A case report of arrhythmogenic mitral valve disease: still a long way to go.
Mitral valve prolapse (MVP) is a common valvular heart disease and has often been associated with an increased risk of sudden cardiac death (SCD). This underlines the pressing need for the establishment of consistent tools for arrhythmic risk prediction. A 73-year-old man with previous diagnosis of MVP was referred to the cardiology outpatient consult for a 1-month history of near-syncope and light-headedness. He had no family history of SCD. Physical examination was unremarkable. Holter monitoring recorded frequent and multiple long episodes of non-sustained ventricular tachycardia (VT) and paroxysmal atrial fibrillation with controlled ventricular response. Echocardiogram revealed mitral bileaflet billowing, systolic curling, and annular disjunction, as well as increased peak systolic strain dispersion with two-dimensional speckle tracking. Cardiac magnetic resonance disclosed additional tricuspid annular dilatation and disjunction, as non-ischaemic late gadolinium enhancement on the left ventricular basal inferolateral wall. The Heart Team decided to implant a defibrillator as primary prevention for SCD due to arrhythmogenic mitral valve disease (AMVD) with high-risk features. The patient remained asymptomatic over the next 2 years, when he suffered an appropriate shock due to VT at 200 b.p.m. Here, we present a case of a patient with AMVD with classic features of high arrhythmic risk but also with some unusual characteristics such as older age, male gender, and only little pronounced mitral valve billowing, emphasizing the wide heterogeneity and lack of knowledge surrounding this entity.


Leishmania infantum leishmaniasis in corticosteroid--treated patients.
The number of leishmaniasis cases associated with immunosuppression has increased regularly over the past 20 years. Immunosuppression related to HIV infection, immunosuppressive treatment, organ transplantation, and neoplastic diseases increases the risk for Leishmania-infected people to develop visceral illness. Three cases of Leishmania infantum leishmaniasis in corticosteroid (CS)-treated patients are reported: an isolated lingual leishmaniasis in a farmer treated with CS for asthma, a severe visceral leishmaniasis associated with cutaneous lesions in a woman with myasthenia gravis, and a visceral involvement after cutaneous leishmaniasis in a man receiving CS. Physicians should recognise CS-treated patients as a population likely to be immune-suppressed. In immunodeficiency conditions, unusual forms of leishmaniasis can develop and foster the risk of a diagnostic delay and of poor response to therapy.


What makes multiplication facts difficult. Problem size or neighborhood consistency?
Two current models of arithmetic fact retrieval, the network interference theory (NIT; Campbell, 1995) and the interacting neighbors (IN) model (Verguts & Fias, 2005a), predict that errors in simple multiplication should be more probable, if they include the same digit as the correct result (i.e., if they are "consistent," compared with "inconsistent" errors). In a reanalysis of error data originally reported by Campbell (1997), we provide first empirical evidence for this prediction. Furthermore, these results support the notion of different quantity representations for decades and units as proposed by Nuerk, Weger, and Willmes (2001). However, the NIT and IN-model differ in their explanations of the problem-size effect, a hallmark finding robustly observed in arithmetic fact retrieval. Only the IN-model predicts that a correct answer's neighborhood consistency can fully account for the problem-size effect, which was confirmed in our analysis.


Next-generation sequencing of circulating tumor DNA to predict recurrence in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy.
Next-generation sequencing to detect circulating tumor DNA is a minimally invasive method for tumor genotyping and monitoring therapeutic response. The majority of studies have focused on detecting circulating tumor DNA from patients with metastatic disease. Herein, we tested whether circulating tumor DNA could be used as a biomarker to predict relapse in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy. In this study, we analyzed samples from 38 early-stage triple-negative breast cancer patients with matched tumor, blood, and plasma. Extracted DNA underwent library preparation and amplification using the Oncomine Research Panel consisting of 134 cancer genes, followed by high-coverage sequencing and bioinformatics. We detected high-quality somatic mutations from primary tumors in 33 of 38 patients. TP53 mutations were the most prevalent (82%) followed by PIK3CA (16%). Of the 33 patients who had a mutation identified in their primary tumor, we were able to detect circulating tumor DNA mutations in the plasma of four patients (three TP53 mutations, one AKT1 mutation, one CDKN2A mutation). All four patients had recurrence of their disease (100% specificity), but sensitivity was limited to detecting only 4 of 13 patients who clinically relapsed (31% sensitivity). Notably, all four patients had a rapid recurrence (0.3, 4.0, 5.3, and 8.9 months). Patients with detectable circulating tumor DNA had an inferior disease free survival (p < 0.0001; median disease-free survival: 4.6 mos. vs. not reached; hazard ratio = 12.6, 95% confidence interval: 3.06-52.2). Our study shows that next-generation circulating tumor DNA sequencing of triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy can predict recurrence with high specificity, but moderate sensitivity. For those patients where circulating tumor DNA is detected, recurrence is rapid.


[Differences in inpatient medical costs for the aged within one prefecture].
The rapid increase in the proportion of the elderly population has made the problem of medical costs increasingly important. This problem, however, is not uniform over all regions in Japan. In order to determine what factors are associated with per capita medical care expenditure of inpatients aged 70 years and over, in fiscal 1991, correlation analyses were performed using several indices of medical services, socioeconomic factors and medical supplies among 208 municipalities in one prefecture. Data from a survey in 1992 conducted by the Ministry of Health and Welfare was used in the analysis. Requests were sent to all 218 municipalities in one prefecture, and 208 responses were received a response rate of 95.4%. The main findings were as follows: 1) There were large differences in per capita medical care expenditure for those aged 70 years and over among the secondary medical areas in the prefecture. 2) Both the inpatient expenditures per person per year and bed-days in hospitals per person per year were positively correlated with number of hospital beds per 1,000, the aging population rate and death rate of those aged 70 years and over; but correlated negatively with the primary industry population rate for both sexes. 3) Inpatient expenditure per person per day was negatively correlated with the aging population rate, especially for men. 4) Three major factors that correlated significantly and positively with per capita medical care expenditure for those aged 70 years and over were bed days of inpatients per receipt, the total receipts per inpatient per year, and the number of the admission days of inpatients per year. These three major factors were negatively correlated but not significantly, with the per capita medical care expenditure per day. 5) Multiple regression analyses indicate that the aging population rate, the number of hospital beds per 1,000 of those aged 70 years and over, and death rate of those aged 70 years and over were independently correlated with the inpatient expenditure per person per year for both sexes. 6) Results of this analysis indicate that data from secondary medical regions within the prefecture rather than the municipalities yield a stronger possibility of clarifying those factors contributing to differences in per capita medical care expenditure.


Identifying the Barriers and Enablers to Nutrition Care in Head and Neck and Esophageal Cancers: An International Qualitative Study.
The goal of this work was to identify barriers and enablers to the implementation of nutrition care in head and neck and esophageal (HNE) cancers and to prioritize barriers to help improve the nutrition care process. This study used a multimethod qualitative study design (including semistructured interviews, focus group). Interviews (n = 29) were conducted at 5 European sites providing care and treatment to patients with HNE cancers. A focus group (n = 21) reviewed and corroborated interview findings and identified priorities for nutrition care. Participants were healthcare providers and researchers with direct experience in the field of HNE cancer. Five themes with accompanying barriers and enablers were identified related to nutrition care: (1) evidence for the benefit of nutrition interventions, (2) implementation of nutrition care processes (assessment, intervention, and follow-up), (3) characteristics of healthcare providers, (4) site factors, and (5) patient characteristics. Focus group discussions identified 2 priorities that must be acted on to improve nutrition care: (1) improve the evidence base and (2) develop standardized nutrition care pathways. Themes related to nutrition care in HNE cancers were similar between sites, but barriers and enablers differed. Interview and focus group participants agreed the following actions will result in improvements in nutrition care: (1) enhance the evidence base to test the benefit of nutrition interventions, with a focus on resolving specific controversies regarding nutrition therapy, and (2) establish a minimum data set with a goal to create standardized nutrition care pathways where roles and responsibilities for care are clearly defined.


Oldest leaf mine trace fossil from East Asia provides insight into ancient nutritional flow in a plant-herbivore interaction.
The Late Triassic saw a flourish of plant-arthropod interactions. By the Late Triassic, insects had developed all distinct strategies of herbivory, notably including some of the earliest occurrences of leaf-mining. Herein we describe exceptionally well-preserved leaf-mine trace fossils on a Cladophlebis Brongniart fern pinnule from the Momonoki Formation, Mine Group, Japan (Middle Carnian), representing the oldest unequivocal leaf-mines from East Asia. The mines all display a distinctive frass trail-a continuous meandering line, which later becomes a broad band containing spheroidal particles-demonstrating larval development. Although the shapes of the frass trails are generally comparable to those of Lepidoptera or Coleoptera, they cannot be unequivocally assigned to a specific extant leaf-mining taxon. Furthermore, elemental analyses by X-ray fluorescence (XRF) reveals that the frass trail comprises phosphate coprolites. The quantitative variations in P, S, and Si between coprolites and leaf veins may reflect physiological processes (e.g., consumption, absorption, and excretion) mediated by plant chemicals. Our findings reinforce the idea that leaf-mining had become a pervasive feeding strategy of herbivorous insects by the Late Triassic.


The critical role of coastal protected areas in buffering impacts of extreme climatic conditions on bird diversity and their ecosystem services' provisioning in the Eastern Cape Province, South Africa.
In this study, we documented the diversity of bird species in the Eastern Cape coastal nature reserves (i.e., Hluleka, Dwesa, Silaka and Mkhambati nature reserves), and determined the potential role of each bird species in habitat maintenance using two functional traits (i.e., body mass and feeding mode) as the function's proxy. We applied the timed species count approach during bird observations, coupled with drive-by surveys to maximise spatial coverage of each nature reserve over four years. To evaluate functional diversity, bird species were classified based on functional traits such as the adult body, and their potential ecological role derived from their feeding mode and habitat associations. Over 864 h, we accumulated 818 bird records containing 178 different bird species that were classified into 58 families with 32 species occurring in all nature reserves. Shannon-Wiener Diversity Indices showed very high overall species diversity across the nature reserves (H > 3.5) with no differences detected across sites. Although no significant correlations between vegetation changes measured through Normalised Difference vegetation Index (NDVI) in each nature reserve and the number of bird records, forest bird species were dominant (42.1%; N = 178) throughout years of observation and diversity remained high (H > 3.5). Bird species abundance only increased significantly across all nature reserves during 2018-2019. All four nature reserves had a similar distribution of bird functional traits with both high functional richness (FRic = 1), and divergence (FDiv = 0.8) and moderate evenness (FEve = 0.4). Multiple Correspondence Analysis (MCA) demonstrated a positive correlation between bird sizes and functions with large birds mainly associated with predators and carrion. Small birds and medium birds had a similar composition of species in terms of functionality being seed dispersers across the nature reserves. A significant effect that insectivores and carrions displayed in MCA plots, suggest the availability of indirect pollination services. Despite extreme drought conditions across the country in 2019, NDVI levels remained largely consistent over time in these four reserves; and thus, they offer important refuge for birds during extreme climatic conditions such as drought.


