Currently approved and emerging oral therapies in multiple sclerosis: An update for the ophthalmologist.
Although our understanding of multiple sclerosis (MS) has grown substantially, its cause remains unknown. Nonetheless, in the past 3 decades, there have been tremendous advancements in the development of disease-modifying drugs (DMDs). In July 1993, the United States Food and Drug Administration approved the first disease-modifying drug-interferon β- and there are currently 13 medications approved for use in relapsing MS. All the early medications are administered either as a subcutaneous or intramuscular injection, and despite the clinical efficacy and safety of these medications, many patients were hampered by the inconvenience of injections and injection-related side effects. In September 2010, the first oral DMD-fingolimod-was approved. Since then, 2 additional oral DMDs (teriflunomide and dimethyl fumarate) have been approved, and several other oral medications are being evaluated in extensive MS development programs. Because of frequent ocular involvement, ophthalmologists are often involved in the care of MS patients and therefore need to be aware of the current treatment regimens prescribed by neurologists, some of which can have significant ophthalmic adverse events. We update the current advancements in the treatment of MS and discuss the published clinical data on the efficacy and safety of the currently approved and emerging oral therapies in MS.


Folate receptor-mediated cervical staining as an adjunct to colposcopy which can improve the diagnostic accuracy of detecting high grade squamous intraepithelial lesions.
Cervical cancer is rated fourth in terms of incidence and cancer-related mortality in women. Cytology-based screening programs and colposcopy provided insufficient rates of detecting cervical intraepithelial neoplasia (CIN) prompting researchers to develop new tools. The aim of this study was to evaluate whether folate receptor-mediated staining is useful in detecting CIN2+ during gynecological examination with colposcopy. In total 96 women with abnormal cytology findings were enrolled. The study was conducted on the Polish population. The diagnostic process consisted of colposcopy, receptor-mediated diagnosis (FRD), and histopathology examination. All women were subjected to the same diagnostic procedure. The patient mean age of 96 women was 38 ± 14.5 years. On colposcopy, high-grade lesions were detected in 83 women. The FRD gave positive results in 63 women. Histopathology revealed 1 case of carcinoma plano epithelial akeratodes, 21 cases of high-grade squamous intraepithelial lesions, 13 cases of low-grade squamous intraepithelial lesions. A total of 61 cases presented no pathology. FRD as an adjunct to colposcopy gave the following test results in detecting CIN2+ lesions: sensitivity - 94.29%, specificity - 46.67%, PPV - 50.77%, NPV - 93.33%, and accuracy - 64.21%. Using both techniques provided better results than using each of the tests alone. FRD is a promising test for the diagnosing CIN2+ cervical pathologies because it can increase the probability of detecting CIN2+ without any additional burden posed on patients. Further studies should be conducted on large and various populations to complement current evidence.


[Synaptic organization of the vestibular nucleus in the medulla oblongata of the frog Rana temporaria].
Studies have been made on the synaptic organization of ventral vestibular nucleus of the frog R. temporaria. Besides numerous axo-somatic and axo-dendritic synapses, 3-component axo-axonal synaptic contacts were revealed which indicate a possibility of presynaptic inhibition in the nucleus studied. Three types of membrane specializations were found in axo-somatic and axo-dendritic synaptic contacts-active zone of chemical synapse, symmetric thickening of the membranes of desmosomal type and close linking of the membranes of electrotonic synapse. Functional role of the observed contacts is discussed.


Oncogenes as regulators of apoptosis.
Although cancer is a disease that will afflict one out of three people in the Western world, when considered at a cellular level, it is a rare clonal event. Long-lived organisms, such as humans, have evolved strategies to restrict the development of potentially malignant cells, and one such mechanism is the coupling of proliferative and apoptotic pathways. Multiple oncogenes have the ability to trigger apoptosis when expressed in an inappropriate fashion, and this is thought to restrict tumour formation by eliminating potentially malignant cells that have acquired a mutation stimulating proliferation. Hence for a tumour to arise, in addition to mutations that drive proliferation, mutations that prevent apoptosis are also a prerequisite.


Today's doctors: What do men and women value in a training post?
Recent studies suggest that traditional male-female differences may be changing in terms of what is valued in a medical career but there have been no studies directly quantifying the relationship between gender and stated career-related preferences. To address this gap, we examined the differences between male and female doctors in terms of the strength of their work-related preferences at the point of eligibility to enter residency or specialty training in the UK. This was a quantitative study using a survey incorporating a discrete choice experiment (DCE). Respondents were asked a series of questions in which they had to choose between two or more scenarios, differing in terms of attributes. The attributes were: location; familiarity with specialty; culture of the working and learning environment; earnings; working conditions, and opportunities for professional development. The main outcome measure was willingness to accept compensation to forgo a desirable attribute within a training position. Conditional logistic regression models were run separately for males and females. A total of 5005 out of 6890 (73%) Foundation Year 2 doctors completed the DCE. The relative value of each attribute was similar for males and females, with location most valued and familiarity with the specialty least valued. There was a pattern of female respondents valuing the move between the best and worst levels of each training attribute more than men, and significantly more than men in respect of the importance of working culture. This study adds to existing knowledge in terms of quantifying gendered values in respect of training or residency preferences. That men value a supportive working culture significantly less than women is well established. However, our findings that location, working conditions and working culture are increasingly important to both men and women, suggests that traditional gender norms may be changing. This intelligence can inform gender-responsive workforce planning and innovation, and future research.


Neural-network design for small training sets of high dimension.
We introduce a statistically based methodology for the design of neural networks when the dimension d of the network input is comparable to the size n of the training set. If one proceeds straightforwardly, then one is committed to a network of complexity exceeding n. The result will be good performance on the training set but poor generalization performance when the network is presented with new data. To avoid this we need to select carefully the network architecture, including control over the input variables. Our approach to selecting a network architecture first selects a subset of input variables (features) using the nonparametric statistical process of difference-based variance estimation and then selects a simple network architecture using projection pursuit regression (PPR) ideas combined with the statistical idea of slicing inverse regression (SIR). The resulting network, which is then retrained without regard to the PPR/SIR determined parameters, is one of moderate complexity (number of parameters significantly less than n) whose performance on the training set can be expected to generalize well. The application of this methodology is illustrated in detail in the context of short-term forecasting of the demand for electric power from an electric utility.


A Review of the Nutritional Approach and the Role of Dietary Components in Children with Autism Spectrum Disorders in Light of the Latest Scientific Research.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects several areas of mental development. The onset of ASD occurs in the first few years of life, usually before the age of 3 years. Proper nutrition is important to ensure that an individual's nutrient and energy requirements are met, and it can also have a moderating effect on the progression of the disorder. A systematic database search was conducted as a narrative review to determine whether nutrition and specific diets can potentially alter gastrointestinal symptoms and neurobehavioral disorders. Databases such as Science Direct, PubMed, Scopus, Web of Science (WoS), and Google Scholar were searched to find studies published between 2000 and September 2023 on the relationship between ASD, dietary approaches, and the role of dietary components. The review may indicate that despite extensive research into dietary interventions, there is a general lack of conclusive scientific data about the effect of therapeutic diets on ASD; therefore, no definitive recommendation can be made for any specific nutritional therapy as a standard treatment for ASD. An individualized dietary approach and the dietician's role in the therapeutic team are very important elements of every therapy. Parents and caregivers should work with nutrition specialists, such as registered dietitians or healthcare providers, to design meal plans for autistic individuals, especially those who would like to implement an elimination diet.


State-of-the-art of irritable bowel syndrome and inflammatory bowel disease research in 2008.
Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are two of the leading causes of chronic intestinal conditions in the world. This issue of World Journal of Gastroenterology (WJG) presents a series of papers from world experts who discuss the current knowledge and opinions on these important conditions. Although great strides have been made in the diagnosis, treatment and pathology of IBS and IBD; much has yet to be explained. The etiologies and risk factors of these multifactorial conditions remain elusive. Specific diagnostic biomarkers need to be developed and safer treatments developed. The burden of IBS and IBD on the healthcare system is felt with repeated medical care visits and high costs. IBS and IBD patients can account for 30%-50% of office visits at gastroenterology services/clinics. Over one million people have IBD in the United States, with 30000 new cases being diagnosed every year. One-quarter million people in the UK are afflicted with IBD. The cost of medical care in the United States for IBD is estimated to be 1.8 billion dollars/year.


ChromLoops: a comprehensive database for specific protein-mediated chromatin loops in diverse organisms.
Chromatin loops (or chromatin interactions) are important elements of chromatin structures. Disruption of chromatin loops is associated with many diseases, such as cancer and polydactyly. A few methods, including ChIA-PET, HiChIP and PLAC-Seq, have been proposed to detect high-resolution, specific protein-mediated chromatin loops. With rapid progress in 3D genomic research, ChIA-PET, HiChIP and PLAC-Seq datasets continue to accumulate, and effective collection and processing for these datasets are urgently needed. Here, we developed a comprehensive, multispecies and specific protein-mediated chromatin loop database (ChromLoops, https://3dgenomics.hzau.edu.cn/chromloops), which integrated 1030 ChIA-PET, HiChIP and PLAC-Seq datasets from 13 species, and documented 1 491 416 813 high-quality chromatin loops. We annotated genes and regions overlapping with chromatin loop anchors with rich functional annotations, such as regulatory elements (enhancers, super-enhancers and silencers), variations (common SNPs, somatic SNPs and eQTLs), and transcription factor binding sites. Moreover, we identified genes with high-frequency chromatin interactions in the collected species. In particular, we identified genes with high-frequency interactions in cancer samples. We hope that ChromLoops will provide a new platform for studying chromatin interaction regulation in relation to biological processes and disease.


Culturally sensitive care for the elderly.
The opportunities for nurse practitioners to work with elderly minorities and immigrants are on the rise. Both populations are witnessing steady growth. The nurse practitioner is in a unique position to serve this population because of advanced clinical skills and traditional nursing values. When combined, these competencies make the practitioner more capable of interacting with individuals of other cultures and ages. However, skill and professional concepts still require a foundation. This article proposes that a key element in interacting with members of other cultures is understanding one's own history and sensitivities and then approaching the individual with respect.


