MHC-Fine: Fine-tuned AlphaFold for Precise MHC-Peptide Complex Prediction.
The precise prediction of Major Histocompatibility Complex (MHC)-peptide complex structures is pivotal for understanding cellular immune responses and advancing vaccine design. In this study, we enhanced AlphaFold's capabilities by fine-tuning it with a specialized dataset comprised by exclusively high-resolution MHC-peptide crystal structures. This tailored approach aimed to address the generalist nature of AlphaFold's original training, which, while broad-ranging, lacked the granularity necessary for the high-precision demands of MHC-peptide interaction prediction. A comparative analysis was conducted against the homology-modeling-based method Pandora [13], as well as the AlphaFold multimer model [8]. Our results demonstrate that our fine-tuned model outperforms both in terms of RMSD (median value is 0.65 Å) but also provides enhanced predicted lDDT scores, offering a more reliable assessment of the predicted structures. These advances have substantial implications for computational immunology, potentially accelerating the development of novel therapeutics and vaccines by providing a more precise computational lens through which to view MHC-peptide interactions.


Multiple-cause coding of death from myocardial infarction: population-based study of trends in death certificate data.
Data on long-term trends in mortality are generally unavailable for multiple-cause coding of deaths. We wanted to know whether multiple-cause coding of deaths for myocardial infarction contributes much to the interpretation of death certificate data on mortality rates for this condition. We analysed all causes of death on death certificates in the former Oxford health service region from 1979 to 1998. Of 69,333 death certificates that included myocardial infarction as a cause of death, it was the underlying cause of death in 93.6 per cent. The ratio of 'mentions' to 'underlying cause' was broadly similar over the study period, during which time there were substantial falls in mortality rates. There were significant changes to the ratios, associated with timing of changes to coding rules; but their effects were small. The ratio of mentions to underlying cause was similar in men and women and in different age groups. The underlying cause of death was a robust and almost complete measure of certified deaths for myocardial infarction.


Simvastatin as a neuroprotective treatment for Parkinson's disease (PD STAT): protocol for a double-blind, randomised, placebo-controlled futility study.
Parkinson's disease (PD) is a progressive neurodegenerative condition affecting approximately 185,000 people in the UK. No drug has been proven to slow disease progression. Epidemiological and pre-clinical data support simvastatin, a widely used cholesterol-lowering drug with a well-established safety profile, having neuroprotective properties. The aim of this study (Simvastatin as a neuroprotective treatment for PD (PD STAT)) is to determine whether simvastatin has the potential to slow PD progression. The study is part of the International Linked Clinical Trials initiative coordinated by The Cure Parkinson's Trust. This paper describes the protocol for the PD STAT study. PD STAT is a double-blind, randomised, placebo-controlled, multi-centre, parallel group, futility trial in patients with PD of mild-moderate severity. 235 participants have been recruited and randomly allocated in a 1:1 ratio to receive either oral simvastatin or matched placebo. Treatment involves a 1-month low-dose phase (40 mg daily), followed by a 23-month high-dose phase (80 mg daily) and ends with a 2-month washout period. Participants are reviewed at clinic visits at 1 month, 6, 12, 18, 24 and 26 months post-baseline, with interim telephone follow-up to monitor for adverse events.The primary outcome is the change in the Movement Disorder Society Unified Parkinson's Disease Rating Scale part III motor subscale score in the practically defined OFF medication state (OFF state) between baseline and 24 months. Primary analysis will be on a modified intention to treat basis and will include only those participants who progress to the high-dose phase of the study. The protocol has been approved by the North East-Newcastle and North Tyneside 2 Research Ethics Committee. The results will be disseminated via research articles in peer-reviewed journals and presentations at local, national and international scientific meetings, as well as disseminated via patient groups, websites and networks. A summary of the study findings will be posted to participants at the end of the study. ISRCTN16108482 (prospectively registered); EudraCT 2015-000148-40; ClinicalTrials.gov NCT02787590; Pre-results.


Neurogenic potential of engineered mesenchymal stem cells overexpressing VEGF.
Numerous signaling molecules are altered following nerve injury, serving as a blueprint for drug delivery approaches that promote nerve repair. However, challenges with achieving the appropriate temporal duration of recombinant protein delivery have limited the therapeutic success of this approach. Genetic engineering of mesenchymal stem cells (MSCs) to enhance the secretion of proangiogenic molecules such as vascular endothelial growth factor (VEGF) may provide an alternative. We hypothesized that the administration of VEGF-expressing human MSCs would stimulate neurite outgrowth and proliferation of cell-types involved in neural repair. When cultured with dorsal root ganglion (DRG) explants in vitro, control and VEGF-expressing MSCs (VEGF-MSCs) increased neurite extension and proliferation of Schwann cells (SCs) and endothelial cells, while VEGF-MSCs stimulated significantly greater proliferation of endothelial cells. When embedded within a 3D fibrin matrix, VEGF-MSCs maintained overexpression and expressed detectable levels over 21 days. After transplantation into a murine sciatic nerve injury model, VEGF-MSCs maintained high VEGF levels for 2 weeks. This study provides new insight into the role of VEGF on peripheral nerve injury and the viability of transplanted genetically engineered MSCs. The study aims to provide a framework for future studies with the ultimate goal of developing an improved therapy for nerve repair.


Purification and characterization of pheromaxein, the porcine steroid-binding protein. A member of the secretoglobin superfamily.
Low molecular mass proteins are implicated in chemical communication throughout mammalian species, being involved in both perception and delivery of pheromonal compounds. In boars, pheromones are secreted in saliva to cause oestrous sows to take up the mating stance. These pheromones are the 16-androstene steroids, 5alpha-androsten-3alpha-ol and 5alpha-androsten-3-one. The submaxillary glands of boars contain a low molecular mass protein, pheromaxein, which is capable of binding these 16-androstene pheromones. Pheromaxein was purified, cloned and characterized. It was found to be a nonglycosylated heterodimeric protein, belonging to the secretoglobin superfamily and the major 16-androstene-binding protein present in submaxillary salivary glands of the boar. One subunit, pheromaxein A, was found to be homologous to prostatein peptides, C1 and C2 and lipophilin A and B, whereas the other subunit, pheromaxein C, was homologous to prostatein peptide C3 and lipophilin C. Transcription of pheromaxein A was limited to the prostate and submaxillary salivary glands from both the boar and sow, whereas transcription of the other subunit, pheromaxein C, was more widespread. This is similar to the transcription distribution of lipophilin in humans. Many isoforms of pheromaxein were found to exist, with a molecular mass range of 17,415-18,159 Da; these are probably products of a multigene family. Post-translational modifications, to generate mature pheromaxein isoforms, probably include C-terminal cleavage of pheromaxein A, followed by additional modifications.


The internal organization of hospitals: a descriptive study.
This study presents descriptive information on several dimensions of the internal organization of hospitals, with particular emphasis on medical staff, using data from two unique national surveys. Three alternative theories of hospital behavior by economists are described and evaluated with these data. The study also shows how standard bed size, teaching, and ownership categories relate to important features of hospital organization. In this way, understanding of these standard "control" variables is enhanced. For example, systematic organizational differences between proprietary and other hospitals are reported, holding bed size and teaching status constant. No single theory of hospital behavior emerges as dominant. The tables demonstrate the diversity of hospitals and the likelihood that no single model can adequately describe the behavior of all hospitals.


Novel expandable architected breathing tube for improving airway securement in emergency care.
Life-saving interventions utilize endotracheal intubation to secure a patient's airway, but performance of the clinical standard of care endotracheal tube (ETT) is inadequate. For instance, in the current COVID-19 crisis, patients can expect prolonged intubation. This protracted intubation may produce health complications such as tracheal stenosis, pneumonia, and necrosis of tracheal tissue, as current ETTs are not designed for extended use. In this work, we propose an improved ETT design that seeks to overcome these limitations by utilizing unique geometries which enable a novel expanding cylinder. The mechanism provides a better distribution of the contact forces between the ETT and the trachea, which should enhance patient tolerability. Results show that at full expansion, our new ETT exerts pressures in a silicone tracheal phantom well within the recommended standard of care. Also, preliminary manikin tests demonstrated that the new ETT can deliver similar performance in terms of air pressure and air volume when compared with the current gold standard ETT. The potential benefits of this new architected ETT are threefold, by limiting exposure of healthcare providers to patient pathogens through streamlining the intubation process, reducing downstream complications, and eliminating the need of multiple size ETT as one architected ETT fits all.


Height distribution of equipotential lines in a region confined by a rough conducting boundary.
This work considers the behavior of the height distributions of the equipotential lines in a region confined by two interfaces: a cathode with an irregular interface and a distant flat anode. Both boundaries, which are maintained at distinct and constant potential values, are assumed to be conductors. The morphology of the cathode interface results from the deposit of 2 × 10(4) monolayers that are produced using a single competitive growth model based on the rules of the Restricted Solid on Solid and Ballistic Deposition models, both of which belong to the Kadar-Parisi-Zhang (KPZ) universality class. At each time step, these rules are selected with probability p and q = 1 - p. For several irregular profiles that depend on p, a family of equipotential lines is evaluated. The lines are characterized by the skewness and kurtosis of the height distribution. The results indicate that the skewness of the equipotential line increases when they approach the flat anode and this increase has a non-trivial convergence to a delta distribution that characterizes the equipotential line in a uniform electric field. The morphology of the equipotential lines is discussed; the discussion emphasizes their features for different ranges of p that correspond to positive, null and negative values of the coefficient of the non-linear term in the KPZ equation.


Biomarkers of Atrial Fibrillation in Metabolic Syndrome.
Whether the increased atrial fibrillation (AF) risk in metabolic syndrome (MetS) patients is due to the syndrome as a whole or simply the sum of the risks of its individual component parts is still obscure. These two clinical entities share many pathophysiological links and thus distinction between a casual observation and a significant association is difficult. Biomarkers associated with pathogenesis of AF in the context of MetS have the ability to refine future risk prediction. In the present review we identify circulating substances that could be regarded as potential biomarkers for prediction of incident AF, or of cardiovascular events in the setting of AF in patients with MetS. Cardiac myocyte injury and stress markers (troponin and natriuretic peptides), markers of renal function (glomeral filtration rate, cystatin-C), and inflammation markers/mediators (interleukin- 6, CRP) are promising biomarkers of patients with AF and MetS.