Quantification of Achilles and patellar tendon structure on imaging does not enhance ability to predict self-reported symptoms beyond grey-scale ultrasound and previous history.
Tendon pathology on imaging has been associated with an increased risk of developing symptoms. This evidence is based on classifying the tendon as normal or pathological. It is unclear whether the extent of tendon pathology is associated with the development or severity of symptoms. To investigate whether the presence and extent of tendon pathology on ultrasound tissue characterisation (UTC), or a previous history of symptoms, were associated with the development of symptoms over a football season. 179 male Australian football players underwent UTC imaging of their Achilles and/or patellar tendon at the start of the pre-season. Players completed monthly OSTRC overuse questionnaires to quantify the presence and severity of Achilles and/or patellar tendon symptoms. Risk factor analysis was performed to identify associations between imaging and the development of symptoms. A pathological Achilles tendon increased the risk of developing symptoms (RR=3.2, 95%CI 1.7-5.9). Conversely, a pathological patellar tendon was not significantly associated with the development of symptoms (RR=1.8, 95%CI 0.9-3.7). Quantification of tendon structure using UTC did not enhance the ability to identify athletes who developed symptoms. Previous history of symptoms was the strongest predictor for the development of symptoms (Achilles RR=3.0 95%CI 1.8-4.8; patellar RR=3.7 95%CI 2.2-6.1). Tendon pathology was associated with the development of self-reported symptoms; however previous history of symptoms was a stronger risk factor. The extent of disorganisation quantified by UTC should not be used as a marker for the presence or severity of current and future symptoms.


Surfactant protein A activation of atypical protein kinase C zeta in IkappaB-alpha-dependent anti-inflammatory immune regulation.
The pulmonary collectin surfactant protein (SP)-A has a pivotal role in anti-inflammatory modulation of lung immunity. The mechanisms underlying SP-A-mediated inhibition of LPS-induced NF-kappaB activation in vivo and in vitro are only partially understood. We previously demonstrated that SP-A stabilizes IkappaB-alpha, the primary regulator of NF-kappaB, in alveolar macrophages (AM) both constitutively and in the presence of LPS. In this study, we show that in AM and PBMC from IkappaB-alpha knockout/IkappaB-beta knockin mice, SP-A fails to inhibit LPS-induced TNF-alpha production and p65 nuclear translocation, confirming a critical role for IkappaB-alpha in SP-A-mediated LPS inhibition. We identify atypical (a) protein kinase C (PKC) zeta as a pivotal upstream regulator of SP-A-mediated IkappaB-alpha/NF-kappaB pathway modulation deduced from blocking experiments and confirmed by using AM from PKCzeta-/- mice. SP-A transiently triggers aPKCThr(410/403) phosphorylation, aPKC kinase activity, and translocation in primary rat AM. Coimmunoprecipitation experiments reveal that SP-A induces aPKC/p65 binding under constitutive conditions. Together the data indicate that anti-inflammatory macrophage activation via IkappaB-alpha by SP-A critically depends on PKCzeta activity, and thus attribute a novel, stimulus-specific signaling function to PKCzeta in SP-A-modulated pulmonary immune response.


Metformin: mechanisms of antihyperglycemic action, other pharmacodynamic properties, and safety perspectives.
To characterize the mechanisms of action of metformin and describe its effects and safety profile. Results of more than 30 years of clinical use in countries other than the United States are summarized. In addition, the pharmacologic properties of metformin are compared with those of other antihyperglycemic agents. Approximately 90% of all cases of diabetes are non-insulin-dependent diabetes mellitus (NIDDM)--a heterogeneous disease that involves several pathogenic factors and is associated with other coexisting conditions, such as cardiovascular disease, hypertension, and obesity. Thus, an agent that controls blood glucose levels and has favorable effects on the concomitant conditions should be considered when pharmacologic intervention is needed for the treatment of NIDDM. Metformin possesses the pharmacodynamic properties to do both. Its mechanisms of action include the reduction of hepatic glucose production and enhancement of peripheral glucose disposal, making metformin an effective antihyperglycemic agent. It also has other pharmacologic properties, independent of its glycemic effects, that offer additional clinical benefits in comparison with other pharmacologic NIDDM treatments. These benefits include stabilization or even loss of weight in patients for whom weight gain is a concern and reduction of plasma lipid levels in patients with hyperlipidemia. On the basis of 3 decades of clinical experience, metformin has been shown to be not only a well tolerated but also a highly effective antihyperglycemic agent.


[Corneal curvature of myopia].
We classified myopia by total refractive error, measured the corneal curvature, and analyzed the relationship between the diopter value and corneal curvature in growing teen-agers and in adults in their twenties, whose myopic progress is presumed to have stopped. We adopted as the harmonic average the central 3.0 mm of the cornea. We also examined peripheral corneal curvature in upper side, lower side, temporal side and nasal side at about 4.5 mm and 6.5 mm diameter from the center. There was very little difference in the harmonic average of corneal curvature from -1D to -6D. Similarly, there was very little difference in the peripheral corneal curvature. The corneal curvature was larger from central to periphery in all directions. The upper side was larger than lower side and the nasal side was larger than the temporal side. We concluded that the refractive power did not depend on the corneal refractive power in mild to moderate myopic patients.


Identification of prognostic and bone metastatic alternative splicing signatures in bladder cancer.
Bladder cancer (BLCA), originating from the epithelium of the urinary bladder, was the second most common malignancy in the urinary system with a high metastasis rate and poor post-metastasis prognosis. Alternative splicing events (ASEs) were regarded as important markers of tumor progression and prognosis, however, their roles in bladder cancer bone metastasis have not been recognized. In this study, we constructed a predictive model based on ASEs and explored the molecular mechanism of ASEs in BLCA bone metastasis, based on data from the Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases. We proposed the hypothesis that the splicing events of ITGB4 was regulated by the splicing factor JUP, and this regulation might play a key role in BLCA bone metastasis through the glycosphingolipid biosynthesis ganglio series pathway.


Factors influencing the preimmune antibody repertoire.
Preimmune antibody repertoire is not a statistical representation of all germ-line VH, D, JH and VL, JL segments encoding heavy and light chains, respectively. The antibody repertoire is biased towards a fraction of VH and VL gene segments in fetal/neonatal as well as adult life. The repertoire bias starts at the surface Ig-negative pre-B cells and persists throughout B-cell ontogeny. Antigen-independent processes like preferential rearrangements of VH, D and JH segments and pairing of the heavy and surrogate light chain operate at the surface Ig-negative pre-B cell stage. Subsequently B cells may be subject to self-antigen selection based on the specificity of their surface receptors.


Kapitza-Dirac diffraction without standing waves: diffraction without a grating?
We discuss electron diffraction from two counterpropagating light waves with two different frequencies. We show that, even though these waves do not form a standing wave, electron diffraction similar to the conventional Kapitza-Dirac effect, i.e., scattering on a standing wave, is still possible. The nonlinear response of the electron to the laser fields creates a stationary diffraction grating from which the same electron scatters.


Myiasis as a risk factor for prion diseases in humans.
Prion diseases are transmissible spongiform encephalopathies of humans and animals. The oral route is clearly associated with some prion diseases, according to the dissemination of bovine spongiform encephalopathy (BSE or mad cow disease) in cattle and kuru in humans. However, other prion diseases such as scrapie (in sheep) and chronic wasting disease (CWD) (in cervids) cannot be explained in this way and are probably more associated with a pattern of horizontal transmission in both domestic and wild animals. The skin and mucous membranes are a potential target for prion infections because keratinocytes and lymphocytes are susceptible to the abnormal infective isoform of the prion protein. Iatrogenic transmission of Creutzfeldt-Jakob disease (CJD) was also recognized after corneal transplants in humans and scrapie was successfully transmitted to mice after ocular instillation of infected brain tissue, confirming that these new routes could also be important in prion infections. Some ectoparasites have been proven to harbour prion rods in laboratory experiments. Prion rods were identified in both fly larvae and pupae; adult flies are also able to express prion proteins. The most common causes of myiasis in cattle and sheep, closely related animals with previous prion infections, are Hypoderma bovis and Oestrus ovis, respectively. Both species of flies present a life cycle very different from human myiasis, as they have a long contact with neurological structures, such as spinal canal and epidural fat, which are potentially rich in prion rods. Ophthalmomyiases in humans is commonly caused by both species of fly larvae worldwide, providing almost direct contact with the central nervous system (CNS). The high expression of the prion protein on the skin and mucosa and the severity of the inflammatory response to the larvae could readily increase the efficiency of transmission of prions in both animals and humans.


Hepatosplenic T-cell lymphoma in a young man with Crohn's disease: case report and literature review.
Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of peripheral T-cell lymphoma. It is associated with an aggressive clinical course, a poor response to conventional treatment, and an exceedingly high mortality rate. Recent reports suggest an excessive number of cases of HSTCL in young patients with Crohn's disease who are treated with thiopurines (azathioprine or 6-mercaptopurine [6-MP]) either in conjunction with or without agents that inhibit tumor necrosis factor-alpha (TNF-alpha). Herein, we describe the case of an 18-year-old man with Crohn's disease who developed HSTCL after 5 years of 6-MP treatment. He died 7 months after diagnosis from chemotherapy-refractory lymphoma. Through a literature review, we identified 28 cases of HSTCL in Crohn's patients. All patients were treated with azathioprine or 6-MP; 22 of 28 (79%) received concomitant treatment with infliximab, and 3 of these 22 patients later received treatment with adalimumab. The median age at diagnosis of HSTCL was 22 years (range, 12-40 years). The median survival for all patients was 8 months (range, 5 days-31+ months), with only 1 patient achieving remission. Additional research is needed to better understand the role of thiopurines and TNF-alpha inhibitors in promoting HSTCL and what can be done to prevent and treat this devastating malignancy in young patients with Crohn's disease.