Snail shape and growth rates: Evidence for plastic shell allometry in Littorina littorea.
The periwinkle Littorina littorea exhibits morphological variation among southern New England populations that appear to be genetically continuous. In dense populations, individuals have relatively elongate shells in comparison to individuals in sparse populations, which have rounder, globose shells. We experimentally demonstrate that this shell variation is a function of snail growth rate. Rapidly growing snails develop thin, globose shells that accommodate more body mass than thicker, more elongate shells. The implications of these results are discussed in relation to interpreting morphological variation in extant gastropods and in the molluscan fossil record.


Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19.
The global pandemic of SARS-CoV-2, the causative viral pathogen of COVID-19, has driven the biomedical community to action-to uncover and develop antiviral interventions. One potential therapeutic approach currently being evaluated in numerous clinical trials is the agent remdesivir, which has endured a long and winding developmental path. Remdesivir is a nucleotide analogue prodrug that perturbs viral replication, originally evaluated in clinical trials to thwart the Ebola outbreak in 2014. Subsequent evaluation by numerous virology laboratories demonstrated the ability of remdesivir to inhibit coronavirus replication, including SARS-CoV-2. Here, we provide an overview of remdesivir's discovery, mechanism of action, and the current studies exploring its clinical effectiveness.


Machine-learning from Pseudomonas putida KT2440 transcriptomes reveals its transcriptional regulatory network.
Bacterial gene expression is orchestrated by numerous transcription factors (TFs). Elucidating how gene expression is regulated is fundamental to understanding bacterial physiology and engineering it for practical use. In this study, a machine-learning approach was applied to uncover the genome-scale transcriptional regulatory network (TRN) in Pseudomonas putida KT2440, an important organism for bioproduction. We performed independent component analysis of a compendium of 321 high-quality gene expression profiles, which were previously published or newly generated in this study. We identified 84 groups of independently modulated genes (iModulons) that explain 75.7% of the total variance in the compendium. With these iModulons, we (i) expand our understanding of the regulatory functions of 39 iModulon associated TFs (e.g., HexR, Zur) by systematic comparison with 1993 previously reported TF-gene interactions; (ii) outline transcriptional changes after the transition from the exponential growth to stationary phases; (iii) capture group of genes required for utilizing diverse carbon sources and increased stationary response with slower growth rates; (iv) unveil multiple evolutionary strategies of transcriptome reallocation to achieve fast growth rates; and (v) define an osmotic stimulon, which includes the Type VI secretion system, as coordination of multiple iModulon activity changes. Taken together, this study provides the first quantitative genome-scale TRN for P. putida KT2440 and a basis for a comprehensive understanding of its complex transcriptome changes in a variety of physiological states.


Defective B-cell-negative selection and terminal differentiation in the ICF syndrome.
Immunodeficiency, centromeric region instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disease. Mutations in the DNA methyltransferase 3B (DNMT3B) gene are responsible for most ICF cases reported. We investigated the B-cell defects associated with agammaglobulinemia in this syndrome by analyzing primary B cells from 4 ICF patients. ICF peripheral blood (PB) contains only naive B cells; memory and gut plasma cells are absent. Naive ICF B cells bear potentially autoreactive long heavy chain variable regions complementarity determining region 3's (V(H)CDR3's) enriched with positively charged residues, in contrast to normal PB transitional and mature B cells, indicating that negative selection is impaired in patients. Like anergic B cells in transgenic models, newly generated and immature B cells accumulate in PB. Moreover, these cells secrete immunoglobulins and exhibit increased apoptosis following in vitro activation. However, they are able to up-regulate CD86, indicating that mechanisms other than anergy participate in silencing of ICF B cells. One patient without DNMT3B mutations shows differences in immunoglobulin E (IgE) switch induction, suggesting that immunodeficiency could vary with the genetic origin of the syndrome. In this study, we determined that negative selection breakdown and peripheral B-cell maturation blockage contribute to agammaglobulinemia in the ICF syndrome.


Multiple sclerosing haemangiomas of the lung.
A case of mulitple sclerosing haemangiomas of the lung is described from a 40-year-old woman, who presented with haemoptysis. A chest X-ray revealed multiple circumscribed coin lesions in both lungs. A right upper lobectomy was done for diagnosis. The patient has remained well for 2 years after surgery. Multiplicity of tumour masses of pulmonary sclerosing haemangiomas is extremely rare and, although benign, may pose a great diagnostic problem.


Pseudomonas folliculitis associated with the use of health-spa whirlpools.
The occurrence of pustular folliculitis in eight people after the use of health-spa whirlpools is described for the first time in Australia. The lesions were discovered ad identified during the peak season in two resorts in the Snowy Mountains area near Jindabyne, New South Wales. Pseudomonas aeruginosa, identified as serotype 0:6, was isolated from pus swabs of the lesions, water in the spa pools and pool filters.


Novel Acetamide Indirectly Targets Mycobacterial Transporter MmpL3 by Proton Motive Force Disruption.
To identify novel inhibitors of Mycobacterium tuberculosis cell envelope biosynthesis, we employed a two-step approach. First, we screened the diverse synthetic small molecule 71,544-compound Enamine library for growth inhibitors using the non-pathogenic surrogate Mycobacterium bovis BCG as screening strain and turbidity as readout. Second, 16 confirmed hits were tested for their ability to induce the cell envelope stress responsive promoter piniBAC controlling expression of red fluorescent protein in an M. bovis BCG reporter strain. Using a fluorescence readout, the acetamide E11 was identified. Resistant mutant selection and whole genome sequencing revealed the mycolic acid transporter Mmpl3 as a candidate target of E11. Biochemical analysis using mycobacterial spheroplasts and various membrane assays suggest that E11 indirectly inhibits MmpL3-facilitated translocation of trehalose monomycolates by proton motive force disruption. E11 showed potent bactericidal activity against growing and non-growing M. tuberculosis, low cytotoxic, and hemolytic activity and a dynamic structure activity relationship. In addition to activity against M. tuberculosis, E11 was active against the non-tuberculous mycobacterium M. abscessus, an emerging opportunistic pathogen. In conclusion, we identified a novel bactericidal anti-mycobacterial lead compound targeting MmpL3 providing an attractive starting point for optimization.


Effect of Public Deliberation on Patient Attitudes Regarding Consent and Data Use in a Learning Health Care System for Oncology.
We sought to generate informed and considered opinions regarding acceptable secondary uses of deidentified health information and consent models for oncology learning health care systems. Day-long democratic deliberation sessions included 217 patients with cancer at four geographically and sociodemographically diverse sites. Patients completed three surveys (at baseline, immediately after deliberation, and 1-month follow-up). Participants were 67.3% female, 21.7% black, and 6.0% Hispanic. The most notable changes in perceptions after deliberation related to use of deidentified medical-record data by insurance companies. After discussion, 72.3% of participants felt comfortable if the purpose was to make sure patients receive recommended care (v 79.5% at baseline; P = .03); 24.9% felt comfortable if the purpose was to determine eligibility for coverage or reimbursement (v 50.9% at baseline; P < .001). The most notable change about secondary research use related to believing it was important that doctors ask patients at least once whether researchers can use deidentified medical-records data for future research. The proportion endorsing high importance decreased from baseline (82.2%) to 68.7% immediately after discussion (P < .001), and remained decreased at 73.1% (P = .01) at follow-up. At follow-up, non-Hispanic whites were more likely to consider it highly important to be able to conduct medical research with deidentified electronic health records (96.8% v 87.7%; P = .01) and less likely to consider it highly important for doctors to get a patient's permission each time deidentified medical record information is used for research (23.2% v 51.6%; P < .001). This research confirms that most patients wish to be asked before deidentified medical records are used for research. Policies designed to realize the potential benefits of learning health care systems can, and should be, grounded in informed and considered public opinion.


Ulnar nerve entrapment in Guyon's canal due to recurrent carpal tunnel syndrome: case report.
Guyon's canal syndrome is a compression neuropathy of the ulnar nerve entrapment at the wrist. Compression of the ulnar nerve at the wrist by a ganglion, lipomas, diseases of the ulnar artery, fractures of the hamate and trauma are common etiologcal factors. Unlike Guyon's canal syndrome, carpal tunnel syndrome (CTS) is the most common nerve entrapment of the upper extremity. Although, open (OCTR) or endoscopic carpal tunnel release (ECTR) is highly effective in relieving pain, failure with carpal tunnel release is seldom seen. In this paper, we presented a patient with ulnar nerve entrapment associated with recurrent CTS and discussed the possible pathomechanism with a review of current literature.


A multivariate twin study of trait mindfulness, depressive symptoms, and anxiety sensitivity.
Mindfulness-based therapies have been shown to be effective in treating depression and reducing cognitive biases. Anxiety sensitivity is one cognitive bias that may play a role in the association between mindfulness and depressive symptoms. It refers to an enhanced sensitivity toward symptoms of anxiety, with a belief that these are harmful. Currently, little is known about the mechanisms underpinning the association between mindfulness, depression, and anxiety sensitivity. The aim of this study was to examine the role of genetic and environmental factors in trait mindfulness, and its genetic and environmental overlap with depressive symptoms and anxiety sensitivity. Over 2,100 16-year-old twins from a population-based study rated their mindfulness, depressive symptoms, and anxiety sensitivity. Twin modeling analyses revealed that mindfulness is 32% heritable and 66% due to nonshared environmental factors, with no significant influence of shared environment. Genetic influences explained over half of the moderate phenotypic associations between low mindfulness, depressive symptoms, and anxiety sensitivity. About two-thirds of genetic influences and almost all nonshared environmental influences on mindfulness were independent of depression and anxiety sensitivity. This is the first study to show that both genes and environment play an important role in the etiology of mindfulness in adolescence. Future research should identify the specific environmental factors that influence trait mindfulness during development to inform targeted treatment and resilience interventions. Shared genetic liability underpinning the co-occurrence of low mindfulness, depression, and anxiety sensitivity suggests that the biological pathways shared between these traits should also be examined.