Restoration of Vision After Brain Injury Using Magnet Glasses.
Visual impairments are common after traumatic brain injury (TBI) and negatively affect quality of life. We describe a 39-year-old woman with a severe TBI who was evaluated by the inpatient optometry and vision rehabilitation service with findings of complete right homonymous hemianopia and right cranial nerve III palsy with 30-degree right exotropia (eye turn out) and complete right ptosis (eyelid will not open). The 30-degree exotropia advantageously generated 30 degrees of right visual field expansion when the right ptosis was treated with a magnetic levator prosthesis, which restores eyelid opening. Once opened, the patient used visual field expansion derived from a right exotropia to overcome functional impairments caused by right hemianopia. Field expansion improved the patient's wheelchair mobility and reaching tasks during inpatient therapy. This is the first report of visual field expansion by strabismus facilitated by correction of ptosis. Strabismus should be considered for its potential field expansion benefits when homonymous visual deficits are present, before considering patching. A multidisciplinary vision rehabilitation team is well suited to make this determination.


Incidence and predictors of sexually transmitted infections among adult HIV-positive patients receiving antiretroviral therapy at Themba Lethu HIV clinic in Johannesburg, South Africa.
Sexually transmitted infections (STIs) among people living with HIV/AIDS can facilitate the spread of HIV. To estimate STI incidence and identify predictors of STI acquisition among HIV-positive patients during their first 24 months of antiretroviral therapy (ART) in Johannesburg, South Africa. We conducted a cohort study using prospectively collected routine data on patients who initiated ART between January 2004 and January 2015 at the Themba Lethu HIV clinic in Johannesburg. Kaplan-Meier analysis was used to estimate STI incidence rates (based on evidence of laboratory diagnosis and STI syndromic treatment prescription records). STI predictors were identified using Cox regression analysis. Among 26 762 adult patients on ART, there were 1 906 (7.1%) cases of STI (incidence 4.8/100 person-years; 95% confidence interval (CI) 4.7 - 5.1). Non-pregnant women were 60% more likely than men to be diagnosed with an STI (adjusted hazard ratio (aHR) 1.6; 95% CI 1.4 - 1.8). The risk of STI decreased with increasing baseline CD4 count (aHR 0.8, 0.5 and 0.4 for CD4 counts 101 - 200, 201 - 350 and >350 cells/µL, respectively, compared with CD4 count <100 cells/µL). Patients with advanced baseline World Health Organization (WHO) clinical stages had a higher risk (aHR 1.6 for WHO stage 4; 95% CI 1.3 - 1.9) compared with those with WHO stage 1. However, there was a 20% increase in the risk of STI among obese patients compared with underweight patients (aHR 1.3; 95% CI 1.0 - 1.7). Over 80% of obese patients diagnosed with an STI had a CD4 count <200 cells/µL. STIs are common in HIV-infected patients who are receiving ART. While both ART and the syndromic management of STIs are high-impact interventions for controlling the spread of HIV, closer monitoring of STI occurrences is warranted, particularly among immunologically vulnerable patients.


COVID-19 and the flu: data simulations and computational modelling to guide public health strategies.
Pandemics threaten lives and economies. This article addresses the global threat of the anticipated overlap of COVID-19 with seasonal-influenza. Scientific evidence based on simulation methodology is presented to reveal the impact of a dual outbreak, with scenarios intended for propagation analysis. This article aims at researchers, clinicians of family medicine, general practice and policy-makers worldwide. The implications for the clinical practice of primary health care are discussed. Current research is an effort to explore new directions in epidemiology and health services delivery. Projections consisted of machine learning, dynamic modelling algorithms and whole simulations. Input data consisted of global indicators of infectious diseases. Four simulations were run for '20% versus 60% flu-vaccinated populations' and '10 versus 20 personal contacts'. Outputs consisted of numerical values and mathematical graphs. Outputs consisted of numbers for 'never infected', 'vaccinated', 'infected/recovered', 'symptomatic/asymptomatic' and 'deceased' individuals. Peaks, percentages, R0, durations are reported. The best-case scenario was one with a higher flu-vaccination rate and fewer contacts. The reverse generated the worst outcomes, likely to disrupt the provision of vital community services. Both measures were proven effective; however, results demonstrated that 'increasing flu-vaccination rates' is a more powerful strategy than 'limiting social contacts'. Results support two affordable preventive measures: (i) to globally increase influenza-vaccination rates, (ii) to limit the number of personal contacts during outbreaks. The authors endorse changing practices and research incentives towards multidisciplinary collaborations. The urgency of the situation is a call for international health policy to promote interdisciplinary modern technologies in public health engineering.


One compared with two cycles of mitomycin C in chemoradiotherapy for anal cancer: analysis of outcomes and toxicity.
Concurrent chemoradiation with fluorouracil (5fu) and mitomycin C (mmc) is standard treatment for anal canal carcinoma (acc). The current protocol in Alberta is administration of 5fu and mmc during weeks 1 and 5 of radiation. However, administration of the second bolus of mmc has been based largely on centre preference. Given limited published data on outcomes with different mmc regimens, our objective was to compare the efficacy and toxicity of 1 compared with 2 cycles of mmc in acc treatment. Our retrospective study evaluated 169 acc patients treated with radical chemoradiotherapy between 2000 and 2010 at two tertiary cancer centres. All patients were treated with 2 cycles of 5fu and with 1 cycle (mmc1) or 2 cycles (mmc2) of mmc. Acute toxicities, disease-free (dfs) and overall survival (os) were analyzed. Baseline demographics, performance status, and stage were similar in the groups of patients who received mmc1 (52%) and mmc2 (48%). Before treatment, median hematologic parameters were comparable, except for white blood cell count, which was higher in the mmc2 group, but within normal range. The 5-year os and dfs were similar (75.1% and 54.2% for mmc1 vs. 70.7% and 44.2% for mmc2, p = 0.98 and p = 0.63 respectively). On multivariate analysis, mmc2 was the factor most strongly associated with specific acute toxicities: grade 3+ leukopenia (hazard ratio: 4.82; p < 0.01), grade 3+ skin toxicity (hazard ratio: 4.76; p < 0.001), and hospitalizations secondary to febrile neutropenia (hazard ratio: 9.91; p = 0.001). In definitive chemoradiotherapy for acc, 1 cycle of mmc appears to offer outcomes similar to those achieved with 2 cycles, with significantly less acute toxicity.


Work-Life Balance of the Employed Population During the Emergency Situation of COVID-19 in Latvia.
All the employees face the challenge of finding the right work-life balance. The ability of employees to deal with the successful combining of work, family responsibilities, and personal life is crucial for both employers and family members of employees. During the COVID-19 emergency situation, many people around the world were forced to work remotely. Initially, there were observed some certain expectations about the possibility of working from home as a positive factor that will promote work-life balance. However, over time, negative tendencies were also revealed, as employees were only one call or message away from the employer, and uncertainty and leisure time with family often created more stress. As many organizations and individuals were not ready for this sudden change, many mistakes were made, which further raised the issue of work-life balance. The aim of the research was to evaluate the flexibility of reconciling work and private life of Latvian employees in various socio-demographic groups during the COVID-19 emergency situation in spring 2020, to investigate how family life influenced employees' ability to perform work duties, to find out if employees had any additional housework responsibilities and how their workload changed concerning housework amount during the COVID-19 emergency situation. The research is based on the data obtained in the survey of the Latvian employed population, which was conducted within the framework of the Latvian National Research Programme Project "CoLife" in the second half of 2020. As a result, the hypothesis of the research that all groups of employees experienced work-life balance difficulties during the COVID-19 emergency situation has been partially confirmed, i.e., women in the 18-44 age group and respondents with minor children in the household more likely faced difficulties of work-life balance. The scientific research methods that were used in the research are the monographic method, content analysis, survey, data processing with SPSS to determine the mutual independence of the data from the questionnaires.


Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ Study.
Age-related frailty is an increasing societal challenge with growing emphasis on identifying its underlying pathophysiology and prospects for intervention. We report findings from the first comprehensive study of frailty and biomarkers of inflammation, immunosenescence and cellular ageing in the very old. Using cross-sectional data from the Newcastle 85+ Study (n=845, aged 85), frailty was operationalized by the Fried and Rockwood models and biomarker associations explored using regression analysis. We confirmed the importance of inflammatory markers (IL-6, TNF-alpha, CRP, neutrophils) in frailty in the very old, previously established only in younger-old populations. Limited evidence was found for immunosenescence in frailty; although total lymphocyte count was inversely related, no association was found with the immune risk profile and the inverse associations observed with memory/naïve CD8 T and B cell ratios were in the opposite direction to that expected. We found no association with frailty in the very old for CMV sero-positivity, telomere length, markers of oxidative stress or DNA damage and repair. The Fried and Rockwood frailty models measure different albeit overlapping concepts yet biomarker associations were generally consistent between models. Difficulties in operationalizing the Fried model, due to high levels of co-morbidity, limit its utility in the very old.


Rapid detection of mycobacteria in clinical specimens by using the automated BACTEC 9000 MB system and comparison with radiometric and solid-culture systems.
Recovery rates of acid-fast bacilli (AFB) and the mean time to their detection from clinical specimens were determined by using the fluorescent BACTEC 9000 MB system. Data were compared to those assessed by the radiometric BACTEC 460 system and by cultivation on solid media. A total of 3,095 specimens were processed with N-acetyl-L-cysteine-NaOH by two laboratories. The contamination rates for the BACTEC 9000 MB system were 6.8% (center 1) and 9.8% (center 2). A total of 451 mycobacterial isolates were detected (Mycobacterium tuberculosis complex, n = 296; nontuberculous mycobacteria [NTM], n = 155). These isolates originated from 94 (20.8%) smear-positive and 357 (79.2%) smear-negative specimens. The BACTEC 9000 MB system was significantly better than solid media (P < 0.05) in detecting AFB, but it was less efficient than the radiometric system (P < 0.01). The BACTEC 9000 MB system plus solid media (combination A) recovered 393 (87.1%) of the isolates, while the BACTEC 460 system plus solid media (combination B) detected 430 (95.3%) of all AFB isolates. Between combination A and B there was no statistically significant difference for the detection of isolates from smear-positive specimens (P > 0.05), in contrast to the recovery of AFB from smear-negative specimens for M. tuberculosis complex, P < 0.05; for NTM, P < 0.01). The mean time to detection of M. tuberculosis complex was 12.2 days for smear-positive specimens and 18.1 days for smear-negative specimens with the BACTEC 9000 MB system; 9.3 and 15.6 days, respectively, with the BACTEC 460 system; and 21.2 and 28.4 days, respectively, with solid media. For NTM, the average detection times were 15.1, 17.3, and 31.3 days by the three methods, respectively. In conclusion, the BACTEC 9000 MB system is a rapid, less labor-intensive detection system which allows for higher levels of recovery of AFB than solid media. There is no risk of cross contamination, which is known to be the case for the BACTEC 460 system, and data management is greatly facilitated. As a whole, however, the BACTEC 9000 MB system should only be used in conjunction with solid media.