Convergent highly stereoselective preparation of the C12-C24 fragment of macrolactin A.
The convergent synthesis of the C12-C24 fragment (lower part) of macrolactin A is described. The adapted strategy allowed building up the lower moiety by the assembly of three key intermediates via organometallic addition. One hydroxylic stereogenic center was introduced by the application of chiral sulfoxides methodology on fragment C19-C24. The preparation of the versatile 1,3-anti diol synthon C12-C16 was achieved via opening of chiral epoxide and subsequent oxidation to a hydroxy ketone. Finally, reductive elimination of the appropriate allylic dibenzoate with Na/Hg introduced directly the C16-C19 (E,E)-diene unit, in a highly efficient stereoselective fashion.


[Four cases of double bypass surgery involving choledochojejunostomy and gastrojejunostomy for inoperable peripancreatic head cancer].
Peripancreatic head cancer often causes obstructive jaundice and duodenal obstruction, which reduces the quality of life and hinders the administration of anti-cancer drugs. Here, we report 4 cases of double bypass surgery( biliary and gastric) for the treatment of inoperable peripancreatic head cancer. The patients' ages ranged from 64 to 72 years. Two patients had pancreatic head cancer and 2 had ampullary cancer. No postoperative morbidity was observed and all 4 patients resumed oral intake within 5 days after surgery and began receiving chemotherapy within 1 month after surgery. There was immediate relief of biliary obstruction in all 3 patients with obstructive jaundice. None of the patients experienced recurrence of obstructive jaundice requiring biliary drainage. Two patients who died of cancer were able to consume food orally just before they died. Although bypass surgery is more invasive than endoscopic stenting, it may be safe and useful not only for palliation, but also for induction or continuation of chemotherapy.


Liquid Biopsy as a Minimally Invasive Source of Thyroid Cancer Genetic and Epigenetic Alterations.
In the blood of cancer patients, some nucleic acid fragments and tumor cells can be found that make it possible to trace tumor changes through a simple blood test called "liquid biopsy". The main components of liquid biopsy are fragments of DNA and RNA shed by tumors into the bloodstream and circulate freely (ctDNAs and ctRNAs). Tumor cells which are shed into the blood (circulating tumor cells or CTCs), and exosomes that have been investigated for non-invasive detection and monitoring several tumors including thyroid cancer. Genetic and epigenetic alterations of a thyroid tumor can be a driver for tumor genesis or essential for tumor progression and invasion. Liquid biopsy can be real-time representative of such genetic and epigenetic alterations to trace tumors. In thyroid tumors, the circulating BRAF mutation is now taken into account for both thyroid cancer diagnosis and determination of the most effective treatment strategy. Several recent studies have indicated the ctDNA methylation pattern of some iodine transporters and DNA methyltransferase as a diagnostic and prognostic biomarker in thyroid cancer as well. There has been a big hope that the recent advances of genome sequencing together with liquid biopsy can be a game changer in oncology.


The endoplasmic reticulum lumenal domain of the adenovirus type 2 E3-19K protein binds to peptide-filled and peptide-deficient HLA-A*1101 molecules.
E3-19K is a type I membrane glycoprotein expressed by adenoviruses (Ads) to modulate host antiviral immune responses. We have developed an expression system for the endoplasmic reticulum lumenal domain (residues 1 to 100) of Ad type 2 E3-19K tagged with a C-terminal His6 sequence in baculovirus-infected insect cells. In this system, recombinant E3-19K is secreted into the culture medium. A characterization of soluble E3-19K by analytical ultracentrifugation and circular dichroism showed that the protein is monomeric and adopts a stable and correctly folded tertiary structure. Using a gel mobility shift assay and analytical ultracentrifugation, we showed that soluble E3-19K associates with soluble peptide-filled and peptide-deficient HLA-A*1101 molecules. This is the first example of a viral immunomodulatory protein that interacts with conformationally distinct forms of class I major histocompatibility complex molecules. The E3-19K/HLA-A*1101 complexes formed in a 1:1 stoichiometry with equilibrium dissociation constants (Kd) of 50 +/- 10 nM for peptide-filled molecules and of about 10 microM for peptide-deficient molecules. A temperature-dependent proteolysis study revealed that the association of E3-19K with peptide-deficient HLA-A*1101 molecules stabilizes the binding groove. Importantly, our studies showed that peptide-deficient HLA-A*1101 molecules sequestered by E3-19K are capable of binding antigenic peptides and maturing into peptide-filled molecules. This firmly establishes that E3-19K does not block binding of antigenic peptides. Together, our results suggest that Ads have evolved to exploit the late and early stages of the class I antigen presentation pathway.


Pediatric Cancer Predisposition Imaging: Focus on Whole-Body MRI.
The American Association for Cancer Research convened a meeting of international pediatric oncologists, geneticists, genetic counselors, and radiologists expert in childhood cancer predisposition syndromes (CPS) in October 2016 to propose consensus surveillance guidelines. Imaging plays a central role in surveillance for most, though not all, syndromes discussed. While encompassing the full gamut of modalities, there is increasing emphasis on use of nonionizing radiation imaging options such as magnetic resonance imaging (MRI) in children and adolescents, especially in the pediatric CPS population. In view of rapid evolution and widespread adoption of whole-body MRI (WBMRI), the purpose of our review is to address WBMRI in detail. We discuss its place in the surveillance of a range of pediatric CPS, the technical and logistical aspects of acquiring and interpreting these studies, and the inherent limitations of WBMRI. We also address issues associated with sedation and use of gadolinium-based contrast agents in MRI in children. Clin Cancer Res; 23(11); e6-e13. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.


Practice and Challenges of Building a Semantic Framework for Chemogenomics Research.
Effective discovery of new drugs for complex diseases demands an integrative analysis of big data aggregated from diverse sources in chemical and biological domains, to help better understand the mechanism of drug actions and to quickly translate discovery to clinical applications. Conventional approaches are confronting critical challenges in the integration of those huge heterogeneous datasets and the rapid transformation from data to knowledge. Semantic technologies aimed at facilitating the building of a common framework that allows data sharing and utilization across applications and domains in the web, have been developed quickly and have been exhibiting a broad impact in life science. Chemogenomics serves as a bridge to connect various chemical and biological data, thus building a semantic framework for chemogenomics research could not only facilitate the development of this field but also advance the intersection among other domains. During the last few years, such framework has been developed and applied in addressing real problems. In the review, we will describe the major techniques needed to build a semantic framework, and will discuss the challenges of having such framework making a broader impact.


Decreased bactericidal activity of leukocytes of stressed newborn infants.
Previous studies have established that leukocyte phagocytosis and intracellular killing are normal in term and low-birthweight newborns who are well. To determine the effect of stress or illness on newborn leukocyte function, the phagocytic and bactericidal activity of leukocytes from 40 sick newborns was compared with that of leukocytes from 12 newborns and 23 normal adults. To eliminate abnormal phagocytosis resulting from serum opsonic defects in newborn sera, pooled adult sera were used in all assays. Twenty-five of the 40 stressed newborns (63%) had decreased in vitro activity against either Staphylococcus aureus 502A or Escherichia coli, or both, compared with decreased activity in two of 12 well infants (17%) and in four of 23 adult controls (17%). The mean bactericidal activity (percentage of organisms killed after two hours) of leukocytes from stressed newborns against S. aureus (83% +/- 2 [SEM]) and E. coli. (87% +/- 4 [SEM]) was significantly less than in the combined well infant and adult control group (94% +/- 1 for S. aureus and 97% +/- .5 for E. coli). Although the more severely ill infants had an increased incidence of impaired antibacterial activity, the degree of impairment was not related to the severity of illness. No consistent relationship of decreased activity to birthweight, gestational age, age when studied, or specific diagnosis was seen. The leukocyte abnormality in stressed infants against S. aureus was principally a killing defect, while against E. coli both phagocytosis and killing were abnormal. This study indicates that a wide variety of neonatal disorders may affect one or more of the steps required for normal bacterial killing. The lability of leukocytic antibacterial function under stress is an additional mechanism for the newborn's increased susceptibility to infection.


Glomerular filtration rate in adults estimated from 123iodine-hippuran and 99mtechnetium-diethylenetriaminepenta-acetic acid gamma camera renography.
In a retrospective study a close relationship was found between the rate constant for renal clearance of the radioactive indicator (lambda pk) and the glomerular filtration rate (GFR) measured by 51Cr-EDTA plasma clearance. The material comprised eighteen adult subjects submitted to 123I-hippuran gamma camera renography (IHGR) and twenty-two adult subjects to 99mTc-DTPA gamma camera renography (TDGR). The rate constant was calculated from a bi-exponential decomposition of the activity-time curve recorded within a small region of interest over the left ventricle. The total cleared renal fraction (TCRF) of the cardiac output with respect to the radioactive indicator has previously been shown to be closely related to GFR. A pooled estimate of GFR (GFRp) was calculated from the stochastically independent estimates of GFR based on lambda pk and TCRF. The comparison of GFRp with measured GFR was satisfactory and yielded substantially smaller standard deviations (SD) of GFRp than estimates based on lambda pk and TCRF separately. The standard deviations of GFRp were about 7 and 12 ml/min/1.73 m2 in IHGR for GFR equal to 50 and 100 ml/min/1.73 m2, respectively. The corresponding SD in TDGR were about 7 and 11 ml/min/1.73 m2. These standard deviations are sufficiently small for many clinical purposes and the method requires no blood samples or urine collections.


Long-Term Comparison of Aesthetical Outcomes After Oncoplastic Surgery and Lumpectomy in Breast Cancer Patients.
Lumpectomy may result in major deformities and asymmetries in approximately one-third of patients. Although oncoplastic surgery (OP) could be a useful alternative to avoid them, lack of strong data is causing some debate. The purpose of this study was to compare aesthetic outcomes in patients undergoing OP versus lumpectomy using three different assessment methods. A total of 122 patients were included in this cross-sectional multicentric study; 57 underwent OP (46.7 %), and 65 underwent lumpectomy (53.3 %). Two breast surgeons and two plastic surgeons from different institutions using the Garbay scale independently evaluated aesthetic outcomes. BCCT.core software was applied in both groups, and the patients evaluated their aesthetic outcomes answering a questionnaire about their satisfaction rate. OP group had a higher proportion of excellent aesthetic results according to the BCCT.core software analysis (p = 0.028) and the specialists (p = 0.002). Multifactorial analyses showed that age ≥70 years (RP = 6.02; 95 % confidence interval [CI] 1.73-21.0; p = 0.005), tumors in the medial, inferior, and central quadrants (RP = 4.21; 95 % CI 1.88-9.44; p < 0.001), and large breasts (RP = 7.55; 95 % CI 2.48-23.0; p < 0.001) were significant risk factors for poor aesthetic outcomes after lumpectomy. The patients classified their results as better than those by the specialists and by the software, with no statistical difference between the groups. Excellent aesthetic results were more frequent in the OP group according to BCCT.core software analysis and specialists. In addition, some clinical conditions and tumor locations in the breast can be considered risky factors for poor aesthetic outcomes in lumpectomy.