Inflammatory mediators in autoimmune lacrimal gland disease in MRL/Mpj mice.
MRL/MpJ-fas(+)/fas(+) (MRL/+) and MRL/MpJ-fas(lpr)/fas(lpr) (MRL/lpr) mice are congenic substrains of mice that have spontaneously developing lacrimal and salivary gland inflammation and are models for the human disorder Sjögren's syndrome. Nitric oxide (NO) and tumor necrosis factor (TNF)-alpha are proinflammatory and potential mediators of tissue damage. The presence of the inducible form of nitric oxide synthase (iNOS), which catalyzes the production of NO, and the presence TNF-alpha in the lacrimal glands of MRL/MpJ mice were assessed. Lacrimal glands from MRL/+ and MRL/lpr mice, at ages 1 through 9 months, were evaluated by real-time RT-PCR for iNOS and TNF-alpha mRNA and by immunohistochemistry for the presence of iNOS and of TNF-alpha. Age-matched BALB/c lacrimal glands were used as the control. By quantitative real-time PCR (qPCR), mRNA for iNOS was detected in the lacrimal glands in significantly greater amounts in both MRL/+ (median, normalized to 18S rRNA, 2.90; P < 0.0003) and MRL/lpr mice (median 6.84, P < 0.001) than in BALB/c mice (median 0.34). By qPCR, mRNA for TNF-alpha in the lacrimal glands was detected in significantly greater amounts in aged MRL/+ mice than in BALB/c mice (median, normalized to actin, 221.8 vs. 77.8, P = 0.011) and in MRL/lpr mice than in BALB/c mice (median 136.7 vs. 72.5, P = 0.001). Immunohistochemistry demonstrated both iNOS and TNF-alpha in scattered mononuclear cells throughout the lacrimal glands and in mononuclear cells at the junction of the focal inflammatory infiltrates and normal acinar tissue in both MRL/+ and MRL/lpr mice. As demonstrated by the greater presence of iNOS and TNF-alpha in the lacrimal glands of MRL/MpJ mice than in control glands, both NO and TNF-alpha are potential mediators of lacrimal gland damage in these murine models of Sjögren's syndrome.


Phosphorylation of HPr by the bifunctional HPr Kinase/P-ser-HPr phosphatase from Lactobacillus casei controls catabolite repression and inducer exclusion but not inducer expulsion.
We have cloned and sequenced the Lactobacillus casei hprK gene encoding the bifunctional enzyme HPr kinase/P-Ser-HPr phosphatase (HprK/P). Purified recombinant L. casei HprK/P catalyzes the ATP-dependent phosphorylation of HPr, a phosphocarrier protein of the phosphoenolpyruvate:carbohydrate phosphotransferase system at the regulatory Ser-46 as well as the dephosphorylation of seryl-phosphorylated HPr (P-Ser-HPr). The two opposing activities of HprK/P were regulated by fructose-1,6-bisphosphate, which stimulated HPr phosphorylation, and by inorganic phosphate, which stimulated the P-Ser-HPr phosphatase activity. A mutant producing truncated HprK/P was found to be devoid of both HPr kinase and P-Ser-HPr phosphatase activities. When hprK was inactivated, carbon catabolite repression of N-acetylglucosaminidase disappeared, and the lag phase observed during diauxic growth of the wild-type strain on media containing glucose plus either lactose or maltose was strongly diminished. In addition, inducer exclusion exerted by the presence of glucose on maltose transport in the wild-type strain was abolished in the hprK mutant. However, inducer expulsion of methyl beta-D-thiogalactoside triggered by rapidly metabolizable carbon sources was still operative in ptsH mutants altered at Ser-46 of HPr and the hprK mutant, suggesting that, in contrast to the model proposed for inducer expulsion in gram-positive bacteria, P-Ser-HPr might not be involved in this regulatory process.


Surgical management of epiretinal membrane in combined hamartomas of the retina and retinal pigment epithelium.
The purpose of this study was to evaluate the surgical outcome of combined hamartomas of the retina and retinal pigment epithelium in five patients. In this interventional retrospective case series study, five patients with combined hamartomas of the retina and retinal pigment epithelium received vitrectomy and epiretinal component peeling. Pre- and postoperative best-corrected visual acuity, fundus examination, photography and fundus fluorescein angiography, optical coherence tomography, and B-ultrasound scan examination were analyzed. The 5 patients were all men, ranging in age from 6 years to 21 years (mean 12.6 +/- 6.5 years). The lesions were unilateral. Preoperative best-corrected visual acuity ranged from 20/340 to 20/50 (median 20/200), and postoperative best-corrected visual acuity ranged from 20/340 to 20/30 (median 20/100). Best-corrected visual acuity improved in 3 patients (60%) after the surgeries and remained unchanged in 2 patients. Epiretinal components were completely removed, except for a small residual membrane left in two cases. Tortuosity of the retinal vessels improved in all the cases after the surgeries. Fundus fluorescein angiography showed reduction in vascular tortuosity and decrease of dye leakage. Optical coherence tomography demonstrated disappearance or reduction of high reflectivity of the inner retina and decrease of underlying retina edema. In two cases, the only complication was temporary ocular hypertension. Selected patients with combined hamartomas of the retina and retinal pigment epithelium may benefit from surgical management at the appropriate time.


Determinants of health in children and the problem of early childhood caries.
Early childhood caries (ECC) is a significant dental problem for many low-income and minority children in the United States. The diagnosis, prevention, and management of ECC have been based upon both experiential knowledge and scientific evidence. In the prevention and management of ECC, the focus has been on modifying the dental, infectious, and behavioral determinants of the disease. The purpose of this concept paper is to expand the paradigm used to understand the etiology of ECC and design programs to prevent and manage this condition.


Nanogram-scale boron isotope analysis through micro-distillation and Nu Plasma 3 MC-ICP-MS.
The determination of boron isotopes (δ11B) represents a powerful tool for a variety of applications such as the reconstruction of past ocean pH and atmospheric pCO2 from the analysis of marine biogenic carbonates. In recent years, MC-ICP-MS has gained popularity over other techniques thanks to its superior sample throughput and high ionization efficiency. This study evaluates, for the first time, the performance of the Nu Instruments Plasma 3 MC-ICP-MS for measuring δ11B using different sample introduction systems and detector configurations. The main goal is to provide a detailed methodology for nanogram-scale boron isotope analysis through a straightforward approach that can be easily adopted. Boron (B) purification from the carbonate matrix was performed through micro-distillation, using a temperature of 95 °C and a minimum heating duration of 15 h, allowing the full recovery of B from up to 3 mg of carbonate mass. We attained blank values (on average 14 ± 6 pg, 1 SD, n = 27) comparable to the lowest micro-distillation blanks reported in the literature. Three sample introduction systems were tested, and the 30 μL min-1 nebuliser system outperformed the 50 and 170 μL min-1 systems in terms of signal intensity per mass of B. Two detector configurations were used based on the total boron signal intensity achieved: (1) FC11/FC12, with two Faraday cups fitted to 1011 Ω and 1012 Ω amplifier resistors to detect 11B and 10B ion beams, respectively, and (2) FC12/IC, with which we investigated, for the first time, the feasibility of combining an ion counter for detecting 10B, and a Faraday cup fitted to a 1012 Ω amplifier for 11B. The FC12/IC configuration provided accurate results compared to the use of two Faraday cups for total boron signals lower than 0.35 V (∼12 ng of B in the analysed solution). The proposed analytical procedure was validated through the analysis of several reference materials with varying boron amounts, including clam JCt-1, coral JCp-1, NIST RM 8301 Foram and Coral solutions, and boric acid ERM-AE121. Furthermore, the long-term reproducibility was assessed with two in-house standards (coral CLD-1 and foraminifera GINF-1), providing values of 25.68 ± 0.23 ‰ (2SD, n = 53; with 14-36 ng of B) and 14.90 ± 0.16 ‰ (2SD, n = 12; with 11-16 ng of B), respectively.


Community Gardens for Refugee and Immigrant Communities as a Means of Health Promotion.
Refugees and new immigrants arriving in the United States (U.S.) often encounter a multitude of stressors adjusting to a new country and potentially coping with past traumas. Community gardens have been celebrated for their role in improving physical and emotional health, and in the Twin Cities of Minnesota, have been offered as a resource to immigrants and refugees. The purpose of this study is to present a mixed method evaluation of a refugee gardening project hosted by area churches serving primarily Karen and Bhutanese populations. Quantitative data were obtained from early and late season surveys (44 and 45 % response rates, respectively), and seven focus groups conducted at the end of the season provided qualitative data. Although few gardeners (4 %) identified food insecurity as a problem, 86 % indicated that they received some food subsidy, and 78 % reported vegetable intake increased between the early and late season surveys. Twelve percent of gardeners indicated possible depression using the PHQ-2 scale; in focus groups numerous respondents identified the gardens as a healing space for their depression or anxiety. Refugee gardeners expressed receiving physical and emotional benefits from gardening, including a sense of identity with their former selves. Gardens may serve as a meaningful health promotion intervention for refugees and immigrants adjusting to the complexity of their new lives in the U.S. and coping with past traumas.


Predicting metabolic clearance for drugs that are actively transported into hepatocytes: incubational binding as a consequence of in vitro hepatocyte concentration is a key factor.
Incubational binding or the fraction of drug unbound in an in vitro incubation, fuinc, is an important parameter to predict or measure in the pursuit of accurate clearance predictions from in vitro data. Here we describe a method for fuinc determination directly in the hepatocyte intrinsic clearance (CLint) assay with emphasis on compounds that are actively transported into hepatocytes, hypothesizing that for such compounds the typical protocol of 1 million hepatocytes/ml systematically underestimates the maximum attainable unbound intracellular drug concentration. Using the transporter substrate atorvastatin as a test compound, incubations were performed and a mathematical model applied to describe metabolism, distribution, and binding at different hepatocyte concentrations. From these investigations it was evident that, since binding is more extensive intracellularly than in the medium, increased partitioning into the cellular volume, due to active uptake, increases the total amount of atorvastatin bound in the incubation. Consequently, a significant lowering of the hepatocyte concentration impacts the free drug concentration in the incubation and increases the observed rate of metabolism and therefore observed CLint (that is, when viewed from the media drug concentration). The applicability of the findings was tested for a series of 11 actively transported zwitterions for which standard rat hepatocyte metabolic CLint data (1 million cells/ml incubation) poorly predicted in vivo clearance (average fold error of 5.4). Using metabolic CLint determined at a lower hepatocyte concentration (0.125 million cells/ml) considerably improved clearance predictions (average fold error of 2.3).