Challenging the error-likelihood model with a recognition paradigm: an electrophysiological study.
The error-likelihood model (ELM) postulates that activity of the anterior cingulate cortex is not only modulated by the commitment of an error but is rather dependent on the perceived ELM within task context. In this event-related potential (ERP) study we challenge these assumptions with a word-recognition paradigm. While learning phases were constant, ELM was modulated during recognition by varying the ratio of old and new words: old and new words had the same probability in low-risk sessions and the number of new words was tripled in high-risk sessions. Response-locked ERPs of correct yes-responses compared to no-responses revealed two different components with fronto-central distributions. The first negativity (time-range of the error-related negativity) elicited differentiations between yes- and no-responses. Yes-responses in high-risk compared to low-risk sessions resulted in an enlarged negativity. These results support the ELM which states that the activation of the anterior cingulate cortex is also modulated by the participant's perceived likelihood to commit an error and not the correctness of the response per se.


Alveolar Bone Housing- A Modified Wilkodontics Approach- A Case Report.
Accelerated orthodontic treatment is the need of the hour in current scenario as the conventional orthodontics is time taking. Corticotomy assisted orthodontics have been used for years to reduce the treatment duration by reducing the resistance provided by alveolar bone housing. This case report describes the orthodontic treatment combined with the modification in conventional wilkodontic technique in a patient to accelerate tooth movement and shorten the treatment time with an anterior open bite and flared and spaced upper and lower incisors. Firstly plaque control was achieved with supra and subgingival scaling. A modified approach using periodontal access flap followed by vertical bone cuts in the cortical bone from the crest of the alveolar bone margin to 2mm-3mm below the apices of all the anterior teeth extending from upper left canine to upper right canine were performed. These vertical cuts were joined by horizontal cuts apically and flap repositioned. An MBT 0.018 inch appliance was bonded. Orthodontic therapy proceeded with frequent activation of the appliances to retract the incisors every two weeks. The total treatment time was four and half months with active period of two months and no adverse effects were observed at the end of active treatment. The modified decortication technique reduced the treatment time to a considerable extent. The interdental spacing closed and optimum overjet and overbite was achieved.


Evaluating patterns of convergent evolution and trans-species polymorphism at MHC immunogenes in two sympatric stickleback species.
The immunologically important major histocompatibility complex (MHC) harbors some of the most polymorphic genes in vertebrates. These genes presumably evolve under parasite-mediated selection and frequently show inconsistent allelic genealogies, where some alleles are more similar between species than within species. This phenomenon is thought to arise either from convergent evolution under parallel selection or from the preservation of ancient allelic lineages beyond speciation events (trans-species polymorphism, TSP). Here, we examine natural populations of two sympatric stickleback species (Gasterosteus aculeatus and Pungitius pungitius) to investigate the contribution of these two mechanisms to the evolution of inconsistent allelic genealogies at the MHC. Overlapping parasite taxa between the two host species in three different habitats suggest contemporary parallel selection on the MHC genes. Accordingly, we detected a lack of species-specific phylogenetic clustering in the immunologically relevant antigen-binding residues of the MHC IIB genes which contrasted with the rest of the coding and noncoding sequence. However, clustering was not habitat-specific and a codon-usage analysis revealed patterns of similarity by descent. In this light, common descent via TSP, in combination with intraspecies gene conversion, rather than convergent evolution is the more strongly supported scenario for the inconsistent genealogy at the MHC.


A 5-year study of a new kind of photosynthetically active radiation sensor.
Light-emitting diodes (LED), which are designed as quasi-monochromatic light sources, can also function as spectrally selective photodiodes. This provides a new kind of photosynthetically active radiation (PAR) sensor that is inexpensive and has much better stability over time than interference filters used in some PAR sensors. The action spectrum of photosynthesis in green plants has principle peaks in the blue and red regions. LED with response peaks in the UV-A (380 nm) and red (620 nm) regions have been used to measure PAR at or near solar noon in an ongoing study begun on 30 April 1996. The sum of the signals from the two LED is highly correlated with measurements by a calibrated filterless PAR sensor (Apogee QSO; Logan, Utah) from 13 September 1997 to 16 January 2002 (r2 = 0.97). The sum of the LED signals is also highly correlated with measurements by a calibrated filter PAR sensor (LI-COR LI-190SA; Lincoln, Nebraska) from 20 April 1998 to 16 January 2002 (r2 = 0.97). Thus, pairs of spectrally selective LED can function as PAR detectors in economical PAR radiometers. The separate 380 and 620 nm responses also permit an assessment of the differential impact of aerosol events on blue and red PAR and phototropic radiation.


Patients with 3-vessel coronary artery disease and impaired ventricular function undergoing PCI with Impella 2.5 hemodynamic support have improved 90-day outcomes compared to intra-aortic balloon pump: a sub-study of the PROTECT II trial.
To evaluate the efficacy of hemodynamic support using Impella 2.5 (IR2.5) vs intra-aortic balloon pump (IABP) in patients with 3-vessel coronary artery disease (3VD). PROTECT II demonstrated favorable 90-day outcomes in patients with impaired LVEF and left main or 3VD undergoing PCI with hemodynamic support with IR2.5 compared to IABP. It is unclear if this was due to a specific benefit in a patient sub-population and if certain patients may derive particular benefit from PCI with IR2.5 support. Patients in PROTECT II were stratified upon enrollment into the left main/last patent vessel or 3VD subgroups and randomized to IR2.5 or IABP within those groups. Patients in the 3VD substratum were required to have LVEF ≤30%. Among the 3VD subgroup (n = 325 patients; IR2.5 167, IABP 158) patients were well matched, except for prior heart failure or CABG, which were more common in the IR2.5 group (both P ≤ 0.01). Mean number of lesions treated was 3.0 ± 1.5 vs. 2.9 ± 1.4 (P = 0.61). At 30 days after PCI, patients that received IR2.5 compared to IABP support trended toward a reduction in incidence of major adverse events (MAE): 32.9% vs. 42.4% (P = 0.078). At 90 days after PCI, there was a significant difference favoring IR2.5 for incidence of MAE: 39.5% vs. 51.0% (P = 0.039), with this effect being consistent across multiple clinical subgroups. Use of IR2.5 was an independent predictor of improved 90-day outcomes. Patients with 3VD and reduced LVEF show improved outcomes when PCI is performed with IR2.5 hemodynamic support.


Unravelling the in vitro and in vivo potential of selenium nanoparticles in Alzheimer's disease: A bioanalytical review.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and the accumulation of beta-amyloid plaques and tau tangles in the brain. Current therapies have limited efficacy, prompting the search for novel treatments. Selenium nanoparticles (SeNPs) have emerged as promising candidates for AD therapy due to their unique physicochemical properties and potential therapeutic effects. This review provides an overview of SeNPs and their potential application in AD treatment, as well as the main bioanalytical techniques applied in this field. SeNPs possess antioxidant and anti-inflammatory properties, making them potential candidates to combat the oxidative stress and neuroinflammation associated with AD. Moreover, SeNPs have shown the ability to cross the blood-brain barrier (BBB), allowing them to target brain regions affected by AD pathology. Various methods for synthesizing SeNPs are explored, including chemical, physical and biological synthesis approaches. Based on the employment of algae, yeast, fungi, and plants, green methods offer a promising and biocompatible alternative for SeNPs production. In vitro studies have demonstrated the potential of SeNPs in reducing beta-amyloid aggregation and inhibiting tau hyperphosphorylation, providing evidence of their neuroprotective effects on neuronal cells. In vivo studies using transgenic mouse models and AD-induced symptoms have shown promising results, with SeNPs treatment leading to cognitive improvements and reduced amyloid plaque burden in the hippocampus. Looking ahead, future trends in SeNPs research involve developing innovative brain delivery strategies to enhance their therapeutic potential, exploring alternative animal models to complement traditional mouse studies, and investigating multi-targeted SeNPs formulations to address multiple aspects of AD pathology. Overall, SeNPs represent a promising avenue for AD treatment, and further research in this field may pave the way for effective and much-needed therapeutic interventions for individuals affected by this debilitating disease.


Characterization of the DNA-binding motif of the arsenic-responsive transcription factor Yap8p.
Saccharomyces cerevisiae uses several mechanisms for arsenic detoxification including the arsenate reductase Acr2p and the arsenite efflux protein Acr3p. ACR2 and ACR3 are transcribed in opposite directions from the same promoter and expression of these genes is regulated by the AP-1 (activator protein 1)-like transcription factor Yap8p. Yap8p has been shown to permanently associate with this promoter and to stimulate ACR2/ACR3 expression in response to arsenic. In the present study we characterized the DNA sequence that is targeted by Yap8p. We show that Yap8p binds to a pseudo-palindromic TGATTAATAATCA sequence that is related to, but distinct from, the sequence recognized by other fungal AP-1 proteins. Probing the promoter by mutational analysis, we confirm the importance of the TTAATAA core element and pin-point nucleotides that flank this element as crucial for Yap8p binding and in vivo activation of ACR3 expression. A genome-wide search for this element combined with global gene expression analysis indicates that the principal function of Yap8p is to control expression of ACR2 and ACR3. We conclude that Yap8p and other yeast AP-1 proteins require distinct DNA-binding motifs to induce gene expression and propose that this fact contributed towards a separation of function between AP-1 proteins during evolution.


