a T4 residue which accounts for over half the molecular weight of the peptide. Its structure is large and consists of a double benzene ring structure with four iodine atoms. It will be interesting to see how such a peptide can be presented and which residues bind T cell receptor or MHC. In summary we can say that autoimmune disease is due to a cocktail of factors which all contrive to tip the delicate balance of the immune system into an autoimmune state. HLA association may play a role in conferring an enhanced ability to select from a restricted repertoire of pathogenic epitopes, those epitopes perhaps only becoming available for presentation after interaction with environmental agents, whatever they may be. Following this, the normal regulation of self presentation and tolerance mechanisms break down and autoimmunity supervenes.


Potential synthetic lethality for breast cancer: A selective sirtuin 2 inhibitor combined with a multiple kinase inhibitor sorafenib.
Sorafenib is a clinically useful multiple kinase inhibitor for the treatment of kidney cancer, liver cancer and acute myelocytic leukemia, while it has shown weak efficacy in suppressing breast cancer. Since sirtuin2 (SIRT2) is an important epigenetic regulator and associated with several cancer types including breast cancer, development and evaluation of new SIRT2 inhibitors to probe their therapeutic potentials is currently desirable. A highly selective SIRT2 inhibitor named I was previously developed by us, which showed activity to inhibit non-small cell lung cancer cell lines in vitro. We herein report expanded screening of I and its structurally similar inactive compound II against other cancer cell lines, and found that I had a wide spectrum of anticancer activity while II had no such effects. The I-sorafenib combination treatment exerted obvious synergistic reduction on cell viability of MCF-7 cells. We observed that the combination treatment could suppress cell proliferation, survival and migration, arrest cell cycle at G0/G1 phase, and induce apoptosis in MCF-7 cells, when compared with the single treatment. In vivo studies revealed that the combination treatment showed stronger tumor growth inhibition (87%), comparing with I-(42.8%) or sorafenib-solely-treated groups (61.1%) in MCF-7 xenograft model. In conclusion, this work clearly revealed a potential synthetic lethality effect for I combined with sorafenib, and will probably offer a new strategy at least for breast cancer treatment.


Membrane-based microfluidic solvent extraction of Ga-68 from aqueous Zn solutions: towards an automated cyclotron production loop.
The radionuclide Ga-68 is commonly used in nuclear medicine, specifically in positron emission tomography (PET). Recently, the interest in producing Ga-68 by cyclotron irradiation of [68Zn]Zn nitrate liquid targets is increasing. However, current purification methods of Ga-68 from the target solution consist of multi-step procedures, thus, leading to a significant loss of activity through natural decay. Additionally, several processing steps are needed to recycle the costly, enriched target material. To eventually allow switching from batch to continuous production, conventional batch extraction and membrane-based microfluidic extraction were compared. In both approaches, Ga-68 was extracted using N-benzoyl-N-phenylhydroxylamine in chloroform as the organic extracting phase. Extraction efficiencies of up to 99.5% ± 0.6% were achieved within 10 min, using the batch approach. Back-extraction of Ga-68 into 2 M HCl was accomplished within 1 min with efficiencies of up to 94.5% ± 0.6%. Membrane-based microfluidic extraction achieved 99.2% ± 0.3% extraction efficiency and 95.8% ± 0.8% back-extraction efficiency into 6 M HCl. When executed on a solution irradiated with a 13 MeV cyclotron at TRIUMF, Canada, comparable efficiencies of 97.0% ± 0.4% were achieved. Zn contamination in the back-extracted Ga-68 solution was found to be below 3 ppm. Microfluidic solvent extraction is a promising method in the production of Ga-68 achieving high efficiencies in a short amount of time, potentially allowing for direct target recycling.


Contributions by ionic and steric features of ligands to their binding with phosphorylcholine-specific immunoglobulin IgA H-8 as determined by fluorescence spectroscopy.
The murine myeloma IgA H-8 Fab' fragment which exhibits a binding specificity for phosphorylcholine was assayed for its ability to bind with a number of charged ligands. Monitoring of the ligand-induced changes of protein fluorescence provided a fast and accurate method of determining the equilibrium binding constants. The binding data along with fluorescence spectral properties of the protein permitted an assessment of the relative importance of some binding parameters as well as an evaluation of certain ionic and steric contributions made by ligands exhibiting significant binding affinity for the antibody fragment. Among the conclusions reached is that the dielectric of the binding site microenvironment is important in determining the strength of binding and that hydrophobic groups surrounding a quaternary cationic ligand are important in creating an appropriate binding site of low dielectric value.