The Endoplasmic Reticulum Stress Sensor Inositol-Requiring Enzyme 1α Augments Bacterial Killing through Sustained Oxidant Production.
Bacterial infection can trigger cellular stress programs, such as the unfolded protein response (UPR), which occurs when misfolded proteins accumulate within the endoplasmic reticulum (ER). Here, we used the human pathogen methicillin-resistant Staphylococcus aureus (MRSA) as an infection model to probe how ER stress promotes antimicrobial function. MRSA infection activated the most highly conserved unfolded protein response sensor, inositol-requiring enzyme 1α (IRE1α), which was necessary for robust bacterial killing in vitro and in vivo. The macrophage IRE1-dependent bactericidal activity required reactive oxygen species (ROS). Viable MRSA cells excluded ROS from the nascent phagosome and strongly triggered IRE1 activation, leading to sustained generation of ROS that were largely Nox2 independent. In contrast, dead MRSA showed early colocalization with ROS but was a poor activator of IRE1 and did not trigger sustained ROS generation. The global ROS stimulated by IRE1 signaling was necessary, but not sufficient, for MRSA killing, which also required the ER resident SNARE Sec22B for accumulation of ROS in the phagosomal compartment. Taken together, these results suggest that IRE1-mediated persistent ROS generation might act as a fail-safe mechanism to kill bacterial pathogens that evade the initial macrophage oxidative burst. Cellular stress programs have been implicated as important components of the innate immune response to infection. The role of the IRE1 pathway of the ER stress response in immune secretory functions, such as antibody production, is well established, but its contribution to innate immunity is less well defined. Here, we show that infection of macrophages with viable MRSA induces IRE1 activation, leading to bacterial killing. IRE1-dependent bactericidal activity required generation of reactive oxygen species in a sustained manner over hours of infection. The SNARE protein Sec22B, which was previously demonstrated to control ER-phagosome trafficking, was dispensable for IRE1-driven global ROS production but necessary for late ROS accumulation in bacteria-containing phagosomes. Our study highlights a key role for IRE1 in promoting macrophage bactericidal capacity and reveals a fail-safe mechanism that leads to the concentration of antimicrobial effector molecules in the macrophage phagosome.


The relationship between iron bone marrow stores and response to treatment in pediatric acute lymphoblastic leukemia.
Iron is an intracellular element whose accumulation in the body is associated with tissue damage. This study examines the effect of iron on pediatric acute lymphoblastic leukemia (ALL) and its "response to treatment." At the end of the first year of treatment, bone marrow iron store (BMIS) was evaluated in children with ALL and the relationship between iron store and minimal residual disease was investigated. Moreover, the 3-year disease-free survival (3-DFS) of patients was determined. Patients' BMIS were compared with that of subjects with normal bone marrow. The study examined 93 children, including 78 Pre-B and 15 T-cell ALL patients. BMIS did not differ between the children with ALL and those with no evidence of cancer. BMIS was increased in 26.6% of patients at the end of the first year of treatment. Drug resistance and BM relapses were more prevalent in cases with high BMIS in both Pre-B and T-cell groups. Bone marrow iron store is not considered a risk factor for childhood ALL. However, high levels of BMIS are associated with poor response to treatment and the risk of relapse. Bone marrow iron store control during treatment can therefore help achieve better outcomes and improve the chances of recovery.


Second-generation antipsychotics for obsessive compulsive disorder.
Obsessive compulsive disorder (OCD) is a psychiatric disorder which has been shown to affect 2 to 3.5% of people during their lifetimes. Inadequate response occurs in 40% to 60% of people that are prescribed first line pharmaceutical treatments (selective serotonin reuptake inhibitors (SSRIs)). To date not much is known about the efficacy and adverse effects of second-generation antipsychotic drugs (SGAs) in people suffering from OCD. To evaluate the effects of SGAs (monotherapy or add on) compared with placebo or other forms of pharmaceutical treatment for people with OCD. The Cochrane Depression, Anxiety and Neurosis Group's controlled trial registers (CCDANCTR-Studies and CCDANCTR-References) were searched up to 21 July 2010. The author team ran complementary searches on ClinicalTrials.gov and contacted key authors and drug companies. We included double-blind randomised controlled trials (RCTs) comparing oral SGAs (monotherapy or add on) in adults with other forms of pharmaceutical treatment or placebo in people with primary OCD. We extracted data independently. For dichotomous data we calculated the odds ratio (OR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated mean differences (MD), again based on a random-effects model. We included 11 RCTs with 396 participants on three SGAs. All trials investigated the effects of adding these SGAs to antidepressants (usually SSRIs). The duration of all trials was less than six months. Only 13% of the participants left the trials early. Most trials were limited in terms of quality aspects.Two trials examined olanzapine and found no difference in the primary outcome (response to treatment) and most other efficacy-related outcomes but it was associated with more weight gain than monotherapy with antidepressants.Quetiapine combined with antidepressants was also not any more efficacious than placebo combined with antidepressants in terms of the primary outcome, but there was a significant superiority in the mean Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score at endpoint (MD -2.28, 95% CI -4.05 to -0.52). There were also some beneficial effects of quetiapine in terms of anxiety or depressive symptoms.Risperidone was more efficacious than placebo in terms of the primary outcome (number of participants without a significant response) (OR 0.17, 95% CI 0.04 to 0.66) and in the reduction of anxiety and depression (MD -7.60, 95% CI -12.37 to -2.83). The available data of the effects of olanzapine in OCD are too limited to draw any conclusions. There is some evidence that adding quetiapine or risperidone to antidepressants increases efficacy, but this must be weighed against less tolerability and limited data.


Anti-beta-crystallin antibodies (mouse) or sera from humans with age-related cataract are cytotoxic for lens epithelial cells in culture.
Circulating autoantibodies against lens antigens are prevalent in patients with age-related cataract (ARC), but their pathogenic significance is unknown. We hypothesized that these autoantibodies are cytotoxic for lens epithelial cells (LECs). To test this hypothesis. We incubated LECs with mouse polyclonal or monoclonal antibodies against beta-crystallin (anti-beta) in the presence or absence of guinea pig complement. We found that anti-beta in the presence of the complement bound to and killed mouse LECs (MLECs) and human LECs (HLECs). Sera obtained from patients with ARC also were cytotoxic to both HLECs and MLECs in culture. Heat-inactivated human sera were not cytotoxic to LECs in the absence of the complement, but were cytotoxic to both HLECs and MLECs in the presence of additional complement. These results support the hypothesis that autoantibodies against lens antigens are cytotoxic to LECs, and that cell death may involve complement-mediated pathways.


Assessment of Treatment Approaches and Outcomes in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Insights From a Pan-European Multicenter Study.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug reactions associated with a high rate of mortality and morbidity. There is no consensus on the treatment strategy. To explore treatment approaches across Europe and outcomes associated with the SJS/TEN disease course, as well as risk factors and culprit drugs. A retrospective pan-European multicenter cohort study including 13 referral centers belonging to the ToxiTEN ERN-skin subgroup was conducted. A total of 212 adults with SJS/TEN were included between January 1, 2015, and December 31, 2019, and data were collected from a follow-up period of 6 weeks. Risk factors for severe acute-phase complications (acute kidney failure, septicemia, and need for mechanical ventilation) and mortality 6 weeks following admission were evaluated using a multivariable-adjusted logistic regression model. One tool used in evaluation of severity was the Score of Toxic Epidermal Necrolysis (SCORTEN), which ranges from 0 to 7, with 7 the highest level of severity. Of 212 patients (134 of 211 [63.7%] women; mean [SD] age, 51.0 [19.3] years), the mean (SD) body surface area detachment was 27% (32.8%). In 176 (83.0%) patients, a culprit drug was identified. Antibiotics (21.2%), followed by anticonvulsants (18.9%), nonsteroidal anti-inflammatory drugs (11.8%), allopurinol (11.3%), and sulfonamides (10.4%), were the most common suspected agents. Treatment approaches ranged from best supportive care only (38.2%) to systemic glucocorticoids (35.4%), intravenous immunoglobulins (23.6%), cyclosporine (10.4%), and antitumor necrosis factor agents (3.3%). Most patients (63.7%) developed severe acute-phase complications. The 6-week mortality rate was 20.8%. Maximal body surface area detachment (≥30%) was found to be independently associated with severe acute-phase complications (fully adjusted odds ratio [OR], 2.49; 95% CI, 1.21-5.12; P = .01) and SCORTEN greater than or equal to 2 was significantly associated with mortality (fully adjusted OR, 10.30; 95% CI, 3.82-27.78; P < .001). Cyclosporine was associated with a higher frequency of greater than or equal to 20% increase in body surface area detachment in the acute phase (adjusted OR, 3.44; 95% CI, 1.12-10.52; P = .03) and an increased risk of infections (adjusted OR, 7.16; 95% CI, 1.52-33.74; P = .01). Systemic glucocorticoids and intravenous immunoglobulins were associated with a decreased risk of infections (adjusted OR, 0.40; 95% CI, 0.18-0.88; P = .02). No significant difference in 6-week mortality was found between treatment groups. This cohort study noted differences in treatment strategies for SJS/TEN in Europe; the findings suggest the need for prospective therapeutic studies to be conducted and registries to be developed.