RETRACTED: Ehlers-Danlos syndrome caused by the c.934C>T, p. Arg312Cys mutation in COL1A1 gene: an Italian family without cardiovascular events.
The article entitled "Ehlers-Danlos syndrome caused by the c.934C>T, p. Arg312Cys mutation in COL1A1 gene: an Italian family without cardiovascular events" has been retracted because the description and characterization of the disease in a family may have been previously published. Upon publication of this article we were notified by an author of a study appearing in 2016 in another journal claiming that characteristics and symptoms of the family described closely matched their study, and that the two studies describe the same family. Whereas constituent family members appearing in both articles were not identical (differing by one member), symptoms and diagnoses of each family proband appeared to be consistent in both studies, leading to the editors' conclusion that it is likely that the same family was being described in two separate articles.The corresponding author of the article in Dermatology Online Journal was informed of this incident, and responded with the assertion that they were unaware of the study published in 2016, and provided no additional information. They further requested that their article be retracted. In light of the available information and author's request, the editors of Dermatology Online Journal have retracted this article.The original article was published on July15, 2018 and corrected on September 15, 2018.The original article was published on July15, 2018 and corrected on September 15, 2018.


Isolation of novel peptides, cabin-1, -2, -3, and -4, that inhibit cathepsin B from a thermolysin digest of human plasma.
Four novel peptides that inhibit cathepsin B, designated as Cabin-1, -2, -3, and -4, were isolated from a thermolysin digest of human plasma. After gel filtration and cation-exchange chromatography, the peptide mixture was purified by reverse-phase HPLC to isolate Cabin-1, -2, -3, and 4, with the amino acid sequences LGPVTQE, VLQSSGLYS, VVSVLT, and LVYDAY, respectively. These peptides correspond to f(64-70) of human apolipoprotein A-I for Cabin-1, f(56-64) and f(185-190) of the human immunoglobulin G gamma chain for Cabin-2 and -3, and f(66-71) of human transferrin for Cabin-4. Synthetic Cabin-1, -2, -3, and -4 showed dose-dependent inhibition of cathepsin B. Their IC50 values were 450, 500, 20, and 5.0 micromol/l, respectively. Lineweaver-Burk plots suggested that Cabin-3 is a noncompetitive inhibitor, while Cabin-4 is a competitive inhibitor. Among the N- and C-terminal deletion peptides of Cabin-2 and -4, Cabin-2(1-8), VLQSSGLY, was found to have the most potent inhibitory activity, with an IC50 of 3.8 micromol/l.


Protegiendo Nuestra Comunidad: empowerment participatory education for HIV prevention.
To be effective, HIV/AIDS interventions must be culturally and linguistically appropriate and must occur within the context of the specific community in which they are delivered. In this article, the development of a culture-specific lay health advisor (LHA) program, Protegiendo Nuestra Comunidad, for recently immigrated Mexicans is described. This program is one component of a collaborative inquiry research project involving community participants and researchers working as partners in carrying out and assessing a program for the prevention of HIV/AIDS. The collaborative inquiry process was applied as an empowerment philosophy and methodology of Paulo Freire and an ecological framework was used for the development of Protegiendo Nuestra Comunidad. The use of principles of empowerment for curriculum development, teaching methodology, and program delivery are described.


An autopsy case of disseminated histoplasmosis probably due to infection from a renal allograft.
An autopsy case of a 52-year-old Japanese male, who died of disseminated histoplasmosis, is reported. He had received a cadaveric renal allograft 4 years prior to death. The donor was a 33-year-old American negro male, who had resided in Texas. The patient had been treated with immunosuppressive drugs after renal transplantation, and mycotic pneumonia developed 3 months before death. At autopsy, acute necrotizing lesions composed of histiocytes were observed in the transplanted kidney, lungs, prostate gland and various lymph nodes. Abundant yeast-like fungal elements, measuring 2-5 micron in diameter, were engulfed by the histiocytes, and were identified as Histoplasma capsulatum by the immunoperoxidase method. The transplanted kidney was considered to have been the source of the infection.


No Differences in Auditory Steady-State Responses in Children with Autism Spectrum Disorder and Typically Developing Children.
Auditory steady-state response (ASSR) has been studied as a potential biomarker for abnormal auditory sensory processing in autism spectrum disorder (ASD), with mixed results. Motivated by prior somatosensory findings of group differences in inter-trial coherence (ITC) between ASD and typically developing (TD) individuals at twice the steady-state stimulation frequency, we examined ASSR at 25 and 50 as well as 43 and 86 Hz in response to 25-Hz and 43-Hz auditory stimuli, respectively, using magnetoencephalography. Data were recorded from 22 ASD and 31 TD children, ages 6-17 years. ITC measures showed prominent ASSRs at the stimulation and double frequencies, without significant group differences. These results do not support ASSR as a robust ASD biomarker of abnormal auditory processing in ASD. Furthermore, the previously observed atypical double-frequency somatosensory response in ASD did not generalize to the auditory modality. Thus, the hypothesis about modality-independent abnormal local connectivity in ASD was not supported.


Impact of ductus arteriosus constriction and restrictive foramen ovale on global hemodynamics for term fetuses with d-TGA.
The ductus arteriosus (DA) constriction and restrictive foramen ovale (FO) are known as the leading cause of compromise and death of fetuses with dextro-transposition of the great arteries (d-TGA). Although the d-TGA fetal hemodynamics is of great importance in making diagnosis and management of the congenital heart defect, it remains poorly understood, particularly in terms of abnormal DA and FO. In this study, we developed a closed-loop 0-1D multiscale model of the fetal cardiovascular system (CVS) specified for the d-TGA circulation and conducted a systematic study of the impact of the DA constriction and restrictive FO on fetal hemodynamics. We found that the DA constriction led to a pronounced increase in the pulmonary artery pressure, pulmonary and mitral valve (PV and MV) regurgitation as well as left heart volume; the restrictive FO was responsible for reducing MV E/A ratio, ie, the ratio of peak early filling and late diastolic filling velocities, and PV peak systolic flow (PSV) but could increase both aortic valve (AV) PSV and aortic isthmus systolic index (ISI). Moreover, the amount of blood flowing through the DA was observed equivalent to that through the FO; the influence of DA constriction on the cerebral and placental perfusions are larger than that of the FO. Our results demonstrate that the proposed fetal cardiovascular model may be a useful tool for studying the underlying mechanisms associated with d-TGA fetal circulation and providing insights into its complex physiology and pathology.


Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome.
Antley-Bixler syndrome (ABS) is characterized by skeletal defects including craniosynostosis and radiohumeral synostosis. Although mutations in the FGFR2 gene have been found in some patients called ABS, genetic heterogeneity of this syndrome has been proposed. We have previously reported three ABS patients with unique abnormalities in steroidogenesis (apparent decreased activity of 17alpha-hydroxylase, 17,20-lyase, and 21-hydroxylase). Decreased activity of lanosterol 14alpha-demethylase has also been described in an ABS patient. Since all these enzymes require cytochrome P450 oxidoreductase (encoded by POR) as an electron donor, we studied POR in two unrelated ABS patients with abnormal steroidogenesis. Direct sequencing of POR revealed that both patients had compound heterozygous mutations (1329insC and R454H in a male patient, 1698insC and R454H in a female patient). The two insertional mutations were assumed to generate truncated and unstable mRNAs. The R454H mutation was assumed to be deleterious because the R454 resides in the FAD-binding domain and is highly conserved among diverse species. Our results demonstrate that mutations in POR cause the ABS phenotype with autosomal recessive inheritance and with characteristic abnormalities in steroidogenesis.


Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease.
Hereditary hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, leading to hypertonia and apnea episodes. Missense, nonsense, frameshift, splice site mutations, and large deletions in the human glycine receptor α1 subunit gene (GLRA1) are the major known cause of this disorder. However, mutations are also found in the genes encoding the glycine receptor β subunit (GLRB) and the presynaptic Na(+)/Cl(-)-dependent glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of SLC6A5 in 93 new unrelated human hyperekplexia patients revealed 20 sequence variants in 17 index cases presenting with homozygous or compound heterozygous recessive inheritance. Five apparently unrelated cases had the truncating mutation R439X. Genotype-phenotype analysis revealed a high rate of neonatal apneas and learning difficulties associated with SLC6A5 mutations. From the 20 SLC6A5 sequence variants, we investigated glycine uptake for 16 novel mutations, confirming that all were defective in glycine transport. Although the most common mechanism of disrupting GlyT2 function is protein truncation, new pathogenic mechanisms included splice site mutations and missense mutations affecting residues implicated in Cl(-) binding, conformational changes mediated by extracellular loop 4, and cation-π interactions. Detailed electrophysiology of mutation A275T revealed that this substitution results in a voltage-sensitive decrease in glycine transport caused by lower Na(+) affinity. This study firmly establishes the combination of missense, nonsense, frameshift, and splice site mutations in the GlyT2 gene as the second major cause of startle disease.


Differentially regulated ADAMTS1, 8, 9, and 18 in pancreas adenocarcinoma.
Despite recent diagnostic and therapeutic improvements, pancreas cancer remains one of the highly lethal cancers. The extracellular matrix (ECM) is a physiological barrier that limits the spread of cancer cells into surrounding tissues and distant organs. Disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) is a family of 19 proteases, which is involved in various biological processes such as ECM remodelling and anti-angiogenesis. To investigate the expression of ADAMTS1, 8, 9, and 18 proteinases in pancreas adenocarcinoma and its nodal metastasis. The immunostaining status of ADAMTS1, 8, 9, and 18 were investigated in formalin-fixed paraffin-embedded samples of 25 patients who underwent pancreaticoduodenectomy for an adenocarcinoma located at the head of the pancreas. In semi-quantitive grading pathologically, ADAMTS1, 8, 9, and 18 were found to be highly stained in all cancerous pancreas samples compared with normal pancreas. In addition, the immune positivity of ADAMTS1, 9, and 18 was found to be higher in metastatic lymph nodes than in non-metastatic lymph tissue. Tumour size was correlated with ADAMTS9 and 18 expressions in cancerous pancreas. According to the data obtained from the study, we suggest that these four ADAMTSs may have significant roles in the tumorigenesis and nodal spread of pancreas adenocarcinoma.