Role of arthroconidia in biofilm formation by Trichosporon asahii.
Trichosporon asahii is the major causative agent of disseminated and deep-seated trichosporonosis. It is capable of forming biofilms on surfaces, leading to medical device-related infection.Trichosporon asahii may be present as yeast form, hyphae and/or arthroconidia; however, the relationship between its biofilm-forming ability and its morphological transition is unclear. We investigated whether the T. asahii morphological transition contributes to its biofilm formation. We also determined the conditions required to induce each of the morphologies. Three high- and three low-biofilm-producing strains (HBS and LBS, respectively) were selected using a biofilm formation assay, and the cell surface hydrophobicity of these six strains was measured. For each strain, the morphology was observed and the number of each morphological form (yeast form, hypha and arthroconidium) was counted to calculate the ratio. Finally, the ability of cells each morphological type to adhere to the polystyrene substrate was evaluated. The HBS exhibited abundant arthroconidia and hyphae; in contrast, the LBS produced mainly hyphae with few or no arthroconidia. The production of hyphae was increased by nitrogen-containing medium, and the production of arthroconidia was increased by nitrogen-deficient medium. Cells incubated under nitrogen-deficient conditions showed higher adherence to a polystyrene surface than those incubated in the presence of nitrogen. Arthroconidia of T. asahii play a key role in biofilm formation by promoting cellular adhesion.


Sonographic lesion size of ductal carcinoma in situ as a preoperative predictor for the presence of an invasive focus.
To investigate the preoperative factors associated with upstage to invasive cancer in patients with core needle biopsy (CNB) diagnosis of ductal carcinoma in situ (DCIS) by ultrasound guidance alone. Between 2000 and 2007, 201 patients with DCIS diagnosed at 11- or 14-gauge CNB by ultrasound guidance alone were examined. Preoperative factors were all analyzed to correlate with the presence of invasive cancer after definitive resection. The Pearson chi-square test and stratified analysis with the Mantel-Haenszel chi-squire test were used to assess the association between the preoperative factors and upstage to invasive cancer. Compared with the overall underestimation rate (84 of 201, 41.8%), 47 (60.3%) of 78 patients with abnormal breast palpation, 46 (55.4%) of 83 patients with mammographic finding of a mass lesion, and 38 (67.9%) of 56 patients with a sonographic lesion size >20 mm had invasive cancer components on the final pathology review (Odds ratio [OR] = 2.45; P = 0.04, OR = 3.66; P = 0.002, and OR = 4.13; P = 0.002 respectively). A sonographic lesion size >20 mm can be used as another guideline for surgeons to consider sentinel lymph node biopsy in patients with DCIS diagnosed by a sonographically guided CNB.


Brain areas associated with clinical and cognitive insight in psychotic disorders: A systematic review and meta-analysis.
In the past years, ample interest in brain abnormalities related to clinical and cognitive insight in psychosis has contributed several neuroimaging studies to the literature. In the current study, published findings on the neural substrates of clinical and cognitive insight in psychosis are integrated by performing a systematic review and meta-analysis. Coordinate-based meta-analyses were performed with the parametric coordinate-based meta-analysis approach, non-coordinate based meta-analyses were conducted with the metafor package in R. Papers that could not be included in the meta-analyses were systematically reviewed. Thirty-seven studies were retrieved, of which 21 studies were included in meta-analyses. Poorer clinical insight was related to smaller whole brain gray and white matter volume and gray matter volume of the frontal gyri. Cognitive insight was predominantly positively associated with structure and function of the hippocampus and ventrolateral prefrontal cortex. Impaired clinical insight is not associated with abnormalities of isolated brain regions, but with spatially diffuse global and frontal abnormalities suggesting it might rely on a range of cognitive and self-evaluative processes. Cognitive insight is associated with specific areas and appears to rely more on retrieving and integrating self-related information.