Diurnal changes in serum unconjugated bile acids in normal man.
Unconjugated bile acids were measured using gas chromatography-mass spectrometry in the serum of two subjects throughout a 24 hour period and in two other subjects over a six hour period after breakfast. Unconjugated bile acids were found in all samples of serum and included cholic, chenodeoxycholic, deoxycholic, 3 beta, 7 alpha-dihydroxy-5 beta-cholanic (iso-chenodeoxycholic), ursodeoxycholic, 3 beta, 7 beta-dihydroxy-5 beta-cholanic (iso-ursodeoxycholic), 3 beta-hydroxy-5-cholenoic, and lithocholic acids. The maximum concentration of each bile acid generally occurred between breakfast and dinner and total unconjugated bile acid concentrations attained levels of between 2-3 mumol/l. Concentrations increased after breakfast and were often as high as 30-40% of the conjugated bile acid glycocholate, but returned to fasting levels in the absence of lunch. The intestinal absorption of unconjugated bile acids is therefore of greater quantitative importance than was previously thought.


The Canadian Organ Replacement Register.
The analyses presented in this chapter are a subset of the yearly audit of organ donation and transplantation in Canada published in the CORR Annual Report. They represent the collaborative efforts and the voluntary contributions of many of the transplant physicians, surgeons, nurses and coordinators in Canada. In Canada, organ donation has remained static at approximately 14 per million population. Despite many local and provincial as well as corporate initiatives, this rate is approximately half the current rate in many regions of the U.S.A. and Spain. The modest increases in transplant activity represent an increase in the use of living donors, reassessment of the traditional donor risk factors (including age) and expansion of the potential donors for each organ. Analysis of the renal transplant activity has determined that the likelihood of being transplanted during the first year on the list was less than 40%. A graft loss rate of 4% per year after the first year was observed for a cadaveric kidney, compared with graft loss rates of 3% and 2% per year for living-related and living-unrelated donor kidneys, respectively. Cox regressional analysis identified that the major determinants of patient survival were the transplant year, the region where the transplant was performed, the presence of diabetes, the recipient's age, and whether the kidney was from a living donor. Liver transplantation has increased each year at the transplant centers in Vancouver, Edmonton, London, Toronto, Montreal, and Halifax. Patient and graft survival rates have improved since 1985 and the most significant determinant of patient survival following transplantation was the patient's medical status at the time of transplantation. Living-related liver donor transplant programs have begun in London and Toronto. Pancreas transplantation remains limited across Canada, but with the development of new pancreas programs in Toronto and Halifax, an increase in the availability of this therapy for Type 1 diabetics is anticipated. Heart transplantation has recovered from a decline in 1991-1992 to approximately 6 hearts per million population. There has been a trend towards better one- and 3-year patient survival rates since 1985. With the development of a lung transplantation program in Winnipeg, lung transplantation has increased. This likely reflects increased utilization of the available donor lungs. A particular increase in double-lung transplants was noted.


Synaptic activity of frog retinal photoreceptors. A peroxidase uptake study.
The uptake of horseradish peroxidase (HRP) into membranous structures, detectable by light and electron microscopy, is used here to monitor the synaptic activity of photoreceptors of isolated frog retinas maintained in the dark or under various illumination conditions. The major findings are: (a) Neurotransmission from photoreceptor terminals seems to involve the same types of endocytic membrane-retrieval processes that occur at other nerve terminals. Presumably, the endocytic processes compensate for exocytic events associated with neurotransmission. The retrieved membrane is "recycled" to form vesicles. Some of these accumulate near the synaptic ribbons, perhaps indicating reutilization for exocytosis. On the other hand, some retrieved membrane evidently is degraded via multivesicular bodies that appear to undergo "retrograde" transport from the receptor synapses to the myoid regions. (b) Photoreceptor terminals take up much HRP in the dark. Steady illumination markedly decreases uptake by rods. Uptake by cones is notably reduced only at illumination intensities higher than those that have maximal effects on rods. (c) The decrease in rod HRP uptake with light is reversible when retinas are allowed to adapt to the dark, if the light exposures used were at intensities that bleach very little visual pigment. Such "recovery" is not observed after light exposures that bleach a considerable amount of visual pigment. The cones recover their dark levels of HRP uptake even after light exposures that bleach considerable amounts of visual pigment. The changes in HRP uptake that we observe parallel expectations for photoreceptor synaptic neurotransmission derived from indirect physiological evidence.


A combined long-range phasing and long haplotype imputation method to impute phase for SNP genotypes.
Knowing the phase of marker genotype data can be useful in genome-wide association studies, because it makes it possible to use analysis frameworks that account for identity by descent or parent of origin of alleles and it can lead to a large increase in data quantities via genotype or sequence imputation. Long-range phasing and haplotype library imputation constitute a fast and accurate method to impute phase for SNP data. A long-range phasing and haplotype library imputation algorithm was developed. It combines information from surrogate parents and long haplotypes to resolve phase in a manner that is not dependent on the family structure of a dataset or on the presence of pedigree information. The algorithm performed well in both simulated and real livestock and human datasets in terms of both phasing accuracy and computation efficiency. The percentage of alleles that could be phased in both simulated and real datasets of varying size generally exceeded 98% while the percentage of alleles incorrectly phased in simulated data was generally less than 0.5%. The accuracy of phasing was affected by dataset size, with lower accuracy for dataset sizes less than 1000, but was not affected by effective population size, family data structure, presence or absence of pedigree information, and SNP density. The method was computationally fast. In comparison to a commonly used statistical method (fastPHASE), the current method made about 8% less phasing mistakes and ran about 26 times faster for a small dataset. For larger datasets, the differences in computational time are expected to be even greater. A computer program implementing these methods has been made available. The algorithm and software developed in this study make feasible the routine phasing of high-density SNP chips in large datasets.


PGK1 induction by a hydrogen peroxide treatment is suppressed by antioxidants in human colon carcinoma cells.
Few protein biomarkers for oxidative stress have been reported. In this study, we attempted to identify the proteins selectively overexpressed in human colon tumor cells by treating with hydrogen peroxide as oxidative stress. A proteomic analysis followed by western blotting showed that phosphoglycerate kinase 1 (PGK1) was induced by hydrogen peroxide in a dose-dependent manner, while its expression was suppressed by a co-treatment with delphinidin, a known antioxidant. Furthermore, several antioxidants, including alpha-tocopherol, butylated hydroxytoluene (BHT), and Trolox, also inhibited the PGK1 induction caused by hydrogen peroxide. The data suggest that PGK1 might be a potential protein biomarker of intracellular oxidative status.


Obesity, health-care utilization, and health-related quality of life after fracture in postmenopausal women: Global Longitudinal Study of Osteoporosis in Women (GLOW).
Fractures may be associated with higher morbidity in obese postmenopausal women than in nonobese women. We compared health-care utilization, functional status, and health-related quality of life (HRQL) in obese, nonobese, and underweight women with fractures. Information from the GLOW study, started in 2006, was collected at baseline and at 1, 2, and 3 years. In this subanalysis, self-reported incident clinical fractures, health-care utilization, HRQL, and functional status were recorded and examined. Women in GLOW (n = 60,393) were aged ≥55 years, from 723 physician practices at 17 sites in 10 countries. Complete data for fracture and body mass index were available for 90 underweight, 3,270 nonobese, and 941 obese women with one or more incident clinical fractures during the 3-year follow-up. The median hospital length of stay, adjusted for age, comorbidities, and fracture type, was significantly greater in obese than nonobese women (6 vs. 5 days, p = 0.017). Physical function and vitality score were significantly worse in obese than in nonobese women, both before and after fracture; but changes after fracture were similar across groups. Use of antiosteoporosis medication was significantly lower in obese than in nonobese or underweight women. In conclusion, obese women with fracture undergo a longer period of hospitalization for treatment and have poorer functional status and HRQL than nonobese women. Whether these differences translate into higher economic costs and adverse effects on longer-term outcomes remains to be established.


Activity in the human amygdala corresponds to early, rather than late period autonomic responses to a signal for shock.
Laboratory animal and human subject studies report that the amygdala is a critical brain structure that supports the acquisition and expression of conditional fear. Recent functional neuroimaging studies in humans have reported that activity in this region is closely related to the behavioral expression of conditional skin conductance responses (SCR). However, SCR waveforms following conditional stimulus (CS) presentation contain both early period and late period responses that may differ with respect to underlying central processes. It is not known whether amygdala activity corresponds to the expression of early conditional responses (CRs) that occur shortly following CS onset or late CRs that closely precede UCS onset. The present study used event-related functional magnetic resonance imaging and concurrent skin conductance measurements to determine whether amygdala activity is more closely related to the expression of early or late period CRs. Increased amygdala activity was detected during the formation of early, but not late period CRs. Additionally, this pattern of amygdala activity did not dissipate, but persisted into late stages of the experiment. These findings are consistent with the idea that amygdala responding is critically involved in the generation of CRs formed shortly following CS onset.


Structural basis of diverse peptide accommodation by the rhesus macaque MHC class I molecule Mamu-B*17: insights into immune protection from simian immunodeficiency virus.
The MHC class I molecule Mamu-B*17 has been associated with elite control of SIV infection in rhesus macaques, akin to the protective effects described for HLA-B*57 in HIV-infected individuals. In this study, we determined the crystal structures of Mamu-B*17 in complex with eight different peptides corresponding to immunodominant SIV(mac)239-derived CD8(+) T cell epitopes: HW8 (HLEVQGYW), GW10 (GSHLEVQGYW), MW9 (MHPAQTSQW), QW9 (QTSQWDDPW), FW9 (FQWMGYELW), MF8 (MRHVLEPF), IW9 (IRYPKTFGW), and IW11 (IRYPKTFGWLW). The structures reveal that not only P2, but also P1 and P3, can be used as N-terminal anchor residues by Mamu-B*17-restricted peptides. Moreover, the N-terminal anchor residues exhibit a broad chemical specificity, encompassing basic (H and R), bulky polar aliphatic (Q), and small (T) residues. In contrast, Mamu-B*17 exhibits a very narrow preference for aromatic residues (W and F) at the C terminus, similar to that displayed by HLA-B*57. Flexibility within the whole peptide-binding groove contributes to the accommodation of these diverse peptides, which adopt distinct conformations. Furthermore, the unusually large pocket D enables compensation from other peptide residues if P3 is occupied by an amino acid with a small side chain. In addition, residues located at likely TCR contact regions present highly flexible conformations, which may impact TCR repertoire profiles. These findings provide novel insights into the structural basis of diverse peptide accommodation by Mamu-B*17 and highlight unique atomic features that might contribute to the protective effect of this MHC I molecule in SIV-infected rhesus macaques.