Virtual classroom helps medical education for both Chinese and foreign students.
The rapid development of computer and internet technology has a strong influence over one's quality of education within different fields of study. To determine the potential benefits of introducing internet into medical school classes, a pilot study was conducted in three different Chinese medical schools. Seven hundred and eight medical school undergraduates, 385 dental school students and 366 foreign students were randomly recruited to complete a self-administered questionnaire. The contents included personal information, current usage of computer and internet, and attitudes towards the computerised teaching methods. Two forum groups were created using instant message software and were randomly assigned to two classes, allowing students to freely ask or discuss questions with the help of their teachers in these two virtual classrooms. All 1539 questionnaires were accepted and analysed. Although there were some differences between Chinese and foreign undergraduates, both group of students were highly proficient in internet usage and navigation. Overwhelmingly, 88.37% of the students owned a computer and frequently logged onto the internet. Most of them believed that the internet is a helpful adjunct to their studies and held positive attitudes towards computerised teaching. Compared to the classes that were not assigned internet forums, the two experimental classes performed significantly better on the examination. Our results suggest that computerised teaching methods have significant potential to assist in learning for both Chinese and foreign medical undergraduates.


Identification of protein phosphatases-1 and 2A and inhibitor-2 in oocytes of the starfish Asterias rubens and Marthasterias glacialis.
Protein phosphatases present in the particulate and soluble fractions of oocytes of the starfish Asterias rubens and Marthasterias glacialis have been classified according to the criteria used for these enzymes from mammalian cells. The major protein phosphatase activity in the particulate fraction had very similar properties to protein phosphatase-1 from mammalian tissues, including preferential dephosphorylation of the beta subunit of phosphorylase kinase, sensitivity to inhibitor-1 and inhibitor-2, inhibition of phosphorylase phosphatase activity by protamine and heparin, and retention by heparin-Sepharose. The major protein phosphatase in the soluble fraction had very similar properties to mammalian protein phosphatase-2A, including preferential dephosphorylation of the alpha subunit of phosphorylase kinase, insensitivity to inhibitors-1 and 2, activation by protamine and heparin, and exclusion from heparin-Sepharose. An acid-stable and heat-stable protein was detected in the soluble fraction of starfish oocytes, whose properties were indistinguishable from those of inhibitor-2 from mammalian tissues. It inhibited protein phosphatase-1 specifically, and its apparent molecular mass on SDS polyacrylamide gels was 31 kDa. Furthermore, an inactive hybrid formed between the starfish oocyte inhibitor and the catalytic subunit of mammalian protein phosphatase-1 could be reactivated by preincubation with MgATP and mammalian glycogen synthase kinase-3. The remarkable similarities between starfish oocyte protein phosphatases and their mammalian counterparts are indicative of strict phylogenetic conservation of these enzymes. The results will facilitate further analysis of the role of protein phosphorylation in the control of starfish oocyte maturation by the hormone 1-methyladenine.


Management of ASCUS findings in Papanicolaou smears. A retrospective study.
Atypical squamous cells of undetermined significance (ASCUS) are a cervical cytologic finding category suggestive but not definitive of squamous intraepithelial lesions. ASCUS remains an incompletely described entity and accounts for even 5%-10% of reported Papanicolaou (Pap) smears. The management of women with such cytologic findings remains controversial. The aim of this study was to evaluate the cytology laboratory findings with regards to ASCUS diagnosis, using cervical Pap smears, and colposcopic biopsies, as well as their management. This is a retrospective study of patients with ASCUS Pap smears taken during the period January 2010 - December 2010 in the Second Department of Obstetrics and Gynecology, Aretaieion Hospital. During the study period, 657 Pap smears were examined at the Aretaieion Hospital; moreover, seven patients, whose Pap smears were cytologically diagnosed with ASCUS, were referred from other clinics, providing a total of 42 cases with a descriptive diagnosis of ASCUS for review. Of the 42 cases, eight were not studied because they were either lost in follow-up or they did not have available data. The remaining 34/42 patients were evaluated by colposcopic examination and directed biopsies where necessary. The ratio of ASCUS to low-grade squamous intraepithelial lesion (LGSIL), high-grade squamous cell intraepithelial lesion (HGSIL) or squamous cell carcinoma (SCC) was 5/34, 1/34, and 0/34, respectively. In the 34 ASCUS cases evaluated by colposcopy, the age distribution varied from 22 to 54 years. Eight of 34 cases did not have a child, 7/34 were primigravida, 18/34 were secondi-gravida, and 1/34 had four children. Four out of 34 cases were postmenopausal, 3/34 referred no history of abnormal bleeding, 21/34 were smokers, 6/34 used oral contraceptives, 2/34 used intrauterine devices, 1/34 took replacement of hormones, 4/34 had prior abnormal Pap smears human papillomavirus (HPV), or 1/34 had previous cancer (breast cancer). Colposcopy was inconclusive in 4/34 patients, while 8/34 cases were negative for Schiller and acetic acid tests and also had normal colposcopy. Infectious organisms were found in 8/34 patients with ASCUS, including actinomyces (1/8), trichomonas (5/8), and candida albicans (2/8). Histologic tests revealed 16/34 koilocytosis cases, 5/34 LGSIL, 1/34 HGSIL, and 0/34 SCC. The dilemma in the management of patients with an ASCUS diagnosis still exists as a significant problem for clinicians.


Design, synthesis, and biological investigation of selective human carbonic anhydrase II, IX, and XII inhibitors using 7-aryl/heteroaryl triazolopyrimidines bearing a sulfanilamide scaffold.
A novel library of human carbonic anhydrase (hCA) inhibitors based on the 2-sulfanilamido[1,2,4]triazolo[1,5-a]pyrimidine skeleton modified at its 7-position was prepared by an efficient convergent procedure. These derivatives were evaluated in vitro for their inhibition properties against a representative panel of hCA isoforms (hCA I, II, IV, IX, and XII). The target tumour-associated isoforms hCA IX and XII were potently inhibited with KIs in the low nanomolar range of 5-96 nM and 4-72 nM, respectively. Compounds 1d, 1j, 1v, and 1x were the most potent hCA IX inhibitors with KIs of 5.1, 8.6, 4.7, and 5.1 nM, respectively. Along with derivatives 1d and 1j, compounds 1r and 1ab potently inhibited hCA XII isoform with KIs in a single-digit nanomolar range of 8.8, 5.4, 4.3, and 9.0 nM, respectively. Compounds 1e, 1m, and 1p exhibited the best selectivity against hCA IX and hCA XII isoforms over off-target hCA II, with selectivity indexes ranging from 5 to 14.


Anion-Activated Bases and Nucleophiles Characterized by Photoelectron Spectroscopy.
Negative ion photoelectron spectra at 20 K along with ab initio [CCSD(T)] and M06-2X density functional theory calculations are reported for a series of six basic and nucleophilic pyridine derivatives with an anionic substituent [i.e., 3- and 4-PyrBX3-, where X = F, 4-t-BuC6H4, 4-MeOC6H4, and 3,5-(MeO)2C6H3]. Vertical detachment energies (VDEs) of these charge-activated reagents span from 4.50-5.85 eV and are well reproduced by M06-2X/aug-cc-pVTZ and CCSD(T)/maug-cc-pVTZ computations. Surprisingly, the VDEs are found to correlate with the SN2 reactivity of the PPh4+ salts of the substituted pyridine anions with 1-iodooctane in dichloromethane. This provides an experimental measure of the nucleophilicity of these charge-activated anions, which represent a new class of chemical reagent.


Timing of dexamethasone treatment in experimental Staphylococcus aureus endophthalmitis.
This study sought to determine whether intravitreal dexamethasone with vancomycin preserves retinal function in eyes with experimental Staphylococcus aureus endophthalmitis better than intravitreal vancomycin alone. Twenty-four rabbits received intravitreal injections in both eyes with S. aureus. Right eyes were treated with intravitreal dexamethasone plus vancomycin and left eyes were treated with vancomycin alone at 24, 36, 48, or 72 hours after inoculation. Evaluation was performed by slit-lamp biomicroscopy, indirect ophthalmoscopy, and electroretinogram. Vitreous humor cultures and histopathologic examinations were performed on the eyes after the rabbits were killed. The combination of intravitreal dexamethasone and vancomycin resulted in significantly less inflammation than vancomycin alone at 24 and 36 hours after inoculation, but electroretinograms showed significantly better preservation only at 36 hours after bacterial inoculation. Viable bacteria were cultured from eyes treated 48 and 72 hours after inoculation. Intravitreal dexamethasone was found to be beneficial by electroretinography when administered 36 hours after infection. In the authors' model, a single intravitreal injection of vancomycin with or without the addition of dexamethasone was insufficient to sterilize eyes 48 and 72 hours after bacterial inoculation.


Cytotoxicity of alkaloids isolated from Argemone mexicana on SW480 human colon cancer cell line.
Argemone mexicana Linn. (Papaveraceae) has been used as traditional medicine in India and Taiwan for the treatment of skin diseases, inflammations, bilious, fever, etc. Some alkaloids of A. mexicana have been screened for their cytotoxicity on different cancer cell lines. The study investigates potential cytotoxic effects of alkaloids isolated from aerial part of A. mexicana on SW480 human colon cancer cell line. Six alkaloids, 13-oxoprotopine, protomexicine, 8-methoxydihydrosanguinarine, dehydrocorydalmine, jatrorrhizine, and 8-oxyberberine were isolated from the methanol extract of A. mexicana. Cytotoxicity of these alkaloids was studied on SW480 human colon cancer cell line at 1, 25, 50, 75, 100, 125, 150, and 200 µg/mL for 24 and 48 h. Cells were seeded in a 96-well micro-plate at a concentration of 2 × 10(4) cells per well and MTS assay was performed to assess cytotoxicity in terms of cell viability. At 200 µg/mL, protomexicine and 13-oxoprotopine showed mild cytotoxicity (∼24-28%) whereas dehydrocorydalmine exhibited moderate cytotoxicity (∼48%). 8-Oxyberberine was mildly cytotoxic (∼27%) at 24 h but was more potent (∼76%) at 48 h. Jatrorrhizine and 8-methoxydihydrosanguinarine were most potent (∼95-100%) in inhibiting the human colon cancer cell proliferation showing complete reduction in cell viability. This is the first study on the effect of these alkaloids on SW480 human colon cancer cell line. This study indicates that some alkaloids of A. mexicana strongly inhibit the cell proliferation in human colon cancer cells, and it might be a basis for future development of a potent chemotherapeutic drug.