Treatment of chronic myelogenous leukemia with nucleoside analogs deoxycoformycin and fludarabine.
In vitro studies suggest that nucleoside analogs have an antileukemic effect against chronic myelogenous leukemia (CML). We investigated the antileukemia effect of deoxycoformycin (DCF) and fludarabine in patients with CML. Four patients with Philadelphia chromosome (Ph)-positive CML were treated with DCF at 4 mg/m2 every week for 4 weeks, then every other week for four doses, and then every month as maintenance. Two patients were in late chronic phase and two in accelerated phase. All had previously failed therapy with interferon-alpha (IFN-A). Nine patients were treated with fludarabine 30 mg/m2/day for 5 days every 28 days. Three had Ph-positive CML, and six Ph-negative disease. Five patients were in accelerated phase and four in late chronic phase. Three patients treated with DCF had normalization of WBC counts while on the weekly schedule but progressed when changed to every other week. The fourth patient had no objective response. There were no cytogenetic responses. DCF was well tolerated with only mild nausea and vomiting in all patients. Patients treated with fludarabine received a median of two courses (range 1-4). In two patients (both Ph-positive), disease progressed to blastic phase upon recovery. Two other patients died of hemorrhagic complications secondary to thrombocytopenia. In all other cases fludarabine produced a transient reduction of WBC counts, but counts recovered to levels equal to or greater than the pre-treatment values. There were no cytogenetic responses. These results, together with previous experience with 2-CDA producing only hematologic responses, suggest that nucleoside analogs may not have a significant role in the management of CML.


Photobacterium aphoticum sp. nov., isolated from coastal water.
A facultatively anaerobic marine gammaproteobacterium, designated strain M46(T), was isolated from Mediterranean seawater at Malvarrosa beach, Valencia, Spain. The strain was characterized by using a polyphasic approach and was found to be situated within the genus Photobacterium in the family Vibrionaceae. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain M46(T) was closely related to P. rosenbergii CECT 7644(T), P. halotolerans CECT 5860(T) and P. ganghwense CECT 7641(T), showing sequence similarities of 96.8, 96.4 and 96.2 %, respectively. According to the results of phylogenetic analyses based on recA and gyrB gene sequences, the most closely related taxon was P. ganghwense CECT 7641(T) with 87.4 and 85.0 % sequence similarity, respectively. Regardless of the gene used in phylogenetic analysis, strain M46(T) always formed a separate and stable clade containing these three species of the genus Photobacterium. Strain M46(T) was not luminescent and produced a diffusible brown pigment. It required NaCl to grow, reduced nitrate to nitrite and oxidized a small number of substrates in Biolog GN plates. Strain M46(T) was positive for arginine dihydrolase (ADH), β-galactosidase, aesculin hydrolysis and DNase activity. In API ZYM tests, the novel strain was positive for alkaline phosphatase, leucine arylamidase and acidic phosphatase activities. The major cellular fatty acids were unsaturated C(18) and C(16), as in other members of the genus Photobacterium, but their relative amounts and the presence or absence of other fatty acids differentiated strain M46(T) from its closest relatives. Based on the results of this polyphasic taxonomic study, strain M46(T) represents a novel species of the genus Photobacterium, for which the name Photobacterium aphoticum is proposed. The type strain is M46(T) ( = CECT 7614(T) = KCTC 23057(T)).


[Amplification at random of the DNA from 5 Cuban populations of larviphage fishes of the Rivulus genus].
DNA from 10 individuals from 5 populations of Rivulus collected in the western region of Cuba was amplified at random. No monomorphic marker resulted from the amplification by using 5 primers, which showed the high genetic variability existing among the fishes of the 5 populations. According to the genetic distance among the individuals, they were divided into 4 groups, for which there are specific genetic markers of RAPD, since they are not observed in the rest of the subjects. These results support the use of RAPD as an efficient tool for the genetic characterization of Cuban fishes of the Rivulus genus.


Distinction between esterases and lipases: comparative biochemical properties of sequence-related carboxylesterases.
Carboxylesterases (Carboxyl ester hydrolase) include two groups of enzymes, namely non-specific esterases (EC 184.108.40.206) and lipases (EC 126.96.36.199) which have been early differentiated on the basis of their substrate specificity. Esterases hydrolyse solutions of water-soluble short acyl chain esters and are inactive against water-insoluble long chain triacylglycerols which, in turn, are specifically hydrolyzed by lipases. Based on the comparison of the primary structures, three families of sequence-related carboxylesterases, namely the lipoprotein lipase family (L-family), the hormonesensitive lipase family (H-family) and the cholinesterase family (C-family) have been identified. Using solutions and emulsions of vinyl, glyceryl and p-nitrophenyl esters, we have reinvestigated the kinetic properties of some esterases and lipases of the H- and C-families. Results indicate that esterases and lipases, which are both active on soluble esters, can be differentiated by their value of Km. Moreover, esterase, unlike lipases, are inactive against water-insoluble esters as vinyl laurate and trioctanoylglycerol. From the the comparison of structural features of sequence-related esterases and lipases, it appears that lipases, unlike esterases, display a significant difference in the distribution of hydrophobic amino acid residues at vicinity of their active site. This observation supports the hypothesis of the existence in lipases of a particular surface domain that specifically interacts with lipid-water interfaces and contributes to the transfer a single substrate molecule from the organized lipid-water interface (supersubstrate) to the catalytic site of the enzyme.


Molecular epidemiology of human rotaviruses in Melbourne, Australia, from 1973 to 1979, as determined by electrophoresis of genome ribonucleic acid.
Rotaviruses contain a double-stranded ribonucleic acid genome consisting of 11 segments. Gel electrophoresis separates genome segments and allows identification of strain differences. This electrophoretic typing technique was applied to rotavirus specimens from 116 children and 72 newborn babies. Between 1973 and 1979, 17 different electropherotypes of rotavirus were observed in children with acute gastroenteritis. These electropherotypes showed a sequential pattern of appearance, with a limited number of electropherotypes present at any given time. By contrast, only two electropherotypes were identified from isolates from newborn babies in seven hospitals during 1975 to 1979. These two electropherotypes were very similar and were never identified in children with acute gastroenteritis. One of the neonatal electropherotypes was found in the nurseries of five different hospitals and persisted in one hospital for 4 years. Electrophoretic typing techniques can be applied routinely and reproducibly to small samples of feces and could prove to be of value in epidemiological studies of rotavirus infection


Intraabdominal local anaesthetics for postoperative pain relief following abdominal hysterectomy: a randomized, double-blind, dose-finding study.
Local anaesthetics administered intraabdominally have been found to reduce analgesic requirements postoperatively after hysterectomy. This study was designed to assess the optimal dose of local anaesthetics for best pain relief. Sixty patients undergoing abdominal hysterectomy were randomly divided into three groups to receive 10 ml h infusion of levobupivacaine intraabdominally postoperatively for 48 h in a double-blind manner: group L, 7.5 mg h; group M, 12.5 mg h and group H, 17.5 mg h. Pain intensity was measured using the numeric rating scale, ketobemidone consumption over 48 h was measured with a patient-controlled analgesia pump, recovery parameters, expiratory muscle strength, time to home readiness, plasma concentration of levobupivacaine and health-related quality of life were all measured at defined time points postoperatively. No differences were found between the active groups in pain intensity, recovery parameters or health-related quality of life. Pain intensity was maximal during 0-4 h and during coughing. Expiratory muscle strength decreased significantly during 0-4 h in all active groups, with no differences between the groups. Plasma concentration of levobupivacaine was below known toxic concentrations in humans, and no patient had symptoms of local anaesthetic toxicity. Health-related quality of life showed improved scores at 3 months after the operation compared with preoperative values, but no differences between the groups were found in any of the parameters. Satisfactory analgesia can be achieved with low doses of levobupivacaine administered intraabdominally, except during the early postoperative period. No advantages were seen in this study when higher doses of levobupivacaine were administered as a continuous infusion for postoperative pain relief.


Relationship between neck circumference, insulin resistance and arterial stiffness in overweight and obese subjects.
Background Only a few studies have investigated the relationship between neck circumference and cardiometabolic risk. The aim of this study was to assess the relationships between neck circumference, waist circumference, metabolic variables and arterial stiffness in a group of overweight and obese subjects evaluating a possible independent role of neck circumference in determining arterial stiffness. Methods and results We studied 95 subjects (53 women) with an age range of 20-77 years and body mass index range from 25.69 to 47.04 kg/m2. In each subject we evaluated body mass index, waist, hip and neck circumference, systolic and diastolic blood pressure, insulin, fasting glucose, cholesterol, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWVcf) and carotid-radial pulse wave velocity (PWVcr). Both PWVcf and PWVcr were higher in subjects with high values of neck circumference compared with subjects with normal values of neck circumference. Subjects with high values of neck circumference and abdominal obesity presented higher values of mean arterial pressure, PWVcr and homeostasis model assessment (HOMA) index and lower values of high-density lipoprotein than subjects with only abdominal obesity. Two models of stepwise multiple regression were performed in order to evaluate the combined effect of independent variables on arterial stiffness. In the first model PWVcf was considered a dependent variable, and age, gender, systolic blood pressure, triglycerides, high-density lipoprotein cholesterol, waist circumference, neck circumference, HOMA index and the use of anti-hypertensive medications were considered independent variables. Age, systolic blood pressure, triglycerides and waist circumference were significant predictors of PWVcf, explaining 65% of its variance. In the second model, in which PWVcr was considered a dependent variable, neck circumference and gender were significant predictors of PWVcr, explaining 24% of its variance. Conclusions These findings emphasise the need to measure not only waist but even neck circumference to better stratify and identify individuals at increased cardiometabolic risk, as upper-body subcutaneous fat is a novel, easily measured fat depot.


Evaluation of the Carba NP test for rapid detection of carbapenemase-producing Enterobacteriaceae and Pseudomonas aeruginosa.
The Carba NP test was evaluated against a panel of 244 carbapenemase- and non-carbapenemase-producing Enterobacteriaceae and Pseudomonas aeruginosa isolates. We confirmed the 100% specificity and positive predictive value of the test, but the sensitivity and negative predictive value were 72.5% and 69.2%, respectively, and increased to 80% and 77.3%, respectively, using a more concentrated bacterial extract. False-negative results were associated with mucoid strains or linked to enzymes with low carbapenemase activity, particularly OXA-48-like, which has emerged globally in enterobacteria.