Do depression and anxiety reduce the likelihood of remission in rheumatoid arthritis and psoriatic arthritis? Data from the prospective multicentre NOR-DMARD study.
To investigate the predictive value of baseline depression/anxiety on the likelihood of achieving joint remission in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as the associations between baseline depression/anxiety and the components of the remission criteria at follow-up. We included 1326 patients with RA and 728 patients with PsA from the prospective observational NOR-DMARD study starting first-time tumour necrosis factor inhibitors or methotrexate. The predictive value of depression/anxiety on remission was explored in prespecified logistic regression models and the associations between baseline depression/anxiety and the components of the remission criteria in prespecified multiple linear regression models. Baseline depression/anxiety according to EuroQoL-5D-3L, Short Form-36 (SF-36) Mental Health subscale ≤56 and SF-36 Mental Component Summary ≤38 negatively predicted 28-joint Disease Activity Score <2.6, Simplified Disease Activity Index ≤3.3, Clinical Disease Activity Index ≤2.8, ACR/EULAR Boolean and Disease Activity Index for Psoriatic Arthritis ≤4 remission after 3 and 6 months treatment in RA (p≤0.008) and partly in PsA (p from 0.001 to 0.73). Baseline depression/anxiety was associated with increased patient's and evaluator's global assessment, tender joint count and joint pain in RA at follow-up, but not with swollen joint count and acute phase reactants. Depression and anxiety may reduce likelihood of joint remission based on composite scores in RA and PsA and should be taken into account in individual patients when making a shared decision on a treatment target.


Superlubricity of Materials: Progress, Potential, and Challenges.
This review paper provides a comprehensive overview of the phenomenon of superlubricity, its associated material characteristics, and its potential applications. Superlubricity, the state of near-zero friction between two surfaces, presents significant potential for enhancing the efficiency of mechanical systems, thus attracting significant attention in both academic and industrial realms. We explore the atomic/molecular structures that enable this characteristic and discuss notable superlubric materials, including graphite, diamond-like carbon, and advanced engineering composites. The review further elaborates on the methods of achieving superlubricity at both nanoscale and macroscale levels, highlighting the influence of environmental conditions. We also discuss superlubricity's applications, ranging from mechanical systems to energy conservation and biomedical applications. Despite the promising potential, the realization of superlubricity is laden with challenges. We address these technical difficulties, specifically those related to achieving and maintaining superlubricity, and the issues encountered in scaling up for industrial applications. The paper also underscores the sustainability concerns associated with superlubricity and proposes potential solutions. We conclude with a discussion of the possible future research directions and the impact of technological innovations in this field. This review thus provides a valuable resource for researchers and industry professionals engaged in the development and application of superlubric materials.


Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants.
Vitamin A is necessary for normal lung growth and the integrity of respiratory tract epithelial cells. Preterm infants have low vitamin A status at birth and this has been associated with an increased risk of developing chronic lung disease. To evaluate supplementation with vitamin A on the incidence of death or neonatal chronic lung disease and long-term neurodevelopmental disability in very low birth weight (VLBW) infants compared with a control (placebo or no supplementation), and to consider the effect of the supplementation route, dose, and timing. For the original review and subsequent updates, we searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, Science Citation Index, and the Oxford Database of Perinatal Trials. The reference lists of relevant trials, paediatric and nutrition journals, and conference abstracts and proceedings were handsearched up to 2010.For the 2016 update, we used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 4), MEDLINE via PubMed (1 May 2016), EMBASE (1 May 2016), and CINAHL (1 May 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised controlled trials comparing vitamin A supplementation with a control (placebo or no supplementation) or other dosage regimens in VLBW infants (birth weight ≤ 1500 grams or less than 32 weeks' gestation). Two review authors screened the search results, extracted data, and assessed the trials for risk of bias. Results were reported as risk ratios (RR), risk differences (RD), and number needed to treat to benefit (NNTB), all with 95% confidence intervals (CI). Trialists were contacted for additional data. Eleven trials met the inclusion criteria. Ten trials (1460 infants) compared vitamin A supplementation with a control and one (120 infants) compared different regimens of vitamin A supplementation. Compared to the control group, vitamin A appeared to have a small benefit in reducing the risk of death or oxygen requirement at one month of age (typical RR 0.93, 95% CI 0.88 to 0.99; typical RD -0.05, 95% CI -0.10 to -0.01; NNTB 20, 95% CI 10 to 100; 6 studies, 1165 infants) and the risk of chronic lung disease (oxygen requirement) at 36 weeks' postmenstrual age (typical RR 0.87, 95% CI 0.77 to 0.99; typical RD -0.07, 95% CI -0.13 to -0.01; NNTB 11, 95% CI 6 to 100; 5 studies, 986 infants) (moderate-quality evidence). There was a marginal reduction of the combined outcome of death or chronic lung disease (typical RR 0.92, 95% CI 0.84 to 1.01; typical RD -0.05, 95% CI -0.11 to 0.01; 4 studies, 1089 infants). Neurodevelopmental assessment of 88% of the surviving infants in the largest trial showed no difference between the groups at 18 to 22 months of age, corrected for prematurity (low-quality evidence). There is no evidence to support different vitamin A dosing regimens. No adverse effects of vitamin A supplementation were reported, but it was noted that intramuscular injections of vitamin A were painful. Whether clinicians decide to utilise repeat intramuscular doses of vitamin A to prevent chronic lung disease may depend upon the local incidence of this outcome and the value attached to achieving a modest reduction in the outcome balanced against the lack of other proven benefits and the acceptability of the treatment. Information on long-term neurodevelopmental status suggests no evidence of either benefit or harm from the intervention.


Hypomethylating drugs efficiently decrease cytosine methylation in telomeric DNA and activate telomerase without affecting telomere lengths in tobacco cells.
Telomere homeostasis is regulated at multiple levels, including the local chromatin structure of telomeres and subtelomeres. Recent reports demonstrated that a decrease in repressive chromatin marks, such as levels of cytosine methylation in subtelomeric regions, results in telomere elongation in mouse cells. Here we show that a considerable fraction of cytosines is methylated not only in subtelomeric, but also in telomeric DNA of tobacco BY-2 cells. Drug-induced hypomethylation (demonstrated at subtelomeric, telomeric, and global DNA levels) results in activation of telomerase. However, in contrast to mouse cells, the decrease in 5-methylcytosine levels and upregulation of telomerase do not result in any changes of telomere lengths. These results demonstrate the involvement of epigenetic mechanisms in the multilevel process of regulation of telomerase activity in plant cells and, at the same time, they indicate that changes in telomerase activity can be overridden by other factors governing telomere length stability.


Spectroscopy of a mesospheric ghost reveals iron emissions.
Mesospheric Green emissions from excited Oxygen in Sprite Tops (ghosts) are infrequent and faint greenish transient luminous events that remain for hundreds of milliseconds on top of certain energetic sprites. The main hypothesis to explain this glow persistence is the long lifetime of excited atomic oxygen at 557.73 nm, a well-known emission line in aurora and airglow. However, due to the lack of spectroscopic campaigns to analyse such events to date, the species involved in the process can not yet be identified. Here we report observational results showing the temporal evolution of a ghost spectrum between 500 nm and 600 nm. Besides weak -but certain- traces of excited atomic oxygen, our results show four main contributors related to the slow decay of the glow: atomic iron and nickel, molecular nitrogen and ionic molecular oxygen. Additionally, we are able to identify traces of atomic sodium, and ionic silicon, these observations being consistent with previous direct measurements of density profiles of meteoric metals in the mesosphere and lower thermosphere. This finding calls for an upgrade of current air plasma kinetic understanding under the influence of transient luminous events.


A Large-Scale Fifteen-Year Minimum Survivorship of a Cementless Triple Tapered Femoral Stem.
This study reports the long-term outcomes of a metaphyseal fit-and-fill cementless femoral component in total hip arthroplasty (THA) with a follow-up of 15-19 years. We conducted a retrospective review of 376 consecutive THAs (345 patients), using a triple tapered stem performed between 2000 and 2003 with a view to assessing survivorship and radiological and functional outcomes. Images were assessed for initial alignment, terminal osteolysis, or subsidence, while clinical outcomes were assessed using the St Michael's Hip Score. Forty-five (11.9%) hips were lost to follow-up, 20 (5.31%) had died before our 15-year cutoff follow-up, and 4 (1.06%) had declined follow-up early on, leaving 307 hips (81.64%, 276 patients) available for both clinical and radiological follow-up at a minimum of 15 years (range 15-19). The mean age at the time of operation was 49.6 years (range 19-71) and the cohort included 131 (42.67%) male and 145 (47.23%) female patients. Seven stems (2.28%) were revised: 4 due to periprosthetic fractures, 2 for periprosthetic joint infection, and 1 for adverse reaction to metal debris at the trunnion. The St Michael's Hip Score improved from 14.2 (range 9-23) preoperatively to 22.3 (range 13 to 25) at the last documented follow-up (P = .000). Kaplan-Meier survivorship with stem revision for any reason as the end point was 97.70%. Worst-case scenario Kaplan-Meier survivorship, where all lost to follow-up are considered as failures, was 85.3%. No stem was revised for aseptic loosening. This triple tapered stem in THA shows excellent survivorship beyond a minimum of 15 years.