A retrospective cohort study comparing differences in 30-day mortality among critically ill patients aged ≥ 70 years treated in European tax-based healthcare systems (THS) versus social health insurance systems.
In Europe, tax-based healthcare systems (THS) and social health insurance systems (SHI) coexist. We examined differences in 30-day mortality among critically ill patients aged ≥ 70 years treated in intensive care units in a THS or SHI. Retrospective cohort study. 2406 (THS n = 886; SHI n = 1520) critically ill ≥ 70 years patients in 129 ICUs. Generalized estimation equations with robust standard errors were chosen to create population average adjusted odds ratios (aOR). Data were adjusted for patient-specific variables, organ support and health economic data. The primary outcome was 30-day-mortality. Numerical differences between SHI and THS in SOFA scores (6 ± 3 vs. 5 ± 3; p = 0.002) were observed, but clinical frailty scores were similar (> 4; 17% vs. 14%; p = 0.09). Higher rates of renal replacement therapy (18% vs. 11%; p < 0.001) were found in SHI (aOR 0.61 95%CI 0.40-0.92; p = 0.02). No differences regarding intubation rates (68% vs. 70%; p = 0.33), vasopressor use (67% vs. 67%; p = 0.90) and 30-day-mortality rates (47% vs. 50%; p = 0.16) were found. Mortality remained similar between both systems after multivariable adjustment and sensitivity analyses. The retrospective character of this study. Baseline risk and mortality rates were similar between SHI and THS. The type of health care system does not appear to have played a role in the intensive care treatment of critically ill patients ≥ 70 years with COVID-19 in Europe.


System-on-chip upgrade of millimeter-wave imaging diagnostics for fusion plasma.
Monolithic, millimeter wave "system-on-chip" technology has been employed in chip heterodyne radiometers in a newly developed Electron Cyclotron Emission Imaging (ECEI) system on the DIII-D tokamak for 2D electron temperature and fluctuation diagnostics. The system employs 20 horn-waveguide receiver modules each with customized W-band (75-110 GHz) monolithic microwave integrated circuit chips comprising a W-band low noise amplifier, a balanced mixer, a ×2 local oscillator (LO) frequency doubler, and two intermediate frequency amplifier stages in each module. Compared to previous quasi-optical ECEI arrays with Schottky mixer diodes mounted on planar antennas, the upgraded W-band array exhibits >30 dB additional gain and 20× improvement in noise temperature; an internal eight times multiplier chain is used to provide LO coupling, thereby eliminating the need for quasi-optical coupling. The horn-waveguide shielding housing avoids out-of-band noise interference on each module. The upgraded ECEI system plays an important role for absolute electron temperature and fluctuation measurements for edge and core region transport physics studies. An F-band receiver chip (up to 140 GHz) is under development for additional fusion facilities with a higher toroidal magnetic field. Visualization diagnostics provide multi-scale and multi-dimensional data in plasma profile evolution. A significant aspect of imaging measurement is focusing on artificial intelligence for science applications.


Field programmable gate array in a fast 256-channel data acquisition system.
We describe an FPGA (Field Programmable Gate Array) controlled fast data acquisition system with 256 channels suitable for high resolution electrocardiographic (ECG), electrogastrographic (EGG) and late potential (LP) recordings. The A/D converter provides 800ns conversion time with 12 bits. The S11W, a 16 bit, parallel, I/O interface, is used to connect the data acquisition device to a portable SPARC-compatible computer. With only one A/D converter, we have achieved 2 kHz sampling rate for each channel and more than 1MB/s overall by using an overlapping delay technique. Channel parameters can be selected independently from one of eight gains ranging from 50 to 10,000, and one of three filters ("ECG" 0.05-120Hz, "EGG" 0.001-1Hz and "LP" 60-1kHz). There are eight programmable sampling frequencies from 2Hz to 2kHz. The system is fully battery operated and protected from the defibrillation high voltages to meet the safety requirements. The acquisition system can be widely used in medical research and clinical applications.


Self-changing behaviour in smoking cessation linked to trait and cognitive impulsivity.
To compare impulsivity, measured using self-report and cognitive tasks in people who ceased smoking without treatment (self-changers) with each of the following groups: (i) smoking non-treatment-seekers, (ii) people in smoking cessation treatment and currently abstinent and (iii) people in smoking cessation treatment but non-abstinent. Cross-sectional, observational study. The smoking cessation unit of a public general hospital, Hospital de Santa Maria, in Lleida, Spain. All participants were from the hospital's catchment area. One hundred and twenty participants, classified in four groups: (1) self-changers (n = 30, 21 females, mean age = 41.50 years), (2) non-treatment-seekers (n = 30, 17 females, mean age = 35.27 years), (3) people in smoking cessation treatment and currently abstinent (n = 30, 17 females, mean age = 48.93 years) and (4) people in smoking cessation treatment but non-abstinent (n = 30, 21 females, mean age = 33.70 years). The Barratt Impulsiveness Scale, including measures of non-planning, attentional and motor impulsivity, and two behavioural tasks measuring cognitive inhibition (Stroop test) and choice impulsivity (delay-discounting task). Confounders included sex, age, education, employment, smoking severity, depression and trait and state anxiety. Although not on the other three measures, we found significant group differences on trait non-planning impulsivity and Stroop performance. Self-changers, compared with non-treatment-seekers, had lower non-planning impulsivity (P = 0.018, Cohen's d = 0.62) and better Stroop performance (P = 0.001, Cohen's d = 0.66). Self-changers also had better Stroop performance than participants in treatment and currently abstinent (P = 0.002, Cohen's d = 0.85). People who have stopped smoking without treatment appear to have lower non-planning impulsivity and more effective cognitive inhibition compared with smoking non-treatment-seekers, and better cognitive inhibition than people who cease smoking with treatment aid.


Interaction of a paraneoplastic cerebellar degeneration-associated neuronal protein with the nuclear helix-loop-helix leucine zipper protein MRG X.
Paraneoplastic cerebellar degeneration-associated antigen PCD17/cdr2 is a neuronal protein expressed predominantly in the cytoplasm of cerebellar Purkinje cells. The biological activities of this protein are not known; however, the presence of a leucine zipper motif in its amino acid sequence suggests that this protein might interact with other proteins harboring a leucine zipper motif. In this study we found by means of a yeast two-hybrid system, ligand overlay assay, and co-immunoprecipitation assay that PCD17 interacts with a nuclear helix-loop-helix leucine zipper protein, MRG X. Overexpression of MRG X in T98G glioblastoma cells by transfection caused abnormal morphological changes in the nucleus and induced cell death. On the other hand, coexpression of PCD17 with MRG X prevented nuclear morphological changes and cell death in T98G cells. MRG X, which is thought to be functionally related to the cell cycle and cell growth, may be regulated by PCD17/cdr2 in Purkinje cells.


Pulmonary embolism and internal jugular vein thrombosis as evocative clues of Lemierre's syndrome: A case report and review of the literature.
Lemierre's syndrome (LS) is an uncommon condition with oropharyngeal infections, internal jugular vein thrombosis, and systemic metastatic septic embolization as the main features. Fusobacterium species, a group of strictly anaerobic Gram negative rod shaped bacteria, are advocated to be the main pathogen involved. We report a case of LS complicated by pulmonary embolism and pulmonary septic emboli that mimicked a neoplastic lung condition. A Medline search revealed 173 case reports of LS associated with internal jugular vein thrombosis that documented the type of microorganism. Data confirmed high prevalence in young males with Gram negative infections (83.2%). Pulmonary embolism was reported in 8.7% of cases mainly described in subjects with Gram positive infections (OR = 9.786; 95%CI: 2.577-37.168, P = 0.001), independently of age and gender. Only four fatal cases were reported. LS is an uncommon condition that could be complicated by pulmonary embolism, especially in subjects with Gram positive infections.


Manipulating the Local Coordination and Electronic Structures for Efficient Electrocatalytic Oxygen Evolution.
Non-noble-metal-based nanomaterials can exhibit extraordinary electrocatalytic performance toward the oxygen evolution reaction (OER) by harnessing the structural evolution during catalysis and the synergistic effect between elements. However, the structure of active centers in bimetallic/multimetallic catalysts is under long-time debate in the catalysis community. Here, an efficient bimetallic Ni-Fe selenide-derived OER electrocatalyst is reported and the structure-activity correlation during the OER evolution studied. By combining experiments and theoretical calculations, a conceptual advance is provided, in that the local coordination structure distortion and disordering of active sites inherited from the pre-catalyst and post-formed by a further reconstruction are responsible for boosting the OER performance. The active center is identified on Ni sites showing moderate bindings with oxygenous intermediates rather than Fe sites with strong and poisonous adsorptions. These findings provide crucial understanding in manipulating the local coordination and electronic structures toward rational design and fabrication of efficient OER electrocatalysts.


Hypoparathyroidism-related health care utilization and expenditure during the first postoperative year after total thyroidectomy for cancer: a comprehensive national cohort study.
Hypoparathyroidism is the most common complication of total thyroidectomy for cancer, and requires calcium and/or vitamin D supplementation for an unpredictable period of time. The additional cost associated with this complication has not hitherto been assessed. The aim of this study was to assess the economic burden of postoperative hypoparathyroidism after total thyroidectomy for cancer in France. Based on the French national cancer cohort, which extracts data from the French National Health Data System (SNDS), all adult patients who underwent a total thyroidectomy for cancer in France between 2011 and 2015 were identified, and their healthcare resource use during the first postoperative year was compared according to whether they were treated postoperatively with calcium and/or vitamin D or not. Univariate and multivariate cost analyses were performed with the non-parametric Wilcoxon test and generalized linear model (gamma distribution and log link), respectively. Among the 31,175 patients analyzed (75% female, median age: 52y), 13,247 (42%) started calcium and/or vitamin D supplementation within the first postoperative month, and 2,855 patients (9.1%) were still treated at 1 year. Over the first postoperative year, mean overall and specific health expenditures were significantly higher for treated patients than for untreated patients: €7,233 vs €6,934 per patient (p<0.0001) and €478.6 vs €332.7 per patient (p<0.0001), respectively. After adjusting for age, gender, Charlson Comorbidity index, ecological deprivation index, types of thyroid resection, lymph node dissection and complications, year and region, the incremental cost of overall health care utilization was €142 (p<0.004). Our study found a significant additional cost in respect of health expenditures for patients who had hypoparathyroidism after thyroidectomy for cancer, over the first postoperative year. Five-year follow-up is planned to assess the impact of more severe long-term complications on costs.