Impact of vestibular nerve preservation on facial and hearing outcomes in small vestibular schwannoma surgery: a technical feasibility study.
Management of small vestibular schwannomas (VSs) remains controversial. When surgery is chosen, the preservation of facial and cochlear nerve function is a priority. In this report, we introduce and evaluate a technique to anatomically preserve the vestibular nerves to minimize manipulation and preserve the function of the facial and cochlear nerves. The vestibular nerve preservation technique was prospectively applied to resect small VS tumors in patients with serviceable preoperative hearing (American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) class A or B). Clinical and radiological data were recorded and analyzed. Ten patients met the inclusion criteria. The mean (SD) age was 40.4 (12.5) years. Follow-up ranged from 6 weeks to 2 years. The maximum tumor diameter parallel to the internal auditory canal ranged from 10 to 20 mm (mean, 14.9 (3.1) mm). There were three Koos grade 3 and seven Koos grade 2 tumors. Gross total resection was achieved in all cases. Both the facial and cochlear nerves were anatomically preserved in all cases. Postoperatively, 7 patients (70%) remained in the AAO-HNS class A or B hearing category. None of the patients had new vestibular symptoms, and all had House-Brackmann grade 1 facial function. Nervus intermedius dysfunction was observed in 1 patient preoperatively, which worsened postoperatively. Two patients had new nervus intermedius symptoms postoperatively. Improvement of facial nerve and hearing outcomes is feasible through the intentional preservation of the vestibular nerves in the resection of small VSs. Longer follow-up is required to rule out tumor recurrence.


Can the Fact That Myelin Proteins Are Old and Break down Explain the Origin of Multiple Sclerosis in Some People?
Recent discoveries may change the way that multiple sclerosis (MS) is viewed, particularly with regard to the reasons for the untoward immune response. The fact that myelin proteins are long-lived, and that by the time we are adults, they are extensively degraded, alters our perspective on the reasons for the onset of autoimmunity and the origin of MS. For example, myelin basic protein (MBP) from every human brain past the age of 20 years, is so greatly modified, that it is effectively a different protein from the one that was laid down in childhood. Since only a subset of people with such degraded MBP develop MS, a focus on understanding the mechanism of immune responses to central nervous system (CNS) antigens and cerebral immune tolerance appear to be worthwhile avenues to explore. In accord with this, it will be productive to examine why all people, whose brains contain large quantities of a "foreign antigen", do not develop MS. Importantly for the potential causation of MS, MBP from MS patients breaks down differently from the MBP in aged controls. If the novel structures formed in these MS-specific regions are particularly antigenic, it could help explain the origin of MS. If verified, these findings could provide an avenue for the rational synthesis of drugs to prevent and treat MS.


Risk factors for esophageal and gastric cancers in Shanxi Province, China: a case-control study.
Smoking and alcohol consumption explain little of the risk for upper-gastrointestinal (UGI) cancer in China, where over half of all cases in the world occur. We evaluated questionnaire-based risk factors for UGI cancers in a case-control study from Shanxi Province, China, including 600 esophageal squamous cell carcinomas (ESCCs), 599 gastric cardia adenocarcinomas (GCAs), 316 gastric noncardia adenocarcinomas (GNCAs), and 1514 age- and gender-matched controls. Ever smoking and ever use of any alcohol were not associated with risk of UGI cancer; only modest associations were observed between ESCC risk and highest cumulative smoking exposure, as well as GNCA risk and beer drinking. While several associations were noted for socioeconomic and some dietary variables with one or two UGI cancers, the strongest and most consistent relations for all three individual UGI cancers were observed for consumption of scalding hot foods (risk increased 150-219% for daily vs. never users) and fresh vegetables and fruits (risk decreased 48-70% for vegetables and 46-68% for fruits, respectively, for high vs. low quartiles). This study confirms the minor role of tobacco and alcohol in UGI cancers in this region, and highlights thermal damage as a leading etiologic factor.


Preschool Language Outcomes following Perinatal Hypoxic-Ischemic Encephalopathy in the Age of Therapeutic Hypothermia.
Early studies following perinatal hypoxic-ischemic encephalopathy (HIE) suggested expressive language deficits and academic difficulties, but there is only limited detailed study of language development in this population since the widespread adoption of therapeutic hypothermia (TH). Expressive and receptive language testing was performed as part of a larger battery with 45 children with a mean age of 26 months following perinatal HIE treated with TH. Overall cohort outcomes as well as the effects of gender, estimated household income, initial pH and base excess, and pattern of injury on neonatal brain MRI were assessed. The cohort overall demonstrated expressive language subscore, visual-reception subscore, and early learning composite scores significantly below test norms, with relative sparing of receptive language subscores. Poorer expressive language manifested as decreased vocabulary size and shorter utterances. Expressive language subscores showed a significant gender effect, and estimated socioeconomic status showed a significant effect on both receptive and expressive language subscores. Initial blood gas markers and modified Sarnat scoring did not show a significant effect on language subscores. Binarized MRI abnormality predicted a significant effect on both receptive and expressive language subscores; the presence of specific cortical/subcortical abnormalities predicted receptive language deficits. Overall, the language development profile of children following HIE in the era of hypothermia shows a relative strength in receptive language. Gender and socioeconomic status predominantly predict expressive language deficits; abnormalities detectable on MRI predominantly predict receptive language deficits.


Metal ions affecting the neurological system.
Several individual metals including aluminum, arsenic, cadmium, lead, manganese, and mercury were demonstrated to affect the neurological system. Metals are ubiquitous in the environment. Environmental and occupational exposure to one metal is likely to be accompanied by exposure to other metals, as well. It is, therefore, expected that interactions or "joint toxic actions" may occur in populations exposed to mixtures of metals or to mixtures of metals with other chemicals. Some metals seem to have a protective role against neurotoxicity of other metals, yet other interactions may result in increased neurotoxicity. For example, zinc and copper provided a protective role in cases of lead-induced neurotoxicity. In contrast, arsenic and lead co-exposure resulted in synergistic effects. Similarly, information is available in the current literature on interactions of metals with some organic chemicals such as ethanol, polychlorinated biphenyls, and pesticides. In depth understanding of the toxicity and the mechanism of action (including toxicokinetics and toxicodynamics) of individual chemicals is important for predicting the outcomes of interactions in mixtures. Therefore, plausible mechanisms of action are also described.


Robust HU-based CT ventilation from an integrated mass conservation formulation.
Computed tomography (CT) ventilation algorithms estimate volume changes induced by respiratory motion. Existing Hounsfield Unit (HU) methods approximate volume change from the measured HU variations between spatially corresponding voxel locations within a temporally resolved CT image pair, assuming that volume changes are caused solely by changes in air content. Numerical implementations require a deformable image registration to determine the inhale/exhale spatial correspondence, a preprocessing lung volume segmentation, a preprocessing high-intensity vessel segmentation, and a post-processing smoothing applied to the raw volume change estimates obtained for each lung tissue voxel. We introduce the novel mass-conserving volume change (MCVC) method for estimating voxel volume changes from the HU values within an inhale/exhale CT image pair. MCVC is based on subregional volume change estimates that possess quantitatively characterized and controllable levels of uncertainty. MCVC is therefore robust to small variations in DIR solutions and the resulting ventilation images are overall more reproducible. In contrast to existing HU methods, MCVC does not require a preprocessing lung vessel segmentation or pre/post-processing Gaussian smoothing. Subregional volume change estimates are defined in terms of mean density ratios. As such, the corresponding uncertainty is characterized using Gaussian statistics and standard error analysis of the sample density means. A numerical solution is obtained from the MCVC formulation by solving a constrained linear least squares problem defined by a series of subregional volume change estimates. Reproducibility of the MCVC method with respect to DIR solution was assessed using expert-determined landmark point pairs and inhale/exhale phases from 10 four-dimensional CTs (4DCTs) available on www.dir-lab.com. MCVC was also compared to the robust Integrated Jacobian Formulation (IJF), a transformation-based ventilation method. The ten Dir-Lab 4DCT cases were registered twice with the same DIR algorithm, but using different degrees of freedom (DIR 1 and DIR 2). Standard HU ventilation (HUV) and MCVC ventilation images were computed for both solutions. The average spatial errors (300 landmarks per case) for DIR 1 ranged between 0.74 and 1.50 mm, whereas for DIR 2 they ranged between 0.68 and 1.18 mm. Despite the differences in spatial errors between the two DIR solutions, the average Pearson correlation between the corresponding HUV images was 0.94 (0.03), while for the MCVC images it was 1.00 (0.00). The average correlation between MCVC and IJF ventilation over the ten test cases was 0.81 (0.14), whereas for HUV and IJF it was 0.56 (1.11). While HUV is robust to DIR solution, its implementation depends on heuristic Gaussian smoothing and vessel segmentation. MCVC is based on subregional volume change measurements with quantifiable and controllable levels of uncertainty. The subregional approach eliminates the need for Gaussian smoothing and lung vasculature segmentation. Numerical experiments are consistent with the underlying mathematical theory and indicate that MCVC ventilation is more reproducible with respect to DIR algorithm than standard HU methods. MCVC results are also more consistent with the robust IJF method, which suggests that incorporating robustness leads to more consistent results across both DIRs and ventilation algorithms.


Proteomic discovery of non-invasive biomarkers of localized prostate cancer using mass spectrometry.
Prostate cancer is the second most frequently diagnosed non-skin cancer in men worldwide. Patient outcomes are remarkably heterogeneous and the best existing clinical prognostic tools such as International Society of Urological Pathology Grade Group, pretreatment serum PSA concentration and T-category, do not accurately predict disease outcome for individual patients. Thus, patients newly diagnosed with prostate cancer are often overtreated or undertreated, reducing quality of life and increasing disease-specific mortality. Biomarkers that can improve the risk stratification of these patients are, therefore, urgently needed. The ideal biomarker in this setting will be non-invasive and affordable, enabling longitudinal evaluation of disease status. Prostatic secretions, urine and blood can be sources of biomarker discovery, validation and clinical implementation, and mass spectrometry can be used to detect and quantify proteins in these fluids. Protein biomarkers currently in use for diagnosis, prognosis and relapse-monitoring of localized prostate cancer in fluids remain centred around PSA and its variants, and opportunities exist for clinically validating novel and complimentary candidate protein biomarkers and deploying them into the clinic.