Comparative aging changes in canine uterine tubes (oviducts): electron microscopy.
Uterine tubes (oviducts) from 20 dogs in 3 age groups were evaluated by scanning electron microscopy. Three segments of the left uterine tube from 4 prepubertal dogs, 8 middle-aged dogs (4 to 6 years), and 8 aged dogs (8 to 11 years) were collected after euthanasia or ovariohysterectomy. Specimens were collected while the dogs, except for one in the middle-aged group, were in late metestrus or anestrus (to reduce variation in tubal epithelium by estrogen stimulation). Subdivision of mucosal folds, invaginations of mucosa into the entire length of the folds, and height of the folds, increased with age; the width of the mucosal folds had decreased. Complete dedifferentiation of epithelium of the uterine tube ampulla and isthmus to nonciliated cells in a few aged dogs resembled changes in postmenopausal women. In 3 prepubertal dogs, cilia were present in the infundibulum of the uterine tube, but not in the ampulla and isthmus. In a late prepubertal dog, early ciliation of ampulla and isthmus began before first estrus. Nonciliated cells with a single central cellular projection were present in all segments and all age groups. The significance of the projection was discussed.


The Controversies Surrounding Acne and Suicide: Essential Knowledge for Clinicians.
Over the years, there have been numerous studies linking acne to depression and suicidal thoughts. Although the exact relationship between the two is still unclear, the stigma associated with acne can have a significant impact on an individual's mental health. The critical appraisal of empirical evidence reveals a lack of understanding of the relationship between acne and suicide. Several studies have demonstrated an association between acne and suicide without causal links. Thus, it is clinically important to review the risks associated with isotretinoin and obtain informed consent regarding potential harm. The use of isotretinoin should be limited to cases of severe acne. There have been reports of an increased risk of suicide six months after the completion of isotretinoin treatment, so it is recommended that follow-up monitoring continue for up to one year following the completion of the treatment.


[Remote effects of occupational and non-occupational exposure to electromagnetic fields of power-line frequency. Epidemiological studies].
A retrospective cohort study of mortality in the personnel of power-supply plants in the European regions of Russia was carried out. The exposure of the personnel to electromagnetic fields of power-line frequency (PF) was taken into account. Statistically non-significant raise of mortality from leukemia was found, compared to low mortality rates due to all other causes including cancer of any type. Standardized mortality ratio (SMR) was equal to 2.03 (95% CI = 0.23-7.31). In the retrospective case-control study the haemoblastosis development risk under occupational PF EMF exposure was evaluated. The data of 571 "cases" and 1208 "controls" interview showed that odd ratio (OR) was 1.64 (95% CI = 0.8-3.1). In another retrospective case-control study the risk of the haemoblastosis development in children due to parents PF EMF occupational exposure was evaluated. The data of 208 "cases" and 319 "controls" interview showed that the odd ratio (OR) was 1.69 (95% CI = 0.7-3.3). A retrospective cohort study of mortality in a settlement situated near a high-voltage (500 kV) substation, which took into account PF EMF levels in residential areas, revealed low mortality rates, except leukemia mortality (SMR 1.3; 95% CI = 0.2-7.0). The obtained data do not allow excluding a possibility of PF EMF leukogenic effect.


Decline in overall, smear-negative and HIV-positive TB incidence while smear-positive incidence stays stable in Guinea-Bissau 2004-2011.
To calculate Tuberculosis (TB) incidence rates in Guinea-Bissau over an 8-year period. Since 2003, a surveillance system has registered all TB cases in six suburban districts of Bissau. In this population-based prospective follow-up study, 1205 cases of pulmonary TB were identified between January 2004 and December 2011. Incidence rates were calculated using census data from the Bandim Health and Demographic Surveillance System (HDSS). The overall incidence of pulmonary TB was 279 per 100,000 person-years of observation; the male incidence being 385, and the female 191. TB incidence rates increased significantly with age in both sexes, regardless of smear or HIV status. Despite a peak with unknown cause of 352 per 100,000 in 2007, the overall incidence of pulmonary TB declined over the period. The incidence of HIV infected TB cases declined significantly from 108 to 39 per 100,000, while the incidence of smear-positive TB cases remained stable; the overall figure was 188 per 100,000. Overall incidence of pulmonary TB in Guinea-Bissau has declined from 2004 to 2011. The decline was also seen in the subgroups of smear-negative and HIV-positive TB cases, probably due to antiretroviral treatment. Smear-positive TB incidence remains stable over the period.


Identification of cell cycle-related regulatory motifs using a kernel canonical correlation analysis.
Gene regulation is a key mechanism in higher eukaryotic cellular processes. One of the major challenges in gene regulation studies is to identify regulators affecting the expression of their target genes in specific biological processes. Despite their importance, regulators involved in diverse biological processes still remain largely unrevealed. In the present study, we propose a kernel-based approach to efficiently identify core regulatory elements involved in specific biological processes using gene expression profiles. We developed a framework that can detect correlations between gene expression profiles and the upstream sequences on the basis of the kernel canonical correlation analysis (kernel CCA). Using a yeast cell cycle dataset, we demonstrated that upstream sequence patterns were closely related to gene expression profiles based on the canonical correlation scores obtained by measuring the correlation between them. Our results showed that the cell cycle-specific regulatory motifs could be found successfully based on the motif weights derived through kernel CCA. Furthermore, we identified co-regulatory motif pairs using the same framework. Given expression profiles, our method was able to identify regulatory motifs involved in specific biological processes. The method could be applied to the elucidation of the unknown regulatory mechanisms associated with complex gene regulatory processes.


An antenatal appearance of megacystis-microcolon-intestinal hypoperistalsis syndrome.
We herein present a megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) case followed by ultrasound (US) examinations before birth. During the prenatal US examination of a 34-year-old woman, an enlarged bladder with bilateral hydronephrosis and hydroureter of the fetus were detected. The amniotic fluid was normal in the second trimester but polyhydramnios was observed in the third trimester. A female baby was born by cesarian section weighing 2632 g. Imaging studies detected an enlarged bladder with bilateral hydronephrosis, hydroureter and microcolon. Laparotomy on the 9th day confirmed a short small bowel with caliber change and the existence of ganglion cells and plexus of the nerve in the intestine. These findings correlated with the previously reported characteristics of MMIHS. An enlarged bladder in the second trimester and polyhydramnios in the third trimester have been reported in many cases of MMIHS. These findings may thus help to accurately diagnose MMIHS before birth.


Plasma Desphospho-Uncarboxylated Matrix Gla Protein as a Marker of Kidney Damage and Cardiovascular Risk in Advanced Stage of Chronic Kidney Disease.
Desphospho-uncarboxylated matrix Gla protein (dp-ucMGP) is formed as a result of vitamin K insufficiency. The aim of this study was to investigate the association between plasma dp-ucMGP, kidney function and cardiovascular risk factors before and after 9-months substitution of vitamin K2 in non-dialysis patients with chronic kidney disease (CKD) stage 4 and 5. 38 CKD patients were supplemented for 270±12 days with 90 µg vitamin K2 and 10 µg cholecalciferol or 10 µg cholecalciferol alone. At baseline and at follow-up circulating calcium, phosphate, lipids, hemoglobin, albumin and total protein, dp-ucMGP, osteoprotegerin, fetuin A, osteocalcin and fibroblast grown factor 23 (FGF-23) were assessed. Proteinuria was assessed in the first morning void. Baseline plasma dp-ucMGP was 1018.6±498.3 pmol/l and was significantly higher in patients at stage 5 CKD (1388.3 ±505.4 pmol/l) than at stage 4 (885.1±419.7 pmol/l), p=0.04. Vitamin K2 supplementation resulted in a decrease of dp-ucMGP level by 10.7%. Plasma dp-ucMGP was positively associated with proteinuria, serum creatinine, PTH and FGF-23; and inversely associated with glomerular filtration rate, serum hemoglobin and albumin. High dp-ucMGP level, reflecting a poor vitamin K status seems to be associated with kidney damage and may be also a marker of cardiovascular risk in CKD patients. Supplementation with vitamin K2 may improve the carboxylation status of MGP.


Dietary fat intake in healthy adolescents: inverse relationships between the estimated intake of saturated fatty acids and serum cholesterol.
The objective of the present study was to describe the intake of dietary fatty acids among healthy 15-year-old boys and girls and to relate the intake of specific fatty acids and the fatty acid composition of the serum cholesterol esters to serum lipid, apolipoprotein (Apo) and insulin concentrations respectively. Fifty-two girls and forty-two boys were randomly selected from the official population register. Unexpectedly, significant inverse associations were found between the dietary content of saturated fatty acids with a chain length of four to fifteen C atoms, mainly derived from milk fat, as well as the corresponding fatty acids in the serum cholesterol esters, on the one hand and the serum concentrations of cholesterol and ApoB on the other. The estimated dietary intake of 4:0-10:0, 12:0 and 14:0 respectively, were all significantly inversely related to the serum cholesterol (r -0.32, r -0.31, r -0.30, all and ApoB (r -0.42, r -0.42, and r -0.40, all concentrations in girls and 12:0 to the ApoB concentration (r -0.55, in boys. The proportions of 12:0 and 15:0 in the serum cholesterol esters were negatively correlated with the serum cholesterol concentrations in both girls (r -0.34, r -0.32, and boys (r -0.53, r -0.32, and with the ApoB concentrations among boys (r -0.61, r -0.43, It is conceivable that milk fat contains or is associated with some component in the diet, or some other characteristics of the food intake, which counterbalances the expected positive relationships between saturated fat intake and lipid levels.