[Role of melatonin in calcium overload-induced heart injury].
To investigate the role of melatonin in calcium overload-induced heart injury. Methods: Thirty-two rats were divided into 4 groups: a control group (Control), a melatonin control group (Mel), a calcium overload group (CaP), and a calcium overload plus melatonin group (Mel+CaP). Isolated Sprague Dawley male rat hearts underwent Langendorff perfusion. Left ventricular developed pressure (LVDP) was calculated to evaluate the myocardial performance. Triphenyltetrazolium chloride staining was used to measure the infarct size of myocardium. Lactate dehydrogenase (LDH) activity in the coronary flow was determined. The expressions of caspase-3 and cytochrome c were determined by Western blot. The pathological morphological changes in myocardial fiber were analyzed by HE staining. Results: Compared with the control group, calcium overload significantly induced an enlarged infarct size (P<0.01), accompanied by the disordered arrangement of myocardial fiber, up-regulation of cytochrome c and caspase-3 (P<0.01), and the increased activity of LDH (P<0.01). These effects were significantly attenuated by 10 μmol/L melatonin (P<0.01). Conclusion: Melatonin can alleviate calcium overload-induced heart injury.


Cloning and expression during development of three murine members of the COUP family of nuclear orphan receptors.
We have isolated the murine homologs of the members of the COUP-family of steroid hormone receptors, COUP-TF1, ARP-1 and EAR2. The proteins encoded by the murine genes appeared to be highly conserved when compared to their human counterparts. The expression of COUP-TF1 and ARP-1 was induced during differentiation of P19 embryonal carcinoma (EC) cells into derivatives of all three germ layers. Retinoic acid (RA) treatment rapidly induced expression of both genes, while other methods of differentiation were less effective. Undifferentiated P19 cells were found to express EAR2 mRNA and the expression level was only slightly elevated by RA-treatment. In addition, we analyzed the expression in P19 cells of three members of the retinoid X receptor (RXR) family, which have been shown to heterodimerize with members of the COUP-family. During RA mediated differentiation of P19 cells, RXR alpha expression was induced while RXR beta expression was not modulated and RXR gamma expression was down regulated. Gel shift analysis revealed that in P19 cells the members of the COUP-family comprise the major portion of proteins binding to a RA-responsive direct repeat of the consensus steroid hormone receptor binding half site (AGGTCA) spaced by one nucleotide (DR + 1). The members of the COUP-family appeared to down regulate RA-induced activation of RA-response element-containing reporter constructs in a promoter context-dependent manner. The expression patterns of COUP-TF1, ARP-1 and EAR2 during development were investigated by in situ hybridization. In agreement with the results obtained in vitro, the three genes appeared to be expressed in tissues derived from all three germ layers. However, COUP-TF1 and ARP-1 were found to be expressed predominantly in the developing central nervous system in mutually exclusive domains. Furthermore, strong ARP-1 expression was detected in lung and kidney. Our data strongly suggest an important role for the members of the COUP-family in the hormonal control of gene expression regulating embryogenesis.


Learning shapes the aversion and reward responses of lateral habenula neurons.
The lateral habenula (LHb) is believed to encode negative motivational values. It remains unknown how LHb neurons respond to various stressors and how learning shapes their responses. Here, we used fiber-photometry and electrophysiology to track LHb neuronal activity in freely-behaving mice. Bitterness, pain, and social attack by aggressors intensively excite LHb neurons. Aversive Pavlovian conditioning induced activation by the aversion-predicting cue in a few trials. The experience of social defeat also conditioned excitatory responses to previously neutral social stimuli. In contrast, fiber photometry and single-unit recordings revealed that sucrose reward inhibited LHb neurons and often produced excitatory rebound. It required prolonged conditioning and high reward probability to induce inhibition by reward-predicting cues. Therefore, LHb neurons can bidirectionally process a diverse array of aversive and reward signals. Importantly, their responses are dynamically shaped by learning, suggesting that the LHb participates in experience-dependent selection of behavioral responses to stressors and rewards.


Collectively Answering the Venetoclax BTK Inhibitor Sequencing Question in CLL.
Whether BTK inhibitors are effective when used after venetoclax in patients with chronic lymphocytic leukemia is an important unanswered question. In a large retrospective cohort study examining outcomes for next line treatment after venetoclax, BTK inhibitors were found to result in durable responses in patients who were not previously BTK inhibitor resistant.See related article by Mato et al., p. 3589.


Communication practices of parents and unaffected sibling needs in families impacted by a diagnosis of Angelman syndrome.
Angelman syndrome (AS) is a rare neurodevelopmental condition affecting approximately 1 in 15,000 individuals. To date, limited research elucidates how parents communicate about AS with unaffected siblings and their needs. This study aimed to understand if, when, and what parents are communicating with unaffected siblings. The study also evaluated unaffected siblings' knowledge of AS and their perceptions of their siblings with AS. Recruitment took place through social media platforms and a multidisciplinary Chromosome 15 clinic. Families were eligible for the study if they had a child diagnosed with AS and at least one unaffected sibling age five years or older. Two novel surveys, one for the parent and one for each of the unaffected siblings, were created based on a detailed literature review and input from AS professionals. Eighty-two families met the criteria and completed the required surveys. The majority of parents (94%) discussed AS with the unaffected siblings, but despite these discussions 41% of unaffected siblings still had unanswered questions. This study highlights the need for improved communication between parents and the unaffected siblings and emphasizes the importance of educational materials for unaffected siblings.


Toothprints: a comprehensive recovery, identification, forensic, and prosecution tool.
The Child Identification Program (CHIP) sponsored by the Massachusetts Freemasons and supported by the Massachusetts Dental Society is now recognized as one of the most comprehensive child recovery and identification programs in the country CHIP is hailed by recovery officials of the National Center for Missing and Exploited Children, as well as law enforcement, dental, forensic, and prosecution authorities alike.


Is captopril effective in primary pulmonary hypertension?
Several vasodilating agents have been used for the treatment of primary pulmonary hypertension (PPH). However, no effective therapy is currently available for this distressful disease. We tried to use an angiotensin-I converting enzyme inhibitor, captopril, for one woman suffering from PPH. Her initial treatment with furosemide, digoxin and spironolactone had shown little effect. Further administration of captopril improved her clinical condition from NYHA IV to II and made it possible to treat her at our out-clinic. No adverse effect has been found. We would like to appreciate captopril as one of the effective drugs in the treatment of PPH.


Discrimination of Cricotopus species (Diptera: Chironomidae) by DNA barcoding.
Chironomids (Diptera) typically comprise the most abundant group of macroinvertebrates collected in water quality surveys. Species in the genus Cricotopus display a wide range of tolerance for manmade pollutants, making them excellent bioindicators. Unfortunately, the usefulness of Cricotopus is overshadowed by the difficulty of accurately identifying larvae using current morphological keys. Molecular approaches are now being used for identification and taxonomic resolution in many animal taxa. In this study, a sequence-based approach for the mitochondrial gene, cytochrome oxidase I (COI), was developed to facilitate identification of Cricotopus species collected from Baltimore area streams. Using unique COI sequence variations, we developed profiles for seven described Cricotopus sp., four described Orthocladius sp., one described Paratrichocladius sp. and one putative species of Cricotopus. In addition to providing an accurate method for identification of Cricotopus, this method will make a useful contribution to the development of keys for Nearctic Cricotopus.


Characterisation of two snail genes in the gastropod mollusc Patella vulgata. Implications for understanding the ancestral function of the snail-related genes in Bilateria.
Snail genes have been found to play a role in mesoderm formation in two of the three clades of bilaterians, deuterostomes (comprising the chordates) and ecdysozoans (comprising the arthropods). No clear data are available on the role these genes play in development of the mesoderm in the third clade, that of lophotrochozoans (comprising annelids and molluscs). We identified two new members of the snail gene family in the gastropod mollusc Patella vulgata. Phylogenetic analysis showed that the two genes clearly belong to the snail sub-family. Their expression patterns do not indicate a role during early mesoderm formation. In fact, contrary to expectations, the snail genes of Patella were mostly expressed in the ectoderm. In view of the location of their expression sites, we suggest that these genes could be involved in regulating epithelial-mesenchymal transitions (EMT) and cell motility, as has recently been demonstrated for snail genes in vertebrates. This may well correspond to the ancestral function of these genes. The results are discussed in the light of the evolutionary origin of the mesoderm. Electronic supplementary material to this paper can be obtained by using the Springer LINK server located at http://dx.doi.org/10.1007/s00427-002-0228-1.


Interprofessional collaboration-in-practice: the contested place of ethics.
The main question examined is: How do nurses and other healthcare professionals ensure ethical interprofessional collaboration-in-practice as an everyday practice actuality? Ethical interprofessional collaboration becomes especially relevant and necessary when interprofessional practice decisions are contested. To illustrate, two healthcare scenarios are analyzed through three ethics lenses. Biomedical ethics, relational ethics, and virtue ethics provide different ways of knowing how to be ethical and to act ethically as healthcare professionals. Biomedical ethics focuses on situated, reflective, and nonabsolute principled justification, all things considered; relational ethics on intersubjective, professional, and institutional relations; and virtue ethics on prephilosophical tradition and what it means to be good and to be human embedded in social and political community. Analysis suggests that interprofessional collaboration-in-practice may be more rhetoric than actuality. Key challenges of interprofessional collaboration-in-practice and specific conditions perpetuating dissension and conflict are outlined with specific education and policy recommendations included.


Vision-Language Transformer for Interpretable Pathology Visual Question Answering.
Pathology visual question answering (PathVQA) attempts to answer a medical question posed by pathology images. Despite its great potential in healthcare, it is not widely adopted because it requires interactions on both the image (vision) and question (language) to generate an answer. Existing methods focused on treating vision and language features independently, which were unable to capture the high and low-level interactions that are required for VQA. Further, these methods failed to offer capabilities to interpret the retrieved answers, which are obscure to humans where the models' interpretability to justify the retrieved answers has remained largely unexplored. Motivated by these limitations, we introduce a vision-language transformer that embeds vision (images) and language (questions) features for an interpretable PathVQA. We present an interpretable transformer-based Path-VQA (TraP-VQA), where we embed transformers' encoder layers with vision and language features extracted using pre-trained CNN and domain-specific language model (LM), respectively. A decoder layer is then embedded to upsample the encoded features for the final prediction for PathVQA. Our experiments showed that our TraP-VQA outperformed the state-of-the-art comparative methods with public PathVQA dataset. Our experiments validated the robustness of our model on another medical VQA dataset, and the ablation study demonstrated the capability of our integrated transformer-based vision-language model for PathVQA. Finally, we present the visualization results of both text and images, which explain the reason for a retrieved answer in PathVQA.