Global Tropospheric and Total Ozone Monitoring with a Double-Etalon Fabry-Perot Interferometer. II. Feasibility Analysis.
The feasibility of observing global tropospheric and total ozone (O(3)) fields with a double-etalon Fabry-Perot interferometer (FPI) has been assessed. The FPI provides high spectral resolution and high-throughput capabilities that enable observation in pressure-broadened wings of strong O(3) lines while minimizing the impact of undesirable signal contributions (i.e., from the terrestrial surface and interfering species). A retrieval technique has been implemented and is demonstrated for a tropical atmosphere possessing enhanced tropospheric ozone amounts. An error analysis assessing the impact on retrieved O(3) amounts from the most significant uncertainties associated with this particular measurement has been performed, and findings for a tropical atmosphere are presented. Results show the proposed instrumentation to enable a good measurement of absolute ozone amounts and an even better determination of relative changes.


Ruptured anterior communicating artery aneurysm encased in a tuberculum sellae meningioma. Case report.
This 70-year-old woman suffered a subarachnoid hemorrhage (SAH) from a ruptured anterior communicating artery aneurysm encased in a meningioma in the tuberculum sellae. Although preoperative magnetic resonance imaging disclosed that the aneurysmal complex was completely enclosed in the tumor, angiographic studies did not reveal arterial narrowing. The embedded aneurysm caused diffuse SAH rather than intratumoral hemorrhage. These factors indicated very little adhesion between the tumor and the encased arteries. Surgery was performed on the 20th day post-SAH. Intraoperative findings revealed that the tumor did not adhere to the enclosed vasculature except at the point of rupture of the aneurysm. The authors were able to clip the aneurysm safely after piecemeal removal of the tumor, which was finally extirpated without fear of aneurysm rupture. Careful stepwise procedures were essential to treat the aneurysm and the tumor simultaneously.


[Predictive value of some parameters of immune balance in preeclampsia].
The goal of our research was to reveal correlation between pro- and anti-inflammatory cytokines in preeclamptic women. The research was conducted on pregnant women with physiologic pregnancy and with preeclampsia. Parameters of immune system - pro-inflammatory cytokines (IL-2; TNF-α) and anti-inflammatory cytokine (IL-10) were measured in venous blood by ELISA. The increase of TNF-α and decrease of IL-10 in blood of pregnant women with pre-eclampsia after 20 weeks of gestation were observed; the content of IL-2 was in norm. The highest activation of inflammatory reactions was at the 20-28 weeks of gestation. It was found that women with preeclampsia had high levels of TNF- α in their blood. The increase of TNF- α has a prognostic significance.


Factors Associated With HPV Vaccine Initiation, Vaccine Completion, and Accuracy of Self-Reported Vaccination Status Among 13- to 26-Year-Old Men.
Human papillomavirus (HPV) vaccination coverage in young men is suboptimal. The aims of this study were (a) to examine HPV vaccination and factors associated with HPV vaccination in men 13 to 26 years of age and (b) to examine and determine factors associated with accurate self-report of vaccination. Young men ( n = 400) recruited from a teen health center and a sexually transmitted disease (STD) clinic completed a survey. Accuracy was defined as correct report of at least one dose and number of doses. Mean age was 21.5 years, 104 (26.0%) received at least one vaccine dose and 49 (12.3%) received all three doses. Factors significantly associated with receipt of at least one dose in multivariable models included recruitment site (teen health center vs. STD clinic, adjusted odds ratio [AOR] = 2.75), public versus other insurance (AOR = 2.12), and age (AOR = 0.68). Most young men accurately reported their vaccination status but accuracy of report differed by age: 50.6% of 14- to 18-year-olds, 75.9% of 19- to 21-year-olds, and 93.2% of 22- to 26-year-olds. Most (293, 73.3%) accurately reported number of doses received. Age was associated with accuracy of self-report of at least one vaccine dose (AOR = 1.42), while recruitment site (STD vs. teen health center, AOR = 2.56) and age (AOR = 1.44) were associated with accuracy of self-report of number of vaccine doses. In conclusion, HPV initiation and completion in this study sample were low. Teen health center attendance, public insurance, and younger age were associated with vaccine initiation; older age and STD clinic setting were associated with accurate vaccination self-report.


Immunologic studies on human factor VIII (anti-hemophilic factor A, AHF) components produced by low-ionic-strength dialysis.
Since dialysis of human factor VIII against buffers of low ionic strength yielded two distinct components, and since the factor VIII fraction isolated from normal plasma showed von Willebrand factor activity as defined by the corrective effect on abnormal platelet retention and ristocetin aggregation in von Willebrand's disease, the present studies were performed to determine if the correcting activities could be attributed to one or both of the components. Dialysis of factor VIII against buffers of low ionic strength led, however, to a decrease in factor VIII procoagulant activity and the reduction of the correcting activities, which suggested that the intact aggregate was required for procoagulant activity and for von Willebrand factor activity. In this respect dialysis of factor VIII at low ionic strength differed from dissociation at high salt concentrations. The two low ionic strength components were identified by the use of a rabbit antiserum against factor VIII, and could be distinguished on the basis of specific antigenic structures. Dialysis of factor VIII at low ionic strength led to a decrease in antigenic determinants closely related to factor VIII function. Specific antibodies to the low ionic strength components inhibited factor VIII activity in normal plasma, but the residual factor VIII was higher than that after inhibition with antibodies against intact factor VIII. Both antibodies interfered with von Willebrand factor activity.


An experimental study of tolerance among alcohol dependent individuals.
Continued alcohol use leads to tolerance, however, some dependent individuals lose tolerance despite continued alcohol consumption. The exact mechanism for this is not known. This study evaluated tolerance in alcohol dependent patients in a treatment centre using multiple measures. Male patients with alcohol dependence (DSM III R criteria) were chosen and detoxified in an inpatient setting. On day 14 of detoxification, each subject was given ethanol (0.75 g/kg body wt) mixed in an equal amount of placebo (cola) drink once and an equivalent amount of placebo (cola) during the other occasion in a single blind, randomised, cross over manner. Assessment of each subject was made using multiple measures (clinical, neuro-psychological tests, scales for subjective effect and blood alcohol levels), 30 min after intake of each drink. The subjects (n = 26) did not very under the two conditions (alcohol/placebo) as regards subjective effects, tests on logical memory and Bender Gestalt test (BGT). Cognitive screening scores though different under the two conditions, were within the normative range. Of these 26 subjects, 50 per cent showed clinical signs of intoxication after consumption of alcohol. These two groups (impaired vs unimpaired) were comparable on all base-line clinical parameters, assessment of euphoria and sedation, and various neuropsychological tests except BGT under the two conditions (placebo/alcohol). The non-tolerant (impaired) group scored significantly (P < 0.05) worse on BGT after alcohol consumption. The study suggests that clinical tests were more sensitive in detecting intoxication. Further studies are needed to understand the mechanism of loss of tolerance.


Stereotyped pathway selection by growth cones of early epiphysial neurons in the embryonic zebrafish.
In this report we have examined the development of one of the earliest projections in the embryonic zebrafish brain, that from the epiphysis. Epiphysial axons and growth cones were labelled anterogradely in whole-mounted brains, using either the carbocyanine dye, diI, or horseradish peroxidase (HRP). Some embryos were also either stained with anti-acetylated tubulin or HNK-1 antibodies to reveal other axons in the brain, or were secondarily sectioned for light and electron microscopy. The epiphysial axons have a very specific projection pattern and virtually all axons grow precisely to their target regions without error. The first epiphysial growth cone extends ventrally from the epiphysis into the dorsoventral diencephalic tract at 19-20 h post-fertilisation (h PF). Several hours later, it turns rostrally to grow alongside axons in the tract of the postoptic commissure. The morphology of the leading growth cone changes in predictable ways at different locations along its pathway and these changes correlate with differences in the local environment that it encounters. In contrast to other published descriptions of other developing systems, the epiphysial growth cone is no more complex either when pioneering a pathway, or when encountering divergent axonal pathways. Indeed, it is most complex (i.e. has the greatest number of processes) when it first starts to follow the tract of the postoptic commissure. The presence and selective retention of filopodia within other axonal pathways suggests that growth cones have access to these pathways but do not select them. These observations support the notion that local guidance cues exist within the early scaffold of brain tracts. Subsequent epiphysial axons form a tight fascicle within the dorsoventral diencephalic tract, but abruptly defasciculate from each other upon turning rostrally into the tract of the postoptic commissure. Epiphysial growth cones that enter this tract at abnormal locations still turn in the appropriate direction. Therefore, guidance cues are not restricted solely to the normal intersections but may be distributed along the length of the tracts. The epiphysial growth cones and axons have very characteristic spatial relations to other axons in the tracts of the developing brain. They are restricted to the dorsal region of the tract of the postoptic commissure and the rostral region of the postoptic commissure. At early developmental stages, the epiphysial axons are the only axons within the dorsoventral diencephalic tract and they are located very superficially within the neuroepithelium. At later stages, they are displaced to deeper regions of the neuropil by non-epiphysial axons.