Two evolutionarily duplicated domains individually and post-transcriptionally control SWEET expression for phloem transport.
Cell type-specific gene expression is critical for the specialized functions within multicellular organisms. In Arabidopsis, SWEET11 and SWEET12 sugar transporters are specifically expressed in phloem parenchyma (PP) cells and are responsible for sucrose efflux from the PP, the first step of a two-step apoplasmic phloem-loading strategy that initiates the long-distance transport of sugar from leaves to nonphotosynthetic sink tissues. However, we know nothing about what determines the PP cell-specific expression of these SWEETs. Sequence deletions, histochemical β-glucuronidase (GUS) analysis, cross-sectioning, live-cell imaging, and evolutionary analysis were used to elucidate domains responsible for PP specificity, while a Förster resonance energy transfer (FRET) sensor-based transport assay was used to determine whether substrate specificity coevolved with PP specificity. We identified two domains in the Arabidopsis SWEET11 coding sequence that, along with its promoter (including 5' UTR), regulate PP-specific expression at the post-transcriptional level, probably involving RNA-binding proteins. This mechanism is conserved among vascular plants but independent of transport substrate specificity. We conclude that two evolutionarily duplicated coding sequence domains are essential and individually sufficient for PP-specific expression of SWEET11. We also provide a crucial experimental tool to study PP physiology and development.


Theoretical and experimental investigations of enhanced carbon nanotube-gold interface conductivity through nitrogen doping.
It is necessary to establish high-quality contact between carbon nanotubes and metals in carbon-based devices. However, how to control and reduce contact resistance still remains unsolved. In this study, the effect of N doping in single-walled carbon nanotubes on the contact resistance with gold was studied by combining theoretical calculation with experimental methods. The theoretical results indicate that nitrogen doping in carbon nanotubes can control the bottom of the carbon nanotube conduction band downward, the Fermi level enters the conduction band, the height of the Schottky barrier between the bottom of the carbon nanotube conduction band and the gold Fermi level decreases, and the increase in doping concentration leads to the decrease of Schottky barrier width. As a result, the conductivity between the gold and carbon nanotube interface is enhanced. During experiments, the carrier density and the current of the gold and carbon nanotube device increase gradually with the increase in N doping concentration and a good electron transport channel is established between the gold and carbon nanotubes. The high-quality contact is crucial to reducing the size, improving the performance, and reducing the power consumption of carbon-based devices.


Costs of vaccine programs across 94 low- and middle-income countries.
While new mechanisms such as advance market commitments and co-financing policies of the GAVI Alliance are allowing low- and middle-income countries to gain access to vaccines faster than ever, understanding the full scope of vaccine program costs is essential to ensure adequate resource mobilization. This costing analysis examines the vaccine costs, supply chain costs, and service delivery costs of immunization programs for routine immunization and for supplemental immunization activities (SIAs) for vaccines related to 18 antigens in 94 countries across the decade, 2011-2020. Vaccine costs were calculated using GAVI price forecasts for GAVI-eligible countries, and assumptions from the PAHO Revolving Fund and UNICEF for middle-income countries not supported by the GAVI Alliance. Vaccine introductions and coverage levels were projected primarily based on GAVI's Adjusted Demand Forecast. Supply chain costs including costs of transportation, storage, and labor were estimated by developing a mechanistic model using data generated by the HERMES discrete event simulation models. Service delivery costs were abstracted from comprehensive multi-year plans for the majority of GAVI-eligible countries and regression analysis was conducted to extrapolate costs to additional countries. The analysis shows that the delivery of the full vaccination program across 94 countries would cost a total of $62 billion (95% uncertainty range: $43-$87 billion) over the decade, including $51 billion ($34-$73 billion) for routine immunization and $11 billion ($7-$17 billion) for SIAs. More than half of these costs stem from service delivery at $34 billion ($21-$51 billion)-with an additional $24 billion ($13-$41 billion) in vaccine costs and $4 billion ($3-$5 billion) in supply chain costs. The findings present the global costs to attain the goals envisioned during the Decade of Vaccines to prevent millions of deaths by 2020 through more equitable access to existing vaccines for people in all communities. By projecting the full costs of immunization programs, our findings may aid to garner greater country and donor commitments toward adequate resource mobilization and efficient allocation. As service delivery costs have increasingly become the main driver of vaccination program costs, it is essential to pay additional consideration to health systems strengthening.


Which offers more scope to suppress river phytoplankton blooms: reducing nutrient pollution or riparian shading?
River flow and quality data, including chlorophyll-a as a surrogate for river phytoplankton biomass, were collated for the River Ouse catchment in NE England, which according to established criteria is a largely unpolluted network. Against these data, a daily river quality model (QUESTOR) was setup and successfully tested. Following a review, a river quality classification scheme based on phytoplankton biomass was proposed. Based on climate change predictions the model indicated that a shift from present day oligotrophic/mesotrophic conditions to a mesotrophic/eutrophic system could occur by 2080. Management options were evaluated to mitigate against this predicted decline in quality. Reducing nutrient pollution was found to be less effective at suppressing phytoplankton growth than the less costly option of establishing riparian shading. In the Swale tributary, ongoing efforts to reduce phosphorus loads in sewage treatment works will only reduce peak (95th percentile) phytoplankton by 11%, whereas a reduction of 44% is possible if riparian tree cover is also implemented. Likewise, in the Ure, whilst reducing nitrate loads by curtailing agriculture in the headwaters may bring about a 10% reduction, riparian shading would instead reduce levels by 47%. Such modelling studies are somewhat limited by insufficient field data but offer a potentially very valuable tool to assess the most cost-effective methods of tackling effects of eutrophication.


Feature selection using factor analysis for Alzheimer's diagnosis using 18F-FDG PET images.
This article presents a computer-aided diagnosis technique for improving the accuracy of the early diagnosis of Alzheimer's disease (AD). Two hundred and ten 18F-FDG PET images from the ADNI initiative [52 normal controls (NC), 114 mild cognitive impairment (MCI), and 53 AD subjects] are studied. The proposed methodology is based on the selection of voxels of interest using the t-test and a posterior reduction of the feature dimension using factor analysis. Factor loadings are used as features for three different classifiers: Two multivariate Gaussian mixture model, with linear and quadratic discriminant function, and a support vector machine with linear kernel. An accuracy rate up to 95% when NC and AD are considered and an accuracy rate up to 88% and 86% for NC-MCI and NC-MCI,AD, respectively, are obtained using SVM with linear kernel. Results are compared to the voxel-as-features and a PCA- based approach and the proposed methodology achieves better classification performance.


CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study.
Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose. This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing. Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0-19·4; cohort B1 22·0 months [21·4-22·7], cohort B2 18·2 months [17·0-18·9], cohort C1 17·9 months [14·3-19·7], cohort C2 15·9 months [12·7-16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3-4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2). APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population. Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.


Steric stabilization of poly-L-Lysine/DNA complexes by the covalent attachment of semitelechelic poly[N-(2-hydroxypropyl)methacrylamide].
The concept of steric stabilization was utilized for self-assembling polyelectrolyte poly-L-lysine/DNA (pLL/DNA) complexes using covalent attachment of semitelechelic poly[N-(2-hydroxypropyl)methacrylamide] (pHPMA). We have examined the effect of coating of the complexes with pHPMA on their physicochemical stability, phagocytic uptake in vitro, and biodistribution in vivo. The coated complexes showed stability against aggregation in 0.15 M NaCl and reduced binding of albumin, chosen as a model for the study of the interactions of the complexes with plasma proteins. The presence of coating pHPMA had no effect on the morphology of the complexes as shown by transmission electron microscopy. However, results of the study of polyelectrolyte exchange reactions with heparin and pLL suggested decreased stability of the coated complexes in these types of reactions compared to uncoated pLL/DNA complexes. Coated complexes showed decreased phagocytic capture by mouse peritoneal macrophages in vitro. Decreased phagocytosis in vitro, however, did not correlate with results of in vivo study in mice showing no reduction in the liver uptake and no increase in the circulation times in the blood. We propose that the rapid plasma elimination of coated pLL/DNA complexes is a result of binding serum proteins and also of their low stability toward polyelectrolyte exchange reactions as a consequence of their equilibrium nature.


Enzyme-linked immunosorbent assay using recombinant SAG1 antigen to detect Toxoplasma gondii-specific immunoglobulin G antibodies in human sera and saliva.
Serologic detection of Toxoplasma gondii IgG antibodies is widely accepted as a means to determine immune status and susceptibility to Toxoplasma infection during pregnancy. However, current commercial kits present some drawbacks, such as a requirement for whole-parasite antigen preparation or interassay variability. To address these problems, the purpose of this study was to produce a whole sequence of the recombinant T. gondii SAG1 antigen (rSAG1) to assess its diagnostic performance in Toxoplasma IgG screening and to explore a saliva-based method as a noninvasive alternative to serum-based testing. rSAG1 was expressed in recombinant bacteria as inclusion bodies, purified through one-step affinity chromatography, and refolded in native form by dialysis. A large amount was obtained, and the specific antigen immunoreactivity was confirmed by immunoblotting. Two rSAG1-based enzyme-linked immunosorbent assays (ELISAs) applied to paired serum and saliva samples were designed. The rSAG1-based ELISA evaluation consisted of testing intrinsic sensitivity and specificity of 49 serum samples from patients immune to toxoplasmosis and 42 serum samples from nonimmune controls identified by routinely used kits. To assess agreement between serum-based and saliva-based tests, the positive percent agreement (PPA) and negative percent agreement (NPA) between the 2 tests were estimated. The rSAG1 serum-based ELISA detected specific IgG with 100% sensitivity and specificity. The PPA and NPA between the serum-based and saliva-based tests varied according to the selected optical density threshold in saliva. Thus, for a selected cutoff of 0.14, the PPA was 100% and the NPA was 88.1%, whereas for a selected cutoff of 0.29, the PPA was 67.3% and the NPA was 100%.


Gold-nanoparticle-based catalysts for the oxidative esterification of 1,4-butanediol into dimethyl succinate.
The oxidation of 1,4-butanediol and butyrolactone have been investigated by using supported gold, palladium and gold-palladium nanoparticles. The products of such reactions are valuable chemical intermediates and, for example, can present a viable pathway for the sustainable production of polymers. If both gold and palladium were present, a significant synergistic effect on the selective formation of dimethyl succinate was observed. The support played a significant role in the reaction, with magnesium hydroxide leading to the highest yield of dimethyl succinate. Based on structural characterisation of the fresh and used catalysts, it was determined that small gold-palladium nanoalloys supported on a basic Mg(OH)2 support provided the best catalysts for this reaction.