Defining the gastroesophageal junction in trauma: Epidemiology and management of a challenging injury.
Injuries to the gastroesophageal (GE) junction are infrequently encountered because of the high mortality of associated injuries. Consequently, there is a paucity of literature on the patient demographics and treatment options. The aim of this study was to examine the epidemiology, surgical management, and outcomes of these rare injuries. Patients presenting to LAC + USC Medical Center (January 2008 to August 2016) with traumatic esophageal or gastric injury (DRG International Classification of Diseases-9th Rev.-Clinical Modification and 10th Rev. codes) were extracted from the trauma registry. Patient charts were reviewed, and all patients who sustained an injury to the GE junction were enrolled. Patient demographics, injury characteristics, procedures, and outcomes were analyzed. Of the 238 patients who sustained an injury to the esophagus or stomach during the study period, 28 (12%) were found to have a GE junction injury. Mean age was 26 years (range, 14-57 years), 89% male. Mechanism of injury was penetrating in 96% (n = 27), the majority of which were gunshot wounds (n = 22, 81%). Most patients (n = 18, 64%) were taken directly to the operating room. Ten (36%) underwent computed tomography scan before going to the operating room, all demonstrating a GE junction injury. All patients underwent repair via laparotomy. One (4%) also required thoracotomy to facilitate delayed reconstruction. GE junction injuries were typically managed with primary repair (n = 22, 79%). Associated injuries were frequent (n = 26, 93%), and injury severity was high (mean Injury Severity Score, 25 [9-75]). Mortality was 25% (n = 7), and all patients required intensive care unit admission. Most did not require total parenteral nutrition (n = 25, 89%) or a surgically placed feeding tube (n = 26, 93%). Of the 13 patients who presented for clinical follow-up, all but one (n = 12, 92%) were eating independently by the first clinic visit. GE junction injuries are uncommon and occur almost exclusively after penetrating trauma. Patients are severely injured with a high mortality rate and frequently have associated intracavitary injuries. Most can be fixed through the abdomen alone and do not require thoracotomy for repair. Despite the severity of injuries, the majority of survivors are eating independently by the first clinic visit. Epidemiological, level V.


Activation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice.
GPR37 was discovered more than two decades ago, but its biological functions remain poorly understood. Here we report a protective role of GPR37 in multiple models of infection and sepsis. Mice lacking Gpr37 exhibited increased death and/or hypothermia following challenge by lipopolysaccharide (LPS), Listeria bacteria, and the mouse malaria parasite Plasmodium berghei. Sepsis induced by LPS and Listeria in wild-type mice is protected by artesunate (ARU) and neuroprotectin D1 (NPD1), but the protective actions of these agents are lost in Gpr37-/- mice. Notably, we found that ARU binds to GPR37 in macrophages and promotes phagocytosis and clearance of pathogens. Moreover, ablation of macrophages potentiated infection, sepsis, and their sequelae, whereas adoptive transfer of NPD1- or ARU-primed macrophages reduced infection, sepsis, and pain-like behaviors. Our findings reveal physiological actions of ARU in host cells by activating macrophages and suggest that GPR37 agonists may help to treat sepsis, bacterial infections, and malaria.


Update on drug-related problems in the elderly.
Although pharmacotherapy for the elderly can treat diseases and improve well-being, its benefits can be compromised by drug-related problems. This article reviews recent publications concerning drug-related problems in the elderly, as well as articles describing the development of 3 sets of quality indicators for medication use in the elderly. Relevant articles were identified through a search of MEDLINE (2002-March 2003) for articles on drug-related problems, inappropriate prescribing, and adverse drug events in the elderly. The review included 7 articles published in 2002 and 2003. A study in ambulatory elderly persons reported that approximately 5.0% of patients had > or =1 adverse drug event within the previous year. Another study found that approximately 20.0% of ambulatory elderly persons used > or =1 inappropriate drug, as defined by drug utilization review (DUR) criteria, with drug-disease interactions and duration of use being the most common drug-related problems. A third study involving elderly individuals in assisted living facilities found that 16.0% used > or =1 inappropriate drug, as defined by the Beers criteria. Another study examined whether inappropriate drug use, as defined by the Beers or DUR criteria, was associated with death or a decline in functional status; it found that only use of drugs defined as inappropriate by DUR criteria (particularly those drugs associated with drug-drug or drug-disease interactions) was associated with a decline in the ability to perform basic self-care. Three studies, 1 from the United States, 1 from the United Kingdom, and 1 from Canada, described consensus development of quality indicators for drug use in the elderly, including drugs to avoid, maximum daily dose, drug duplication, limits on duration of use, drug-drug and drug-disease interactions, need for drug monitoring, underuse of necessary drugs to treat or prevent common problems, and inappropriate drug-administration technique. Drug-related problems are common in elderly patients. Data from recently published studies provide guidance to practitioners and directions for future research.


Detecting single stranded DNA with a solid state nanopore.
Voltage biased solid-state nanopores are used to detect and characterize individual single stranded DNA molecules of fixed micrometer length by operating a nanopore detector at pH values greater than approximately 11.6. The distribution of observed molecular event durations and blockade currents shows that a significant fraction of the events obey a rule of constant event charge deficit (ecd) indicating that they correspond to molecules translocating through the nanopore in a distribution of folded and unfolded configurations. A surprisingly large component is unfolded. The result is an important milestone in developing solid-state nanopores for single molecule sequencing applications.


cAMP and genistein stimulate HCO3- conductance through CFTR in human airway epithelia.
We studied the role of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel as an HCO3- conductor during adenosine 3',5'-cyclic monophosphate (cAMP)-dependent regulation in human airway epithelial cell lines. HCO3- or Cl- currents across the apical membrane were measured in the presence of an HCO3- or Cl- gradient under short-circuit conditions in intact and alpha-toxin-permeabilized monolayers, which allowed manipulation of the intracellular regulators cAMP and ATP. CFTR as the current carrier for HCO3- was identified by 1) stimulation by cAMP, 2) ATP dependence, 3) blocker sensitivity, 4) stimulation by genistein, and 5) lack of stimulation in CF epithelia bearing mutated delta F508 CFTR. In pulmonary alpha-toxin-permeabilized Calu-3 monolayers, cytosolic addition of 100 microM cAMP stimulated apical HCO3- currents from -9.4 +/- 1.6 to -31.1 +/- 3.9 microA/cm2 (n = 18), and apical Cl- currents increased from -54.1 +/- 7.1 to -203.2 +/- 15.4 microA/cm2 (n = 27). Average relative permselectivity for HCO3- vs. Cl- was approximately 15%. Absence of cytosolic ATP resulted in loss of cAMP stimulation of HCO3- and Cl- currents. Genistein (50 microM), which has been proposed to inhibit phosphatases controlling apical CFTR, as well as the alkaline phosphatase inhibitor (-)-p-bromotetramisole (1 mM) further activated cAMP-stimulated HCO3- and Cl- currents. Activated currents remained stimulated on removal of cAMP, suggesting inhibition of a protein phosphatase by genistein and bromotetramisole. The Cl- channel blockers glibenclamide (300 microM) and N-phenylanthranilic acid (5 mM), but not 4,4'-dinitro-2,2'-stilbenedisulfonic acid (100 microM), inhibited cAMP- and genistein-stimulated HCO3- and Cl- currents. Blocker effects were absent in human CF tracheal cells homozygous for the delta F508 mutation of CFTR (CFT1); Cl- and HCO3- currents were rescued in CFT1 cells recombinantly expressing wild-type CFTR. Thus CFTR functions as a HCO3- and Cl- conductor, and genistein and bromotetramisole maximize CFTR activity in airway epithelial cells.


Dementia care in European countries, from the perspective of people with dementia and their caregivers.
To investigate persons with dementia and their informal caregivers' views of inter-sectoral information, communication and collaboration throughout the trajectory of dementia care, in eight European countries. Living with dementia and being next of kin to a person with dementia means having to live through stages that have different characteristics, needs, challenges and requirements. Qualitative research. Focus groups were conducted in England, Estonia, Finland, France, Germany, The Netherlands, Spain and Sweden. Persons with dementia and their informal caregivers (N = 137) participated in focus group interviews during 2011. Content analysis generated a tentative model of information, communication and collaboration for people with dementia and their caregivers, which was then tested. The core finding was that information, communication and collaboration were to be focused on the persons with dementia and the informal caregivers. Entering into the trajectory of the disease and its consequences was addressed as an important point of departure. The relation to professional care required establishing a trusting relationship, tailor-made intervention and a single person or organization to contact. Professional knowledge and commitment, variation in service and care adapted to needs were important. As focus of care is on the person with dementia and their informal caregivers, a dyadic approach seems most suitable for dementia care. A trusting relationship and a specific person or organization to contact seem to be indicators of best practice, as does adaptation to the needs of the person with dementia and their informal caregiver.


Selective Targeting of G-Quadruplex Structures by a Benzothiazole-Based Binding Motif.
A benzothiazole derivative was identified as potent ligand for DNA G-quadruplex structures. Fluorescence titrations revealed selective binding to quadruplexes of different topologies including parallel, antiparallel, and (3+1) hybrid structures. The parallel c-MYC sequence was found to constitute the preferred target with dissociation constants in the micromolar range. Binding of the benzothiazole-based ligand to c-MYC was structurally and thermodynamically characterized in detail by employing a comprehensive set of spectroscopic and calorimetric techniques. Job plot analyses and mass spectral data indicate noncooperative ligand binding to form complexes with 1:1 and 2:1 stoichiometries. Whereas stacking interactions are suggested by optical methods, NMR chemical shift perturbations also indicate significant rearrangements of both 5'- and 3'-flanking sequences upon ligand binding. Additional isothermal calorimetry studies yield a thermodynamic profile of the ligand-quadruplex association and reveal enthalpic contributions to be the major driving force for binding. Structural and thermodynamic information obtained in the present work provides the basis for the rational development of benzothiazole derivatives as promising quadruplex binding agents.