Modulation of u-PA, MMPs and their inhibitors by a novel nutrient mixture in pediatric human sarcoma cell lines.
Pediatric sarcomas are highly aggressive tumors that are characterized by high levels of matrix metalloproteinase (MMP)-2 and -9 secretions that degrade the ECM and basement membrane, allowing cancer cells to spread to distal organs. Proteases play a key role in tumor cell invasion and metastasis by digesting the basement membrane and ECM components. Strong clinical and experimental evidence demonstrates association of elevated levels of u-PA and MMPs with cancer progression, metastasis and shortened patient survival. MMP activities are regulated by specific tissue inhibitors of metalloproteinases (TIMPs). Our main objective was to study the effect of a nutrient mixture (NM) on activity of u-PA, MMPs and TIMPs in various human pediatric sarcomas. Human osteosarcoma MNNG-HOS, osteosarcoma U-2OS and rhabdomyosarcoma RD cell lines (ATCC) were cultured in their respective media and treated at confluence with NM at 0, 50, 100, 250, 500 and 1,000 µg/ml. Analysis of u-PA activity was carried out by fibrin zymography, MMPs by gelatinase zymography and TIMPs by reverse zymography. All sarcoma cell lines studied expressed u-PA, which was inhibited by NM in a dose-dependent manner. On gelatinase zymography, osteosarcoma MNNG-HOS showed a band corresponding to MMP-2 and induction of MMP-9 with PMA (100 ng/ml) treatment. U-2OS osteosarcoma cells showed strong bands corresponding to inactive MMP-2 and MMP-9 and faint bands corresponding to active MMP-2 and MMP-9 dimer; PMA treatment enhanced MMP-9 and MMP-9 dimer activity. Rhabdomyosarcoma showed MMP-2 and faint MMP-9 bands; PMA treatment enhanced MMP-9 expression. NM inhibited their expression in a dose-dependent manner. Activity of TIMPs was upregulated by NM in all cancer cell lines in a dose-dependent manner. Analysis revealed a positive correlation between u-PA and MMPs and a negative correlation between u-PA/MMPs and TIMPs. These findings suggest the therapeutic potential of NM in treatment of pediatric sarcomas.


Transient establishment of anteroposterior polarity in the zebrafish pectoral fin bud in the absence of sonic hedgehog activity.
Sonic hedgehog (Shh) is expressed in the posterior vertebrate limb bud mesenchyme and directs anteroposterior patterning and growth during limb development. Here we report an analysis of the pectoral fin phenotype of zebrafish sonic you mutants, which disrupt the shh gene. We show that Shh is required for the establishment of some aspects of anteroposterior polarity, while other aspects of anteroposterior polarity are established independently of Shh, and only later come to depend on Shh for their maintenance. We also demonstrate that Shh is required for the activation of posterior HoxD genes by retinoic acid. Finally, we show that Shh is required for normal development of the apical ectodermal fold, for growth of the fin bud, and for formation of the fin endoskeleton.


Antioxidant axis Nrf2-keap1-ARE in inhibition of alcoholic liver fibrosis by IL-22.
To explore the effect of interleukin (IL)-22 on in vitro model of alcoholic liver fibrosis hepatic stellate cells (HSCs), and whether this is related to regulation of Nrf2-keap1-ARE. HSC-T6 cells were incubated with 25, 50, 100, 200 and 400 μmol/L acetaldehyde. After 24 and 48 h, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect proliferation of HSCs to choose the best concentration and action time. We used the optimal concentration of acetaldehyde (200 μmol/L) to stimulate HSCs for 24 h, and treated the cells with a final concentration of 10, 20 or 50 ng/mL IL-22. The cell proliferation rate was detected by MTT assay. The cell cycle was analyzed by flow cytometry. The expression of nuclear factor-related factor (Nrf)2 and α-smooth muscle antigen was detected by western blotting and immunocytochemistry. The levels of malondialdehyde (MDA) and glutathione (GSH) were measured by spectrophotometry. In the MTT assay, when HSCs were incubated with acetaldehyde, activity and proliferation were higher than in the control group, and were most obvious after 48 h treatment with 200 μmol/L acetaldehyde. The number of cells in G0/G1 phases was decreased and the number in S phase was increased in comparison with the control group. When treated with different concentrations of IL-22, HSC-T6 cell activity and proliferation rate were markedly decreased in a dose-dependent manner, and cell cycle progression was arrested from G1 to S phase. Western blotting and immunocytochemistry demonstrated that expression of Nrf2 total protein was not significantly affected. Expression of Nrf2 nuclear protein was low in the control group, increased slightly in the model group (or acetaldehyde-stimulated group), and increased more obviously in the IL-22 intervention groups. The levels of MDA and GSH in the model group were significantly enhanced in comparison with those in the control group. In cells treated with IL-22, the MDA level was attenuated but the GSH level was further increased. These changes were dose-dependent. IL-22 inhibits acetaldehyde-induced HSC activation and proliferation, which may be related to nuclear translocation of Nrf2 and increased activity of the antioxidant axis Nrf2-keap1-ARE.


Local ecological knowledge among Baka children: a case of "children's culture" ?
Childhood is an extensive life period specific to the human species and a key stage for development. Considering the importance of childhood for cultural transmission, we test the existence of a 'children's culture', or child-specific knowledge and practices not necessarily shared with adults, among the Baka in Southeast Cameroon. Using structured questionnaires, we collected data among 69 children and 175 adults to assess the ability to name, identify, and conceptualize animals and wild edibles. We found that some of the ecological knowledge related to little mammals and birds reported by Baka children was not reported by adults. We also found similarities between children's and adult's knowledge, both regarding the content of knowledge and how knowledge is distributed. Thus, middle childhood children hold similar knowledge than adults, especially related to wild edibles. Moreover, as children age, they start shedding child-specific knowledge and holding more adult's knowledge. Additionally and echoing the gendered knowledge distribution present in adulthood, since middle childhood there are differences in the knowledge hold by boys and girls. We discuss our results highlighting the existence of specific ecological knowledge held by Baka children, the overlap between children's and adults' knowledge, and the changes in children's ecological knowledge as they move into adulthood.


Synthesis and Biological Evaluation of Hydroxylated Monocarbonyl Curcumin Derivatives as Potential Inducers of Neprilysin Activity.
Alzheimer's disease (AD) involves impairment of Aβ clearance. Neprilysin (NEP) is the most efficient Aβ peptidase. Enhancement of the activity or expression of NEP may provide a prominent therapeutic strategy against AD. Ten hydroxylated monocarbonyl curcumin derivatives were designed, synthesized and evaluated for their NEP upregulating potential using sensitive fluorescence-based Aβ digestion and inhibition assays. Compound 4 was the most active one, resulting in a 50% increase in Aβ cleavage activity. Cyclohexanone-bearing derivatives exhibited higher activity enhancement compared to their acetone counterparts. Inhibition experiments with the NEP-specific inhibitor thiorphan resulted in dramatic cleavage reduction. Conclusion: The increased Aβ cleavage activity and the ease of synthesis of 4 renders it an extremely attractive lead compound.


Localization of carboxyl ester lipase in human pituitary gland and pituitary adenomas.
Carboxyl ester lipase (CEL) is an enzyme that hydrolyzes a wide variety of lipid substrates, including ceramides, which are known to show inhibitory regulation of pituitary hormone secretion in experimental models. Because no studies on CEL expression in human pituitary and pituitary adenomas have been reported in the literature, we investigated CEL expression in 10 normal pituitary glands and 86 well-characterized pituitary adenomas [12 FSH/LH cell, 17 α-subunit/null cell, 6 TSH cell, 21 ACTH cell, 11 prolactin (PRL) cell, and 19 GH cell adenomas] using IHC, immunoelectron microscopy, Western blotting, and quantitative RT-PCR. In normal adenohypophysis, CEL was localized in GH, ACTH, and TSH cells. In adenomas, it was mainly found in functioning GH, ACTH, and TSH tumors, whereas its expression was poor in the corresponding silent adenomas and was lacking in FSH/LH cell, null cell, and PRL cell adenomas. Ultrastructurally, CEL was localized in secretory granules close to their membranes. This is the first study demonstrating CEL expression in normal human pituitary glands and in functioning GH, ACTH, and TSH adenomas. Considering that CEL hydrolyzes ceramides, inactivating their inhibitory function on pituitary hormone secretion, our findings suggest a possible role of CEL in the regulation of hormone secretion in both normal and adenomatous pituitary cells.


Cognitive impairment and Charles Bonnet syndrome: a prospective study.
Charles Bonnet syndrome (CBS) is a common cause of visual hallucinations in older people. The relationship between CBS and cognitive impairment is unclear, but anecdotal reports exist of dementia emerging in patients diagnosed with CBS. This work set out to determine if there is an increased incidence of dementia, and increased severity of cognitive impairment, in people with CBS compared to controls from the same clinical setting. People over 65 attending low-vision and glaucoma clinics, and a cohort of age-matched controls, underwent a psychiatric assessment. The cohorts were followed up after one year. Mild cognitive impairment was present in 2/12 CBS participants and 2/10 controls. Partial insight was seen in nine CBS participants. Two participants with CBS, and no controls, developed dementia at follow-up. No significant differences in performance on the ACE-R were found between the groups. Both participants who developed dementia had partial insight and hallucinations of familiar figures at diagnosis of CBS, and one had mild cognitive impairment. Reassurance that CBS is universally benign may be misplaced. Some people given this diagnosis go on to develop dementia. Cognitive testing at the point of diagnosis was unable to identify those at risk of this outcome. Partial insight, the presence of Mild Cognitive Impairment, and hallucinations of familiar figures at diagnosis of CBS may confer an increased risk of subsequent dementia diagnosis. Copyright © 2017 John Wiley & Sons, Ltd.


An examination of the observed placebo effect associated with the treatment of low back pain - a systematic review.
To determine whether the nonspecific effects that occur following the use of sham interventions to treat nonspecific low back pain (LBP) are large enough to be considered clinically meaningful. Electronic databases were searched systematically for randomized placebo-controlled trials of interventions for LBP that used sham ultrasound, sham laser or sham drug therapy as the placebo control. Study selection was accomplished via independent evaluation of scientific admissibility by three reviewers and final decisions of inclusion were based on consensus. None of the studies using sham ultrasound as the placebo control in the treatment of LBP were acceptable for inclusion. Twelve studies were included in the present evaluation of the placebo effect - eight trials that met the strict inclusion criteria for best evidence (three using sham laser placebo and five using sham medication placebo) and four sham medication studies that 'just missed' the inclusion criteria for best evidence. Although the evidence from studies using sham laser was inconclusive, the present review did find a clinically meaningful change in LBP scores following the use of sham oral medications. The present best-evidence review found a clinically meaningful change in pain scores following the use of sham oral medications for the treatment of nonspecific LBP. This finding suggests that further clinical research is warranted to identify which patient subgroups could benefit most from such treatment and to distinguish the true contribution of the placebo effect from other nonspecific effects.


Wounding stress increases the phenolic content and antioxidant capacity of purple-flesh potatoes (Solanum tuberosum L.).
Several abiotic stresses, including ethylene, methyl jasmonate, temperature, light, and wounding, were tested for their ability to induce accumulation of phenolic compounds and antioxidant capacity in purple-flesh potatoes (cv. All Blue). Results indicated that temperature, ethylene, methyl jasmonate, and light treatments did not significantly affect the accumulation of phenolic compounds compared to control samples. Only tubers with low initial anthocyanin levels treated with methyl jasmonate showed approximately 60% anthocyanin accumulation. Wounding induced the accumulation of phenolics compounds and an increase of PAL-activity in sliced tissue compared to the control. Total phenolics increased approximately 60% with a parallel 85% increase in antioxidant capacity. These results show that selection of appropriate abiotic stresses can enhance the nutritional and functional value of potatoes.


Channel reduction in massive array parallel MRI.
This paper presents a method to explore the flexibility of channel reduction in k-domain parallel imaging with massive arrays to improve the computation efficiency. MCMLI and GRAPPA are k-domain reconstruction methods that use a neighborhood of PE columns, FE line(s) and all channels in the interpolation kernels. For massive array which contains a large number of element coils computation cost can be a significant problem. In this paper, channel selection and reduction is performed according to the correlation between channel images for individual channel reconstructions. Simulation results show that the proposed channel reduction algorithm can achieve similar or improved reconstruction quality with significantly reduced computation for massive arrays with localized sensitivity.


Mechanisms of glyceryl trinitrate provoked mast cell degranulation.
Migraine patients develop attacks several hours after intravenous infusion of glyceryl trinitrate. Due to the short half-life of nitric oxide, this delayed migraine cannot be caused by a direct action of nitric oxide derived from glyceryl trinitrate. The involvement of meningeal inflammation and dural mast cell degranulation is supported by the effectiveness of prednisolone on glyceryl trinitrate-induced delayed headache. Using a newly developed rat model mimicking the human glyceryl trinitrate headache model, we have investigated the occurrence of dural mast cell degranulation after a clinically relevant dose of glyceryl trinitrate. A 6-fold increase in degranulation was observed starting at 2 hours after glyceryl trinitrate infusion. Interestingly, pre-treatment with the effective anti-migraine substances L-nitro-arginine methyl ester and sumatriptan prevented glyceryl trinitrate-induced mast cell degranulation whereas the calcitonin gene-related peptide-receptor antagonist olcegepant and the substance P receptor antagonist L-733,060 did not affect mast cell degranulation. However, topical application of two different nitric oxide donors did not cause mast cell degranulation ex vivo. Direct application of an exogenous nitric oxide donor on dural mast cells does not cause mast cell degranulation ex vivo. In vivo application of the nitric oxide donor glyceryl trinitrate leads to a prominent level of degranulation via a yet unknown mechanism. This effect can be completely blocked by inhibition of the endogenous nitric oxide production and by 5-HT1B/1D receptor agonists but is unaffected by calcitonin gene-related peptide and substance P receptor antagonists.


Prevalence of 25(OH) vitamin D (calcidiol) deficiency at time of renal transplantation: a prospective study.
25(OH) Vitamin D (calcidiol) is the major circulating form of vitamin D and is considered the most reliable measure of vitamin D status. Adequate vitamin D status is important for bone health but there is increasing evidence that low serum concentrations of calcidiol (<30 ng/mL) are associated with many adverse health outcomes in the general population. Little is known about calcidiol status at the time of renal transplantation, a period when bone loss is greatest and immunosuppression is highest. We prospectively measured serum calcidiol and parathyroid hormone immediately after transplant from March 2005 onwards. Of 112 patients studied, 29% had calcidiol deficiency (<10 ng/mL), 59% had calcidiol insufficiency (10-29 ng/mL) and only 12% of patients had a normal calcidiol concentration (>30 ng/mL). The prevalence of calcidiol deficiency in black recipients was extremely high at 41%. Serum calcidiol tended to be lower in winter than other seasons. In conclusion, the prevalence of 25(OH) vitamin D (calcidiol) deficiency/insufficiency at the time of renal transplant is very high. The clinical effects of this deficiency/insufficiency deserve further study.


Community Experiences and Perceptions of Clinical and Translational Research and Researchers.
Engaging communities in research is increasingly recognized as critical to translation of research into improved health outcomes. Our objective was to understand community stakeholders' perspectives on researchers, academic institutions, and how community is valued in research. A 45-item survey assessing experiences and perceptions of research (trust, community value, equity, researcher preparedness, and indicators of successful engagement) was distributed to 226 community members involved in health research with academic institutions. Of the 109 respondents, 60% were racial/ethnic minorities and 78% were women, representing a range of community organizations, faith-based organizations, and public health agencies. Most (57%) reported current involvement with a Clinical and Translational Science Award (CTSA). Only 25% viewed researchers as well-prepared to engage communities and few (13%) reported that resources were available and adequate to support community involvement. Most community stakeholders (66%) were compensated for their involvement in research, but only 40% perceived compensation to be appropriate. Trust of research and perceptions that researchers value community were more positive among those who perceived their compensation as appropriate (P = .001). Appropriate compensation and resources to support community involvement in research may improve perceptions of trust and value in academic-community partnerships. Strategies are needed to increase researcher preparedness to engage with communities.


Blood brain-barrier disruption of nonionic iodinated contrast medium following coil embolization of a ruptured intracerebral aneurysm.
Few reports of temporary disruption of the blood-brain barrier (BBB) following neurointerventional procedures, presumably caused by nonionic radiographic contrast medium (CM), exist in the literature. We described such a case in a 72-year-old man presenting with acute subarachnoid hemorrhage, who underwent coil embolization of a ruptured anterior communicating artery complex aneurysm. At the time of his follow-up CT examination, a large amount of iodine was found in the cerebrospinal fluid (CSF). Because of this experience, the iodine concentration in the CSF of five other patients who also underwent an intracranial endovascular procedure was measured. It was concluded that this increased iodine might have been caused by temporary leakage or breakdown of the BBB. Even if the total amount of CM may not be excessive, the disproportionately high concentration injected into a single vascular territory may pose a unique set of variables increasing the risk of BBB disruption.


LEF1 and B9L shield β-catenin from inactivation by Axin, desensitizing colorectal cancer cells to tankyrase inhibitors.
Hyperactive β-catenin drives colorectal cancer, yet inhibiting its activity remains a formidable challenge. Interest is mounting in tankyrase inhibitors (TNKSi), which destabilize β-catenin through stabilizing Axin. Here, we confirm that TNKSi inhibit Wnt-induced transcription, similarly to carnosate, which reduces the transcriptional activity of β-catenin by blocking its binding to BCL9, and attenuates intestinal tumors in Apc(Min) mice. By contrast, β-catenin's activity is unresponsive to TNKSi in colorectal cancer cells and in cells after prolonged Wnt stimulation. This TNKSi insensitivity is conferred by β-catenin's association with LEF1 and BCL9-2/B9L, which accumulate during Wnt stimulation, thereby providing a feed-forward loop that converts transient into chronic β-catenin signaling. This limits the therapeutic value of TNKSi in colorectal carcinomas, most of which express high LEF1 levels. Our study provides proof-of-concept that the successful inhibition of oncogenic β-catenin in colorectal cancer requires the targeting of its interaction with LEF1 and/or BCL9/B9L, as exemplified by carnosate.


The effectiveness of non-pharmacological interventions in older adults with depressive disorders: A systematic review.
It is widely acknowledged that mental health disorders are common in older adults and that depression is one of the most serious threats to the mental health of older adults. Although best practice guidelines point out that moderate to severe depression should be approached with pharmacotherapy together with complementary therapies, the use of antidepressant drugs in older adults has various disadvantages, such as long response time, side effects, potential risk of dependency and tolerance, poor compliance rates and high probability of drug interactions. In addition, qualitative studies of depressed people with a chronic illness have indicated that both patients and healthcare professionals prefer a psychosocial treatment for depression over a pharmacological one. This review aimed to identify and synthesize the best available evidence related to the effectiveness of non-pharmacological interventions for older adults with depressive disorders. Systematic review of studies with any experimental design considering non-pharmacological interventions for older adults with depressive disorders. An initial search of MEDLINE and CINAHL was undertaken, followed by a second search for published and unpublished studies, from January 2000 to March 2012, of major healthcare-related electronic databases. Studies in English, Spanish and Portuguese were included in the review. This review considered studies that included adult patients, aged over 65 years with any type of depressive disorder, regardless of comorbidities and any previous treatments, but excluded those with manic or psychotic episodes/symptoms. All studies that met the inclusion criteria were assessed for methodological quality by two independent reviewers using a standardized critical appraisal checklist for randomized and quasi-randomized controlled studies from the Joanna Briggs Institute. Data extraction was also conducted by two independent reviewers based on the Joanna Briggs Institute data extraction form for experimental studies. Twenty-three studies met the inclusion criteria. Of those, seventeen were excluded after critical appraisal of methodological quality and six were included in this review. These studies included 520 participants and described cognitive behavior therapy, competitive memory training, reminiscence group therapy, problem-adaptation therapy, and problem-solving therapy in home care. Evidence suggests that all these interventions reduce depressive symptoms. According to evidence, non-pharmacological interventions had positive effects on improving patients' depression and may be useful in practice. However, due to the diversity of interventions and the low number of studies per intervention included in this systematic review, evidence is not strong enough to produce a best practice guideline.


Evolutionary stability of collateral sensitivity to antibiotics in the model pathogen Pseudomonas aeruginosa.
Evolution is at the core of the impending antibiotic crisis. Sustainable therapy must thus account for the adaptive potential of pathogens. One option is to exploit evolutionary trade-offs, like collateral sensitivity, where evolved resistance to one antibiotic causes hypersensitivity to another one. To date, the evolutionary stability and thus clinical utility of this trade-off is unclear. We performed a critical experimental test on this key requirement, using evolution experiments with Pseudomonas aeruginosa, and identified three main outcomes: (i) bacteria commonly failed to counter hypersensitivity and went extinct; (ii) hypersensitivity sometimes converted into multidrug resistance; and (iii) resistance gains frequently caused re-sensitization to the previous drug, thereby maintaining the trade-off. Drug order affected the evolutionary outcome, most likely due to variation in the effect size of collateral sensitivity, epistasis among adaptive mutations, and fitness costs. Our finding of robust genetic trade-offs and drug-order effects can guide design of evolution-informed antibiotic therapy.